Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:20]([O:21][CH3:22])=[CH:19][C:13]2[CH:14]=[CH:15][C:16](=[O:18])[O:17][C:12]=2[CH:11]=1)(=O)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[F:43][C:40]1[CH:39]=[CH:38][C:37]([CH:30]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:31]2[CH2:32][CH2:33][N:34]([CH2:6][CH2:7][CH2:8][O:9][C:10]3[C:20]([O:21][CH3:22])=[CH:19][C:13]4[CH:14]=[CH:15][C:16](=[O:18])[O:17][C:12]=4[CH:11]=3)[CH2:35][CH2:36]2)=[CH:42][CH:41]=1
Reactant: COc1cc2ccc(=O)oc2cc1OCCCOS(C)(=O)=O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Product: COc1cc2ccc(=O)oc2cc1OCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 76 %

Procedure:
Method B (36 h at 60° C.); starting materials: 7-[3-(methanesulfonyloxy)propoxy]-6-methoxy-2H-1-benzopyran-2-one (example 68) and 1-[bis(4-fluorophenyl)methyl]-piperazine; yield 76% Ol. Fumarate: method E; yield 82%; fusion point 200°-202° C. (from acetone).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.C(=O)(O)[O-].[Na+].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].O>C(Cl)(Cl)Cl>[Br:9][C:7]1[CH:6]=[CH:5][C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[C:3]([NH:2][C:26]([N:25]([CH3:29])[CH3:24])=[O:27])[CH:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1cc(Br)ccc1N1CCc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C(=O)Nc1cc(Br)ccc1N1CCc2ccccc21
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a stirred mixture, under nitrogen, of 28.9 g (0.10 mole) of 1-(2-amino-4-bromophenyl)indoline hydrochloride and 16.8 g (0.20 mole) of anhydrous powdered sodium bicarbonate in 500 ml of chloroform was added a solution of 21.5 g (0.20 mole) of dimethylcarbamyl chloride in 25 ml of chloroform, over a 10 minute period. The mixture was heated under reflux for 7 hours, and 8.4 g (0.10 mole) of sodium bicarbonate and 10.7 g (0.10 mole) of the dimethylcarbamyl chloride were added. After heating under reflux for 2 days, equivalent amounts (8.4 g of sodium bicarbonate and 10.7 g of dimethylcarbamyl chloride) were added. After three days under reflux, the mixture was cooled and 500 ml of water was added. The phases were stirred vigorously for 0.5 hours and separated. The organic phase was washed three times with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in 200 ml of dichloromethane and adsorbed on a chromatography column containing 1 kg of silica gel packed in and eluted with dichloromethane. The fractions containing product were combined and concentrated to afford 14.5 g (40%) of product. Recrystallization from toluene (charcoal)/hexane gave the analytical sample, mp 119°-121° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:23])[C@H:14]3[CH3:24])=[CH:11][C:10]=1[C@H:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]1[CH3:31].C=O.[B-][C:35]#N.[Na+]>CO.CC(O)=O>[CH3:35][N:28]1[CH2:29][CH2:30][C@H:25]([C:10]2[CH:11]=[C:12]3[C:21](=[CH:22][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[O:20][CH2:19][C:18]2[N:13]3[C@H:14]([CH3:24])[C:15](=[O:23])[NH:16][N:17]=2)[C@H:26]([CH3:31])[CH2:27]1
Reactant: C[C@@H]1CNCC[C@@H]1c1cc2c(cc1-c1ccccc1F)OCC1=NNC(=O)[C@@H](C)N12
Reactant: [B-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1CN(C)CC[C@@H]1c1cc2c(cc1-c1ccccc1F)OCC1=NNC(=O)[C@@H](C)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
A mixture of (R)-7-(2-fluoro-phenyl)-4-methyl-6-((3S,4S)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (3.0 g, 6.74 mmol) and paraformaldehyde (0.506 g, 16.86 mmol) in MeOH (100 mL) and AcOH (10 mL) was stirred at ambient temperature for 2 h. Then, sodium cyanotrihydroborate (0.847 g, 13.49 mmol) was added and the reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on basified silica gel (eluting with 10% MeOH in EA) to give (R)-6-((3S,4S)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.0 g, 65%) as a white solid. The white solid was stirred in HCl/EtOAc (4 M, 15 mL) for 30 min and the reaction mixture was concentrated in vacuo to give (R)-6-((3S,4S)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (1.65 g, 53%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.49-7.40 (m, 1H), 7.33-7.17 (m, 3H), 6.91 (s, 1H), 6.85 (s, 1H), 4.99-4.93 (m, 1H), 4.70-4.65 (m, 2H), 3.60-3.50 (m, 1H), 3.25-3.00 (m, 3H), 2.90-2.85 (m, 1H), 2.80 (s, 3H), 2.55-2.45 (m, 1H), 2.01-1.84 (m, 2H), 1.49 (d, J=6.4 Hz, 3H), 1.00-0.90 (m, 3H). LC/MS (Table 1, Method 4) Rt=1.654 min.; MS m/z: 423 [M+H]+. SFC (Table 1, Method 48), Rt=3.206 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:9]([OH:19])=[CH:10][C:11]([OH:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[Br:7][C:8]1[C:9]([O:19][CH2:13][C:12]2[CH:17]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:10][C:11]([O:18][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(Br)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
1.2 92.6 g of potassium carbonate are added to a solution of 80 g of methyl 5-bromo-2,4-dihydroxybenzoate in 1 l of acetonitrile, and 77 ml of benzyl bromide are added dropwise. The mixture is heated for 3 hours and cooled, the solvent is removed, and the residue is subjected to conventional work-up, giving 150 g of methyl 5-bromo-2,4-dibenzyloxybenzoate (crude product).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:13][CH2:14][CH:15]=[CH2:16])[N:5]=CC1C=CC=CC=1.Cl.O>C(OCC)C>[CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:13][CH2:14][CH:15]=[CH2:16])[NH2:5]
Reactant: C=CCCC(N=Cc1ccccc1)C(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: C=CCCC(N)C(=O)OC
Reaction time: 2 h

Procedure:
Dissolve N-(phenylmethylene)-2-(3-butenyl)glycine methyl ester (25 g) in ethyl ether (400 mL) and stir with 1N hydrochloric acid (150 mL) and water (150 mL). Place under an argon atmosphere and stir for 2 hours. Separate the aqueous phase and adjust to pH 9, extract into chloroform, dry and evaporate the solvent in vacuo to give the title compound as a light oil (4.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C([Li])CCC.[Si:40]([O:47][C:48]1[CH:59]=[CH:58][C:51]([C:52](N(OC)C)=[O:53])=[CH:50][CH:49]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>O1CCCC1.CCCCCC>[Si:40]([O:47][C:48]1[CH:59]=[CH:58][C:51]([C:52]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([O:27][Si:28]([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:29])[CH3:30])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:6][CH:7]=2)=[O:53])=[CH:50][CH:49]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CON(C)C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N(CCc1ccc(C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a solution of tert-butyl N-[2-(4-bromophenyl)-ethyl]-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethyl]carbamate (880 mg) in tetrahydrofuran (13 ml) was added a solution of butyllithium in hexane (1.59M, 1.07 ml) dropwise at −70° C. under nitrogen and the mixture was stirred at −70° C. for 30 minutes. To the reaction mixture was added 4-[[tert-butyl(dimethyl)silyl]oxy]-N-methoxy-N-methylbenzamide (480 mg) at −70° C., and the mixture was stirred at −70° C. for 1 hour. The mixture was allowed to warm to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=10/1) to give tert-butyl N-[2-[4-[4-[[tert-butyl(dimethyl)silyl]oxy]benzoyl]phenyl]ethyl]-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethyl]carbamate (710 mg).
Reaction SMILES: [CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26](O)=[O:27])=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:31][O:32][C:33](=[O:36])[CH2:34][NH2:35].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>ClCCl>[CH3:31][O:32][C:33](=[O:36])[CH3:34].[CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26]([NH2:35])=[O:27])=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(N)=O)s1
Product: COC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
A mixture of 5-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (160 mg, 0.38 mmol), 2-amino-acetic acid methyl ester hydrochloride (53 mg, 0.42 mmol), EDCl (89 mg, 0.46 mmol) and triethylamine (0.134 ml, 0.96 mmol) in dichloromethane (5 ml) is stirred at RT overnight. The reaction is concentrated, partitioned between 1N HCl and EtOAc. The organic layer is concentrated and chromatographed (Hex to 30% EtOAc/Hex) to give the title compound (75 mg, 40%).
Reaction SMILES: CO[C:3](=[O:22])[C:4]([OH:21])=[CH:5][C:6](=[O:20])[N:7]([CH3:19])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[CH2:23]=O.[NH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]>>[OH:21][C:4]1[C:3](=[O:22])[N:25]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:23][C:5]=1[C:6](=[O:20])[N:7]([CH3:19])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: NCCCC(=O)O
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1cccc2ccccc12
Reactant: C=O
Product: CN(Cc1cccc2ccccc12)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Yield: 55 %

Procedure:
2-Hydroxy-3-(methyl-naphthalen-1-ylmethyl-carbamoyl)-acrylic acid methyl ester was treated with paraformaldehyde and 4-amino-butyric acid according to the procedure described in the preparation of compound 12 to give the title compound as a white powder (0.0210 g, 55% yield). 1HNMR (300 MHz, CDCl3) δ: 7.93–7.81 (2H, m), 7.55–7.42 (4H, m), 7.42–7.28 (1H, m), 5.13 (2H, s), 4.14 (2H, s), 3.52–3.50 (2H, m), 2.36–2.29 (2H, m), 1.90–1.87 (2H, m).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(Cl)(Cl)Cl>[C:1]([O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:12][CH2:11]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: OCCN1CCNCC1
Reactant: CCCC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCC(=O)OCCN1CCN(C(=O)CCC)CC1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Butyryl chloride (11.83 g, 0.11 mol) was added dropwise to a cooled solution of 4.84 g (0.04 mol) of 1-(2-hydroxyethyl)-piperazine in 20 ml of chloroform. Cooling was maintained for 2 h, and a white precipitate formed. Chloroform (15 ml) was added and the mixture was stirred overnight, washed with 210 ml of cold 0.6 N sodium hydroxide solution, then washed twice with 50 ml of cold water. The organic fraction was dried over anhydrous sodium sulfate, filtered and, concentrated in vacuo to yield 9.39 g (94%) of a clear yellow liquid. This was distilled: bp 144–146° C., (0.5 mm Hg) to give 6.08 g (65%) of MEB. 1H NMR (CDCl3) δ 0.897 (t, 3H, J=7.4, CH3), 0.901 (t, 3H, J=7.4, CH3), 1.59 (m, 2H, CH3CH2), 1.61 (m, 2H, CH3CH2), 2.24 (t, 2H, J=7.4 CH2CO), 2.25 (t, 2H, J=7.4, CH2CO), 2.42–2.43 (app t, 2H, J=5.2, axial CH ester end of ring), 2.43–2.44 (app t, 2H, J=5.2, equatorial CH ester end of ring), 2.59 (t, 2H, J=5.8, N—CH2—CH2—O), 3.41 (app t, 2H, axial CH amide end of ring), 3.57 (app t, 2H, equatorial CH amide end of ring), 4.16 ( t, 2H, N—CH2—CH2—O); MS m/z 270 (M+), 255, 242, 227, 199, 182, 169 (Base Peak).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[C:12]([CH3:18])=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C1C=CC=CN=1)C.[Cl:28][C:29]1[CH:30]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=1[Cl:35]>N1C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([S:36]([NH:1][C:2]2[C:3]([C:9]([C:11]3[C:12]([CH3:18])=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)(=[O:37])=[O:38])[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1N
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
To a solution of (3-Amino-5-chloro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanone (43 mg, 0.16 mmol) and 10 mg of dimethylaminopyridine in 1.0 ml of pyridine was added 3,4-dichlorobenzenesulfonylchloride (70 mg, 0.28 mmol). The mixture was stirred at 80° C. for 3 hours, cooled to room temperature and concentrated. The residue was directly purified by flash column (50% ethyl acetate in hexane) or preparative HPLC (20-80% acetonitrile in water) to afford 18 mg of title compound as an off-white solid. MS: (M+H)/z =470.4.
Reaction SMILES: COC([C:5]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O.COC(C(S(C)(=O)=O)(CC=CC(OC(=O)C)CCCCC)CCCCCCC(OC)=O)=O>>[CH3:32][S:29]([CH:5]([CH2:16][CH:17]=[CH:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:30])=[O:31]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: CCCCCC(C=CCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Product: CCCCCC(C=CCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O

Procedure:
This compound is prepared by the procedure of Example 3, Step D, except that the methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxyheptadecanoate is replaced by an equivalent quantity of methyl 8-methoxycarbonyl-8methylsulfonyl-12-acetoxy-10-heptadecenoate.
Reaction SMILES: C[N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[OH:20][CH2:21][C:22]([NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2)=[O:23]>>[OH:20][CH2:21][C:22]([NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:16]\[C:13]1[NH:12][C:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][NH:2][CH3:19])[C:6](=[O:18])[C:7]=2[C:14]=1[CH3:15])=[O:23]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Reactant: O=C(CO)Nc1ccc2c(c1)CC(=O)N2
Product: CNCCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(NC(=O)CO)cc43)c(C)c2C1=O
Yield: 50.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 2-hydroxy-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide 44b as starting materials to obtain (Z)-2-hydroxy-N-{3-[3-methyl-5-(2-methylamino-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide 44 (52 mg, yield 50.5%) as an orange solid.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)([F:4])[CH3:3].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>>[F:4][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)([F:1])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(F)(F)c1cc(N)n(-c2cccnc2)n1
Product: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)n(-c2cccnc2)n1
Yield: 28.9 %

Procedure:
Following the procedure in Example 118A, 3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-amine (60 mg, 0.27 mmol) was treated with phenyl chloroformate (0.13 mL, 1.07 mmol) to afford phenyl 3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (27 mg, 0.078 mmol, 30%). 1H NMR (300 MHz, MeOD) δ 8.90 (s, 1H), 8.70 (s, 1H), 8.15 (d, 1H), 7.69 (d, 1H), 7.44-7.12 (m, 5H), 4.87 (s, 3H); LC-MS (ESI) m/z 345 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[C:14]2[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]=1[CH3:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:30]>CN(C)C=O.C(OCC)(=O)C>[ClH:27].[CH2:3]([C:10]1[C:14]2[C:15]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:16][CH:17]=[CH:18][C:13]=2[N:12]([CH3:30])[C:11]=1[CH3:28])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1[nH]c2ccnc(OCc3ccc(Cl)cc3)c2c1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cc2ccccc2)c2c(OCc3ccc(Cl)cc3)nccc2n1C
Product: Cl
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
The compound (30 mg, 0.066 mmol) prepared in Example 77 was treated with a saturated sodium bicarbonate solution to obtain 3-benzyl-2-methyl-4-(4-chlorobenzyloxy)-1H-pyrrolo[3,2-c]pyridine (24 mg, 0.065 mmol). Sodium hydride (60%, 4.9 mg, 0.118 mmol) was added at room temperature to a solution of 3-benzyl-2-methyl-4-(4-chlorobenzyloxy)-1H-pyrrolo[3,2-c]pyridine (24 mg, 0.065 mmol) in N,N-dimethylformamide (1 ml) and then the reaction mixture was stirred for 30 minutes. Iodomethane (0.007 ml, 0.118 mmol) was added to the reaction mixture, which was then stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml) three times. The organic layer was separated, dried on anhydrous magnesium sulfate, and then concentrated. The resulting residue was dissolved in ethyl acetate (1 ml), saturated with hydrochloric acid gas, and then filtered to give the titled compound as a white solid. (Yield: 57.1%)
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH:14]=[N:13][N:12]=[C:11]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[Cl:63])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[Cl:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[O:56][CH:53]1[CH2:52][CH2:51][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:19](=[O:21])[C:18]2[CH:17]=[CH:16][C:15]([C:11]3[O:10][CH:14]=[N:13][N:12]=3)=[CH:23][CH:22]=2)[CH2:55][CH2:54]1
Reactant: O=C(O)c1ccc(-c2nnco2)cc1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1ccc(-c2nnco2)cc1
Reaction time: 0.03 h
Yield: 38.4 %

Procedure:
DIPEA (203 mg, 0.27 mL, 1.57 mmol) was added to a stirred solution of 4-[1,3,4]oxadiazol-2-yl-benzoic acid (100 mg, 0.52 mmol) in DMF (2 mL) followed by HOBt (85 mg, 0.63 mmol) and EDCI (121 mg, 0.63 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (192 mg, 0.63 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 88 mg (38.09% yield) of N-{2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-4-[1,3,4]oxadiazol-2-yl-benzamide. LC/MS [M+H]+: 441.13, 95.23%. 1H NMR (300 MHz, DMSO-d6): δ 9.4 (s, 1H), 8.8 (t, 1H), 8.1 (q, 4H), 7.4 (m, 1H), 7.3 (m, 2H), 7.0 (m, 1H), 4.8 (m, 1H), 4.2 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 2.18 (m, 2H), 1.8-1.5 (m, 4H).
Reaction SMILES: C[CH:2]([NH:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([NH:5][NH:6][C:7](=O)[CH3:8])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[SH2:32].N1C=CC=C[CH:34]=1>ClCCl>[CH3:34][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=1[NH:10][CH2:2][C:3]1[S:32][C:7]([CH3:8])=[N:6][N:5]=1
Reactant: CC(=O)NNC(=O)C(C)Nc1ccccc1C
Reactant: c1ccncc1
Reactant: S
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClCCl
Product: Cc1nnc(CNc2c(C)cccc2C)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 16.0 g (0.068 mol) 1-(2,6-dimethylphenylaminoacetyl)-2-acetylhydrazine in 150 ml pyridine was added 15.1 g (0.068 mol) phosphorus pentasulfide in small portions. A mild exotherm ensued. The reaction mixture was heated to 140°-150° C. when an exotherm ensued. The reaction temperature rose to 170° C., and then subsided. Hydrogen sulfide was liberated. The reaction was kept at 140°-150° C. for 2 hours and then at 25° C. for about 16 hours. The pyridine solution was decanted from a gummy brown residue. The residue was extracted with dichloromethane. The dichloromethane extracts were combined with the pyridine solution and evaporated under reduced pressure to give an oil. The oil was dissolved in dichloromethane and treated with ice water to destroy a small amount of unreacted phosphorus pentasulfide. The dichloromethane solution was then washed with cold dilute aqueous sodium hydroxide solution, water, dried over magnesium sulfate, filtered and evaporated under reduced pressure at 40°-50° C. to give an oil. The oil was column chromatographed on 200 g silica gel using petroleum ether/diethyl ether as eluants. The major fractions were combined in dichloromethane, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a clear oil which crystallized upon trituration with petroleum ether to give 11.6 g of 2-(2,6-dimethylphenylaminomethyl)-5-methyl-1,3,4-thiadiazole, m.p. 68°-69° C. The product is tabulated in Table I as Compound No. 29A.