Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([CH:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:13][C:14]([O:16][CH3:17])=[O:15])([O:10][CH3:11])=[O:9]>C(Cl)Cl>[C:8]([CH:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[CH2:27][NH:28][CH2:29][C:30]([F:31])([F:33])[F:32])[CH2:13][C:14]([O:16][CH3:17])=[O:15])([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(Cc1ccc(OC)cc1CN(CC(F)(F)F)C(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CC(Cc1ccc(OC)cc1CNCC(F)(F)F)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
TFA (55 mL) was added all at once to a solution of methyl (±)-3-carbomethoxy-4-[2-[N-(tert-butoxycarbonyl)-N-(2,2,2-trifluoroethyl)amino]methyl-4-methoxyphenyl]butanoate (7.98 g, 16.71 mmole) in anhydrous CH2Cl2 (42 mL) at 0° C. under argon, and the reaction was warmed to RT. After 1.5 hr, the reaction was concentrated, and the residue was reconcentrated from xylenes. Drying in high vacuum at 40° C. left the title compound (8.70 g, quantitative) as a yellow solid: MS (ES) m/e 378 (M+H)+.
Reaction SMILES: [O:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=4)=[N:14][N:13]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:10]3=[CH:11][N:12]=2)[CH2:4][CH2:3][CH2:2]1.C1CC=CCC=1>[Pd].C(O)C>[F:22][C:18]1[N:17]=[C:16]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([CH:5]4[CH2:4][CH2:3][CH2:2][O:1][CH2:6]4)[CH:8]=3)[N:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:14]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(C4=COCCC4)cc23)n1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(C4CCCOC4)cc23)n1
Yield: 101.7 %

Procedure:
A mixture of 68 mg (0.18 mmol) of 5-(3,4-dihydro-2H-pyran-5-yl)-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine, 2.0 ml (21 mmol) of 1,4-cyclohexadiene and 300 mg of 10% palladium on carbon in 8 ml of ethanol was heated to reflux for 24 hours. The mixture was filtered through celite, the filtrate concentrated in vacuum to afford 70 mg (100%) of 3-(6-Fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 383.1 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[I:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([OH:18])[CH:9]=1.[CH2:19](Br)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C=O)C>[I:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1
Reactant: BrCCc1ccccc1
Reactant: COC(=O)c1ccc(I)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)cc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A suspension of caesium carbonate (35.2 g, 108 mmol), methyl 4-iodo-2-hydroxybenzoate (25 g, 90 mmol), phenethyl bromide (16 ml, 117 mmol) in DMF (500 ml) is stirred for 10 hours at room temperature. Caesium carbonate (20 g, 61.4 mmol) and phenethyl bromide (8.5 ml, 61.4 mmol) are added to the suspension. The organic phase is acidified at room temperature with a 2N hydrochloric acid solution to pH 5. The desired product is extracted by addition of ethyl ether. The organic phase is washed with water, dried with magnesium sulfate and concentrated using a rotary evaporator.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH:15]([F:17])[F:16])[N:6]=1.[O:30]1[C:34]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1>CC(N(C)C)=O>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH:15]([F:17])[F:16])=[C:7]([C:5]2[N:6]=[C:2]([N:37]3[CH2:38][CH2:39][C:34]4([O:33][CH2:32][CH2:31][O:30]4)[CH2:35][CH2:36]3)[S:3][C:4]=2[NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])[CH:12]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Solvent: CC(=O)N(C)C
Product: O=C(Nc1sc(N2CCC3(CC2)OCCO3)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 165 °C
Yield: 58.6 %

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (820 mg, 1.64 mmol) and 1,4 dioxa-8-azaspiro[4.5]decane (1.05 ml, 8.2 mmol) were dissolved in DMA (10 ml) and heated in a microwave at 165° C. for 1 hour. The reaction mixture partitioned between ethyl acetate and water and the phases separated. The organic layer was washed with brine. The combined aqueous layers were extracted with ethyl acetate once and the organic layers combined, dried (Na2SO4), filtered and the solvent removed. The crude product was chromatographed on silica eluting with 50-60% ethyl acetate in cyclohexane. Appropriate fractions were combined and evaporated to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-(5-chloro-2-difluoromethoxy-phenyl)-2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-thiazol-5-yl]-amide as a yellow solid (541 mg, 59%). LCMS (Method 3) [M+H]+=563.3, RT=3.68 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.26 (s, 1H), 9.37 (dd, 1H, J=1.6, 6.9 Hz), 8.69 (s, 1H), 8.64 (dd, 1H, J=1.5, 4.4 Hz), 7.68 (d, 1H, J=2.5 Hz), 7.59 (dd, 1H, J=2.7, 8.7 Hz), 7.42 (d, 1H, J=8.5 Hz), 7.31 (dd, 1H, J=4.3, 7.0 Hz), 7.18 (t, 1H, J=73.8 Hz), 3.94 (s, 4H), 3.52 (dd, 4H, J=5.7, 5.7 Hz), 1.75 (dd, 4H, J=5.7, 5.7 Hz).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[N:19]=[CH:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:42]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:42]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:43][C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[N:19]=[CH:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n2Cc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n2Cc2ccccc2)n1
Temperature: 140 °C
Yield: 30.9 %

Procedure:
1-Benzyl-5-chloro-2-(1-trityl-1H-imidazol-4-yl)-1H-pyrrolo[3,2-b]pyridine (160 mg, 0.29 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (0.10 g, 0.44 mmol) and Cs2CO3 (0.14 g, 0.44 mmol) were combined in toluene (10 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (23 mg, 0.029 mmol) was added. The mixture was degassed with a stream of nitrogen through the solution and was then heated in the microwave to 140° C. for 30 minutes. Excess reagents were added, the mixture was again degassed, then heated in the microwave to 140° C. for 66 additional minutes. The reaction was cooled and diluted with DCM, filtered, and concentrated. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes afforded di-tert-butyl 1-[1-benzyl-2-(1-trityl-1H-imidazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate as a light yellow oil (67 mg). This intermediate was dissolved in AcOH (3.0 mL) and heated in the microwave to 180° C. for 15 minutes. Acetic acid was removed in vacuo. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (16 mg, 17%).
Reaction SMILES: [CH3:1][C:2](=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([NH:5][C@H:6]([C:17]([O:19]C)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[OH-].[Na+]>CO>[CH3:1][C:2](=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([NH:5][C@H:6]([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(C)=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 88.4 %

Procedure:
The same procedures as in Example 149 were carried out from the compound obtained in Example 165 (4.0 g), 1 mol/L of an aqueous sodium hydroxide solution (17 mL), and methanol (170 mL), to give the captioned compound (3.4 g, 89%) as crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=[O:3])[CH3:2].[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH:24]=O.N1CCCCC1>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:24][C:16]1[NH:17][C:18]2[C:23]([C:15]=1[CH3:14])=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:3])[CH3:2]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)c1ccc2c(c1)C(=Cc1[nH]c3ccccc3c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
A mixture of 5-acetyl-2-oxindole (70 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum to give 83 mg (75% yield) of 5-acetyl-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([C:22]([NH2:24])=[O:23])[CH:21]=2)[NH:18][CH:17]=[C:16]3[CH:25]2[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:27][CH2:26]2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].Br[C:37]1[CH:42]=CC(CCNC(=O)C)=C[CH:38]=1>>[CH:2]1([C:1]([NH:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]4[C:19](=[C:20]([C:22]([NH2:24])=[O:23])[CH:21]=3)[NH:18][CH:17]=[C:16]4[CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])[CH2:27][CH2:26]3)=[CH:9][CH:8]=2)=[O:3])[CH2:42][CH2:37][CH2:38]1
Reactant: CC(=O)NCCc1ccc(Br)cc1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC(C)=O)cc4)cc23)CC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC(=O)C5CCC5)cc4)cc23)CC1
Yield: 48.3 %

Procedure:
The title compound was prepared according to the general procedure of 5-{4-[2-(acetylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, substituting N-[2-(4-bromophenyl)ethyl]cyclobutanecarboxamide (100 mg, 0.324 mmol) for N-[2-(4-bromophenyl)ethyl]acetamide. Purified by flash chromatography to afford 28 mg of the title compound (48.3%).
Reaction SMILES: Cl.Br[CH2:3][CH2:4][NH:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH3:7].[Cl-].[Al+3].[Cl-].[Cl-]>C1C2C(CCCC2)CCC1>[CH3:7][CH:6]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH2:3][CH2:4][NH:5]1
Reactant: Cc1ccccc1C(C)NCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCC2CCCCC2C1
Product: Cc1cccc2c1C(C)NCC2
Temperature: 0 °C
Yield: 37.1 %

Procedure:
To a mixed solution of 14.7 g of the compound (45.5 mM) prepared in Step 4 above and 100 ml of decaline, was added aluminium chloride and reacted at 140°-150° C. for 1.5 hours, which was cooled to 0° C. The reaction mixture was diluted by pouring into ice water and washed with ethyl ether. The reaction mixture was basified by adding aqueous NaOH solution and the solids produced were filtered. The filtrate was extracted from ethyl ether and the extracts was dried over anhydrous sodium sulfate, concentrated under a reduced pressure, to give 3.16 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([C:22](O)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH2:23])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(C(C)(O)c4ccccc4)cc3c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(c1ccccc1)c1cc(Cl)c2oc3c(c2c1)CNCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of the product of step A (60.0 mg, 0.14 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (0.5 mL). After stirring for 2 h at ambient temperature the reaction mixture was quenched with 10% sodium bicarbonate solution (15 mL) and extracted with dichloromethane. The organic extract was dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 9:1 dichloromethane/methanol) affording 6-chloro-8-(1-phenylvinyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (40 mg, 74%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.36-7.31 (m, 5H), 7.24-7.20 (m, 2H), 5.47 (d, J=11.4 Hz, 2H), 3.92 (t, J=1.8 Hz, 2H), 3.24 (t, J=5.7 Hz, 2H), 2.84 (t, J=5.7 Hz, 2H)
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7](=[O:23])[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[Cl-].[NH4+]>C1COCC1>[O:23]=[C:7]([CH3:1])[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methylmagnesium bromide (1 M THF solution, 30 mL) was added dropwise to a solution of tert-butyl 4-{3-[methoxy(methyl)amino]-3-oxopropyl}piperidine-1-carboxylate (4.5 g) in THF (50 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.70 g).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[OH-].[K+].[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13](F)[C:12]=1F>CS(C)=O.O>[F:10][C:11]1[C:12]2[N:1]3[CH2:7][CH2:6][CH2:5][CH:2]3[CH2:3][O:4][C:13]=2[CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: OC[C@@H]1CCCN1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)c2c(c1)OCC1CCCN21
Temperature: 65 °C
Yield: 92.9 %

Procedure:
To a suspension of prolinol (2.74 g, 27.11 mmol) and KOH (3.17 g, 56.47 mmol) in DMSO (30 mL) was added 1,2,3-trifluoro-5-nitrobenzene (4.00 g, 22.59 mmol) at rt. The reaction mixture was heated at 65° C. for 4 h. The mixture was diluted with water (150 mL) and extracted with CH2Cl2 (100 mL×2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (5.00 g, 93%).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[I:18]I>>[I:18][C:15]1[CH:16]=[CH:17][C:9]([CH3:8])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12]
Reactant: Cc1ccccc1C(=O)O
Reactant: II
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(I)cc1C(=O)O

Procedure:
Acetic anhydride serving as a dehydrating agent is used in an amount of 0.01 to 2 parts by weight on the basis of 1 part by weight of 2-methylbenzoic acid serving as a starting material, preferably 0.1 to 1.5 parts by weight. Through controlling the amount of acetic anhydride so as to fall within the above ranges, a sufficient reaction-promoting effect can be attained, whereby conversion of 2-methylbenzoic acid serving as a starting material and that of iodine can be enhanced. Thus, 5-iodo-2-methylbenzoic acid can be produced at low cost without increasing load of separation/recovery during the purification step. Notably, in the case in which iodine, iodic acid, periodic acid, or a similar species is dissolved or suspended in water, and the solution or suspension is placed in a reactor, acetic anhydride must be added in an amount in excess of the above amount in order to remove water forming the solution or suspension.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14](Br)[CH:15]=1.[CH2:18]([O:20][C:21](=[O:33])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[CH3:19].[F-].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:17][C:11]1[N:12]=[CH:13][C:14]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:33])=[CH:25][CH:26]=2)=[CH:15][C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: CCOC(=O)COc1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1-c1nc2ccccc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)COc1ccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 3-benzothiazol-2-yl-5-bromopyridin-2-ylamine (BB7) (100 mg, 0.330 mmol), 4-(2-ethoxy-2-oxoethoxy)benzeneboronic acid (100 mg, 0.600 mmol) and potassium fluoride (57 mg, 0.98 mmol) in 1,4-dioxane (9.0 mL) and H2O (3.0 mL) was degassed and refilled with argon (3×) prior to the addition of Pd(dppf)Cl2 (10 mg, 0.020 mmol). The reaction mixture was degassed and refilled with argon (2×) and left to stir at 100° C. for 2 h. The mixture was quickly passed through a silica gel pad (5% MeOH in DCM), which afforded the title compound as a yellow solid. MS (ES+): m/z=406.10 (100) [MH+]. HPLC: tR=3.90 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[CH:10][C:4]=2[C:3]=1[C:27]#[N:28].Cl.[NH2:30][OH:31].C(N(CC)CC)C>C(O)C.O>[Cl:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[CH:10][C:4]=2[C:3]=1/[C:27](=[N:30]/[OH:31])/[NH2:28]
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(C#N)c(Cl)cnc32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(/C(N)=N/O)c(Cl)cnc32)cc1
Temperature: 80 °C

Procedure:
A solution of 5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (Example 138A (160 mg, 0.388 mmol)) in ethanol (4 mL) and water (0.33 mL) was treated with hydroxylamine hydrochloride (54.0 mg, 0.777 mmol) and triethylamine (0.271 mL, 1.942 mmol). The reaction vessel was sealed, and the reaction mixture was heated for 30 minutes at 80° C. Additional hydroxylamine hydrochloride (10.0 mg, 0.143 mmol) added, and the reaction heated for 1 hour at 80° C. The reaction was cooled, diluted with water, and extracted with dichloromethane. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 50 to 70% ethyl acetate in hexanes, to provide the title compound. MS ESI(+) m/z 445.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][O:21][C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=1)=[O:32])[CH3:2]
Reactant: COc1cccc(N=C=O)c1
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1cccc(OC)c1

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and 3-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:37][C:34]4[CH:33]=[CH:32][C:31]([CH2:30][C:27]5[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=5)=[CH:36][CH:35]=4)=[O:3])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(Cc4ccccc4)cc3)(CC1)CC2
Yield: 41.2 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminodiphenylmethane (62.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-phenylmethylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (31.1 mg).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:10][C:9]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH2:1]([C:8]1[S:12][C:11]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[N:10][C:9]=1[C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(N3CCOCC3)sc2Cc2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2nc(N3CCOCC3)sc2Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To 50 ml eggplant-shaped bottle were added 0.60 g (1.64 mmol) 4-[5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-morpholine prepared in Example 70 and 20 ml dichloromethane. The resulting mixture was cooled in ice-bath, added dropwise 2.4 ml (4.92 mmol) 2.034 mol/L solution of boron tribromide in dichloromethane, stirred in ice-bath for 1 hour and then at room temperature for 3 hours, added 2 g ice to decompose the complex. The resulting mixture was concentrated under a reduced pressure to remove dichloromethane, dissolved in 100 ml ethyl acetate, and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified under a reduced pressure by silica gel column chromatography eluted with dichloromethane and methanol at a ratio 10:1-5:1 (V:V) to give a 0.26 g pale yellow thick liquid in a yield of 44.8%, 1H-NMR (DMSO-d6, 400 MHz) δ: 3.50 (2H, m, CH2), 3.63 (2H, m, CH2), 3.97 (2H, s, CH2), 4.27 (4H, s, CH2), 5.18 (1H, m), 6.97 (2H, d, J=8.40 Hz, ArH), 7.15˜7.40 (7H, m, ArH), 10.14 (1H, s, OH); EI-MS m/e (%): 352.0 (M+, 37), 322.0 (100), 240.0 (48); HREI-MS Calcd. for C20H20N2O2S: 352.1245. found: 352.1243.
Reaction SMILES: [C:1](=[O:23])(OC1C=CC=CC=1)[O:2][CH2:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.C([O-])(=O)C.[NH4+:28]>C(O)(=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([C:4]2[NH:28][C:1](=[O:23])[O:2][CH:3]=2)=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(OCC(=O)c1ccc(C(F)(F)F)cc1)Oc1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)co1
Yield: 84.9 %

Procedure:
A mixture of 2-oxo-2-(4-trifluoromethylphenyl)ethyl phenyl carbonate (18.0 g), ammonium acetate (20 g) and acetic acid (100 ml) was stirred with heating under reflux for 1 hour. The reaction mixture was concentrated, and poured into ice water (200 ml). The solid precipitates were filtered, washed with water, and air-dried to give crystals of 4-(4-trifluoromethylphenyl)-2-oxazolone (10.8 g, 85%). Melting point decomposed at 250° C. or more.