Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[C:16]2[NH:32][C:19]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH2:24][C:18]=3[N:17]=2)[CH2:4][CH2:3][CH2:2]1.[ClH:33]>CCOC(C)=O>[ClH:33].[CH:1]1([C:5]2[C:6]([C:16]3[NH:17][C:18]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:19]=4[N:32]=3)=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:9]([CH3:11])[CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CCN(C(=O)OC(C)(C)C)CC3)c(C2CCC2)cc1C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2nc3c([nH]2)CCNCC3)c(C2CCC2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of tert-butyl 2-(2-cyclobutyl-5-(methoxycarbonyl)-4-methylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate (compound 82.6, 200 mg, 0.46 mmol) in EtOAc (10 mL). Hydrogen chloride (gas) was introduced into the solution by bubbling and the solution was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure to yield 136 mg (crude) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(OC(F)(F)F)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
To a mixture of 4.0 g of 4-trifluoromethoxy phenol and 25 ml of acetic acid, a mixture of 2.02 g of 70% nitric acid and 10 ml of acetic acid was added dropwise with the temperature kept at 10-15° C. The reaction mixture was stirred for five hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over sodium sulfate, and then concentrated under reduced pressure to give 4.53 g of 4-trifluoromethoxy-2-nitrophenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12][CH2:13][C:14]#[N:15].C(N(C(C)C)CC)(C)C.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>ClCCl.CN(C1C=CN=CC=1)C>[C:14]([CH2:13][S:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])#[N:15]
Reactant: CCCC(=O)Cl
Reactant: N#CCSc1ccc(C(F)(F)F)cc1N
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)Nc1cc(C(F)(F)F)ccc1SCC#N
Temperature: 0 °C
Reaction time: 24 h

Procedure:
(2-Amino-4-trifluoromethylphenylsulfanyl)acetonitrile (1.33 g) dissolved in dichloromethane (5 ml) was stirred on an ice bath at 0° C. Diisopropylethylamine (1 ml) and butyric acid chloride (0.9 ml) was added, and the resulting solution was allowed to reach room temperature. After 22 h more butyric acid chloride (0.9 ml) and DMAP (0.70 g) were added at 0° C. and stirring was continued at 40° C. for 24 h. The cold mixture was diluted with dichloromethane (20 ml), extracted with saturated aqueous sodium bicarbonate (10 ml), washed with water (2×50 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/heptane 1:1 as eluent. The title compound was obtained as a sirup. Yield 1.72 g (100%). The compound could be crystallised from ethyl acetate/heptane, mp 88.5-89.5° C.; El SP/MS: 302 (M+). 1H-NMR(CDCl3) δ (ppm): 8.85 (br, 1H), 8.38 (br, 1H), 7.28 (d, 1H), 7.38 (dd, 1H), 3.50 (s, 2H), 2.46 (t, 2H), 1.82 (sextet), 1.03 (t, 3H).
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([O:9][C:10]1[CH:15]=[C:14](Br)[C:13]([F:17])=[CH:12][C:11]=1[Cl:18])[CH:7]=[CH2:8].[C:19](=[O:21])=[O:20].Cl>O1CCCC1>[CH2:6]([O:9][C:10]1[C:11]([Cl:18])=[CH:12][C:13]([F:17])=[C:14]([CH:15]=1)[C:19]([OH:21])=[O:20])[CH:7]=[CH2:8]
Reactant: O=C=O
Reactant: C=CCOc1cc(Br)c(F)cc1Cl
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: C=CCOc1cc(C(=O)O)c(F)cc1Cl
Reaction time: 0.5 h

Procedure:
At 20-25 C., 200 ml (0.4 mol) of a 2 M solution of isopropyl-magnesium chloride and tetrahydrofuran were added over a period of 30 minutes to a solution of 85 g (0.32 mol) of 1-allyloxy-5-bromo-2-chloro-4-fluorobenzene in 200 ml of tetrahydrofuran. The mixture was then stirred for 30 minutes and 50 g (1.1 mol) of dry ice were added with ice-cooling. The mixture was subsequently stirred for 16 hours, after which 250 ml of a 10% strength hydrochloric acid were added with ice-cooling. The aqueous phase was separated off and extracted with methyl tert-butyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and finally concentrated. The crude product was purified by trituration with a little n-hexane and the precipitated product of value was filtered off. Yield: 59.7 g.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]2[CH:11]=[CH:10][CH2:9][O:8][C:7]=12.CCO.[OH-].[Na+]>[Pd]>[O:8]1[C:7]2=[CH:2][N:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]2[CH2:11][CH2:10][CH2:9]1
Reactant: OCc1cc2c(c(Cl)n1)OCC=C2
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1cc2c(cn1)OCCC2
Reaction time: 48 h
Yield: 88.4 %

Procedure:
(8-Chloro-2H-pyrano[2,3-c]pyridin-6-yl)methanol (988 mg, 5.0 mmol) is combined with 100 mg 10% Pd/C in 25 ml EtOH containing 3 ml (6 mmol) of 2N aqueous NaOH in a 250 ml PARR shaker bottle. The reaction is hydrogenated at 50 PSI for 48 h, the catalyst is removed by filtration, and the filtrate is concentrated to dryness. The mixture is partitioned between 1×10 ml 1:1 saturated NaCl/conc. NH4OH and 4×10 ml CH2Cl2 and the combined organic layer is dried (K2CO3). The mixture is concentrated in vacuo to give 730 mg (89%) of 3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethanol as an off-white solid. HRMS (FAB) calcd for C9H11NO2+H: 166.0868, found 166.0868 (M+H)+.
Reaction SMILES: C([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[NH:17][CH:16]([N:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21](=[O:23])[CH3:22])[NH:15][C:14]2=[O:28])=[CH:9][CH:8]=1)=[O:6])(=O)C.O>COCCOC>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:14](=[O:28])[NH:15][CH:16]([N:20]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:21](=[O:23])[CH3:22])[NH:17][C:18]2=[O:19])=[CH:11][CH:12]=1)([OH:6])=[O:4]
Reactant: CC(=O)OC(=O)c1ccc(N2C(=O)NC(N(CC(C)C)C(C)=O)NC2=O)cc1
Solvent: O
Solvent: COCCOC
Product: CC(=O)N(CC(C)C)C1NC(=O)N(c2ccc(C(=O)O)cc2)C(=O)N1
Reaction time: 20 h
Yield: 38.8 %

Procedure:
A solution of 3-[4-(acetoxycarbonyl)phenyl]-6-[(N-acetyl)isobutylamino]tetrahydro-1,3,5-triazine-2,4-dione (2.6 g.) in 1,2-dimethoxyethane (20 ml.) containing water (2 ml.) was left for 20 hours and then evaporated. The residue was pressure-chromatographed on silica using a mixture of 44 parts by volume of ethyl acetate and 1 part by volume of acetic acid to yield 3-(4-carboxyphenyl)-6-[(N-acetyl)isobutylamino]tetrahydro-1,3,5-triazine-2,4-dione (0.9 g., 39%), m.p. 191°-193° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42])[CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH2:37][CH3:38])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 55.6 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (150 mg, 0.3 mmol), 2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (Example 143, step C) (87 mg, 0.27 mmol), and p-toluenesulfonic acid (135 mg, 0.71 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 5 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (121 mg, 0.15 mmol, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.31 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.31 Hz, 1H), 8.03 (d, J=2.01 Hz, 1H), 7.73 (dd, J=8.70, 2.11 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.39-7.47 (m, 2H), 7.32-7.39 (m, 1H), 7.24 (d, J=8.79 Hz, 1H), 7.18 (t, J=8.06 Hz, 2H), 6.92 (t, J=7.05 Hz, 1H), 6.66 (d, J=2.38 Hz, 1H), 6.53 (d, J=5.31 Hz, 1H), 6.44-6.49 (m, 1H), 4.24 (q, J=6.90 Hz, 2H), 4.05 (q, J=6.96 Hz, 2H), 3.30-3.34 (m, 2H), 3.08-3.14 (m, 4H), 3.02 (s, 3H), 2.74 (t, J=6.87 Hz, 2H), 2.54-2.59 (m, 4H), 1.41 (t, J=6.87 Hz, 3H), 1.23 (t, J=6.96 Hz, 3H). MS (ESI): 797 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[NH:8][C:9]=1[CH:10]=[CH:14][N:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(=O)[nH]c1C
Product: CC(=O)c1ccc(=O)[nH]c1C=CN(C)C

Procedure:
The process according to claim 9 which comprises reacting 5-acetyl-6-methyl-2(1H)-pyridinone with dimethylformamide dimethyl acetal to produce 5-acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Fc1cccc(Cl)c1CCl
Solvent: C1CCOC1
Product: Fc1cccc(Cl)c1CN1CCNCC1

Procedure:
Synthesized according to General Procedure A: 2-chloro-6-fluorobenzyl chloride (4{7}, 5 mL, 39.1 mmol, 1 equiv.), piperazine (20.2 g, 234.8 mmol, 6 equiv.), THF (85.4 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{7} (6.92 g, 77%) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 7.14-7.08 (m, 2H), 6.94-6.86 (m, 1H), 3.62 (d, 2H, J=2.0 Hz), 2.78 (t, 4H, J=4.8 Hz), 2.44 (br s, 4H), 1.40 (br s, 1H). 13C-NMR (100 MHz, CDCl3): δ 161.8 (d, JC-F=247.5 Hz), 136.4 (d, JC-F=6.0 Hz), 128.8 (d, JC-F=9.6 Hz), 125.2, 123.6 (d, JC-F=18.0 Hz), 113.7 (d, JC-F=23.3 Hz), 54.0, 52.8, 45.9.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[NH2:15][CH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:19]([CH3:30])[CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:15]([CH2:16][C:17]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[C:19]([CH3:30])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)ccc1C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ccc1C(=O)OC(C)(C)C
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (560 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and tert-butyl 4-(aminomethyl)-2-methylbenzoate (400 mg, 1.8 mmol) in a similar manner to Intermediate-2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:24][C:25]1(OCC)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:23]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:25]3([O:24][CH2:22][CH3:23])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC1(OCC)CCCCCCCCCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCCCCCCC1
Yield: 29.2 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-diethoxycyclododecane (2.56 g, 00 mmol) in the same manner as the example 20 to give the compound 33 (162 mg, 29%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([OH:10])=[C:5]([CH3:11])[CH:4]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:10][C:6]1[C:5]([CH3:11])=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][C:7]=1[CH3:9])[CH3:18]
Reactant: Cc1cc(CO)cc(C)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1c(C)cc(CO)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(hydroxymethyl)-2,6-dimethylphenol (P. Claus et al., Monatsh. Chem. 1972, 103(4), 1178–1193) (1.9 g) in acetonitrile (50 ml) was treated with ethyl bromoacetate (2.17 g) and caesium carbonate (4.24 g) and the mixture stirred at room temperature overnight. The solution was concentrated and the residue partitioned between ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](Br)[C:20]#[N:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[C:20]#[N:21]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: N#CC(Br)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CC(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-trifluoromethylphenol (16.2 g., 0.1 mole) and 4-chlorophenyl-α-bromoacetonitrile (23.05 g., 0.1 mole) in methylene chloride (200 ml.) is added potassium carbonate (27.6 g., 0.2 mole). The reaction mixture is stirred and heated under reflux for six hours. The reaction mixture is then cooled to 25°C. and washed with water (300 ml.). The organic layer is dried over sodium sulfate, filtered and the solvent removed to afford crude (3-trifluoromethylphenoxy)(4-chlorophenyl)acetonitrile which is employed in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: O=C1Cc2cccc(Cl)c2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1Cc2cc([N+](=O)[O-])cc(Cl)c2N1
Temperature: -45 °C
Reaction time: 8 h

Procedure:
7-chloro-1,3-dihydro-2H-indol-2-one (8.0 g, 47.7 mmol) was slurried in H2SO4 (conc., 86 ml) and the mixture cooled to −45° C. A solution of fuming nitric acid (>90%, 3.34 g, 52.9 mmol) in H2SO4 (20 ml) was added drop wise, while maintaining the temperature at −45° C. throughout the addition. The mixture was allowed to slowly warm to RT and stirred overnight. The mixture was poured into stirred ice-cold water (1500 ml). A white precipitate resulted, and the slurry was aged at 0° C. for 1 hour. The solid was collected by filtration, triturated with cold water (2×), and dissolved into EtOAc (1 L). This mixture was filtered, washed with basic brine (containing sodium bicarbonate), dried over Na2SO4, filtered, and the volatiles removed in vacuum to give the titled compound.
Reaction SMILES: [Mg].II.Br[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[F:10][CH:11]([F:32])[C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]([CH:26]=[O:27])=[C:14]([C:28]([F:31])([F:30])[F:29])[N:13]=1.Cl>CCOCC.O>[F:32][CH:11]([F:10])[C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]([CH:26]([OH:27])[C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)=[C:14]([C:28]([F:31])([F:29])[F:30])[N:13]=1
Reactant: Brc1cccs1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C=O)c1CC(C)C
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)c2cccs2)c1CC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
This example illustrates the preparation of Compound Number 53. To a suspension of magnesium (1.4 g, 58 mmol) in anhydrous ether (40 mL) containing several iodine crystals was added dropwise a solution of 2-bromothiophene (10 g, 62 mmol) in anhydrous ether (20 mL). The reaction was exothermic; the mixture was stirred at ambient temperature for 1.5 h. The resulting Grignard reagent was cooled to 0°-5° C. and a solution of methyl 2-(difluoromethyl)-5-formyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (6.8 g, 20 mmol) in anhydrous ether (20 mL) was added. The mixture was stirred for 2 h, poured into iced water, and acidified with conc. HCl. The organic layer was separated, washed with water and brine, dried (MgSO4), and conc. The residue was eluted on a silica gel column with 15% ethyl acetate/cyclohexane to yield 6.6 g of methyl 2-(difluoromethyl)-5-(hydroxy-2-thienylmethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate, a 77.6 % yield. m.p. 78°-88° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1.[C:39]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48](O)=[O:49])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(N(CC)CC)C>C(#N)C>[C:39]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48]([NH:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:49])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]
Reactant: COc1cc2ncnc(N3CCC(CCN)CC3)c2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc2ncnc(N3CCC(CCNC(=O)[C@@H]4CCCN4C(=O)OC(C)(C)C)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
N,N'-dicyclohexylcarbodiimide (0.53 g) was added to a mixture of 4-(2-aminoethyl)-1-(6,7-dimethoxyquinazolin-4-yl)piperidine.2HCl (1.2 g), Boc-L-proline (1.1 g), triethylamine (0.72 ml) and acetonitrile (20 ml). The mixture was stirred at room temperature for 12 hours and filtered. The filtrate was dried and concentrated under reduced pressure. The residue was partitioned between an aqueous solution of 10% NaHCO3 and chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by using a 40 g silica gel column to give 4-{2-(Boc-L-prolylamino)ethyl}-1-(6,7-dimethoxyquinazolin-4-yl)piperidine (1.23 g; 93%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:18]=[C:13]([C:10]([CH3:12])([CH3:11])[C:9]([N:8]([C:5]2[CH:6]=[N:7][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:3][C:4]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH3:28])=[O:27])[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: Cc1ccccc1-c1cc(NS(C)(=O)=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
To a solution of 100 mg (0.2 mmol) N-(6-amino-4-0-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide i (Example 73) in 2 ml pyridine were added 27 μl (0.35 mmol) methanesulfonyl chloride and the mixture was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in ethyl acetate, washed twice with saturated aqueous sodium hydrogencarbonate solution, brine and dried (magnesium sulfate). Chromatography of the residue afforded 24 mg (42%) of the title compound as a white foam.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](=O)C)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([N:31]3[CH2:35][CH2:34][CH2:33][C:32]3=[O:36])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:19]3[CH2:20][CH2:21][CH:22]([C:25]4[CH:26]=[C:27]([N:31]5[CH2:35][CH2:34][CH2:33][C:32]5=[O:36])[CH:28]=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C(C)=O)ccc21
Reactant: O=C1CCCN1c1cccc(C2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCn1c2ccccc2c2cc(CN3CCC(c4cccc(N5CCCC5=O)c4)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
Prepared by Scheme R and Procedure F. A solution of 1-(9-ethyl-9H-carbazol-3-yl)ethanone (22.3 mg, 0.100 mmol) and 1-[3-(4-piperidinyl)phenyl]-2-pyrrolidinone (27.2 mg, 0.100 mmol) in 1,2-dichloroethane (1.00 mL) was treated with sodium triacetoxyborohydride (63.6 mg, 0.300 mmol) and HOAc (5.70 uL, 0.100 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was treated with a saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL) and the combined organic layers were washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product 1-(3-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-pyrrolidinone (4.60 mg, 9.43%): 1H NMR (400 MHz, CDCl3) δ 8.04 (d, 1H, J=7.4 Hz), 7.99 (s, 1H), 7.43–7.28 (m, 5H), 6.96 (d, 1H, J=7.4 Hz), 4.31 (q, 2H, J=6.8 Hz), 3.77 (t, 2H, J=7.3 Hz), 3.70 (s, 2H), 3.06 (d, 2H, J=10.6 Hz), 2.56–2.42 (m, 3H), 2.07 (m, 4H), 1.77 (m, 4H), 1.36 (m, 3H) ESMS m/e: 452.5 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:7](I)=[CH:6][C:5]([O:9][CH3:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[I:1][C:2]1[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(I)c(I)cc1OC
Solvent: CC(=O)O
Product: COc1cc(I)c([N+](=O)[O-])cc1OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
4,5-Diiodo-1,2-dimethoxybenzene (8.8 g, 23 mmol) was added into acetic acid (300 mL), and the mixture was heated to 100° C. to dissolve the solid. The clear mixture was then cooled to room temperature followed by dropwise addition of nitric acid (68-70%, 120 mL). The reaction mixture was stirred at room temperature overnight and then poured into ice-water (200 mL). The mixture was extracted by CH2Cl2 (100 mL) three times. The combined organic phase was washed with saturated NaHCO3 solution (200 mL), brine (100 mL), and dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield 4-iodo-5-nitro-1,2-dimethoxybenzene (5.25 g, 75%). 1H NMR (400 MHz, CDCl3): δ 7.60 (s, 1H, Ph-H), 7.38 (s, 1H, Ph-H), 3.98 (s, 3H, OCH3), 3.92 (s, 3H, OCH3).