Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:17]=[C:16]([C:27]#[N:28])[C:15]=2[CH3:29])=[CH:10][CH:9]=1.[ClH:30].[NH2:31][OH:32]>CO>[Cl:30][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:17]=[C:16]([C:27](=[NH:28])[NH:31][OH:32])[C:15]=2[CH3:29])=[CH:10][CH:9]=1
Reactant: Cl
Reactant: NO
Reactant: Cc1c(C#N)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1c(C(=N)NO)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
Potassium carbonate (0.58 g, 4.14 mmol) was added to a sealed tube containing a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonitrile (1.0 g, 2.76 mmol) obtained in Step 2, hydroxylamine hydrochloride (0.39 g, 5.52 mmol) dissolved in MeOH (16 mL). The mixture was stirred vigorously and heated at 100° C. for 16 hr. The white precipitate formed was filtered and washed twice with cold water. It was further dried under a high vacuum. The filtrate was extracted with chloroform (30 mL×2), dried over MgSO4, filtered and evaporated under a vacuum, to obtain the title product in a compound amount of 1.04 g (2.63 mmol, 95%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][O:10][CH3:11].[CH:12]1([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[N:28]([C:29]5[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=5)[N:27]=[CH:26][CH:25]=4)[CH:22]=3)[C:17]([CH2:36][CH3:37])=[N:16]2)[CH2:14][CH2:13]1.O.C(#N)C>CN(C)C=O>[CH:12]1([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:8][CH2:9][O:10][CH3:11])[CH:30]=5)[N:27]=[CH:26][CH:25]=4)[CH:22]=3)[C:17]([CH2:36][CH3:37])=[N:16]2)[CH2:14][CH2:13]1
Reactant: CCc1nn(C2CC2)c2cc(-c3ccnn3-c3cccc(O)c3)ccc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CCc1nn(C2CC2)c2cc(-c3ccnn3-c3cccc(OCCOC)c3)ccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
Potassium carbonate (60.2 mg, 4.36 mmol), and 1-bromo-2-methoxyethane (40.9 μl, 4.36 mmol) were added to a solution of 3-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenol (50 mg, 1.0 mmol) in N,N-dimethylformamide (3 mL), and the resulting mixture was stirred at 60° C. for 16 hours, then at 80° C. for a further 24 hours. After cooling, the reaction mixture was diluted by the addition of water/acetonitrile (1.0 mL), which was then filtered. The filtrate was purified by preparative HPLC (C18 column, 30×100 mm) using a gradient of 35-80% acetonitrile:water (with 0.1% formic acid) as the eluent at a flow rate of 45 mL/min to afford 24 mg (40%) of 1-cyclopropyl-3-ethyl-6-{1-[3-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-1H-indazole. LC/MS (EI) tR 4.3 (Method E), m/z 403.2 (M++1). 1H NMR (CDCl3) δ 1.0 (m, 4H); 1.4 (t, 3H); 3.0 (q, 2H) 3.5 (r, 4H); 3.7 (d, 2H); 4.1 (d, 2H) 6.6 (s, 1H); 6.8-6.9 (dd, 2H); 7.1 (m, 2H); 7.2 (m, 1H); 7.3 (s, 1H); 7.5 (d, 1H); 7.8 (s, 1H).
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:2]=1.Cl.C(OCC)C>O1CCOCC1.O1C=COC=C1>[NH:13]1[CH2:12][CH2:11][CH:10]([N:3]2[C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:9]=3[N:1]=[CH:2]2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc3ccncc32)CC1
Agent: C1=COC=CO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1cc2ncn(C3CCNCC3)c2cn1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(3H-imidazo[4,5-c]pyridine-3-yl)piperidine-1-carboxylate (1.12 g) in 1,4 dioxan (10 ml) was added 4M hydrochloric acid in dioxin (10 ml) and the resulting mixture was stirred for 3 hours. Diethyl ether (30 ml) was added and the mixture was filtered and washed with diethyl ether (50 ml) to give the title compound which was used without further purification. Yield 1.1 g. NMR (d6 DMSO) 2.35 (m, 2H), 2.5 (m, 2H), 3.1 (m, 2H), 3.5 (m, 2H), 5.05 (m, 1H), 8.3 (d, 1H), 8.65 (d, 1H), 9.3 (bd, 2H), 9.9 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:25])[CH:13]([C:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)[OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])(=O)=O.CC1C=CC=C(C)N=1.O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:25])[CH:13]([C:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)[O:14][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)C1(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(O[Si](C)(C)C(C)(C)C)C1(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
A solution of tert-butyl 1-((2S)-2-{[(benzyloxy)carbonyl]amino}-1-hydroxypropyl)cyclopropanecarboxylate (1.58 g) in THF (15 mL) was cooled to 0° C., tert-butyl(dimethyl)silyl trifluoromethanesulfonate (1.56 mL) and 2,6-dimethylpyridine (1.05 mL) were added, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→1/1) to give the title compound as a colorless oil (yield: 1.57 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[C:16]([F:25])([F:24])[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18].O>CC(N(C)C)=O.C1(C)C=CC=CC=1>[F:24][C:16]([F:25])([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18]
Reactant: CCN(CC)C(=O)C(F)(F)Br
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)C(F)(F)Oc1cccc(F)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-fluoro-phenol (4.9 g, 43.5 mmol), and K2CO3 (6.6 g, 47.8 mmol) in 43 g of DMAC at 100° C. was added 2-bromo-2,2-difluoro-N,N-diethyl-acetamide (10 g, 43.5 mmol). The mixture was kept at that temperature for 1 h and then heated to 120° C. for 2 h. The reaction mixture was then cooled to room temperature and poured on 120 mL of H2O and 50 mL of toluene. The aqueous phase was extracted with 25 g of toluene. The combined organic layers were extracted with 5% NaOH (20 g) and H2O (2×20 g) and dried over Na2SO4. The product (10.2 g, >90% purity by NMR) was obtained after removal of all volatiles under reduced pressure as a slightly yellow liquid. The material could be used in subsequent steps without further purification.
Reaction SMILES: [F:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[C:4]([C:11]#[N:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27].O>ClCCl>[C:26]([NH:30][C:31]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([F:1])=[C:3]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:4]([C:11]#[N:12])=[C:5]2[CH2:10]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: N#Cc1c(-c2ccccc2)c(F)n2c1CNCC2
Reactant: CC(C)(C)N=C=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CCn2c(F)c(-c3ccccc3)c(C#N)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution cooled to 0° C. of 0.75 g (3.1 mmol) of 6-fluoro-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile in 50 ml of dichloromethane are added 1.4 ml (10 mmol) of triethylamine and then 0.37 g (3.7 mmol) of tert-butyl isocyanate (CAS1609-86-5) dropwise. After stirring for 2 hours at room temperature, the medium is poured into water, the organic phase is separated out and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give a solid in the form of a green foam, which is purified by chromatography on a column of silica gel, eluting with a mixture of 20 to 50% ethyl acetate in cyclohexane, to give 0.36 g of N-tert-butyl-8-cyano-6-fluoro-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide in the form of an orange-coloured gummy solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([CH3:19])=[C:14]([CH2:20][CH3:21])[N:13]=1>>[CH3:19][C:15]1[C:16]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[N:17][C:12]([Cl:11])=[N:13][C:14]=1[CH2:20][CH3:21]
Reactant: CCc1nc(Cl)nc(Cl)c1C
Reactant: c1ccc2c(c1)CCNC2
Product: CCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Yield: 62.7 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 1,2,3,4-tetrahydroisoquinoline(3.5 ml, 28 mmol) and 2,4-dichloro-5-methyl-6-ethylpyrimidine(4.9 g, 27.7 mmol) prepared in Preparation 4 were used as starting materials, 5.0 g of the titled compound was prepared.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][N:9](CC2C=CC=CC=2)[CH2:8][CH2:7][N:6]1CC1C=CC=CC=1)[CH3:3]>C(O)C.C1CCCCC1.C(O)(=O)C.[Pd]>[CH3:1][N:2]([CH3:3])[CH2:4][CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1
Reactant: CN(C)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)CC1CNCCN1

Procedure:
A 4.7 g portion of 2-dimethylaminomethyl-1,4-bis(phenylmethyl)piperazine was dissolved in a mixture of 50 ml of ethanol, 20 ml of cyclohexane and 10 ml of glacial acetic acid. A 2.0 g portion of 10% palladium on carbon was added, the mixture was refluxed overnight and then filtered. The filtrate was evaporated, 5 ml of saturated aqueous potassium bicarbonate was added to the residue and this was extracted several times with dichloromethane. The extracts were combined, dried, filtered and evaporated, giving a gum which solidified on standing, giving 1.02 g of N,N-dimethyl-2-piperazinemethanamine.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].S(=O)(=O)(O)O.[C:23](=O)(O)[O-].[Na+]>>[CH:15]([O:17][CH:11]([CH3:10])[CH3:3])([CH3:14])[CH3:23].[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=C([O-])O
Reactant: NCCC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)OC(C)C
Product: N#Cc1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
4.96 g of 4-cyanobenzoyl chloride and 2.67 g of β-alanine were stirred at room temperature for 4 hours in 450 ml of sodium bicarbonate solution (2%) and the mixture was acidified using concentrated sulphuric acid (pH 6). The solution was evaporated and extracted using ethyl acetate. Drying and evaporation of the organic phase gave a residue which, with diisopropyl ether, yielded 4.69 g of N-(p-cyanobenzoyl)-β-alanine, m.p. 155°-157° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:11](OCCCC)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1cc(-c2ccc(N)cc2)c2c(N)ncnn12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(CO)n3ncnc(N)c23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a cooled (0° C.) solution of the product of step 4 of Example 96 (220.0 mg, 0.68 mmol) in THF (23 mL) was added diisobutylaluminum hydride (1 M in THF, 7.4 mL, 7.4 mmol). The mixture was allowed to warm to rt and stirred for 30 min. The reaction was cooled (0° C.) and quenched with methanol (1 mL). The mixture was poured into a vigorously stirred 1.2 M aqueous Rochelle's salt solution (50 mL). The resultant mixture was stirred for 30 min and then extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to dryness under reduced pressure. The crude material was purified by HPLC using a gradient of 50-90% MeCN in water to yield 170.0 mg (99%) of the desired product containing trace impurities. 1H-NMR (DMSO-d6) δ 8.14 (s, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.76 (s, 1H), 4.75 (s, 2H); MS [M+H]+=256.2; LCMS RT=1.05 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=2[CH:18]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CC([O-])(C)C.[Na+]>CC(O)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[CH:8][N:7]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=3[CH:18]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: C[Si](C)(C)CCOCn1cnc2ccc(Br)cc21
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CN1CCN(c2ccc3ncn(COCC[Si](C)(C)C)c3c2)CC1
Temperature: 100 °C
Yield: 73 %

Procedure:
(Buchwald coupling): In a microwave reaction vial a suspension of 6-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (500 mg, 1.53 mmol), 1-methyl-piperazine (0.203 mL, 1.83 mmol) Pd2(dba)3 (0) (14 mg, 0.015 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (36 mg, 0.076 mmol) and NaOtBu (206 mg, 2.14 mmol) in 2-methyl-propan-2-ol (1.5 mL) was degassed with nitrogen. The reaction was heated in a microwave reaction at 100° C. for 1 hour. The mixture was diluted with H2O, acidified by the addition of 2M aqueous HCl, stirred with EtOAc and then filtered. The EtOAc layer was then extracted with H2O (×3). The combined aqueous fractions were neutralized with saturated NaHCO3 solution and then extracted with CHCl3/iPrOH (2:1) (×3). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The product was purified by SiO2 chromatography providing the title compound (387 mg).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+]>C(O)CCCCC>[ClH:1].[NH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1=[O:11]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCO
Product: NC1CCCCNC1=O
Yield: 74.9 %

Procedure:
A stirred mixture of L-lysine hydrochloride 1 (55 g, 300 mmol) and NaOH (12 g, 300 mmol) in hexanol (1.2 L) is heated to reflux with a Dean-Stark trap used to remove H2O. The suspension is refluxed for 8 hours until all starting material is consumed (which maybe determined by 1 H NMR). The suspension is then cooled and filtered to remove byproduct NaCl. The filtrate is concentrated and the resulting crude α-amino-ε-caprolactam 2 is dissolved in water. After acidification to pH 6 with addition of concentrated HCl and partial concentration, crystals maybe formed at room temperature to afford α-amino-εcaprolactam hydrochloride (37 g) in 75% yield.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42]>CN(C=O)C>[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])=[O:42]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)CCCCCCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCCCCCCCBr)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
WSC (990 mg, 5.2 mmols) and HOBt (698 mg, 5.2 mmols) were added to a DMF (10 ml) solution of 2,4-difluoroaniline (1.29 g, 10 mmols) and 10-bromodecanoic acid (1.18 g, 4.7 mmols), and stirred at room temperature for 15 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer:hexane/acetone=10/1) aid the resulting crystals were recrystallized from ether-hexane to obtain 763 mg (yield, 45%) of 10-bromo-N-(2,4-difluorophenyl) decanamide as colorless needle-like crystals.
Reaction SMILES: [CH3:1][C:2]([CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4]O.P(Br)(Br)[Br:18]>C1C=CC=CC=1>[Br:18][CH2:4][CH:3]=[C:2]([CH3:1])[CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14]
Reactant: CC(C)=CCCC(C)CC=CC(C)=CCO
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Product: CC(C)=CCCC(C)CC=CC(C)=CCBr
Reaction time: 1 h

Procedure:
To a mixture of 4 g. of 3,7,11-trimethyldodeca-2,4,10-trien-1-ol, and 25 ml. of benzene at 0° is added a solution of 5 ml. of phosphorus tribromide in 18 ml. of benzene over about 15 minutes. The mixture is stirred at 0° for 1 hour. The mixture is then poured onto ice and extracted with pentane. The organic phase is washed with aqueous sodium bicarbonate, water and then brine, dried over magnesium sulfate and evaporated to yield 1-bromo-3,7,11-trimethyldodeca-2,4,10-triene.
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[S:32]1[CH:36]=[CH:35][C:34]([C:37](O)=[O:38])=[N:33]1>>[CH2:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]3[NH:24][C:25]4[CH2:30][CH2:29][N:28]([C:37]([C:34]5[CH:35]=[CH:36][S:32][N:33]=5)=[O:38])[CH2:27][C:26]=4[N:31]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1)[CH3:5]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=C(O)c1ccsn1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccsn3)C4)n[nH]c2c1
Yield: 19.7 %

Procedure:
The title compound was prepared from 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) and isothiazole-3-carboxylic acid (11 mg, 80 μmol) using the same method as described in Example 1. The crude material was purified by HPLC Method A to afford 7.7 mg of the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.O.[C:27]([O-:30])(=[O:29])C.[Na+].O.[CH3:33]O>[Cu](Cl)Cl.[Pd](Cl)Cl>[C:27]([C:23]#[C:22][C:15]1([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]1)([O:30][CH3:33])=[O:29]
Reactant: CC(=O)[O-]
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reactant: CO
Agent: Cl[Cu]Cl
Agent: Cl[Pd]Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reaction time: 2.5 h

Procedure:
3-(3Cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclohexan-1-one (0.30 g, 0.98 mmol) was dissolved in dry methanol (20 mL) and carbon monoxide was bubbled into the solution for 10 min. A mixture of copper (II) chloride (0.264 g, 1.96 mmol) and sodium acetate trihydrate (0.267 g, 1.96 mmol) was added, then trace palladium (II) chloride was added. After 2.5 h at room temperature, water was added and the methanol was evaporated The aqueous residue was extracted three times with ether, the combined extract was washed with brine, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, provided a pale yellow oil. 1H NMR(400 MHz, CDCl3) δ7.0 (d, J=2.3Hz, 1H), 6.95 (dd, J=8.4, 2.3Hz, 1H), 6.84 (d, J=8.4Hz, 1H), 4.78 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 2.82 (d, J=25Hz, 1H), 2.78 (d, J=25Hz, 1H), 2.5-2.1 (m, 5H), 2.0-1.8 (m, 7H), 1.61 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][NH:9][C:10]2=[O:13])=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:15]=2)[CH:5]=1)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]3[C:7]=2[CH2:8][NH:9][C:10]3=[O:13])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc([N+](=O)[O-])cc3c2CNC3=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2cc([N+](=O)[O-])cc3c2CNC3=O)cc1
Yield: 42.2 %

Procedure:
A solution of tert-butyl 4-(6-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenylcarbamate (0.276 g, prepared by substituting Example 128B for Example 1A in Examples 1B and 1C) in TFA (3 mL) and CH2Cl2 (3 mL) was stirred at room temperature for 1 hour, then concentrated to give 0.085 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 4.66 (s, 2H), 5.50 (s, 2H), 6.70 (d, J=8.5 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 8.20 (d, J=2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 9.03 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:18][C:16]2[S:17][C:13]([CH3:12])=[CH:14][CH:15]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(C=O)s1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(NCc2ccc(C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a mixture of 200 mg (1.32 mmol) methyl 4-aminobenzoate and 167 mg (1.32 mmol) 5-methyl-2-thiophenecarboxaldehyde dissolved in 8 mL dichloromethane was added 420 mg (1.98 mmol) sodium triacetoxyborohydride. The mixture was stirred at room temperature overnight, then partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated. Column chromatography, eluting with 20% ethyl acetate/hexane, provided 316 mg (1.2 mmol) of 4-[(5-Methyl-thiophen-2-ylmethyl)-amino]-benzoic acid methyl ester. This product was then dissolved in 10 mL methanol and treated with 127 mg (3.0 mmol) of lithium hydroxide dissolved in 5 mL water. The mixture was stirred at room temperature overnight, then partitioned between ethyl acetate and 1 N HCl, dried over magnesium sulfate and concentrated to provide 276 mg (92% yield) of 4-[(5-methyl-thiophen-2-ylmethyl)-amino]-benzoic acid (used in preparation of compound 64 of Table 1) as a pale yellow solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15](=[O:18])[CH2:16][CH3:17].C(Cl)(Cl)Cl.O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:14][C:15](=[O:18])[CH2:16][CH3:17])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCC(=O)CBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C

Procedure:
To a stirred suspension of potassium phthalimide (5.0 g, 0.027 mmole) in 25ml of dimethylformamide is added, dropwise, 3.80 g (0.025 mmole) of 1-bromobutanone. The mixture is heated for 10 hours at 80° C under nitrogen and then 150 ml of chloroform is added. The resulting mixture is poured into 30 ml of water and the organic layer is separated and washed with 10 ml of 0.2N sodium hydroxide. The resulting chloroform and dimethylformamide solution is dried over anhydrous sodium sulfate, and evaporated in vacuo to give 1-phthalimidobutanone.