Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[CH3:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:31][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(S(C)(=O)=O)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(S(C)(=O)=O)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)phenyl)piperidine-1-carboxylate (505 mg, 1.23 mmol) (from example 38, step 1) was suspended in MeOH (5 mL) and cooled to −40° C. 3.8 M sodium hydroxide (0.323 mL, 1.23 mmol) in water was added. After 20 min, hydroxylamine (50% in water, 0.075 mL, 1.23 mmol) was added and stirring continued at −40° C. for 3 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (6.14 mL, 36.82 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The residue was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 15-40% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 25 minutes with a flow of 19 mL/min. Trans-methyl 2-(4-(methylsulfonyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (301 mg, 64.5%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.61-1.73 (m, 1H), 1.91-1.99 (m, 1H), 2.05-2.14 (m, 1H), 2.66-2.82 (m, 2H), 2.91 (t, 1H), 3.05 (s, 3H), 3.77 (s, 3H), 4.12-4.46 (m, 1H), 5.60-5.80 (m, 2H), 7.44 (d, 2H), 7.95 (d, 2H). MS m/z 381 (M+H)+
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]>CN1CCCC1=O>[CH3:1][S:2][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(C(F)(F)F)cc1SC
Reaction time: 3 h
Yield: 94.5 %

Procedure:
Dry sodium thiomethoxide (0.385 g, 0.0055M) was added to a solution of methyl 2-chloro-4-trifluoromethylbenzoate (1.19 g, 0.005M) in anhydrous N-methylpyrrolidinone (10 ml) at 5° C. After 3 hours the mixture was acidified, extracted (ether), washed (water) and evaporated to give methyl 2-methylthio-4-trifluoromethylbenzoate (1.18 g, 94% yield), 1H NMR 2.44(s,3H), 3.89(s,3H), 7.33(1H), 7.41(1H), 8.02(1H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([CH:9]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NCCc1cccc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)C(CN)c2cccc(Br)c2)cc1
Reaction time: 16 h
Yield: 68.4 %

Procedure:
3-Bromophenylethylamine hydrochloride (9.44 g) was added to THF (60 ml) containing triethylamine (12.24 ml) and stirred-under argon at 5° C. during the portionwise addition over 15 minutes of 4-methylphenylsulphonyl chloride (11.44 g). The slurry was diluted with THF (50 ml) and stirred for 16 h. The solid was filtered off, washed with THF and the filtrate evaporated. The residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid, water, brine and dried (MgSO4). Chromatography on flash silica, eluting with 0 to 25% ethyl acetate in isohexane gave the product (9.67 g).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O>C(O)(=O)C>[CH3:13][C:11]1[NH:2][N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[C:9](=[O:14])[CH:10]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccccn1
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2ccccn2)[nH]1

Procedure:
A solution of 2-hydrazinopyridine (1.35 g; 0.012 mol.) and ethyl acetoacetate (1.60 mL; 0.012 mol.) in glacial acetic acid (50.0 mL) was stirred and heated at 100° for 24 h.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1[N:25]([CH3:27])[CH3:26])=O)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][C@H:13]1[N:25]([CH3:27])[CH3:26]
Reactant: [H][H]
Reactant: CN(C)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Yield: 100.3 %

Procedure:
20% Palladium hydroxide (15 mg) was added to a solution of tert-butyl cis(±)-4-{[benzyloxy)carbonyl]amino}-3-(dimethylamino)piperidine-1-carboxylate obtained in Example (200b) (144 mg, 0.381 mmol) in methanol (4 mL) at room temperature, and the mixture was stirred in a hydrogen atmosphere at 50° C. for six hours. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain 93 mg of the title compound (100%) as a colorless oily substance.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[N:9]=[C:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH2:19][CH2:18]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][S:31](O)(=[O:33])=[O:32]>C(Cl)Cl.CCOCC.CCOCC>[CH3:30][S:31]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:20]1[CH2:19][CH2:18][N:17]([C:8]2[N:7]=[C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:11]=[C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[N:9]=2)[CH2:22][CH2:21]1)(=[O:33])=[O:32]
Reactant: OCCCCCCN1CCN(c2nc(N3CCCC3)nc(N3CCCC3)n2)CC1
Reactant: CS(=O)(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCN1CCN(c2nc(N3CCCC3)nc(N3CCCC3)n2)CC1

Procedure:
A mixture of 4-[4,6-bis(1-pyrrolidinyl)-1,3,5-triazin-2-yl]-1-piperazinehexanol (EXAMPLE 1, 1.22 g) in methylene chloride/ether (1/1, 30 ml) is mixed with a solution of methanesulfonic acid (0.28 g) in ether (15 ml). The mixture is concentrated and the residue crystallized twice from methanol/ether to give the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+].CO>C1COCC1>[CH2:27]([N:9]1[C:8]2[CH:31]=[CH:32][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:24])([F:25])[F:26])[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 89.1 %

Procedure:
1-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (570.0 mg) was prepared by following General Procedure E starting from 1-isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (660.0 mg) and lithium hydroxide (2.0 N solution, 3.0 mL) MeOH (1.0 mL) and THF (3.0 mL). LCMS: m/z 452; and 1H NMR (DMSO-d6, 400 MHz): δ 8.16 (1H, m), 7.97-7.94 (1H, m), 7.85-7.82 (1H, m), 7.57-7.55 (2H, m), 7.39-7.37 (1H, m), 4.03-4.01 (2H, d), 2.29-2.24 (1H, m), 0.93-0.91 (6H, d), 2 —NH proton signals were not observed.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18](I)=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:28]B(O)O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]([CH3:28])=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CB(O)O
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(I)c2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c(COc2ccccc2)nn2c1CN(C(=O)c1ccc(F)cc1)CC2
Temperature: 100 °C
Reaction time: 21 h
Yield: 41.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (15.7 mg, 0.014 mmol) was added to a stirred solution of (4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (0.13 g, 0.27 mmol), methylboronic acid (0.122 g, 2.04 mmol) and saturated solution of Na2CO3 (2 mL) in 1,4-dioxane (4 mL) under N2. The mixture was stirred at 100° C. for 21 hours and then the mixture was diluted with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 70/30). The desired fractions were collected and the solvents evaporated in vacuo. The product was repurified by reverse phase HPLC (gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% MeOH to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% MeOH) to yield (4-fluoro-phenyl)-(3-methyl-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (41 mg, 39% yield). C21H20FN3O2. 1H NMR (400 MHz, CDCl3) δ ppm 2.00 (br. s., 3H), 3.98 (br. s., 2H), 4.22 (br. s., 2H), 4.73 (br. s., 2H), 5.02 (s, 2H), 6.96 (t, J=7.4 Hz, 1H), 7.02 (d, J=7.9 Hz, 2H), 7.16 (t, J=8.7 Hz, 2H), 7.29 (dd, J=8.7, 7.3 Hz, 2H), 7.49 (dd, J=8.8, 5.3 Hz, 2H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[C:9]([C:10]#[N:11])[C:5]=2[CH:4]=[N:3][CH:2]=1.[C:12]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[C:22](=[O:27])[N:21]([C:28]1[C:36]3[CH2:35][O:34]B(O)[C:32]=3[CH:31]=[CH:30][CH:29]=1)[N:20]=[CH:19]2)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1.ClC(Cl)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:12]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[C:22](=[O:27])[N:21]([C:28]1[C:36]([CH2:35][OH:34])=[C:32]([N:7]3[C:6]4[N:1]=[CH:2][N:3]=[CH:4][C:5]=4[C:9]([C:10]#[N:11])=[CH:8]3)[CH:31]=[CH:30][CH:29]=1)[N:20]=[CH:19]2)([CH3:15])([CH3:13])[CH3:14]
Reactant: N#Cc1c[nH]c2ncncc12
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc4c3COB4O)ncc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5cncnc54)c3CO)ncc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
In a 25 mL round-bottomed flask, 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (40.9 mg, 284 μmol, Eq: 1.00), 6-tert-butyl-8-fluoro-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)phthalazin-1(2H)-one (100 mg, 284 μmol, Eq: 1.00), copper acetate (34.8 mg) and pyridine (44.9 mg, 45.9 μl, 568 μmol, Eq: 2) were combined with dichloroethane to give a dark blue suspension. The reaction mixture was flushed with nitrogen. The reaction mixture was heated to 80° C. and stirred for 16 hr. The reaction was diluted with sat NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The mixture was separated by flash column using 30-50% EtOAc in hexanes to give the 7-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (42 mg, 31%) as a lyophilized white powder.
Reaction SMILES: [CH2:1](O)[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[Br:36][CH2:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCC/C=C/CCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCC/C=C/CCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of trans-oct-3-en-1-ol (1.28 g, 10.0 mmol) in DMF (25 mL) was added triphenylphosphine (2.92 g, 11.1 mmol). The solution was cooled to 0° C. and NBS (1.92 g, 10.8 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (100 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford trans-1-bromo-oct-3-ene (1.40 g, 73%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.54 (1H, m), 5.39 (1H, m), 3.37 (2H, t, J=7.2 Hz), 2.54 (2H, m), 2.02 (2H, m) 1.34 (4H, m), 0.89 (3H, t, J=7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 134.09, 126.45, 36.34, 33.21, 32.48, 31.73, 22.45, 14.24.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[C:15]1[CH:24]=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:26]([CH3:29])([O-:28])=[O:27]>CCOC(C)=O>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[C:15]1[CH:24]=[CH:29][N+:26]([O-:28])=[O:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc2ccc(Cl)cc2n1C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])C=Cc1cc2ccc(Cl)cc2n1C(c1ccccc1)c1ccccc1
Yield: 48 %

Procedure:
A solution of 1-benzhydryl-6-chloro-1H-indole-2-carbaldehyde (0.5M, 1 equiv.) and NH4OAc (1 equiv.) in nitromethane was heated at 95° C. for 70 min. The mixture was diluted with EtOAc, washed with water, and dried. Evaporation of the volatiles, followed by trituration with ether/hexane produced 1-Benzhydryl-6-chloro-2-(2-nitro-vinyl)-1H-indole in 48% yield.
Reaction SMILES: C[O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)/[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>CO>[F:19][C:15]1[CH:14]=[C:13](/[C:7](/[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6]\[CH:5]=[CH:4]\[C:3]([OH:20])=[O:2])[CH:18]=[CH:17][CH:16]=1
Reactant: CCCCC/C(=C/C=C/C(=O)OC)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC/C(=C/C=C/C(=O)O)c1cccc(F)c1
Yield: 70.8 %

Procedure:
As described in Example 99, (2E,4Z)-5-(3-fluorophenyl)-2,4-decadienoic acid methyl ester (6.1 g) was saponified in a refluxing mixture of methanol (40 mL) and 2N NaOH (30 mL). After 1 hour the crude acid was isolated in the usual way and crystallized from ether-hexane to give 4.1 g of (2E,4Z)-5-(3-fluorophenyl)-2,4-decadienoic acid, mp 100.5°-101° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:9]([C:11]3[N:12]([CH3:20])[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:15]=3)=[N:10][C:4]=2[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:16]([C:14]1[CH:15]=[C:11]([C:9]2[NH:8][C:5]3[CH:6]=[N:7][C:2]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[Cl:21])=[CH:3][C:4]=3[N:10]=2)[N:12]([CH3:20])[N:13]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: OB(O)c1ccccc1Cl
Reactant: Cn1nc(C(C)(C)C)cc1-c1nc2cc(Br)ncc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1nc(C(C)(C)C)cc1-c1nc2cc(-c3ccccc3Cl)ncc2[nH]1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 6-bromo-2-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3H-imidazo[4,5-c]pyridine (50 mg, 0.15 mmol, prepared as described in the previous step), 2-chlorophenylboronic acid (47 mg, 0.30 mmol), 2M Na2CO3 (0.60 mL, 1.2 mmol) and DME (1 mL) was stirred at 90° C. for 18 h. The resulting mixture was allowed to cool to room temperature and organic layer was separated. The organic layer was purified by direct application to silica preparative TLC plates (2000 micron) and eluted with 3:7 EtOAc-hexanes to yield 2-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-6-(2-chloro-phenyl)-3H-imidazo[4,5-c]pyridine.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][CH2:20][CH2:21]Cl)[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>O1CCOCC1.[OH-].[Na+]>[CH:23]([NH:26][CH2:21][CH2:20][CH2:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:10]([S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[CH:11][NH:12]2)([CH3:25])[CH3:24]
Reactant: CC(C)N
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2cccc(CCCCl)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)NCCCc1cccc2[nH]cc(S(=O)(=O)c3ccccc3)c12
Temperature: 70 °C
Yield: 84.9 %

Procedure:
To a solution of 3-phenylsulfonyl-4-(3-chloro-propyl)-1H-indole (0.255 g, 0.76 mmol) in anhydrous dioxane (5 mL) was added isopropylamine (0.65 mL, 7.64 mmol) and the reaction mixture heated to 70° C. in a sealed vessel for 7 days. The cooled reaction mixture was then diluted with 1 N aqueous NaOH (50 mL) and the resulting milky suspension extracted with ethyl acetate (50 mL). The organic phase was separated, washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography (0 to 10% ammonia saturated methanol/dichloromethane) afforded N-isopropyl-3-[3-(phenylsulfonyl)-1H-indol-4-yl]propan-1-amine as a yellow foam (0.23 g, 86%). The product was dissolved in absolute ethanol (10 mL), 1.25 N HCl in ethanol (0.78 mL, 0.98 mmol, 1.5 equivalents) added, the mixture stirred for 15 min and then concentrated in vacuo to afford a yellow foam. The product was crystallized from 1:1 v/v ethanol:tert-butyl methyl ether (10 mL) to give the title compound as white crystals (0.172 g, 57%). MS (ES+) m/z 357.3 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[NH:13]2
Reactant: Fc1cccc(-c2cccc3[nH]ccc23)c1F
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To the suspension of 4-(2,3-difluoro-phenyl)-1H-indole (2.85 g, 12.4 mmol) in t-BuOH: ethanol: acetic acid (78.5 mL: 46.5 mL: 24.13 mL) was added pyridinium tribromide (11.93 g, 37.3 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added with acetic acid (60 mL). Zinc dust (4.1 g, 62.2 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), sat NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 2.32 g (76%) of 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one as an earth colored solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23][C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=4)=[O:25])=[O:15])[S:13][C:7]=2[CH2:6]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1.Cl>[ClH:35].[Cl:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:24]([NH:23][C@@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]1[NH:16][C:14]([C:12]1[S:13][C:7]3[CH2:6][N:5]([CH2:4][CH2:3][NH:2][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:10][CH2:9][C:8]=3[N:11]=1)=[O:15])=[O:25])=[CH:34]2
Reactant: CS(=O)(=O)Cl
Reactant: NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCN1CCc2nc(C(=O)N[C@H]3CCCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-cis-N1-[[5-(2-Aminoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N2-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride (110 mg) was dissolved in pyridine (3 ml), methanesulfonyl chloride (30 μl) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a 85:15 mixed solvent of dichloromethane and methanol, and water were added to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain a pale yellow foamy substance. This product was suspended in 1N hydrochloric acid (0.3 ml), and the suspension was concentrated under reduced pressure to obtain the title compound (63 mg) as a pale yellow foamy substance.
Reaction SMILES: ClCCC(O[CH2:7][CH2:8][N:9]=C=O)=O.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:18]=[CH:7][CH:8]=1
Reactant: O=C=NCCOC(=O)CCCl
Reactant: Cc1ccccc1
Product: c1ccc2ncccc2c1

Procedure:
A three-necked flask was charged with 250 ml of toluene, 60 g (0.34 mol) of (2-isocyanatoethyl) 3-chloropropionate obtained in Synthesis Example 2, and 63 g (0.49 mol) of quinoline (boiling point: 237.7° C.), followed by heating at 50° C. for 6 hours with stirring. No acryloyloxyethyl isocyanate was confirmed by gas chromatography analysis.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=O.CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[OH:2][CH2:3][C:5]12[CH2:14][CH:9]3[CH2:8][CH:7]([CH2:13][CH:11]([CH2:10]3)[CH2:12]1)[CH2:6]2
Reactant: COC(=O)C12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCC12CC3CC(CC(C3)C1)C2
Reaction time: 2 h

Procedure:
Methyl-1-adamantanecarboxylate (104 gm.) dissolved in 465 ml. anhydrous ether was added over a 2 hour period to 37.5 gm. lithium aluminum hydride in 753 ml. anhydrous ether. The mixture was stirred an additional 2 hours, cooled and water added gradually. The ether was separated. The water was extracted twice with ether and the combined ether layers dried and concentrated. The residual solid was dissolved in methanol and water was added to precipitate the product which was filtered and dried over P2O5 to give 80 gm., m.p. 113.5°-15.5°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([Cl:27])[CH:3]=1.[CH:28]1([CH2:34]I)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:34][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:3][C:4]=1[Cl:27])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](OCc1ccc(Br)cc1Cl)(c1ccccc1)c1ccccc1
Reactant: ICC1CCCCC1
Product: CC(C)(C)[Si](OCc1ccc(CC2CCCCC2)cc1Cl)(c1ccccc1)c1ccccc1

Procedure:
In the same manner as in Preparation Example 70-2, the objective compound (797 mg, 56%) was obtained as a colorless oil from 4-bromo-1-((tert-butyldiphenylsilyloxy)methyl)-2-chlorobenzene and cyclohexylmethyl iodide.