Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:22])[CH:10]=[CH:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]([CH3:21])[O:18][C:19](=[O:20])[C:6]=2[C:5]([O:23]COCC)=[CH:4][C:3]=1[O:28]COCC.CC1(C)O[O:35]1>CC#N>[CH3:21][C@@H:17]1[O:18][C:19](=[O:20])[C:6]2[C:5]([OH:23])=[CH:4][C:3]([OH:28])=[C:2]([Cl:1])[C:7]=2[CH2:8][C:9](=[O:22])[CH:10]=[CH:11][CH2:12][CH2:13][C@H:14]2[O:35][C@@H:15]2[CH2:16]1
Reactant: CCOCOc1cc(OCOCC)c2c(c1Cl)CC(=O)C=CCCC=CCC(C)OC2=O
Reactant: CC1(C)OO1
Agent: C[C@H]1C[C@H]2O[C@@H]2CC/C=C/C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: CC#N
Product: C[C@H]1C[C@H]2O[C@@H]2CCC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reaction time: 1.5 h

Procedure:
To a solution of compound 2-112 (50 mg, 0.11 mmol) in CH3CN (5 mL) at 0° C. was added freshly made DMDO (275 μL, 0.11 mmol, 0.04 M in acetone) and the mixture was stirred for 1.5 h. After evaporation of the solvents under reduced pressure, purification by flash chromatography (silica gel, 0-70% Et2O/hexane gradient) afforded compound 2-122 (41 mg, 79%) as a 1:1 mixture of two diastereoisomers. 1H NMR (400 MHz, CDCl3, 25° C.): δ=7.12 (s, 1H), 7.11 (s, 1H), 6.90-6.76 (m, 2H), 6.11 (d, J=15.6 Hz, 1H), 6.05 (d, J=15.8 Hz, 1H), 5.37-5.27 (m, 6H), 5.26-5.21 (m, 4H), 4.14 (d, J=16.9 Hz, 1H), 4.12 (d, J=17.4 Hz, 1H), 4.04 (d, J=17.2 Hz, 1H), 3.82-3.70 (m, 9H), 2.81-2.78 (m, 1H), 2.74-2.72 (m, 1H), 2.67-2.62 (m, 2H), 2.38-2.11 (m, 8H), 2.05-2.03 (m, 1H), 2.03-2.00 (m, 1H), 1.74-1.60 (m, 2H), 1.41 (d, J=7.2 Hz, 3H), 1.39 (d, J=6.2 Hz, 3H), 1.27-1.22 (m, 12H); 13C NMR (100 MHz, CDCl3, 25° C.): δ=195.1 (×2), 166.7, 166.3, 154.9, 154.8, 154.0, 153.5, 147.8, 147.4, 132.9, 132.4, 129.1, 129.0, 119.7 (×2), 118.0, 117.9, 102.9, 102.8, 93.9 (×2), 93.6 (×2), 71.1, 70.4, 64.8 (×2), 64.6 (×2), 58.4, 57.6, 56.9, 55.1, 43.4 (×2), 39.0, 37.9, 29.9, 29.7, 27.9 (×2), 18.4, 18.0, 15.0 (×4); HRMS (ESI-TOF): m/z: calculated for C24H32ClO8: 483.1780, found 483.1814 [M+H+].
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=[CH:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[S:33](Cl)(=[O:35])=[O:34]>O1CCCC1>[S:1]1[CH:5]=[C:4]([N:6]([S:33]([C:26]2[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=2[F:24])(=[O:35])=[O:34])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of tert-butyl 1,3-thiazol-4-ylcarbamate (Preparation 72, 28.94 g, 144.55 mmol) in anhydrous tetrahydrofuran (600 ml), cooled to −70° C., under nitrogen was added lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1 M in tetrahydrofuran, 144.55 ml, 144.55 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour before cooling −70° C. 2,4,5-trifluoro benzenesulfonyl chloride (40 g, 173.46 mmol) in tetrahydrofuran (80 ml) was added dropwise and then the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. Organic layer was washed with water and saturated aqueous sodium chloride solution before concentrating in vacuo. The crude residue was purified by column chromatography eluting with ethyl acetate:hexane (gradient 1:19 to 3:17, by volume) to afford the title compound as white solid, 37 g, 64% yield.
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Cl:6].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[C:23]1([S:37]([OH:40])(=[O:39])=[O:38])[C:24](S(O)(=O)=O)=[CH:25][CH:26]=[C:27]2[C:32]=1[CH:31]=[CH:30][CH:29]=[CH:28]2>C(#N)C.CC(C)=O>[C:23]1([S:37]([OH:40])(=[O:38])=[O:39])[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:37]([OH:40])(=[O:39])=[O:38])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[Cl:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3](=[O:9])[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: CC(C)(CCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: O=S(=O)(O)c1ccc2ccccc2c1S(=O)(=O)O
Reactant: c1nc[nH]n1
Solvent: CC(C)=O
Solvent: CC#N
Product: CC(C)(CCl)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Product: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Reaction time: 0.5 h
Yield: 192.6 %

Procedure:
268.3 g (0.79 mol) of crude 1-bromo-4-chloro-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one were dissolved in 2 l of absolute acetonitrile. 190 g (2.7 mol) of 1,2,4-triazole were added thereto and the mixture was heated for 20 hours under reflux. It was then concentrated by distilling off the solvent in vacuo and the residue was taken up in 1,000 ml of methylene chloride. The mixture was washed three times with 250 ml of water at a time, dried over sodium sulphate and again concentrated in vacuo. The oil which remained was dissolved in 1,000 ml of acetone and a solution of 140 g (0.48 mol) of naphthalenedisulphonic acid in 500 ml of acetone was added. After 30 minutes, the resulting precipitate was filtered off. 285 g (76.6% of theory) of 4-chloro-1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one naphthalene-1,5-disulphonate of melting point 245° C. (with decomposition) were obtained.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[NH:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.CO>C(Cl)Cl>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:5][CH:6]=2)=[O:22])=[CH:17][CH:16]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc(Cl)nc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 89.1 %

Procedure:
Into a round bottom flask was added aluminum trichloride (16.0 g, 0.12 mol) and methylene chloride (100.0 mL) under an atmosphere of nitrogen. Into the reaction mixture, was added 1H-Pyrrolo[2,3-b]pyridine 1 (3.2 g, 0.027 mol) in methylene dichloride (20.0 mL). The reaction was stirred at room temperature for 70.0 minutes, and then 6-Chloropyridine-3-carbonyl chloride 8 (5.4 g, 0.031 mol) in methylene chloride (10.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. Methanol (10 mL) was added to the reaction mixture and the solvent was evaporated in vacuo. The residue was poured into water, and the precipitated product was removed by filtration. The aqueous layer was extracted with ethyl acetate, and then the organic layer was dried and concentrated and combined with the solid isolated by filtration to give 7 (6.2 g, yield=88.6%) as a white solid (M+1=258).
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[C:6]([CH3:15])=[N+:7]([O-:14])[CH:8]=[CH:9][C:10]=1[N+]([O-])=O.Cl.[CH3:17][OH:18]>>[CH3:1][O:2][C:5]1[C:6]([CH3:15])=[N+:7]([O-:14])[CH:8]=[CH:9][C:10]=1[O:18][CH3:17]
Reactant: Cc1c(F)c([N+](=O)[O-])cc[n+]1[O-]
Reactant: CO
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1cc[n+]([O-])c(C)c1OC
Reaction time: 8 h

Procedure:
A solution of sodium methoxide (from 0.535 g sodium) in dry methanol (40 ml) was added dropwise to a stirred suspension of 3-fluoro-2-methyl-4-nitropyridine N-oxide (2 g) in dry methanol (50 ml) and the mixture was stirred overnight. Additional sodium methoxide (from 0.053 g sodium) was added and the mixture was heated under reflux for 1 hour. The mixture was neutralised with hydrochloric acid and evaporated to dryness. The residue was extracted with chloroform and the extract was evaporated to dryness to give 3,4-dimethoxy-2-methylpyridine N-oxide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].O>ClCCl>[CH3:16][N:12]1[C:13](=[O:15])[C:14]2[C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][C:40](=[O:42])[CH3:41])=[C:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[S:8][C:9]=2[N:10]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:11]1=[O:17]
Reactant: CC(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCN)c(Cc3cccc4ccccc34)sc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCCSc1c(Cc2cccc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reaction time: 8 h

Procedure:
5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (51 mg) and triethylamine (100 μl) were dissolved in dichloromethane (2 ml) and acetyl chloride (25 μl) was added. The reaction was stirred overnight, then water was added and the phases were separated. The aqueous phase was extracted with dichloromethane, then the organic phases were combined, dried, filtered and evaporated. Purification by HPLC (ethanol:dichloromethane 1-10:99-90) gave the title compound (36 mg).
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][C:5]2[N:6]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:21])[C:7](=[O:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[N:51]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[N:50]=1>CN(C)C=O>[F:1][C:2]1[C:35]([F:36])=[CH:34][C:5]2[N:6]([CH2:19][C:20]([N:22]([CH:31]([CH3:32])[CH3:33])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[O:21])[C:7](=[O:18])[CH:8]([CH2:48][C:49]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[N:51]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[N:50]=3)[C:9](=[O:17])[N:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3cc(F)c(F)cc32)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccccc3)c3cc(F)c(F)cc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 71.6 %

Procedure:
To a solution of 0.500 g of 2-(7,8-difluoro-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part B, (1.013 mmol) in 5 mL dimethylformamide at 0° C. under nitrogen is added 2.43 mL (1.22 mmol, 1.2 equiv) potassium bis(trimethylsilyl)amide (0.5M in toluene) dropwise over 5 min. After stirring 5 min., 346 mg of 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole (1.11 mmol, 1.1 equiv) is added. After 1 h at 0° C., the reaction is quenched by addition to a stirring mixture of ethyl acetate, water and saturated aqueous brine. The mixture is transferred to a separatory funnel and the layers were separated. The organic layer is washed with 1:1 water/saturated aqueous brine. The aqueous layers were combined and washed twice with ethyl acetate. The organic layers were combined, washed with saturated aqueous brine, dried over anhydrous sodium sulfate, and then evaporated in vacuo to an oil. The crude product is purified on flash grade silica gel using 25-30% ethyl acetate in hexane. The appropriate fractions were combined, evaporated in vacuo and triturated with hexane. The hexane is evaporated in vacuo and the residual solid is dried under high vacuum to provide 525 mg of the title compound as a white solid: 1H NMR (300 MHz, CDCl3) δ8.06 (d, 1H, J=8.3), 7.84 (d, 1H, J=7.9), 7.49 (m, 1H), 7.38 (m, 2H), 7.29 (m, 6H), 7.12 (m, 1H), 6.98 (m, 2H), 6.78 (dd, 1H, J=8.5, 10.6), 4.99 (m, 1H), 4.36 (dd, 1H, J=4.6, 8.7), 4.20 (s, br, 2H), 3.85 (s, 3H), 3.84 (m, 1H), 3.52 (dd, 1H, J=4.6 16.8), 1.67 (s, 9H), 1.08 (m, 6H); low resolution MS (FAB)m/e 724 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=[C:7]3[C:6]=2[CH:20]=1.C(=O)(O)[O-].[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>COCCOCCOC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:27])[CH2:9][N:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=[C:7]3[C:6]=2[CH:20]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Cn2c(cc3ccccc32)-c2cc(Cl)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: S=C1Cn2c(cc3ccccc32)-c2cc(Cl)ccc2N1
Yield: 40 %

Procedure:
A mixture of 3.74 g 2-chloroindolo[1,2-d][1,4]benzodiazepin-6(7H)-one, 2.58 g sodium bicarbonate, and 13.67 g P2S5 in 85 ml diglyme was heated at 105°-120° C. under nitrogen for one and a half hours. The cooled reaction mixture was diluted with water to precipiate a solid. Recrystallization from toluene yielded 1.58 g solid, which decomposed at 265° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([CH2:15][CH2:16][CH2:17]Cl)(=[O:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][NH:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:34]([O:35][CH3:36])=[C:31]([O:32][CH3:33])[CH:30]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([CH2:15][CH2:16][CH2:17][N:26]([CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:34]([O:35][CH3:36])=[C:31]([O:32][CH3:33])[CH:30]=2)[CH3:25])(=[O:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(NS(=O)(=O)CCCCl)cc(OC)c1
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: COc1cc(NS(=O)(=O)CCCN(C)CCc2ccc(OC)c(OC)c2)cc(OC)c1
Reaction time: 72 h

Procedure:
N-(3,5-Dimethoxyphenyl)-3-chloro-1-propanesulfonamide prepared in the preceding paragraph (16.56 g, 0.057 mol) was dissolved in xylene (300 mL) containing potassium carbonate (7.86 g, 0.057 mol) and N-methylhomoveratrylamine (11.13 g, 0.057 mol) and the reaction warmed and stirred three days. Filtration, stripping of solvent and chromatography on dry-column silica gel (1100 g) with 5% methanol/ethyl acetate provided crude N-(3,5-dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-1-propanesulfonamide (5.32 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[OH:28])/[CH:5]=[CH:6]/[C:7]1[N:15]([CH3:16])[C:14]2[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH3:20])[C:11](=[O:21])[N:10]([CH2:22][CH2:23][CH3:24])[C:9]=2[N:8]=1.CI.[C:31](=O)([O-])[O-].[Li+].[Li+].O>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:31])/[CH:5]=[CH:6]/[C:7]1[N:15]([CH3:16])[C:14]2[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH3:20])[C:11](=[O:21])[N:10]([CH2:22][CH2:23][CH3:24])[C:9]=2[N:8]=1
Reactant: O=C([O-])[O-]
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(O)c3)n2C)n(CCC)c1=O
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(O)c3)n2C)n(CCC)c1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 31.3 %

Procedure:
Compound 53 (500 mg, 1.30 mmol) obtained in Reference Example 46 was dissolved in 10 ml of dimethylformamide. To the solution were added 0.40 ml (6.43 mmol) of methyl iodide and 400 mg (6.50 mmol) of lithium carbonate, and the mixture was stirred at 80° C. for 5 hours. Water was added thereto to dissolve lithium carbonate and deposited crystals were collected by filtration. The collected crude crystals were dissolved in chloroform, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to give 162 mg (yield 31%) of Compound 63 as yellow grains.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([C:5]1[C:14]2[C:9](=[C:10]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:24])[CH:6]=1)[OH:4].[CH3:27][N:28]=[C:29]=[O:30].C(N(CC)CC)C>ClCCl>[F:26][C:2]([F:1])([F:25])[CH:3]([O:4][C:29](=[O:30])[NH:28][CH3:27])[C:5]1[C:14]2[C:9](=[C:10]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:24])[CH:6]=1
Reactant: CN=C=O
Reactant: Cc1cc(C)c(-c2cccc3c(C(O)C(F)(F)F)cc(C)nc23)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)OC(c1cc(C)nc2c(-c3c(C)cc(C)cc3C)cccc12)C(F)(F)F

Procedure:
A mixture of 2,2,2-trifluoro-1-[2-methyl-8-(2,4,6-trimethyl-phenyl)quinolin-4-yl]-ethanol (50 mg), methyl isocyanate (0.5 ml), triethylamine (0.1 ml) in dichloromethane (2 ml) was heated at reflux for 2 hrs. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give the crude material which was purified by silica gel column chromatography using chloroform as eluent to give the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15](C=O)[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[CH3:25][O:26][C:27](=[O:48])[CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[CH2:50]Cl>>[CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH:50]=[CH:28][C:27]([O:26][CH3:25])=[O:48])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:11])[CH2:3][CH2:2]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(C=O)cc2cccnc12)C1CC1
Reactant: ClCCl
Product: COC(=O)C=Cc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2ncccc2c1
Temperature: 25 °C

Procedure:
To a solution of 1,1-dimethylethyl cyclopropyl[(6-formyl-8-quinolinyl)methyl]carbamate (1 eq.) from the previous step in dichloromethane (0.06 M) was added methyl(triphenylphosphoranylidene)acetate (1.1 eq.) at 0° C. The resulting solution was then allowed to warm slowly to RT over 4 h. The volatiles were then removed in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:53]=[CH:52][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:16]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:11]3[C:10]([C:36]#[C:37][C:38]3[CH:39]=[N:40][N:41]([CH2:43][C:44]4[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=4)[CH:42]=3)=[N:9]2)=[CH:5][CH:4]=1.N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:16]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]4)=[C:11]3[C:10](/[CH:36]=[CH:37]\[C:38]3[CH:39]=[N:40][N:41]([CH2:43][C:44]4[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=4)[CH:42]=3)=[N:9]2)=[CH:52][CH:53]=1
Reactant: COc1ccc(Cn2cc(C#Cc3nn(Cc4ccc(OC)cc4)c4ncc(-c5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)c34)cn2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccccc1
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: COc1ccc(Cn2cc(/C=C\c3nn(Cc4ccc(OC)cc4)c4ncc(-c5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)c34)cn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
A solution of tert-butyl 4-(1-(4-methoxybenzyl)-3-((1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethynyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.12 g, 0.169 mmol), quinoline (0.011 g, 0.085 mmol) and Lindlar's Catalyst (0.18 g, 0.085 mmol) in MeOH (3 mL) and benzene (3 mL) was charged with 1 atmosphere H2 and stirred at room temperature for 6 hours. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo, and the residue obtained was purified flash chromatography on silica gel (hexane:ethyl acetate=1:1) to give (Z)-tert-butyl 4-(1-(4-methoxybenzyl)-3-(2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)vinyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.089 g, 74%) as a solid.
Reaction SMILES: [F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#N)=[CH:7][CH:6]=1.[H-].C([Al+]CC(C)C)C(C)C.FC(F)(C(F)F)COC1C=CC(C=O)=CC=1.C(OP([CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])(OCC)=O)C>>[F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:51]/[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(OCC(F)(F)C(F)F)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Agent: [H-]
Product: CCOC(=O)/C=C/c1ccc(OCC(F)(F)C(F)F)cc1

Procedure:
In a first step, p-chlorobenzonitrile is reacted with 2,2,3,3-tetrafluoropropanol in the presence of bases, for example sodium hydride, with exchange of the p-chlorine atom to give 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile. The second step is to reduce the 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile by metal hydrides, for example diisobutylaluminum hydride, 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde being formed. The 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde is reacted stereoselectively with ethyl diethylphosphonoacetate in a third reaction step to give ethyl (E)-4-(2,2,3,3-tetrafluoropropoxy)cinnamate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6](OS(C(F)(F)F)(=O)=O)[N:5]=[C:4]2[S:21][CH:22]=[CH:23][C:3]=12.C([O-])([O-])=O.[K+].[K+].[CH2:30]([SH:32])[CH3:31]>CN(C=O)C.O>[CH2:30]([S:32][C:6]1[N:5]=[C:4]2[S:21][CH:22]=[CH:23][C:3]2=[C:2]([CH3:1])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:31]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2sccc2c1C
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(SCC)nc2sccc2c1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
To a solution of ethyl 4-methyl-6-(trifluoro-methyl-sulfonyloxy)thieno[2,3-b]pyridine-5-carboxylate (1.84 g, 4.9 mmol, 1 eq.) in DMF (30 ml) were added K2CO3 (2.70 g, 19.6 mmol, 4 eq.) and ethanethiol (3.73 ml, 49.8 mmol, 10 eq.) at RT. The reaction mixture was stirred at 80° C. for 2 h. Afterwards the mixture was diluted with water (50 ml) and was extracted with EtOAc (2×50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over Na2SO4 and evaporated. The crude product was purified by CC (EtOAc/hexane 1:49) to yield ethyl 6-(ethylthio)-4-methylthieno[2,3-b]pyridine-5-carboxylate (0.26 g, 0.92 mmol, 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[N:19]([C:21]1[CH:35]=[CH:34][C:24]2[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][S:27][C:23]=2[CH:22]=1)[CH3:20]>N.CO>[ClH:1].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[N:19]([C:21]1[CH:35]=[CH:34][C:24]2[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][S:27][C:23]=2[CH:22]=1)[CH3:20]
Reactant: CN(c1ccc2c(-c3ccccc3)csc2c1)c1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: N
Solvent: CO
Product: CN(c1ccc2c(-c3ccccc3)csc2c1)c1c(Cl)ccc2c1CCNCC2
Product: Cl
Yield: 37.1 %

Procedure:
Use a procedure similar to General Procedure 1-1 to deprotect 7-chloro-6-(3-phenyl-benzothiophen-6-yl-methylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (234 mg, 0.45 mmol) in 7M ammonia in methanol (20 mL). Purify by reverse phase HPLC (Vydac C18 5×25 cm, 30% to 100% acetonitrile in 0.1% TFA-water solution). Recover the free base by SCX chromatography and form the salt according to General Procedure 2-3 to obtain the title compound (38 mg, 17%). HRMS (ES+) m/z: 419.1340 (M+H)+.