Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[N+:21]([C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[OH:31])([O-:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.O>[Cl:30][C:28]1[CH:27]=[CH:26][C:25]([O:31][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:24]([N+:21]([O-:23])=[O:22])[CH:29]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (1.0 g, 3.35 mmol) in butanone (35 mL) was added 2-nitro-4-chlorophenol (0.64 g, 3.69 mmol), potassium carbonate (0.93 g, 6.7mmol) and potassium iodide (0.56 g, 3.35 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was then cooled, diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give an orange oil. Chromatography on silica gel gave the title compound (1.35 g).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=2[CH:7]=O)[CH2:3][CH2:2]1.[C:16]([S@@:20]([NH2:22])=[O:21])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[CH:1]1([S:4][C:5]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=2/[CH:7]=[N:22]/[S@:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:21])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1cc([N+](=O)[O-])ccc1SC1CC1
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1cc([N+](=O)[O-])ccc1SC1CC1
Temperature: 73 °C
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
To 76A (2.02 g, 9.0 mmol), (S)-tert-butylsulfinamide (1.21 g, 10 mmol) in CH2Cl2 (40 mL) was added Ti(OEt)4 (10 mL, 45 mmol). The mixture was heated at 73° C. for 6.0 h. CH2Cl2 was removed under vacuo and the residue was suspended in EtOAc. To this suspension was added brine. The mixture was stirred at rt for 15 min before it was filtered through a pad of wet Celite®. The filtrate was extracted with EtOAc (3×50 mL). The organic layer was washed with brine and dried over Na2SO4. After removal of solvent, 85A (3.0 g, 100% yield) was obtained as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.72-0.81 (m, 2H) 1.21 (m, 2H) 1.28 (s, 9H) 2.14-2.21 (m, 1H) 7.89 (d, J=8.79 Hz, 1H) 8.24 (dd, J=8.79, 2.64 Hz, 1H) 8.60 (d, J=2.64 Hz, 1H) 8.77 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][CH2:17][C:18](Cl)=[O:19].C([O-])(=O)C.[Na+]>CC(C)=O.O>[Cl:16][CH2:17][C:18]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:19]
Reactant: O=C(Cl)CCl
Reactant: c1ccc(C2CNc3ccccc32)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCl)N1CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.1 g of 3-phenylindoline in 60 ml of acetone was cooled to 0° C, 5.1 ml of chloroacetylchloride was added and the mixture poured into an ice cold solution of 10 g of sodium acetate in 50 ml of water. The mixture was then stirred for one hour at room temperature and the residual solid removed by filtration. Recrystallization from ethanol gave a yield of 13.0 g of the desired N-chloroacetyl-3-phenylindoline having a melting point of 76°-78° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:19])=O>O1CCOCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:19])=[O:11])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(N2CCOCC2)c1
Solvent: C1COCCO1
Product: O=C(Cl)c1cccc(N2CCOCC2)c1
Reaction time: 1 h
Yield: 81.8 %

Procedure:
The above reagents, including 25 g of 3-morpholinobenzoic acid and 15.2 g of oxalyl chloride, were mixed in dioxane at 0° C. under argon gas. The reaction proceeded for about 2 hours, one hour at 0° C. and one hour at room temperature. The solvent was then removed under reduced pressure to yield 22.1 g of 3-morpholinobenzoyl chloride, which was used without further purification.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]([CH3:13])[N:4]=1.[OH-].[Na+].Cl>>[F:14][CH:2]([F:1])[C:3]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]([CH3:13])[N:4]=1
Reactant: CCOC(=O)c1cn(C)nc1C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc(C(=O)O)c(C(F)F)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of ethyl 3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate (1.4 g, 52 mmol) and aqueous sodium hydroxide solution (10% strength, 3.1 g, 8 mmol) was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature, and the pH was then adjusted to 1 using concentrated hydrochloric acid. The reaction mixture was cooled further to 0° C., resulting in the precipitation of a solid. The precipitated solid was filtered off, washed with cyclohexane and dried under reduced pressure. This gave 3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acid as a solid (amount: 0.8 g; yield: 87%). 1H-NMR (DMSO-d6): δ=3.9 (s, 2H), 7.2 (t, 1H), 8.35 ppm (s, 1H).
Reaction SMILES: [C:1](=[C:4]1[CH:8]2[C:9]3[C:14]([CH:5]1[CH:6]=[CH:7]2)=[CH:13][CH:12]=[CH:11][C:10]=3[N+:15]([O-])=O)([CH3:3])[CH3:2]>O1CCCC1.[Rh]>[CH:1]([CH:4]1[CH:8]2[C:9]3[C:14]([CH:5]1[CH2:6][CH2:7]2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH2:15])([CH3:3])[CH3:2]
Reactant: CC(C)=C1C2C=CC1c1c2cccc1[N+](=O)[O-]
Agent: [Rh]
Solvent: C1CCOC1
Product: CC(C)C1C2CCC1c1c(N)cccc12
Reaction time: 96 h

Procedure:
9-Isopropylidene-5-nitro-1,4-dihydro-1,4-methano-naphthalene (5) (6.5 g, 29 mmol) was stirred in tetrahydrofuran (150 mL) at room temperature with rhodium (5%) on carbon (3 g). The head space was evacuated and was replaced with hydrogen. Positive pressure was maintained by the use of a balloon filled with hydrogen. After 4 days, the reaction mixture was filtered and was evaporated to afford the title compound as an 87:13 syn:anti mixture (5.6 g, 97.4%) as a pale brown oil: 1H NMR (600 MHz, CDCl3) δ 6.91-6.87 (m, 1H), 6.63 (d, J=7.2 Hz, 1H), 6.47 (d, J=8.0 Hz, 1H), 3.51 (s, 2H), 3.18 (s, 1H), 3.13 (s, 1H), 1.94-1.87 (m, 2H), 1.52 (d, J=9.9 Hz, 1H), 1.21-1.13 (m, 2H), 1.05-0.97 (m, 1H), 0.80 (d, J=2.0 Hz, 3H), 0.79 (d, J=2.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 147.94, 140.30, 130.32, 126.60, 113.52, 112.86, 69.17, 46.79, 42.23, 27.94, 27.02, 25.65, 22.54, 22.26; EIMS m/z 201; two peaks; 83:17 ratio.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](O)([CH3:12])[CH3:11].CCOC(C)=O>CCO.[Pd]>[CH:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH2:1])([CH3:12])[CH3:11]
Reactant: COc1ccc(C(C)(C)O)c(N)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(C)C)c(N)c1
Yield: 80.7 %

Procedure:
To a solution of 2-(2-amino-4-methoxyphenyl)propan-2-ol (210 mg; 1.2 mmol; 1 eq) in a mixture of EtOH (10 mL), EtOAc (3 mL) and 5 N (1 mL) under nitrogen atmosphere is added palladium on charcoal (130 mg; 10%) and the reaction mixture is hydrogenated for 1 week at room temperature at 1 atmosphere. The catalyst is filtered through celite and the organic solvents are removed under vacuum. The residue is taken up in EtOAc. The organic phase is washed with a saturated aqueous solution of Na2CO3 and dried over MgSO4. The solvent is evaporated under reduced pressure to afford 160 mg (84%) of the title compound as a red oil. The compound is used in the next step without further purification. 1H NMR (DMSO-d6) δ 6.89 (d, J=9.0 Hz, 1H), 6.18 (d, J=3.0 Hz, 1H), 6.05 (dd, J=9.0, 3.0 Hz, 1H), 5.45-5.39 (m, 2H), 3.85 (s, 3H), 3.30-3.11 (m, 1H), 1.97 (s, 6H). HPLC (max plot) 70%; Rt 1.88 min.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C[Al](C)C.[CH2:9]([N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C:14](OC)=[O:15])[CH:10]=[CH2:11]>C1(C)C=CC=CC=1.C1COCC1>[CH2:9]([N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C:14]([N:3]([CH3:4])[CH3:2])=[O:15])[CH:10]=[CH2:11]
Reactant: CNC
Reactant: C=CCN(CC(=O)OC)Cc1ccccc1
Agent: C[Al](C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCN(CC(=O)N(C)C)Cc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of dimethylamine hydrochloride (2.08 g, 25.5 mmol, 8.0 eq) in anhydrous toluene (10 mL) at 5° C. under N2 was added trimethyl aluminum (1.0M in toluene, 25.5 mL, 25.5 mmol, 8.0 eq) dropwise over 1 h. The reaction mixture was heated to 20° C. and stirred for another 2 h. To a mixture of methyl 2-(allyl(benzyl)amino)acetate (0.70 g, 3.19 mmol, 1.0 eq) in anhydrous toluene (50 mL) and THF (15 mL) at 5° C. was added the above reaction mixture and the reaction mixture was heated at 70° C. for 48 h. Then the mixture was cooled to 0° C. and quenched with a small amount of water. The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and filtrated. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (50:1 (v/v) CH2Cl2/CH3OH) to afford the title compound as colorless oil (0.62 g, 77%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 233.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.86 (3H, s), 2.94 (3H, s), 3.16 (2H, d, J=6.8 Hz), 3.24 (2H, s), 5.16 (2H, m), 5.86 (1H, m), 7.18-7.27 (5H, m) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][C:15](=[O:17])[N:14]([C:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:20][C:19]=3[C:29]([OH:31])=[O:30])[C@H:13]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.CCN(CC)CC>CN(C=O)C>[CH:32]1([C@@H:13]2[CH2:12][N:11]([S:8]([C:5]3[CH:6]=[N:7][C:2]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:16][C:15](=[O:17])[N:14]2[C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:20][C:19]=2[C:29]([OH:31])=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccc(Cl)nc2)C[C@H]1C1CCCCC1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccc(N3CCCC3)nc2)C[C@H]1C1CCCCC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To a solution of 3-[(R)-4-(6-chloro-pyridine-3-sulfonyl)-2-cyclohexyl-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic acid (100 mg, 0.18 mmol, 1.0 equiv) in DMF (0.8 mL) at room temperature was added pyrrolidine (127 mg, 1.79 mmol, 10.0 equiv) and Et3N (0.37 mL, 2.68 mmol, 15.0 equiv). The mixture was stirred at 70° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated and purified by HPLC (0.1% NH4OH) to give product (35 mg, 33%) as white solid. MS: 595 [M−H+]. 1H-NMR (400 MHZ, MeOD): δ 1.10-1.23 (m, 5H), 1.40-2.00 (m, 10H), 3.04-3.12 (m, 2H), 3.20 (t, 2H), 3.42 (d, 2H), 3.88 (d, 1H), 3.97 (br, 1H), 4.07 (d, 1H), 6.62 (s, 1H), 7.19 (s, 1H), 7.32 (t, 1H), 7.40 (t, 2H), 7.63 (d, 2H), 7.83 (m, 1H), 8.44 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[C:31]([CH:32]=[O:33])=[C:30]([N:34]3[CH:46]=[CH:45][N:37]4[C:38]5[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=5[CH:44]=[C:36]4[C:35]3=[O:47])[N:29]=[CH:28][CH:27]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:33][CH2:32][C:31]1[C:30]([N:34]2[CH:46]=[CH:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[N:29][CH:28]=[CH:27][C:26]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2ccnc(-n3ccn4c5c(cc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(-n3ccn4c5c(cc4c3=O)CCCC5)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
At 0° C., to a suspension of 121a (76 mg, 0.12 mmol) in methanol (4 mL) was added sodium borohydride (20 mg, 0.7 mmol) and stirred for 30 minutes. Then the reaction mixture was quenched with water (1.0 mL) and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 121 (56 mg, 74%). LCMS: [M+H]+ 635. 1H NMR (500 MHz, DMSO) δ 8.66 (d, J=2.0, 1H), 8.57 (d, J=5.0, 1H), 7.93 (d, J=3.0, 1H), 7.85 (d, J=2.5, 1H), 7.80 (s, 1H), 7.50 (d, J=5.0, 1H), 7.24-7.27 (m, 1H), 7.06 (s, 1H), 6.97 (d, J=6.0, 1H), 6.81 (d, J=8.0, 1H), 6.67 (d, J=6.0, 1H), 5.08 (d, J=11.5, 1H), 4.67-4.72 (m, 4H), 4.51 (d, J=12.0, 1H), 4.35 (t, J=12.0, 1H), 3.72 (s, 3H), 3.57-3.59 (m, 1H), 3.16-3.17 (m, 4H), 2.70-2.74 (m, 4H), 2.52-2.53 (m, 4H), 1.94-1.95 (m, 2H), 1.84-1.86 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH:22]([CH3:24])[CH3:23])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])=[CH:10][CH:9]=1.C(=O)(O)[O-].[Na+].[C:31](Cl)(=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35]>O.C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH:22]([CH3:23])[CH3:24])[N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])=[CH:10][CH:9]=1)[C:31](=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OC)C(C)C
Temperature: 28 °C
Reaction time: 0.42 h
Yield: 107.7 %

Procedure:
150 g N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride was charged into a round bottomed flask containing a mixture of sodium bicarbonate (158.1 g), water (450 ml) and toluene (900 ml). The contents were stirred at 28° C. for 25 minutes and then cooled to 0° C. 110.9 g of valeryl chloride was added slowly to the reaction mass at 0-20° C. over about 55 minutes. The reaction mass was stirred at about 2-4° C. for about 2 hours. Reaction completion was confirmed by thin layer chromatography and the reaction mixture was allowed to attain 28° C. 450 ml of water was added to the reaction mass and stirred for about 20 minutes. The organic layer was separated, washed with a solution of sodium bicarbonate (30 g) in water (450 ml) twice, followed by washing with water (450 ml). The organic layer was concentrated under reduced pressure at 60-68° C. to obtain 183 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:30])([F:29])[CH2:27]I>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH2:27][C:26]([F:30])([F:29])[F:25])[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: FC(F)(F)CI
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CC(F)(F)F
Temperature: 70 °C
Reaction time: 18 h
Yield: 33.5 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.4 g, 1.311 mmol), potassium carbonate (0.544 g, 3.93 mmol) and 1,1,1-trifluoro-2-iodoethane (0.826 g, 3.93 mmol) in DMF (2 ml) was heated at 70° C. under stirring for 18 h The reaction mixture was cooled down and diluted with water (15 ml) and extracted with DCM (15 mlX3). The combined organic phase was washed with water (25 ml) and dried with Na2SO4 and concentrated. The residue was purified by column chromatography (biotage 25 g) eluted with ethyl acetate/cyclohexane 0-60% to afford product 6-bromo-7-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.17 g) 1H NMR (500 MHz, CDCl3) 7.45-7.50 (m, 3H), 7.38-7.40 (m, 2H), 7.28 (s, 1H), 4.94 (s, 2H), 4.55 (q, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[N:4]=[CH:3]1.O[NH:12][C:13]([CH:15]1[CH2:17][CH2:16]1)=[NH:14]>>[CH:15]1([C:13]2[N:14]=[C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][C:5]=3[CH3:10])[O:9][N:12]=2)[CH2:17][CH2:16]1
Reactant: N=C(NO)C1CC1
Reactant: Cc1ncn(C)c1C(=O)O
Product: Cc1ncn(C)c1-c1nc(C2CC2)no1

Procedure:
The title compound, off-white solid, m.p. 88° C. and MS: m/e=204.3 (M+), was prepared from 3,5-dimethyl-3H-imidazole-4-carboxylic acid and N-hydroxy-cyclopropanecarboxamidine in accordance with the general procedure of example 12a.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=O.Cl.C[O:16][NH2:17]>N1C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:4]([C:2](=[N:17][OH:16])[CH3:1])=[CH:5][CH:6]=1
Reactant: CON
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Trifluoromethylacetophenone (13.6 g, 72.3 mmol) and O-methylhydroxylamine hydrochloride were combined in pyridine (100 mL) and stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was suspended in diethyl ether. The suspension was filtered and the filter cake was washed with diethyl ether. The filtrate was washed with water, 1N HCl, and water. The organic phase was concentrated to provide the title compound. 1H NMR (300 MHz, d6-DMSO) 7.90-7.68 (m, 4H), 3.97 and 3.78 (2s, 1H), 2.20 and 2.17 (2s, 3H); MS (DCI/NH3) m/e 218 (M+H)+.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[ClH:17].Cl.[CH:19]([CH:32]1[NH:37][CH2:36][CH2:35][N:34]([CH2:38][C:39]2[CH:44]=[C:43]([N:45]3[C:49]([C:50]([F:53])([F:52])[F:51])=[N:48][N:47]=[N:46]3)[CH:42]=[CH:41][C:40]=2[O:54][CH3:55])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.CO>[ClH:17].[ClH:17].[CH:19]([CH:32]1[CH2:33][N:34]([CH2:38][C:39]2[CH:44]=[C:43]([N:45]3[C:49]([C:50]([F:53])([F:52])[F:51])=[N:48][N:47]=[N:46]3)[CH:42]=[CH:41][C:40]=2[O:54][CH3:55])[CH2:35][CH2:36][N:37]1[CH3:1])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1CCNC(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1CCN(C)C(C(c2ccccc2)c2ccccc2)C1
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (146 mg) was added portionwise to a mixture of 37% aqueous formaldehyde (30 mg) and 3-benzhydryl-1-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]piperazine dihydrochloride in a mixture of dichloromethane (4 ml) and methanol (2 drops) at 0° C. and the whole was stirred at 5° C.˜room temperature overnight. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (60:1). The fractions containing the objective compound were collected and evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution to give 2-benzhydryl-4-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]-1-methylpiperazine dihydrochloride (32.9 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:36])[C:11]([C:32]([O:34]C)=[O:33])=[CH:12][N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:36])[C:11]([C:32]([OH:34])=[O:33])=[CH:12][N:13]([CH2:26][CH:27]([O:28][CH3:29])[O:30][CH3:31])[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(Cn1cc(C(=O)O)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 70 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a solution of methyl 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (2.0 g) in tetrahydrofuran (20 ml)-methanol (10 ml) was added 4N aqueous lithium hydroxide solution (1.5 ml) and the mixture was stirred at 70° C. for 1 hr. The precipitated solid was removed by thin layer of celite and washed with methanol. The solvent was evaporated and 1N aqueous hydrochloric acid (6.5 ml) and water (50 ml) were added. The mixture was extracted twice with ethyl acetate (75 ml each). The ethyl acetate layer was dried, concentrated and crystallized from ethyl acetate-diisopropyl ether to give 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1.2 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:24])[N:17]([CH2:21][CH2:22]Cl)[CH2:18][CH2:19]Cl)([CH3:14])([CH3:13])[CH3:12]>CS(C)=O.CCOC(C)=O>[C:11]([O:15][C:16]([N:17]1[CH2:21][CH2:22][C:8]([C:9]#[N:10])([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)=[O:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccc(I)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 4-iodophenylacetonitrile (6.88 g, 28.3 mmol, 1 eq.) and bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (7.2 g, 30 mmol, 1.05 eq.) in DMSO (100 mL) under argon (Ar) was added NaNH2 (2.46 g, 60 mmol, 2 eq.) in portions over 15 min. The reaction was stirred at room temperature for 0.5 h, then poured onto ice (200 g), diluted with EtOAc (250 mL) and stirred for 1 h. The organic layer was separated and the aqueous layer was washed repeatedly with EtOAc until colorless. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to afford an orange oil which was purified by flash column chromatography by eluting with 7-12% EtOAc/hexanes to yield 4-cyano-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a pale orange oil/solid (8.28 g, 18.96 mmol, 67%). 1H NMR (300 MHz, CDCl3): δ 7.82 (dd, 2H), 7.26 (dd, 2H), 4.38 (br. s, 2H), 4.28 (br. t, 2H), 2.15 (m, 2H), 2.0 (td, 2H), 1.59 (s, 9H). (Ref.: D. Gnecco et al, Org. Prep. Proceed. Int., (1996) 28 (4), 478-480.