Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@@H:10]([CH3:22])[C:11]2=[O:21])[CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@H:10]([CH3:22])[C:11]2=[O:21])[CH2:3]1
Reactant: [H][H]
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](C)C[C@@H]32)C1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@@H](C)C[C@@H]32)C1

Procedure:
To a solution of 3β,16β-dimethylandrost-5-en-17-one prepared in Example I in 500 ml of ethanol is added 5% Pd on C and the mixture is exposed to a hydrogen atmosphere while stirring. The catalyst is filtered off and the above-identified product is isolated.
Reaction SMILES: [CH3:1][N:2]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C@@H:35]([OH:71])[CH2:36][C@@H:37]([NH:45][C:46](=[O:70])[C@H:47]([CH:67]([CH3:69])[CH3:68])[NH:48][C:49]([N:51]([CH2:53][C:54]1[N:55]=[C:56]([NH:59]C(OC(C)(C)C)=O)[S:57][CH:58]=1)[CH3:52])=[O:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:3][C:4]1[N:5]=[C:6]([NH:9]C(OC(C)(C)C)=O)[S:7][CH:8]=1.CO>C(Cl)(Cl)Cl>[CH3:1][N:2]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C@@H:35]([OH:71])[CH2:36][C@@H:37]([NH:45][C:46](=[O:70])[C@H:47]([CH:67]([CH3:69])[CH3:68])[NH:48][C:49]([N:51]([CH2:53][C:54]1[N:55]=[C:56]([NH2:59])[S:57][CH:58]=1)[CH3:52])=[O:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1
Reactant: CC(C)[C@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)N(C)Cc1csc(N)n1)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(N)n1)C(C)C

Procedure:
Using the procedure of Example 58B but replacing the resultant compound of Example 58A with the resultant compound of Example 94 provided, after silica gel chromatography using first 5% then 10% methanol in chloroform, 52 mg (72%) of the desired compound (Rf 0.18, 10% methanol in chloroform) as a white solid, m.p. 110°-114° C. Mass spectrum: (M+1)+ =821.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][O:13][CH2:12][O:11][CH2:10]1)=[O:7].[CH2:20]([O:22][C:23](=[O:33])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.N1C(C)=CC(C)=CC=1C>CS(C)=O>[CH2:20]([O:22][C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:15]([C:9]2([NH:8][C:6]([O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:19])[CH3:18])=[O:7])[CH2:10][O:11][CH2:12][O:13][CH2:14]2)=[O:17])=[CH:30][CH:31]=1)[CH3:21]
Reactant: C[Si](C)(C)CCOC(=O)NC1(C(=O)O)COCOC1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: Cc1cc(C)nc(C)c1
Solvent: CS(C)=O
Product: CCOC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)OCC[Si](C)(C)C)COCOC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
5-(2-trimethylsilanylethoxycarbonylamino)-1,3-dioxane-5-carboxylic acid from above (0.050 g, 0.17 mmol), ethyl-4-aminocinnamate (0.036 g, 0.19 mmol), HATU (0.098 g, 0.26 mmol), HOAt (0.035 g, 0.26 mmol) and 2,4,6-collidine (0.062 mL, 0.51 mmol) were combined in anhydrous DMSO (1 mL). The solution was warmed to 60° C. and stirred for 6 h before another 1.5 equivalents of HATU was added and stirring was continued for another 2 hours to ensure complete consumption of the acid. The reaction mixture was diluted with dichloromethane and washed with 1N HCl (×2). The organic phase was dried with MgSO4, filtered and concentrated. The residue was subjected to flash chromatography to afford 0.043 g (54%) of the protected amide derivative as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[OH:11])=[O:5])[CH3:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCCC1OC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
A solution of 2-hydroxy-cyclopentanecarboxylic acid ethyl ester (3.5 g, 22.12 mmol) in methylene chloride (147.5 mL) was treated with 3,4-dihydro-2H-pyran (3.03 mL, 33.1 mmol) and pyridiniump-toluenesulfonate (556 mg, 2.21 mmol). This solution was stirred at 25° C. for 5 h. The reaction was then washed with a half-saturated aqueous sodium chloride solution (2×75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(tetrahydro-pyran-2-yloxy)-cyclopentanecarboxylic acid ethyl ester (4.7 g, 87.7%) as a clear liquid: EI-HRMS m/e calcd for C13H22O4 (M+) 242.1518. found 242.1521.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:4]2[N:3]=1.O.[SH2:20].[Na].Cl>O>[SH:20][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:4]2[N:3]=1
Reactant: S
Reactant: COC(=O)c1cnn2c(C(F)(F)F)cc(Cl)nc12
Agent: Cl
Agent: [Na]
Solvent: O
Product: COC(=O)c1cnn2c(C(F)(F)F)cc(S)nc12
Reaction time: 1 h

Procedure:
A mixture of 2.30 g of methyl 5-chloro-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and 2.0 g of sodium hydrogen sulphide monohydrate in 60 ml of water was stirred at 60° for 1 hour. The reaction mixture was cooled, acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in a vacuum until crystallization occurred. Petroleum ether was added and the solid product was filtered off under suction. There was obtained methyl 5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31]>ClCCl>[N+:30]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:20]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:28][CH:27]=[CH:26][CH:25]=2)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
Triethylamine (66.8 g, 0.33 mol) was added to a solution of tert-butyl N-(2-aminoethyl)carbamate (55.0 g, 0.34 mol) in anhydrous dichloromethane (500 mL). 4-Chloro-3-nitroquinoline (68.2 g, 0.33 mol) was slowly added and the reaction exothermed. The reaction mixture was allowed to stir at ambient temperature overnight. The resulting precipitate was isolated by filtration to provide product as a yellow solid. The filtrate was washed with water, dried over magnesium sulfate and then concentrated under vacuum. The resulting residue was slurried with hexane and filtered to provide additional product as a yellow solid. The two crops were combined to provide 101 g of tert-butyl N-[2-(3-nitroquinolin-4-yl)aminoethyl]carbamate as a yellow solid, m.p. 157-158.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([C:27]1[C:28]2[CH:29]=[CH:30][NH:31][C:32]=2[CH:33]=[CH:34][CH:35]=1)O)([CH3:13])[CH3:12]>C(OCC)(=O)C>[C:1]([O:9][CH:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH2:17][CH2:16][CH2:15][NH:14][C:11]([CH3:13])([CH3:12])[CH3:10])[C:27]1[C:28]2[CH:29]=[CH:30][NH:31][C:32]=2[CH:33]=[CH:34][CH:35]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NCCCOc1ccccc1C(O)c1cccc2[nH]ccc12
Reactant: O=C(O)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)NCCCOc1ccccc1C(OC(=O)c1ccccc1)c1cccc2[nH]ccc12
Yield: 94.1 %

Procedure:
A solution of 0.745 g of benzoic acid in 11 ml of ethyl acetate was added 70° C. to a mixture of 2.15 g of product of Step A and 400 ml of ethyl acetate. The solution obtained was filtered hot and cooled to obtain 2.62 g of the desired product melting at 185° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[NH:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:24]4[NH:23][CH:27]=[CH:26][CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc[nH]1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccc[nH]4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 143 mg (1.5 mmol) of pyrrole-2-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(1H-pyrrol-2-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in DIPE yield 4-(3-chloro-phenylamino)-3-[(1H-pyrrol-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=8.2; FAB-MS: (M+H)+=340.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COCCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
90 mg (purity 77%, 0.17 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoic acid (racemate) and 35 mg (0.18 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 66 mg (67% of theory)
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:20]([NH:28][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCc1ccccc1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccccc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and phenethyl-amine to afford the title compound. MS: m/e=362 (M+H).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([OH:21])[CH2:4][C@@H:5]([OH:20])[CH2:6][C:7]([O:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].Cl[CH2:23][C@@H:24](O)[CH2:25][C@@H](O)CC(OC(C)(C)CC1C=CC=CC=1)=O>>[Br:1][CH2:2][C@H:3]1[O:21][C:24]([CH3:25])([CH3:23])[O:20][C@@H:5]([CH2:6][C:7]([O:9][C:10]([CH3:18])([CH3:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:4]1
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H](O)C[C@H](O)CCl
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H](O)C[C@H](O)CBr
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CBr)OC(C)(C)O1

Procedure:
The procedure was carried out in the same manner as in Example 5, except that the crude compound (3R,5S)-2-methyl-1-phenylpropan-2-yl 6-bromo-3,5-dihydroxy-hexanoate (21.0 g) prepared in Example 4 was used in place of the crude compound (3R,5S)-2-methyl-1-phenylpropan-2-yl 6-chloro-3,5-dihydroxy-hexanoate (21.1 g) prepared in Example 3. The crude title compound was obtained (22.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH2:31][CH3:32])=[C:4](/[C:17](/[CH3:29])=[CH:18]\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>>[Cl:1][C:2]1[C:3]([O:30][CH2:31][CH3:32])=[C:4](/[C:17](/[CH3:29])=[CH:18]\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/C)c1cc2c(c(Cl)c1OCC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCOc1c(/C(C)=C\C=C\C(C)=C\C(=O)O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure G, ethyl 7-(8-chloro-4-isopropyl-7-ethoxy-2,2-dimethyl-2H-chromen-6-yl)-3-methyl-octa-2E,4E,6Z-trienoate (Compound 40, 42 mg, 0.092 mmol) was hydrolyzed with 1M NaOH. Purification by column chromatography (silica gel, 25% ethyl acetate in hexanes) followed by recrystallization from acetonitrile gave rise to the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[C:32]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:45][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]([CH3:1])=[N:3]3)=[CH:19][CH:18]=2)=[O:31])(=[O:43])=[O:44])=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-tert-butyl-benzenesulfonamide: 1H-NMR (CDCl3) δ 7.76 (2H, d, J=8.7 Hz), 7.53-7.24 (11H, m), 6.43 (1H, br.s), 3.54-3.47 (2H, m), 2.87 (2H, t, J=6.6 Hz), 2.33 (3H, s), 2.26 (3H, s), 1.32 (9H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([Cl:24])=[CH:10][N:11]2[S:14]([C:17]2[CH:22]=[CH:21][C:20](C)=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)=O.[CH3:25]C(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Cl:24][C:9]1[C:8]2[C:12](=[CH:13][C:5]([CH2:3][OH:2])=[CH:6][CH:7]=2)[N:11]([S:14]([C:17]2([CH3:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH2:18]2)(=[O:15])=[O:16])[CH:10]=1
Reactant: CC(C)C[AlH]CC(C)C
Reactant: COC(=O)c1ccc2c(Cl)cn(S(=O)(=O)c3ccc(C)cc3)c2c1
Solvent: Cc1ccccc1
Product: CC1(S(=O)(=O)n2cc(Cl)c3ccc(CO)cc32)C=CC=CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-1-(toluene-4-sulfonyl)-1H-Indole-6-carboxylic acid methyl ester (3.10 g, 8.53 mmol) in 50 mL of toluene at −78° C. is added DIBAL (13.8 mL of a 1.5M solution in toluene, 20.8 mmol) dropwise. The mixture is stirred at −78° C. for 2 h, then warmed to room temperature and stirred for 2 hours. The reaction mixture is quenched by the addition of MeOH and washed with saturated disodium tartrate solution. The aqueuos layer is extracted with Et2O. The combined organics are washed with saturated disodium tartrate solution, water and saturated NaCl solution. The organic phase is then dried over anhydrous MgSO4, filtered and concentrated to give the title compound (2.88 g). The crude product is used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.01 (s, 1H), 7.79 (d, 2H), 7.56 (s, 1H), 7.53 (d, 1H), 7.31 (d, 1H), 7.25 (d, 2H), 4.84 (s, 2H), 2.37 (s, 3H), 1.88 (bs, 1H).
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[C:21]1([CH:18]2[C:12]3[C:11]4=[C:16]([CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9][N:10]4[CH2:20][CH2:19]2)[CH:15]=[C:14]([NH:17][C:35](=[O:36])[O:37][CH3:38])[CH:13]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-amine (Intermediate 4), (207 mg, 0.608 mmol) in dichloromethane (10 mL) was added three equivalent of triethyl amine (0.252 mL, 1.8 mmol), followed by methyl chloroformate (0.071 mL, 0.91 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give methyl 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-ylcarbamate (272), (181 mg 75%). 1H NMR (300 MHz, CDCl3) δ ppm 2.00-2.18 (m, 2H) 2.22-2.39 (m, 2H) 3.03-3.22 (m, 4H) 3.50-3.64 (m, 3H) 3.54-3.65 (m, 3H) 4.05-4.23 (m, 2 H) 6.61 (br. s., 2H) 7.08-7.38 (m, 10H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH3:13].[C-:14]#[N:15].[K+].CCO>O>[CH3:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:2][C:14]#[N:15]
Reactant: [C-]#N
Reactant: Cc1ccc2ccccc2c1CCl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2ccccc2c1CC#N
Temperature: 80 °C
Reaction time: 18 h

Procedure:
1-Chloromethyl-2-methylnaphthalene (5.00 g, 26.3 mmol) and KCN (5.12 g, 78.8 mmol) were combined in H2O (20 mL) and EtOH (40 mL) in a round bottom flask fitted with a reflux condenser. The mix was stirred at 80° C. for 18 hours. TLC analysis (silica, 10% acetone-hexanes) indicated consumption of the starting chloromethylnaphthalene. The reaction was allowed to cool to room temperature and then was diluted with H2O. The dilution was extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, decanted, and concentrated to give (2-methyl-naphthalen-1-yl)-acetonitrile in quantitative yield. MS (APCI) m/z 180.1 (M−H). 1H NMR (400 MHz) CDCl3 δ 7.96 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.61 (m ,1H), 7.50 (m, 1H), 7.34 (d, J=8.4, 1H), 4.07 (s, 2H), 2.58 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C:17]1[C:18]([F:43])=[CH:19][C:20]([F:42])=[C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:35])=[C:30](F)[C:31]=3[Cl:33])[C:26](=[O:36])[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:24]2)[CH:22]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCCC1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([NH:8][C:30]1[C:31]([Cl:33])=[C:32]2[C:27]([C:26](=[O:36])[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:24][N:23]2[C:21]2[CH:22]=[C:17]([NH:16][C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])[C:18]([F:43])=[CH:19][C:20]=2[F:42])=[CH:28][C:29]=1[F:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: NCc1ccccc1
Agent: CN1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(NCc3ccccc3)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Benzylamine (750 mg) and ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (4,200 mg) were added to a solution of N-methylpyrrolidine (800 mg) and N,N-dimethylformamide (20 ml), and the mixture was stirred overnight at 80° C. After the reaction mixture was cooled to room temperature, ethyl acetate (100 ml) was added to the reaction mixture, and the resultant mixture was washed 3 times with water (100 ml). After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent; chloroform) to obtain the title compound (3,200 mg) as an amorphous substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27]>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: COc1ccccc1S
Product: COc1ccccc1SC1=C/C(=C2/C(=O)NN=C2C)Nc2ccccc21

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 2-methoxythiophenol using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.96 (s, 3H) 3.68 (s, 3H) 6.77 (s, 1H) 7.65-7.69 (m, 3H) 7.83-7.93 (m, 3H) 7.99 (d, J=8.08 Hz, 1H) 8.16 (d, J=8.34 Hz, 1H) 10.35 (s, 1H) 13.04 (bs, 1H); ESI-MS: m/z calc'd for C20H17N3O2S 363.10. found 364.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](=[S:6])[NH2:5].Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[F:1][C:2]([F:8])([F:7])[CH2:3][C:4]1[S:6][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:5]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)CC(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(CC(F)(F)F)n1

Procedure:
A solution of 3,3,3-trifluoropropanethioamide (example 67, step b) (4 g) and ethyl 3-bromo-2-oxopropanoate (5.45 g) in THF (120 mL) was heated at reflux for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 17% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.9 g.