Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:40]CC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 48 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (0.96 g, 1.8 mmol), THF (21 mL) and water (7 mL) with 2.5% osmium tetroxide in t-butanol (46 mg, 0.18 mmol). Add sodium periodate (1.17 g, 5.5 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 0.46 g (48%) of desired product. MS (m/z): 526 (M+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([OH:11])[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([I:22])=[CH:20][N:19]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17]=2[N:18]=1>C1COCC1>[Cl:12][C:13]1[N:14]=[C:15]([O:10][CH:7]2[CH2:8][CH2:9][C:4]([CH3:3])([OH:11])[CH2:5][CH2:6]2)[C:16]2[C:21]([I:22])=[CH:20][N:19]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17]=2[N:18]=1
Reactant: CC1(O)CCC(O)CC1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(O)CCC(Oc2nc(Cl)nc3c2c(I)cn3COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 1.36 equiv) in dry THF (0.68 M) under nitrogen atmosphere was added 1-methylcyclohexane-1,4-diol (1 equiv). The reaction mixture was stirred at room temperature for 30 min before a solution of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.9 equiv,) in dry THF (0.45 M) was added. The mixture was stirred at room temperature for 2 h. The reaction was monitored by thin layer chromatography. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography (0-30% ethyl acetate in petroleum ether) to afford the title compound as a white solid (78% yield). MS (ESI) m/z 538.4 [M+1]+.
Reaction SMILES: [C:1]1([N:10]=[C:11]=[O:12])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2[N:25]([CH3:27])[CH3:26]>CN(C)C=O>[CH3:27][N:25]([CH3:26])[C:17]1[C:16]2[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:8]([NH:7][C:4]3[CH:3]=[CH:2][C:1]([NH:10][C:11]([NH:13][C:14]4[CH:15]=[C:16]5[C:21](=[CH:22][CH:23]=4)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]5[N:25]([CH3:26])[CH3:27])=[O:12])=[CH:6][CH:5]=3)=[O:9])[CH:15]=2)[N:20]=[C:19]([CH3:24])[CH:18]=1
Reactant: Cc1cc(N(C)C)c2cc(N)ccc2n1
Reactant: O=C=Nc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: Cc1cc(N(C)C)c2cc(NC(=O)Nc3ccc(NC(=O)Nc4ccc5nc(C)cc(N(C)C)c5c4)cc3)ccc2n1
Temperature: 20 °C
Reaction time: 17 h
Yield: 48.3 %

Procedure:
A solution of 25 mg of 1,4-phenylene diisocyanate and 62.8 mg of 6-amino-4-dimethylamino-2-methylquinoline in 1 mL of dimethylformamide is stirred at a temperature in the region of 20° C. for 5 hours. 2 mL of dimethylformamide, 218 mg of polystyrene-isocyanate resin (Argonaut, 1.49 mmol/g) and 42 mg of polystyrene-trisamine resin (Argonaut, 3.75 mmol/g) are then added to the reaction mixture. The suspension obtained is stirred at a temperature in the region of 20° C. for 17 hours, filtered on sintered glass, and then the solid residue is washed with 10 mL of a dichloromethane-methanol (90-10 by volume) mixture. The filtrate obtained is concentrated under air stream at a temperature in the region of 50° C. 42.4 mg of 1-(4-dimethylamino-2-methylquinolin-6-yl)-3-{4-[3-(4-dimethylamino-2-methylquinolin-6-yl)ureido]phenyl}urea are thus obtained in the form of a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:15](NC1(C(O)=O)CCCCCC1)=[O:16].[OH-:33].[Li+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:15]([OH:16])=[O:33]
Reactant: COc1ccc(C(=O)NC2(C(=O)O)CCCCCC2)cc1OCCc1cc(C)ccc1F
Reactant: [OH-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)cc1OCCc1cc(C)ccc1F
Reaction time: 0.33 h

Procedure:
The compound of step 1 (530 mg, 1.66 mmol) was dissolved in dioxane (8.3 ml). Lithium hydroxide (8.3 ml of an aqueous 1 M solution) was added and the mixture was kept for 20 min at 60° C. After cooling, the mixture was partitioned between an excess of 2 N hydrochloric acid and EA and the aqueous phase extracted with EA. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was stirred overnight with a mixture of diethyl ether and HEP, filtered, and the solid was dried in vacuo to give 500 mg of the title compound.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][C:13]#[C:14][C@@H:15]([O:21][C:22](=[O:24])[CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O.O>[CH2:1]([O:8][CH2:12][C:13]#[C:14][C@@H:15]([O:21][C:22](=[O:24])[CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC[C@@H](C#CCBr)OC(C)=O
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC[C@@H](C#CCOCc1ccccc1)OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl alcohol (1 molar equivalent) is added dropwise to a stirred suspension of sodium hydride (1 molar equivalent) in dry dimethylformamide maintained at 0° to 5° C. throughout the addition. The reaction mixture is allowed to warm to and then is maintained at room temperature for 1/2 hour. After cooling to 0° to 5° C., the reaction mixture is treated with 1-bromo-4(S)-acetyloxy-2-nonyne (1 molar equivalent) added dropwise over 1/2 hour. The resulting reaction mixture is stirred at ambient temperature for 2 hours and then diluted with water providing a turbid mixture which is extracted with ether. The organic extract is washed with water and saturated aqueous brine, dried over sodium sulfate and filtered. Evaporation (in vacuo at 40° to 50° C.) of the filtrate leaves an oily residue which is distilled to provide the pure title compound.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:29])[CH2:20][N:21]1[CH2:26][C@H:25]([CH3:27])[NH:24][C@H:23]([CH3:28])[CH2:22]1>N1C=CC=CC=1>[C:1]1([S:7]([N:24]2[C@@H:25]([CH3:27])[CH2:26][N:21]([CH2:20][C:19]([NH:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[Cl:11])=[O:29])[CH2:22][C@H:23]2[CH3:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C[C@@H]1CN(CC(=O)Nc2ccccc2Cl)C[C@H](C)N1
Solvent: c1ccncc1
Product: C[C@@H]1CN(CC(=O)Nc2ccccc2Cl)C[C@H](C)N1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzenesulphonyl chloride (0.124 g) was added to a solution of the product from Example 15 step (ii) (0.2 g) in pyridine (2 ml). The mixture was stirred at room temperature for 16 hours and then the solvent was evaporated under reduced pressure. The residue was purified by flash silica-gel chromatography eluting with 1% EtOH, 1% Et3N, 98% CH2Cl2 followed by trituration with ethyl acetate to give the title compound. Yield 0.03 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20])=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:21][C@H:19]1[NH:20][C:31](=[O:33])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:12][CH:13]=2)[C:18]1=[O:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C)c(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N1-(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)-D-alaninamide (Intermediate 16, 118 mg) was dissolved in dry dichloromethane (18 mL). The reaction mixture was cooled down in an ice bath. Triethylamine 0.327 mL, 2.350 mmol) was added. Then a solution of triphosgene in dry dichloromethane (46.5 mg, 0.157 mmol) dissolved in 7 mL of dichloromethane was added. The reaction was stirred at 0° C. for 10 min under argon. A saturated aqueous solution of NaHCO3 was added (18 mL) and the aqueous layer was extracted with dichloromethane 4 times (4×15 mL). After drying over sodium sulphate, the solvents were removed under vacuum. The residue was purified by silica gel chromatography (Companion system, 12 g cartridge) eluting with a gradient cHex/EOAc from to 100/0 to 60/40 during 20 min and 60/40 during 30 min. This afforded the title compound (91 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
2-Bromophenol (6.7 ml, 57.8 mmole) was dissolved in 200 ml acetonitrile in a 500 ml one neck round bottom flask under nitrogen. The solution was treated successively potassium carbonate (32 g, 231 mmole) and benzyl bromide (6.9 ml, 57.8 mmole). The reaction mixture was stirred for 6 hours at room temperature. The insoluble salts were removed by filtration and the filtrate was concentrated in vacuo to a pale oil. The oil was taken up in 100 ml diethyl ether and the mixture was washed successively with 2×25 ml 1N sodium hydroxide and 1×25 ml saturated sodium chloride. The organics were dried over magnesium sulfate and were concentrated in vacuo to give 14.8 g (97%) of 2-benzyloxy-bromobenzene as a pale oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17].[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])=[CH:23][CH:22]=1
Reactant: COc1cccc(CCCCCCBr)c1OC
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCCCc2cccc(OC)c2OC)cc1
Yield: 98.4 %

Procedure:
A mixture of 1.00 g (3.3 mmol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene, 0.45 g (3.0 mmol) of 4-hydroxybenzoic acid methyl ester, 0.62 g (4.5 mmol) of potassium carbonate and 0.75 g (4.5 mmol) of potassium iodide in 25 mL of acetone was stirred at reflux for 23 hours. Workup as in Example 16 and purification by HPLC using 15% ethyl acetate-hexane gave 1.10 g (89% yield) of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]benzoic acid methyl ester as an oil.
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.[CH3:17][O-:18].[Na+].[C-]#N.[Na+].C(Cl)Cl>CO>[Cl:7][C:5]1[N:6]=[C:2]([O:18][CH3:17])[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[Cl:8]
Reactant: C[O-]
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Cl)c1Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Yield: 67 %

Procedure:
A solution of 2-bromo-4,5-dichloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (0.12 g, 0.35 mmol), sodium methoxide (0.12 mL of a 25% solution in methanol, 0.53 mmol) and CuBr (0.010 g, 0.07 mmol) in methanol (0.5 mL) was heated at 100° C. for 6 h. Dilute aqueous NaCN and CH2Cl2 were added and the solution was stirred for a few minutes. The solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-40% EtOAc/hex) to afford the title compound (0.070 g, 67%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.11 (s, 2H) 4.02 (s, 3H) 3.51-3.63 (m, 2H) 0.88-0.97 (m, 2H) −0.01 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][C@@H:24]1[CH2:32][NH:33][CH3:34]>>[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][C@@H:24]1[CH2:32][N:33]([CH3:34])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: CNC[C@H]1Cc2ccccc2O1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(C[C@H]1Cc2ccccc2O1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-1-(2,3-dihydrobenzofuran-2-yl)-N-methylmethanamine (1.2 equiv) to give 187 (16.8 mg, M+1 459.1)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:12]=1)=[N+:6]([O-])[CH:7]=[CH:8][C:9]=2[CH3:10].C(Cl)(Cl)[Cl:14]>P(Cl)(Cl)(Cl)=O>[Cl:14][C:7]1[N:6]=[C:5]2[N:12]=[C:2]([CH3:1])[NH:3][C:4]2=[C:9]([CH3:10])[CH:8]=1
Reactant: Cc1nc2c([nH]1)c(C)cc[n+]2[O-]
Reactant: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2nc(Cl)cc(C)c2[nH]1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2,7-dimethyl-1H-imidazo[4,5-b]pyridine-4-oxide (4.45 g) in chloroform (4.5 ml) and phosphorous oxychloride (25.4 ml) was stirred at 80° C. for 3 hr and concentrated to dryness under reduced pressure. The residue was poured to ice (75 g), and which was neutralized with aqueous ammonia under ice-cooling. The mixture was stirred at room temperature for 30 min and the precipitated solid was washed with water to give the objective compound (3.66 g) as a gray powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19].C=O.[C:25](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:9][C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH3:25])[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21]
Reactant: CC(=O)O
Reactant: O=C(Nc1ccc(NCc2ccc(Cl)s2)cc1Cl)C(F)(F)F
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(Cc1ccc(Cl)s1)c1ccc(NC(=O)C(F)(F)F)c(Cl)c1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a mixture of N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2,2-trifluoroacetamide (3.28 g, 8.88 mmol), 37% aqueous formaldehyde (5 mL), and acetic acid (3 mL), sodium cyanoborohydride (NaBH3CN) (1.1 g) in methanol (10 mL) was added dropwise with stirring during 30 minutes. The reaction mixture was allowed to stand at room temperature for 2 hours and poured into water. After the oil solidified, it was filtered, washed with water and dried in vacuo to give 3.26 g of pale yellow-brown solid. Yield 95%. 1H NMR (DMSO-d6): 2.97 (s, 3H, NMe), 4.72 (s, 2H), 6.82 (m, 1H), 6.91 (m, 2H), 6.97 (d, 1H), 7.21 (d, 1H), 10.92 (br. s, 1H, NHCO). LC/MS (m/z) 382.0 (M+); RT=3.66, (UV, ELSD) 85%, 98%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([Cl:12])[CH:5]=1)=[O:3].[H-].[Na+].C([O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1)C>CN(C=O)C>[Cl:12][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:17])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: CCOC(=O)c1cccnc1
Reactant: COc1ccc(C(C)=O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CC(=O)c2cccnc2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-chloro-4-methoxy acetophenone (3.0 g, 16.30 mmol) in DMF (15 mL) was added 60% NaH [0.717 g (0.430 g, 17.93 mmol)] at 0° C. under a nitrogen atmosphere. The mixture was stirred for 30 min and a solution of nicotinic acid ethyl ester (2.95 g, 19.56 mmol) in DMF (10 mL) was added slowly to it. The mixture was stirred at temperature in the range of 20-40° C. for 12 hour. It was then poured into ice-cold water (100 mL) and stirred for 15 minutes. The solid was filtered and dried to give the desired compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].O=[C:25]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)(=O)C>C(O)C>[C:19]([O:18][C:16]([CH2:15][N:4]1[CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7][CH2:8][CH:2]([NH:1][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:3]1=[O:23])=[O:17])([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCCC1c1ccccc1
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)NC1CCCC(c2ccccc2)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
A solution of 3.8 g of this amine, 3.7 g ethyl 2-oxo-4-phenylbutyrate and 0.68 ml acetic acid in 50 ml ethanol is hydrogenated and the isomers separated as described in Example 27 to afford 1-t-butoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropyl)amino-7-phenylperhydroazepin-2-one:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9]([O:12][CH2:13][CH3:14])(=[O:11])[CH3:10]>>[CH2:13]([O:12][C:9]([CH2:10][N:4]1[CH:3]=[C:2]([F:1])[CH:7]=[N:6][C:5]1=[O:8])=[O:11])[CH3:14]
Reactant: CCOC(C)=O
Reactant: O=c1ncc(F)c[nH]1
Product: CCOC(=O)Cn1cc(F)cnc1=O
Yield: 31 %

Procedure:
Prepared as above from 5-fluoropyrimid-2-one in 31% yield, m.p. 121° (ethyl acetate). (Found: C, 47.90; H, 4.70. Calc. for C8H9FN2O3 : C, 48.02; H, 4.53).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:35])[CH2:19][S:20][C:21]2[N:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[CH:23][N:22]=2)[CH2:12]1.ClC(Cl)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOCC>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:35])[CH2:19][S:20][C:21]2[N:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[CH:25][N:26]=2)[CH2:12]1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: COc1ccc(-c2cnc(SCC(=O)NCC3CCNC3)nc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(-c2cnc(SCC(=O)NCC3CCN(Cc4cccc(Cl)c4Cl)C3)nc2)cc1
Reaction time: 8 h

Procedure:
2,3-Dichlorobenzaldehyde (115 mg, 0.66 mmol, 1.5 equiv.) was added to N-(pyrrolidin-3-(RS)-ylmethyl)-2-[5-(4-methoxyphenyl)pyrimidin-2-ylthio]acetamide in dichloroethane (3.4 mL, 0.44 mmol). Excess Na(OAc)3BH (0.2 g, 0.9 mmol, ~3 equiv.) was added and the resulting suspension was stirred vigorously overnight. The reaction mixture was diluted with ether and quenched with 1 M hydrochloric acid to afford a cloudy mixture. The organic layer was carefully removed and the aqueous phase made basic with 5 M aqueous sodium hydroxide to pH 11. After thorough extraction with ethyl acetate, the combined organic phases was washed with brine, then dried over sodium sulfate and concentrated. Chromatography on silica (0-10% methanol in ethyl acetate) afforded N-(1-(2,3-dichlorobenzyl)pyrrolidin-3-(RS)-ylmethyl)-2-[5-(4-methoxyphenyl)pyrimidin-2-ylsulfanyl]acetamide that was converted to the hydrochloride salt using 4 M hydrochloric acid solution in dioxane and ether (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]([NH2:23])=O)=[N:11][N:10]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]#[N:23])=[N:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C(N)=O)c2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C#N)c2c1
Yield: 32.7 %

Procedure:
A solution of 4(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-phthalazine-1-carboxylic acid amide (1.06 g, 2.92 mmoles), prepared as described in example 109, in pyridine (80 ml) and trifluoroacetic anhydride (1.65 ml, 11.67 mmoles), under dry N2 at room temperature, was stirred for 3 hours, then dried, taken up in CH2Cl2, washed with citric acid, 5% NaOH and water. The organic phase was anhydrified and dried to give a solid which was flash chromatographed (eluent: CH2Cl2/CH3OH 99:1) to give 0.33 g of the title compound (yield: 33%).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].Cl.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C@@H:15]2[CH2:19][NH:18][C@H:17]([CH2:20][OH:21])[CH2:16]2)=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1.[OH-].[Na+]>O1CCCC1.O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C@@H:15]2[CH2:19][N:18]3[C@H:17]([CH2:20][O:21][CH2:2][C:3]3=[O:4])[CH2:16]2)=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: O=[N+]([O-])c1cc(Br)ccc1N[C@@H]1CN[C@H](CO)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1COC[C@@H]2C[C@H](Nc3ccc(Br)cc3[N+](=O)[O-])CN12
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
Add chloroacetyl chloride (0.49 mol, 55.7 g) drop wise to a solution of (2S,4S)-[4-(4-bromo-2-nitro-phenylamino)-pyrrolidin-2-yl]-methanol, hydrochloride (0.22 mol, 79 g) in tetrahydrofuran/water (1:1) mixture (1180 mL) at room temperature. Maintain the reaction pH between 10-12 by continuous addition of 4 M sodium hydroxide solution. After complete addition of chloroacetyl chloride, stir the reaction mixture for 4 h at room temperature. Remove tetrahydrofuran under reduced pressure and extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (50 g, 62%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 1.59-1.67 (m, 1H), 2.58-2.64 (m, 1H), 3.40 (t, 1H), 3.71 (dd, 1H), 3.91-4.01 (m, 2H), 4.09 (d, 1H), 4.20 (dd, 1H), 4.29-4.35 (m, 2H), 6.75 (d, 1H), 7.54 (dd, 1H), 8.05 (d, 1H), 8.32 (d, 1H).