Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.Cl.Cl.[OH:89][CH2:90][CH2:91][N:92]1[CH2:97][CH2:96][N:95]([CH2:98][C:99](O)=[O:100])[CH2:94][CH2:93]1>>[OH:89][CH2:90][CH2:91][N:92]1[CH2:97][CH2:96][N:95]([CH2:98][C:99]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:100])[CH2:94][CH2:93]1
Reactant: O=C(O)CN1CCN(CCO)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCN(CCO)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except [4-(2-hydroxy-ethyl)-piperazine-1-yl]-acetic acid dihydrochloride was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 700.6 (M+H)+, 2.03 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.96 (s, 1H), 5.30 (dd, J=1.7, 6.0 Hz, 1H), 4.76 (s, 1H), 4.66 (s, 1H), 3.93-3.89 (m, 2H), 3.42 (br. s., 2H), 3.30-3.25 (m, 2H), 3.22 (d, J=4.6 Hz, 2H), 2.97 (br. s., 3H), 2.68-2.60 (m, 1H), 2.55-2.47 (m, 1H), 2.44 (dd, J=8.2, 12.5 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.91-1.77 (m, 2H), 1.75 (br. s., 1H), 1.72 (s, 3H), 1.72-1.68 (m, 1H), 1.62-1.31 (m, 11H), 1.30-1.24 (m, 1H), 1.15 (d, J=13.1 Hz, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:12][C@H:13]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[C:15](=[C:16](Cl)[N:17]=[CH:18][N:19]=3)[C:14]1=2)[C:10]#[N:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:33]1([CH:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN1C(=O)CCC1.C(Cl)Cl>[Si:1]([O:8][CH:9]([CH2:12][C@H:13]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[C:15](=[C:16]([NH:45][CH:42]4[CH2:41][CH2:40][CH:39]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH2:44][CH2:43]4)[N:17]=[CH:18][N:19]=3)[C:14]1=2)[C:10]#[N:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(Cl)c3c21
Reactant: NC1CCC(N2CCOCC2)CC1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 75 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanenitrile (150 mg, 0.38 mmol, 1.00 equiv) in NMP (1 mL) was added triethylamine (310 mg, 3.06 mmol, 8.00 equiv) and 4-(morpholin-4-yl)cyclohexan-1-amine (560 mg, 3.04 mmol, 8.00 equiv) at room temperature. The resulting solution was stirred overnight at 75° C. under nitrogen. After cooling to room temperature, the resulting solution was diluted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to give 185 mg (90%) of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2 (6),8,10-tetraen-3-yl]propanenitrile as a white solid. MS: m/z 542 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH2:8]([O:15][CH2:16][CH2:17][CH2:18]O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][N:3]1[C:4](=[O:6])[CH2:5][NH:1][C:2]1=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CNC(=O)N1
Reactant: OCCCOCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CNC(=O)N1CCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
Imidazolidine-2,4-dione (1.0 g, 9.99 mmol), 3-benzyloxypropan-1-ol (1.91 ml, 12.0 mmol) and triphenylphosphine (3.1 g, 12.0 mmol) were stirred in methylene chloride (20 ml) and cooled to 0° C. Diisopropyl azodicarboxylate (2.36 μl, 12.0 mmol) in dichloromethane (5 ml) was slowly added and the mixture stirred at ambient temperature overnight. The mixture was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (98/2) to give 3-(3-benzyloxypropyl)imidazolidine-2,4-dione (1.3 g, 53%, containing 7% w/w triphenylphosphine oxide) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19](O)=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[F:37][C:38]([F:42])([F:41])[CH2:39][NH2:40]>O1CCCC1>[F:37][C:38]([F:42])([F:41])[CH2:39][NH:40][C:19]([C:10]1[C:11](=[O:18])[C:12]2[C:17](=[N:16][CH:15]=[CH:14][CH:13]=2)[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:9]=1)=[O:20]
Reactant: O=C(O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: NCC(F)(F)F
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid from Step 2 (1 eq) and triethylamine (3 eq) in tetrahydrofuran (0.08M) at 0° C. was added isobutyl chloroformate (1.8 eq). After stirring at 0° C. for 2 hours, 2,2,2-trifluoroethylamine (5 eq) was added and the mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then partitioned between ethyl acetate and water, the organic phase was dried and evaporated to a solid which was stirred in ether at room temperature for 3 hours and filtered to afford the N-(2,2,2-trifluoroethyl)-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][CH:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=2)[CH2:29][CH2:30]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Reactant: COc1ccc(O)cc1OC
Product: COc1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2F)cc1OC

Procedure:
Prepared by Procedure A and Scheme AN using 3,4-dimethoxyphenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 577.6 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([NH2:12])=[O:11].S(Cl)(Cl)=O.[CH3:17][C@H:18]1[CH2:23][N:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[CH2:21][C@@H:20]([CH3:35])[N:19]1[S:36](C1C=CC=C2C=1CC(C(O)=O)C2)(=[O:38])=[O:37]>C1COCC1>[CH3:35][C@H:20]1[CH2:21][N:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=2)[CH2:23][C@@H:18]([CH3:17])[N:19]1[S:36]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH2:3][CH:2]([C:10]([NH2:12])=[O:11])[CH2:1]2)(=[O:37])=[O:38]
Reactant: NC(=O)C1Cc2ccccc2C1
Reactant: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(C(N)=O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
4-|cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl|-indan-2-carboxylic acid amide. Thionyl chloride (42 μL, 0.577 mmol) was added to 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxyphenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid (250 mg, 0.502 mmol) in THF (4 mL) at 50 C for 1 h and then concentrated. The crude mixture was then dissolved in THF (4 mL) and ammonium hydroxide (300 μL) was added. The cloudy brown solution was stirred for an additional 3 h at room temperature. The solution was then concentrated and purified by silica gel column chromatography (0-20% MeOH in dichloromethane) to afford 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid amide (190 mg, 76%). 1H NMR (400 MHz, CD3OD) δ ppm. 7.71 (d, 1H), 7.47 (d, 1H), 7.34 (t, 1H), 7.10 (d, 2H), 6.94-6.91 (m, 2H), 4.20-4.14 (m, 1H), 4.05-3.90 (m, 1H), 3.54 (d, 2H), 3.41-3.21 (m, 5H), 2.77 (dd, 1H), 2.68 (dd, 1H), 1.51 (d, 3H), 1.49 (d, 3H). LCMS: 498.7 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:43])[C:12](=[O:42])[C:13]([CH3:41])=[C:14]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:16](=[O:30])[N:15]2[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([O:36]C)=[O:35].O[Li].O.O>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:43])[C:12](=[O:42])[C:13]([CH3:41])=[C:14]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:16](=[O:30])[N:15]2[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([OH:36])=[O:35]
Reactant: COC(=O)c1cccc(-n2c(=O)n(Cc3ccc(OC)cc3)c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(C(=O)O)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.7 %

Procedure:
A mixture of methyl 3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoate (0.500 g, 0.718 mmol) and LiOH.H2O (0.120 g, 2.87 mmol) in THF (5.0 ml), MeOH (5.0 ml), and Water (5.0 ml) was stirred at room temperature for 17 h. The solvents were evaporated in vacuo and the residue was acidified with 1 N HCl until solid was precipitated. The product was collected by filtration and triturated in pentane, drying of this solid under vacuum afforded titled compound (3d), (0.312 g, 63.7%); which was carried forward for the next step without further purification.
Reaction SMILES: [CH2:1](P(=O)(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH2:24]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][CH:38]=2)[C:33]([CH:47]=O)=[C:32]1[CH:49]([CH3:51])[CH3:50])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.CCOC(C)=O>[CH2:24]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][CH:38]=2)[C:33](/[CH:47]=[CH:1]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:32]1[CH:49]([CH3:51])[CH3:50])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: CC(C)c1c(C=O)c2cc(OC3CCCCO3)ccc2n1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1c(/C=C/c2ccccc2)c2cc(OC3CCCCO3)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of diethyl benzylphoshonate (91 mg, 0.4 mmol) in THF (5 mL) was added a 2 M solution of LDA and THF (0.2 mL, 0.4 mmol), and the solution was warmed to RT over 20 min. A solution of 1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indole-3-carboxaldehyde (Compound 13, 100 mg, 0.27 mmol) and THF (2 mL) was added, and the solution was stirred for 1 h at ambient temperature. The solution was diluted with EtOAc (50 mL), and washed with brine (10 mL), and dried (Na2SO4), and the solvent was removed under vacuum. Silica gel flash chromatography using 20% EtOAc in hexane gave (E)-1-benzyl-2-isopropyl-3-(2-phenylethen-1-yl)-5-(tetrahydropyran-2-yloxy)-1H-indole (Compound 26) as a colorless oil.
Reaction SMILES: [NH3:1].[F:2][CH:3]([F:20])[C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][C:10]=2[O:18][CH3:19])[CH:8]=1>>[F:20][CH:3]([F:2])[C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:1])=[S:17])=[CH:11][C:10]=2[O:18][CH3:19])[CH:8]=1
Reactant: COc1cc(N=C=S)ccc1-n1cnc(C(F)F)c1
Reactant: N
Product: COc1cc(NC(N)=S)ccc1-n1cnc(C(F)F)c1
Reaction time: 16 h
Yield: 86.1 %

Procedure:
Step N (6): Methanolic ammonia (2.0 M, 100 mL, 200 mmol) was added to a flask charged with 4-(difluoromethyl)-1-(4-isothiocyanato-2-methoxyphenyl)-1H-imidazole (2.26 g, 8.1 mmol). After 16 h, the reaction mixture was concentrated in vacuo to afford 1-(4-(4-(difluoromethyl)-1H-imidazol-1-yl)-3-methoxyphenyl)thiourea (2.08 g, 87% yield). LC-MS (M+H)+ 299.1.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][C@@H:9]([C@H:15]([OH:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:10](OCC)=[O:11])=[O:7])=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30][NH2:31]>C(O)C>[CH3:30][NH:31][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[C:5]1[CH:24]=[CH:25][C:2]([F:1])=[CH:3][C:4]=1[C:26]([F:29])([F:28])[F:27])[C@H:15]([OH:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: CCOC(=O)[C@@H](NC(=O)c1ccc(F)cc1C(F)(F)F)[C@H](O)c1ccccc1C
Reactant: CN
Solvent: CCO
Product: CNC(=O)[C@@H](NC(=O)c1ccc(F)cc1C(F)(F)F)[C@H](O)c1ccccc1C
Temperature: 32.5 °C
Reaction time: 1.5 h

Procedure:
3.4 g (0.0082 mol) of ethyl (2S,3R)-2-(4-fluoro-2-trifluoromethylbenzoylamino)-3-hydroxy-3-o-tolylpropionate were dissolved in ethanol. Methylamine gas was introduced at room temperature. After 1.5 h, the mixture was warmed to 30-35° C. for 1 h. Removal of the solvents gave 3.1 g of the title compound as colorless crystals.
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][NH2:12])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:13][N:14]1[CH:19]=[C:18]([C:20](O)=[O:21])[C:17]([C:23](OC)=[O:24])=[C:16]([Cl:27])[C:15]1=[O:28]>>[Cl:27][C:16]1[C:15](=[O:28])[N:14]([CH3:13])[CH:19]=[C:18]2[C:20](=[O:21])[N:12]([CH2:11][CH2:10][C:2]3[N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[C:23](=[O:24])[C:17]=12
Reactant: COC(=O)c1c(C(=O)O)cn(C)c(=O)c1Cl
Reactant: NCCc1nc2ccccn2n1
Product: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1nc3ccccn3n1)C2=O

Procedure:
The title compound was prepared in analogy to the process described in Example c1) starting from 2-([1,2,4]triazolo[1,5-a]pyridin-2-yl)ethanamine and compound (4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13](OC)=[C:12](F)[CH:11]=2)[CH:5]=[C:4]([Cl:19])[C:3]=1[N:20]=[CH:21][N:22]([CH3:24])[CH3:23].[F:25][C:26]([F:36])([F:35])C1C=C(C=CC=1)C=O.C(O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:26]([F:36])([F:35])[F:25])[CH:11]=2)[CH:5]=[C:4]([Cl:19])[C:3]=1[N:20]=[CH:21][N:22]([CH3:24])[CH3:23]
Reactant: COc1ccc(C=Nc2cc(Cl)c(N=CN(C)C)c(Cl)c2)cc1F
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN(C)C=Nc1c(Cl)cc(N=Cc2cccc(C(F)(F)F)c2)cc1Cl

Procedure:
A mixture of 9.3 g. of N'-(4-amino-2,6-dichlorophenyl)-N,N-dimethylformamidine (Example 9) and 6.9 g. of m-trifluoromethylbenzaldehyde in 25 ml. of absolute ethanol is refluxed for 18 hours. The solution is evaporated in vacuo to give a syrup. The syrup is extracted into hot heptane. The solvent is evaporated to provide an oil. The oil is dissolved in chloroform and the solution is filtered through a magnesium silicate column packed with chloroform. The column is washed with chloroform until the wash is colorless. The filtrate is evaporated to give a yellow syrup which crystallizes on cooling. The product is recrystallized from n-hexane to give 8.3 g. of the product of the Example as granular yellow crystals, m.p. 62°-64° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[C:6]([O:17][CH2:18][CH3:19])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.O=[Mn]=O>[CH2:18]([O:17][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=1)[CH:3]=[O:2])[CH3:19]
Reactant: CCOc1cc(OC2CCOCC2)cc(C(=O)OC)c1
Agent: O=[Mn]=O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1cc(C=O)cc(OC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-ethoxy-5-(tetrahydro-pyran-4-yloxy)-benzoic acid methyl ester (0.64 g, 2.28 mmol, 1.0 equiv) in anhydrous THF (20 mL) was added lithium aluminium hydride (0.217 g, 5.71 mmol, 2.5 equiv) and the reaction mixture stirred at rt for 4 h. The crude reaction mixture was filtered over Hyflo Super Cel, the filtrate extracted with diethyl ether (3×50 mL) and the combined organic phases dried over MgSO4 providing 0.56 g (100%) of the benzyl alcohol. The crude reaction product (0.56 g, 2.22 mmol, 1.0 equiv) was dissolved in THF (20 mL) and activated MnO2 (1.93 g, 22.2 mmol, 10.0 equiv) was added. After stirring at rt for 3 h, the reaction mixture was filtered over Hyflo Super Cel and the solvent removed by evaporation under reduced pressure. A conc. solution of sodium chloride (100 mL) was added, the mixture extracted with ethyl acetate (3×100 mL) and the combined organic phases dried over MgSO4 providing 0.46 g (83%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.34 (t, J=7.0 Hz, 3H), 1.66-1.76 (m, 2H), 1.91-1.98 (m, 2H), 3.46-3.53 (m, 2H), 3.85-3.92 (m, 2H), 3.98 (q, J=7.0 Hz, 2H), 4.41-4.47 (m, 1H), 6.62-6.63 (m, 1H), 6.89-6.91 (m, 2H), 9.79 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.62, 31.67, 63.90, 64.96, 72.02, 107.96, 108.68, 109.44, 138.49, 158.85, 160.71, 191.72. MS (ISP): 251.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC1C2C(=CC=CC=2)C=CC=1.[C-]#N.[Na+].[CH2:28]([N:32]1C=CN=C1)CCC>[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:28]#[N:32])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CCCCn1ccnc1
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc2ccccc12
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL, three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (99.1% purity, 5.0 g, 0.02 mol) and 1-methylnaphthalene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and sodium cyanide (ground to a powder just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.003 mol, 98% purity) and 1-butyl-1H-imidazole (2.15 g, 0.017 mol, 98% purity) were added. The mixture was heated to between 158 and 167° C. for 5 h and then allowed to cool overnight. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 1 h, the reaction mixture was filtered, and the solid collected was washed water (3×10 mL), xylenes (10 mL) and dried to a constant weight in a vacuum-oven at 80° C. to give the title compound as a light brown solid (3.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18]C)=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[CH:7]=1.O>Br.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-n1c(=O)[nH]c2ccccc21
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2ccccc2n1-c1cc(Cl)ccc1O
Yield: 52.7 %

Procedure:
1-(5-chloro-2-methoxyphenyl)-1,3-dihydro-2H-benzimidazol-2-one (0.3 g) was refluxed for 32 hours in 48% HBr (1 ml) in acetic acid (5 ml). The reaction mixture was then cooled and 25 ml water was added, whereby the crude product precipitated. To the mixture was added 5 ml diethylether whereafter it was filtered to give 150 mg of the title compound, M.p. 248°-250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.N[C:25](N)=[O:26]>>[O:26]=[C:25]1[N:12]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[NH:1]1
Reactant: CCOC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2N)CC1
Reactant: NC(N)=O
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(C(F)(F)F)ccc32)CC1
Temperature: 100 °C

Procedure:
56.27 parts of ethyl 4-[2-amino-4-(trifluoromethyl)-phenylamino]-1-piperidinecarboxylate and 15.6 parts of urea are mixed thoroughly in a mortar. The mixture is stirred and heated on an oil-bath at 170°-180° C for 3 hours. The reaction mixture is cooled to 100° C and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding ethyl 4-[1,3-dihydro-2-oxo-5-(trifluoromethyl)-2H-benzimidazol-1-yl]-1-piperidinecarboxylate.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[S:6](Cl)([Cl:9])(=[O:8])=[O:7]>>[CH2:1]([N:3]([CH2:4][CH3:5])[S:6]([Cl:9])(=[O:8])=[O:7])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCNCC
Product: CCN(CC)S(=O)(=O)Cl
Temperature: 0 °C

Procedure:
N,N-Disubstituted sulfamoyl chlorides were prepared as described by Binkley and Degering [J. Am. Chem. Soc., 61, 3250-3251 (1939)], herein incorporated by reference. For example, diethylamine (0.33 mole) was added very slowly to sulfuryl chloride (0.33 mole) with vigorous stirring and ice water chilling. The mixture was warmed and heated under reflux for 24 hours. The cooled mixture was extracted with anhydrous ethyl ether, and the extract was concentrated and the residue distilled under reduced pressure to afford N,N-diethyl sulfamoyl chloride, b.p. 69° (10 mmHg). N,N-Dimethyl-sulfamoyl chloride was purchased commercially.