Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([CH2:27][C@H:28]1[CH2:33][CH2:32][C@@H:31]([OH:34])[CH2:30][CH2:29]1)[CH2:5][CH2:6][NH:7][C@@H:8]1[C@@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:22])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH2:25][CH3:26])[CH2:23][CH3:24].O.[OH-].[Na+]>CO.CC(O)=O>[C:20]([C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][C@H:17]([O:18][CH3:19])[C@@H:8]([NH:7][CH2:6][CH2:5][CH:4]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@@H:31]([OH:34])[CH2:30][CH2:29]3)[C:3]([OH:35])=[O:2])[C:9]2([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:14][CH:13]=1)(=[O:22])[NH2:21]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCCC(C[C@H]1CC[C@@H](O)CC1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCCC(C[C@H]1CC[C@@H](O)CC1)C(=O)O
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-2-(cis-4-hydroxy-cyclohexylmethyl)-butyric acid methyl ester (f2) (56 mg, 0.11 mmol) in MeOH (0.50 mL) was added water (66 μL) and 10 N NaOH (66 μL, 0.66 mmol). The mixture was heated at 50° C. After 15 h, the reaction mixture was cooled to RT, dissolved in 50% aqueous AcOH (6 mL) and purified by preparative HPLC to give the title compound (54 mg) as a lyophylized powder. (m/z): [M+H]+ calcd for C27H42N2O5 475.32. Found 475.2. 1H NMR (CD3OD, 400 mHz) δ (ppm) 7.78 (d, J=1.8 Hz, 1H), 7.72 (dd, J=8.0 Hz, 1.7 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 4.09 (m, 1H), 3.88 (br s, 1H), 3.58 (dd, J=16.6, 5.6 Hz, 1H), 3.52 (s, 3H), 3.52-3.46 (m, 2H) 3.30-3.20 (m, 1H), 2.77 (m, 1H), 2.59 (m, 1H), 2.31 (m, 1H), 2.05-1.92 (m, 2H), 1.79-1.65 (m, 6H), 1.60-1.35 (m, 8H), 0.79 (t, J=7.5 Hz, 3H), 0.70 (dt, J=7.2, 1.6 Hz).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([Cl:26])=[O:25])[CH3:22]>C(Cl)Cl>[ClH:26].[CH2:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:25])[CH3:22]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(CC)C(=O)NCCCSc1ccncc1
Yield: 92.8 %

Procedure:
To a solution of 800 mg (3.32 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.22 ml (15.9 mmol) of triethylamine in 30 ml of methylene chloride was added 0.69 ml (3.98 mmol) of 2-ethylhexanoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.02 g of the desired compound (free base) (quant., pale yellow oil).
Reaction SMILES: [C:1]1([C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](=[O:20])(O)[OH:18].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:21]([O:18][C:17]([N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)O
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A 25.0 g portion of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 24.5 g of benzyl chloride carbonate were added to a mixture of 125 ml of toluene, 19.8 g of potassium carbonate and 75 ml of water and stirred at 20° C. for 4 hours, and the organic layer was washed with 75 ml of water. The thus obtained organic layer was concentrated under a reduced pressure, purified by a silica gel column chromatography and then dried to obtain 38.0 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (1H-NMR (DMSO-d6, tetramethylsilane internal standard): δ 2.73-2.83 (1H, m), 2.84-2.94 (1H, m), 3.31-3.41 (1H, m), 3.86-3.96 (1H, m), 5.12 (1H, d, J=12.8 Hz), 5.18 (1H, d, J=12.8 Hz), 6.28 (1H, s), 7.10-7.38 (14H, m), mass spectrum: m/z=344 [M+H]+ (FAB)).
Reaction SMILES: [C:1]([C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[C:7]([O:36][CH2:37][CH3:38])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:45][CH2:44][C:43](=[O:46])[NH:42][CH2:41][CH2:40]1>>[ClH:25].[C:1]([C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]2[N:15]([C:33]([N:39]3[CH2:45][CH2:44][C:43](=[O:46])[NH:42][CH2:41][CH2:40]3)=[O:34])[C@H:16]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[C:7]([O:36][CH2:37][CH3:38])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)c(OCC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CCNCCN1
Product: CCOc1cc(C(C)(C)C)c(OCC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)CC1
Product: Cl

Procedure:
1-[(4S,5R)-2-(4-tert-Butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-5-one hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12f) and [1,4]diazepan-5-one (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 651.4 [(M+H)+]
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].C=C1O[C:17](=[O:18])C1.Cl.[CH2:21]1COCC1>>[OH:18][C:17]1[CH:11]=[C:10]([CH3:21])[O:9][C:1](=[O:8])[C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C1CCOC1
Reactant: C=C1CC(=O)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(O)cc(C)oc1=O
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of diethyl malonate (10.0 g, 62.43 mmol) in THF (50 mL) was added sodium hydride (oil about 60%; 2.50 g, 62.43 mmol) under ice-cooling, and the mixture was stirred for 30 min. To this mixture was added a solution of diketene (2.62 g, 31.22 mmol) in THF (15 mL) under ice-cooling, and the mixture was stirred at 0° C. for 1 hr, and then at room temperature for 3 days. The reaction mixture was acidified with 1 N hydrochloric acid (70 mL) under ice-cooling, and extracted three times with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=1:1) to give the title compound (1.79 g, 29%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38])([O-:33])=[O:32]>ClCCl>[F:23][C:2]([F:22])([F:1])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:37]([C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=3)=[O:38])[CH2:20][CH2:21]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a stirred mixture of 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)-propan-2-ol (3.21 mmol, 1.1 g) and triethylamine (3.21 mmol, 0.448 mL, 0.325 g) in dichloromethane at 0° C. was added 3-nitrobenzoyl chloride (3.21 mmol, 0.596 g). The reaction was stirred at 0° C. for 2 hours then was allowed to warm to room temperature and stir overnight. The reaction was purified by chromatography on silica (eluting dichloromethane to dichloromethane/methanol) and SCX column chromatography to give the title compound (850 mg). MS (ESI) m/z 492.3 [M+H]+
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[CH:5][N:4]=1.O.[NH2:16][NH2:17]>C(O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH:16][NH2:17])[N:8]=1
Reactant: NN
Reactant: CSc1ncnc(-c2ccccn2)n1
Solvent: CCO
Solvent: O
Product: NNc1ncnc(-c2ccccn2)n1

Procedure:
A stirred solution of the product of step 2 (0.763 g, 3.74 mmol) and hydrazine hydrate (0.22 mL, 3.9 mmol) in ethanol (8 mL) was heated at reflux for 30 minutes. The reaction was cooled in an ice bath and the precipitate was filtered off. Vacuum oven drying afforded crude product as light brown solid. This material was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:31][C:18]3=4)[CH2:10][CH:9]2[C:36]#[N:37])=[CH:4][CH:3]=1.[OH-:38].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:31][C:18]3=4)[CH2:10][CH:9]2[C:36]([NH2:37])=[O:38])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)cc3)C(C#N)C1)c1cccnc1CO2
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)cc3)C(C(N)=O)C1)c1cccnc1CO2
Temperature: 80 °C

Procedure:
To a solution of 1-(4-chloro-phenyl)-4-{3-[7-(1-hydroxy-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-piperazine-2-carbonitrile (0.12 g, 0.23 mmol) in methanol (0.5 mL) and THF (0.5 mL) was added 1.0 N NaOH (0.5 mL, 0.5 mmol) and the resulting mixture was heated to reflux at 80° C. for 18 h. Additional 2.0 N NaOH (0.5 mL, 0.5 mmol) was added to the reaction mixture and refluxed further for 18 h. The reaction mixture was concentrated, acidified to pH 5.0 using 1.0 N HCl and extracted with ethyl acetate (3×). The combined organics were dried over sodium sulfate and concentrated. The crude product was purified on a short plug of silica gel using gradient elution from ethyl acetate/methanol (2–10%) to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]([CH2:11][CH:12]=[CH2:13])C(OCC)=O)C.C([O:17][C:18](=[O:22])[CH:19](Br)[CH3:20])C>COCCOCCOC>[CH2:11]([CH:5]([CH:19]([CH3:20])[C:18]([OH:17])=[O:22])[C:4]([OH:14])=[O:3])[CH:12]=[CH2:13]
Reactant: CCOC(=O)C(C)Br
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Solvent: COCCOCCOC
Product: C=CCC(C(=O)O)C(C)C(=O)O
Yield: 96 %

Procedure:
90.5 g (0.5 moles) of 2-allylmalonic acid diethyl ester are reacted in diethylene glycol dimethyl ether with 0.5 moles of alcohol-free sodium ethoxide. 0.5 moles of 2-bromopropionic acid ethyl ester is added dropwise to this solution, with stirring. The mixture is heated for a further 2 hours under reflux and the solvent is then removed. The residue is subsequently subjected to hydrolysis in alcoholic KOH. After drying the organic layer that has separated, it is fractionated. The desired 2-allyl-1-methylethane-tricarboxylic acid 1,2,2-triethyl ester boils under 0.02 torr at 92° to 95° C. The ester is hydrolyzed in alcoholic KOH and, after working up in the customary manner, is decarboxylated at 170° C. with water being split off. The anhydride of 2-allyl-3-methylsuccinic acid (b.p. at 0.1 torr: 108° to 110° C.) is obtained in a 96% yield (based on the ester).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH:13]=1
Reactant: COc1cc(CNc2c(F)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a solution of 4-fluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]-2-methyl-phenol (390 mg, 1.1 mmol, 1.0 eq) in DMF (6 mL) was added Cs2CO3 (538 mg, 1.65 mmol, 1.5 eq). The reaction was stirred 30 min, then isopropyl 2-bromoacetate (239 mg, 1.32 mmol, 1.2 eq) was added at room temperature. The reaction mixture was stirred at room temperature for a further 1 h, then water was added and the aqueous layer was extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified by column chromatography (petroleum ether:EtOAc, 1:0, 100:1, to 20:1) to give the title compound as a colorless oil (400 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=1)[C:5]2=[O:53].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:70](Cl)(=[O:72])[CH3:71]>C(Cl)Cl>[C:70]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=1)[C:5]2=[O:53])(=[O:72])[CH3:71]
Reactant: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2ccc(NC(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of 0.12 g (0.17 mmol) of the aminoquinazolinone from Example 40 in 2 mL of CH2Cl2 was added 33 mg (0.32 mmol) of triethylamine followed by 10 mg of dimethylaminopyridine. The reaction mixture was cooled to 0° C. and treated with 14 mg (0.19 mmol) of acetyl chloride. The solution was allowed to warm to room temperature at which time a further 0.3 equivalents of acetyl chloride was added and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluting with 50% EtOAc/hexanes containing a gradually increasing concentration of CH2Cl2 to 10% to give 0.073 g of the title compound, 57% yield. 1H-NMR (CDCl3 250 MHz): 0.88 (t, 3H, J=7.08 Hz), 1.32 (m, 2H), 1.70 (m, 2H), 2.19 (s, 3H), 2.64 (3 line m, 2H, J=7.2 Hz), 5.30 (bs, 2H), 6.89-6.98 (m, 8H), 7.09 (d, 2H, J=8.1 Hz), 7.20-7.35 (m, 10H), 7.46 (m, 2H), 7.66 (d, 1H, J=8.8 Hz), 7.73 (bs, 1H), 7.92 (m, 1H), 8.14 (d, 1H), 8.26 (dd, 1H, J=8.8, 2.3 Hz).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[C:36]([CH3:40])=[C:35]([C:41]([O:43][CH3:44])=[O:42])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[Br:45]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:45][CH2:40][C:36]1[C:37]2[C:32](=[CH:31][C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:10]=3)[CH:3]([CH3:5])[CH3:4])=[CH:39][CH:38]=2)[CH:33]=[CH:34][C:35]=1[C:41]([O:43][CH3:44])=[O:42]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1CBr

Procedure:
Methyl 6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-1-methyl-2-naphthoate (34.61 g) was suspended in carbon tetrachloride (0.8 L) and N-bromosuccinimide (12.28 g) and 2,2′-azobisisobutyronitrile (0.99 g) were added. The reaction mixture was heated under reflux for 21 hrs., and the solvent was evaporated. The residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate-THF (1:1). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by column chromatography (carrier;silica gel, developing solvent; ethyl acetate) to give a mixture of the title compound and the starting material (title compound:starting material=about 7:1, 23.10 g) as brown crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]#[N:23])=[CH:12][CH:11]=3)[C:7]3[CH:24]=[C:25]([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=5[N:30]=4)[CH:26]=[C:27]([CH3:28])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]4[NH:41][N:40]=[N:39][N:23]=4)=[CH:14][CH:15]=3)[C:7]3[CH:24]=[C:25]([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=5[N:30]=4)[CH:26]=[C:27]([CH3:28])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5](F)=[CH:4][N:3]=1.[Cl:10]C1N=C(Cl)C(F)=CN=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: Cc1nc(Cl)ncc1F
Reactant: Fc1cnc(Cl)nc1Cl
Product: Cc1nc(Cl)ncc1Cl

Procedure:
The title compound was prepared in a manner analogous to Intermediate 65, substituting 2,4,5-trichloropyrimidine for 2,4-dichloro-5-fluoropyrimidine. 1H NMR (500 MHz, CDCl3): 8.47 (s, 1H), 2.61 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[F:12][C:13]([F:44])([F:43])[C:14]1[CH:15]=[C:16]([CH:40]=[CH:41][CH:42]=1)[CH2:17][NH:18][C:19](=[O:39])[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[CH:31]=[C:30]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:29]=[CH:28][C:27]=2[NH2:38])[CH:21]=1.C(N(C(C)C)CC)(C)C.ClCCl>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:38][C:27]1[CH:28]=[CH:29][C:30]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:31][C:26]=1[C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][N:23]=1)[C:19]([NH:18][CH2:17][C:16]1[CH:40]=[CH:41][CH:42]=[C:14]([C:13]([F:44])([F:12])[F:43])[CH:15]=1)=[O:39])=[O:7]
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(Chloromethyl)benzoyl chloride was added dropwise to a 0° C. solution of 900 mg of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(piperidin-1-yl)phenyl)isonicotinamide 4.1c 1.02 g of diisopropylethylamine in 10 mL of a 1:1 mixture of dichloromethane and THF. The mixture was warmed to 25° C. and stirred for 1 h, after which it was washed five times with aqueous hydrochloric acid, once with a saturated aqueous solution of sodium bicarbonate, and once with water. The solution was dried and the solvent was evaporated to give 1.24 g of product as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:19][O:18][CH2:17][CH2:16][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2ccc(O)cc2[nH]1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc2cc(C(=O)OC)[nH]c2c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a light brown, homogeneous solution of methyl 6-hydroxy-1H-indole-2-carboxylate (1.4862 g, 7.77 mmol) and 1-bromo-2-methoxyethane (0.731 mL, 7.77 mmol) in DMF (38.9 mL) under nitrogen was added cesium carbonate (2.53 g, 7.77 mmol). The reaction was heated to 55° C. and stirred overnight. The reaction was cooled to room temperature, diluted with EtOAc (200 mL) and filtered through CELITE®. The filtrate was washed with water (4×50 mL) and brine (2×50 mL), dried over MgSO4, and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 120 g column eluting with 20-60% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give desired product (0.8592 g) as a white solid. Mixed fractions were combined and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 80 g column eluting with 20-60% EtOAc/hexanes to give another crop of desired product (0.1673 g) as a white solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:19]=[C:18]([CH2:20][N:21]2[C:26](=[O:27])[C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=3)=[C:24]([CH3:38])[N:23]=[C:22]2[CH2:39][CH2:40][CH3:41])[CH:17]=[CH:16][C:15]=1[C:42]1[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:19]=[C:18]([CH2:20][N:21]2[C:26](=[O:27])[C:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:32][CH:33]=3)=[C:24]([CH3:38])[N:23]=[C:22]2[CH2:39][CH2:40][CH3:41])[CH:17]=[CH:16][C:15]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]1[NH:3][C:4](=[O:7])[O:5][N:49]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)c(F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)c(F)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.72 g), sodium hydrogen carbonate (1.02 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C. for 30 min, 2′-fluoro-4′-{[5-(4-isopropoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.6 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (8 mL). N,N′-carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.3 g, 45%).