Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:15]2[NH:16][C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH:20]=[O:21])[C@H:11]1[O:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:9][C@@H:10]1[C@H:15]2[N:16]([C:31](=[O:33])[CH3:32])[C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH:20]=[O:21])[C@H:11]1[O:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: O=C[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C(=O)O[C@H]2C[C@H](C=O)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]21
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of (3aS,4R,5R,6S,7aS)-6-formyl-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (580 mg, 1.42 mmol) in dry DCM (10 mL) at 0° C. under N2 was added a solution of acetyl chloride (223 mg, 2.84 mmol) in dry DCM (2.84 mL) followed by a solution of DIPEA (330 mg, 2.56 mmol) in dry DCM (2.56 mL) dropwise. The mixture was stirred at 0° C. for 2 h. The reaction was further diluted with DCM (20 mL), washed with 0.1 N HCl and brine. The solvent was evaporated to give the crude (3aS,4R,5R,6S,7aS)-3-acetyl-6-formyl-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (614 mg, 96%) which was carried onto next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.93 (d, J=7.8 Hz, 2H), 7.90 (d, J=7.8 Hz, 2H), 7.54-7.59 (m, 2H), 7.40-7.44 (m, 4H), 5.79 (dd, J=5.7 Hz, 4.1 Hz, 1H), 5.68 (t, J=5.7 Hz, 1H), 5.01-5.04 (m, 1H), 4.82 (dd, J=7.7 Hz, 4.0 Hz, 1H), 3.13-3.19 (m, 1H), 2.54-2.60 (m, 1H), 2.50 (s, 3H), 2.26-2.34 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][CH3:12])[N:3]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)=[O:31].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([C:30](=[O:31])[CH2:29][N:7]2[C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][CH3:12])[N:3]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:2]2=[O:1])=[CH:33][CH:34]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCCOc1cc(=O)[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a mixture of 4′-[(2,4-dioxo-6-propoxy-3,4-dihydropyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (0.55 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.38 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.073 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.7 g, 90%).
Reaction SMILES: C(S[CH2:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][N+:16]([O-:18])=[O:17])[CH2:11][CH2:10]1)=[O:7])(=O)C.O([C@H:23]1CC[C@H](N)CC1)[N+]([O-])=O.C(SCC(Cl)=O)(=O)C>>[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][N+:16]([O-:18])=[O:17])[CH2:11][CH2:10]1)(=[O:7])[CH2:5][CH3:23]
Reactant: N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Reactant: CC(=O)SCC(=O)N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Agent: CC(=O)SCC(=O)Cl
Product: CCC(=O)N[C@H]1CC[C@H](O[N+](=O)[O-])CC1

Procedure:
2-acetylmercapto-N-(trans-4-nitroxycyclohexyl)acetic acid amide from trans-4-nitroxycyclohexylamine and 2-acetylmercaptoacetic acid chloride melting point: 127°-129° C. (ether), yield: 67% of theory.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]1([NH:19][OH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:11]([O:10][C:1](=[O:9])[C@H:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:20])[CH3:12]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: ONc1ccccc1
Solvent: CCO
Product: CCOC(=O)C[C@@H](C(=O)OCC)N(O)c1ccccc1
Temperature: 25 °C
Yield: 113.8 %

Procedure:
A solution of diethyl maleate (20.65 g, 0.117 mol) in ethanol (25.0 g) was added dropwise to a solution of N-phenylhydroxylamine (14.6 g, 0.129 mol) in ethanol (46.3 g). The reaction mixture was stirred at room temperature for an hour. The analysis of the reaction mixture by thin layer chromatography indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure to give the crude product (37.46 g). The crude product was crystallized from ethylacetate-hexane (28.0 g, 85.0% yield).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[O:6][C:5]1=[O:24])[CH:2]=[CH2:3].Cl.[NH2:27][C@@H:28]([CH2:32][CH3:33])[C@@H:29]([OH:31])[CH3:30].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C@H:8]([C@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[OH:6])[CH2:9][C@:4]([CH3:25])([CH2:1][CH:2]=[CH2:3])[C:5]([NH:27][C@@H:28]([CH2:32][CH3:33])[C@@H:29]([OH:31])[CH3:30])=[O:24])[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cc2)OC1=O
Reactant: CC[C@H](N)[C@H](C)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C(=O)N[C@@H](CC)[C@H](C)O
Temperature: 25 °C

Procedure:
To a 10 mL round-bottom reaction flask was added (3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (750 mg, 1.998 mmol), (2S,3S)-3-aminopentan-2-ol hydrochloride (837 mg, 6.00 mmol, reference: J. Org. Chem., 2003, 68 (26), 9948), and triethylamine (1966 μl, 13.99 mmol). The vessel was fitted with a reflux condensor and heated to 85 to 95° C. for 2d. The reaction was cooled to RT and diluted with ethyl acetate and washed with 1N HCl (2×20 mL) and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography using 40 to 50% ethyl acetate in hexanes afforded (S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-((2S,3S)-2-hydroxypentan-3-yl)-2-methylpent-4-enamide.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl[CH:19]([CH3:23])[C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[CH3:1][C:2]1[N:3]([CH:19]([C:20](=[O:22])[CH3:21])[CH3:23])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(=O)C(C)Cl
Reactant: Cc1[nH]c2ccccc2c1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of tert-butyl 2-methyl-1H-indole-3-carboxylate (2 g, 8.65 mmol) and 3-chlorobutan-2-one (1.1 g, 10.38 mmol) in acetonitrile (18 mL) were added potassium carbonate (3.2 g, 25.8 mmol) and potassium iodide (1.4 g, 8.65 mmol). The reaction mixture was stirred at 90° C. overnight. To the reaction mixture was added water (20 mL). The aqueous layer was extracted with ethyl acetate (50 mL×4). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by silica gel column (petroleum ether/ethyl acetate 100:1 to 80:1) to give tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-indole-3-carboxylate (600 mg, yield: 23%) as a yellow oil. LRMS (M+H+) m/z: calcd 301.17. found 302.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[C:18]([CH2:21][N+]1C=CC=CC=1)(=[O:20])[NH2:19].[OH-].[Na+]>CO.O>[C:11]1([C:9]2[CH:8]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH:19][C:18](=[O:20])[CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: NC(=O)C[n+]1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzylideneacetophenone (41.6 g) and N-carbamoylmethylpyridinium chloride (34.4 g) (prepared according to the method of O. ALBRECHT et al., Helv. Chim. Acta 24, 241E (1941)) in methanol (600 cc), is added, at room temperature, a 1N aqueous solution of sodium hydroxide (200 cc). The initially yellow solution takes on an orange colour and a yellow solid precipitates. The mixture is stirred at room temperature for 15 minutes and acetic acid (400 cc) Is then added. The green solution obtained is stirred for 1 hour at room temperature. The solvent Is then distilled in 4 hours under atmospheric pressure. The solid residue obtained is taken up in distilled water (500 cc). After stirring for 1 hour at room temperature, the solid is separated by filtration, washed with distilled water (3×100 cc) and dried under reduced pressure at 60° C. (whitish solid; m.p.=209°-212° C.).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1.C(#N)C>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: C1CSCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCSCC3)cc21
Temperature: 25 °C
Yield: 65.8 %

Procedure:
A solution of 1.35 g (5.33 mmol) of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.34 ml (13.3 mmol) of thiomorpholine, 40 ml of acetonitrile, and 20 ml of N,N-dimethylformamide was heated under reflux for 21 hours. The reaction mixture was cooled to room temperature and the solid was collected by filtration, washed with water and acetonitrile, and dried to give 1.18 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-thiomorpholinyl)-3-quinolinecarboxylic acid, mp 254°-6°.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:14]1[O:24][C:23]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=2[O:15]1.C(O)(C(F)(F)F)=O>>[CH2:14]1[O:24][C:23]2[CH:22]=[CH:21][C:18]([CH:19]3[C:7]4[NH:6][C:5]5[C:12](=[CH:13][C:2]([F:1])=[CH:3][CH:4]=5)[C:8]=4[CH2:9][CH2:10][NH:11]3)=[CH:17][C:16]=2[O:15]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: NCCc1c[nH]c2ccc(F)cc12
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2[nH]c3c(c2c1)CCNC3c1ccc2c(c1)OCO2
Yield: 84.7 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with 5-fluorotryptamine (1.59 g, 8.9 mmol), 3,4-methylenedioxybenzaldehyde (1.47 g, 1.1 equiv.) and TFA (1.4 mL, 2 equiv.) to give the title compound (2.34 g, 85%) as white crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[C:15](=[O:16])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:21][Li]>O1CCCC1.C(OCC)C>[OH:16][C:15]1([CH3:21])[C:8]2[CH:7]=[CH:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:10]=3[C:9]=2[CH:11]=[CH:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: O=c1c2ccccc2ccc2c1ccc1ccccc12
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)c2ccccc2C=Cc2c1ccc1ccccc21

Procedure:
To a solution of 7H-benzo[4,5]cyclohepta[1,2-a]naphthalen-7-one (1.75 g, prepared by the method of Bergmann et al, J. Org. Chem., 1963, 28, 3341) in dry tetrahydrofuran (40 ml) at 0° C. under nitrogen was added a solution of methyl lithium in diethyl ether (8 ml of 1.4M). After 90 minutes at 0° C. the reaction was quenched by the dropwise addition of water (20 ml) and the reaction mixture extracted into diethyl ether (2×75ml). dried (Na2SO4), filtered and the solvents removed under reduced pressure to give a light brown oil (1.9 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C([Li])CCC.C[O:17][B:18](OC)[O:19]C>C1(C)C=CC=CC=1.C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:18]([OH:19])[OH:17])=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: COB(OC)OC
Reactant: COc1cc(Br)ccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(B(O)O)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To 4-bromo-1-chloro-2-methoxybenzene (2.2 g, 9.9 mmol) in toluene/THF (16/6 mL) at −78° C. was added n-butyl lithium (8.7 mL, 1.6 M in hexane, 14 mmol) dropwise. The reaction was stirred at −78° C. for 30 min, then trimethylborate (2.2 mL, 19.8 mmol) was added. The reaction was allowed to warm to rt and stirred overnight and then quenched with 1 M HCl (15 mL). The organic layer was separated and dried over sodium sulfate. The solvent was removed and the crude product was purified by flash column chromatography to give 25A (1.2 g, 65% yield) as a white solid. 1H NMR (400 MHz, CDOD3) δ ppm 3.87 (m, 3H) 7.11 (d, J=7.83 Hz, 1H) 7.20 (s, 1H) 7.29 (d, J=7.83 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[NH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=[S:24].[H-].[Na+].O>CN(C=O)C>[CH3:17][C:12]1[C:11]([O:10][C:4]2[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([S:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH:3]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Cc1ncccc1Oc1cc(Br)cnc1C#N
Reactant: S=c1cccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1C#N
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
5-Bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (56.9 g, 196 mmol) and pyridine-2(1H)-thione (22.9 g, 206 mmol) were dissolved in DMF (400 mL) and cooled to 0° C. NaH (4.94 g, 206 mmol) was added portionwise and warmed to ambient temperature. The reaction was stirred for 18 hours and then poured into 2.5 L of water and stirred for 30 minutes The solids were filtered to provide 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (60.8 g, 190 mmol, 96.8% yield).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:5]1=[O:34])[CH:2]=[CH2:3].[CH3:36][S:37](Cl)(=[O:39])=[O:38].N1C=CC=CC=1>ClCCCl.CN(C1C=CN=CC=1)C>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]([CH2:27][C:28]([F:29])([F:31])[F:30])[S:37]([CH3:36])(=[O:39])=[O:38])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNCC(F)(F)F)C1=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(CC(F)(F)F)S(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-2-one prepared above in Step A (60.9 mg, 0.115 mmol) in DCE (770 μL) was added DMAP (70.5 mg, 0.577 mmol) and methanesulfonyl chloride (35.9 μL, 0.462 mmol) successively at rt. After being stirred at rt for 3 h, pyridine (46.7 μL, 0.577 mmol), methanesulfonyl chloride (35.9 μL, 0.462 mmol), and DCE (0.77 mL) were added and the resulting solution was stirred for 15 h.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=CC2C=CC=CC=2)[N:4]=1)#[N:2].[O:17]=[O+][O-]>CO.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[O:17])[N:4]=1)#[N:2]
Reactant: N#Cc1ccnc(C=Cc2ccccc2)n1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccnc(C=O)n1
Temperature: 25 °C

Procedure:
2.238 g (10.81 mmol) of 4-cyano-2-(2-phenylethenyl)-pyrimidine in 150 ml of absolute methanol and 75 ml of absolute methylene chloride are cooled to -70° C. Ozone is passed through until a blue solution is produced (about 0.5 hour). Nitrogen is passed through the solution until the excess ozone has been removed (about 0.75 hour) and then 3.5 ml of dimethyl sulfide are added to the reaction mixture. The solution is allowed to warm up to room temperature and is concentrated in a rotary evaporator. The crude product is purified over silica gel (eluant: n-hexane/ethyl acetate 1:3). 1H-NMR (CDCl3): δ=10.11 (s, 1H); 9.23 (d, 1H); 7.82 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:11]([O:16][CH3:15])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Nc1nc2cc(Cl)c(Cl)cc2nc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc2cc(Cl)c(Cl)cc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To 2-amino-3,6,7-trichloroquinoxaline (1.54 g, 6.20 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (2.01 g, 9.30 mmol) in methanol was added at room temperature and stirred further at room temperature for 1 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 1.21 g of the titled compound (yield, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1cncc(Br)c1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Crude 5-bromopyridine-3-sulfonyl chloride from step 1 above was dissolved in THF (14 L, 8 vol) and then transferred to a 20 L RB flask equipped with mechanical stirrer under inert atmosphere. The solution was cooled to 0-5° C. and tert-butyl amine (1.95 Kg, 26.66 moles) was added at 0-5° C. Upon completion of addition, the reaction mixture was warmed to ambient temperature where it stirred for 2 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated that the reaction was complete. The solvent was evaporated under vacuum to give a thick residue. The residue was dissolved in ethyl acetate (18 L, 12 vol). The organic layer was separated, washed with water (9 L, 5 vol) and then concentrated under vacuum to yield a residue. Hexanes (9 L, 5 vol) were added to the residue and the product precipitated out and was collected by filtration to yield a free flowing yellow solid (1.5 Kg, 54.28% overall yield). 1H NMR (DMSO-D6, 400 MHz, δ ppm); 8.99 (d, J=2 Hz, 1H), 8.81 (d, J=2 Hz, 1H), 8.29 (t, J=2 Hz, 1H). [M++1]=293.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].CI.[C:31](=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH3:31][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Agent: [Cu]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2OC)c1
Yield: 91.2 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 0.3292 ml (5.181 mmol) of methyl iodide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 2 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by a silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 25/1) to obtain 188.9 mg (0.4723 mmol, 91%) of 2-methoxy-2'-hydroxy-5, 5'-bis(2-ethoxycarbonylethyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.24 (6H, t, 2CH3), 2.62 (4H, t, 2CH2), 2.9-3.0 (4H, m, 2CH2), 3.87 (3H, s, CH2), 4.13 (4H, q, 2CH2), 6.13 (1H, s, OH), 6.9-7.3 (6H, m, arom-H) MS (FAB): 400 (M)+
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13](C=O)=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13](=[O:30])[CH2:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cccnc32)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC(=O)c3cccnc32)cc1
Temperature: 25 °C
Yield: 9.2 %

Procedure:
1-Tosyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (5 g, 16.65 mmol) was dissolved in DCM (165 mL) and chilled to 0° C. m-Chloroperbenzoic acid (“m-CPBA”; 4.85 g, 21.64 mmol, 77% by weight) was added, and the mixture was allowed to gradually warm to room temperature over a 16 hour period. The mixture was then washed with 10% aqueous sodium sulfite solution, dried over sodium sulfate and concentrated. Flash 65 Biotage (5% ethyl acetate/DCM) afforded 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3 (2H)-one (441 mg, 9%). 1H NMR (400 MHz, CDCl3) δ 8.61-8.66 (m, 1H), 8.00-8.05 (m, 2H), 7.92-7.97 (m, 1H), 7.29-7.34 (m, 2H), 7.06-7.12 (m, 1H), 4.38 (s, 2H), 2.41 (s, 3H).