Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][N:16]=1>>[Cl:14][C:15]1[N:16]=[CH:17][C:18]([N:1]2[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(I)cn1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nc2)C1
Yield: 48 %

Procedure:
tert-Butyl 3-pyrrolidinylcarbamate (0.377 g, 2.03 mmol; TCI) and 2-chloro-5-iodopyridine (0.484 g, 2.03 mmol; Aldrich) were processed according to the procedure of Example 1A to provide the title compound (0.29 g, 48%). MS (CI/NH3) m/z 298/300 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:11][C:10]=2[F:20])[S:6][C:5]=1[NH:21][C:22]1[N:27]=[C:26]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]([O:36]C)=[O:35])[N:31]=[N:30]2)[CH:25]=[CH:24][CH:23]=1)=[O:3].[OH-].[K+:39]>C1COCC1.CO>[NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:10]([F:20])=[CH:11][C:12]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:13][C:14]=2[F:15])[S:6][C:5]=1[NH:21][C:22]1[N:27]=[C:26]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]([O-:36])=[O:35])[N:31]=[N:30]2)[CH:25]=[CH:24][CH:23]=1)=[O:3].[K+:39]
Reactant: COC(=O)c1cn(Cc2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)nn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(Cn4cc(C(=O)[O-])nn4)n3)s2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 1-{[6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4-carboxylate (425 mg, 0.80 mmol) was taken up in THF (5.0 mL) and MeOH (5.0 mL), and KOH (1.0 M, 1.05 mL, 1.05 mmol) was added. The reaction was stirred at room temperature overnight. Additional KOH (1.0 M, 160 μL, 0.16 mmol) was added, and the reaction was stirred for another 8 h at room temperature. The mixture was then concentrated, resuspended in MeOH, and concentrated again to give the title compound as a yellow solid that was carried on without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C.O>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][C:12](=[O:14])[CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(NC(C)=O)cc(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 3,5-dimethoxyaniline (7.13 g, 46.5 mmol) in acetic acid (30 mL) and water (10 mL) was added acetic anhydride (4.61 mL, 48.9 mmol) at room temperature. The reaction was heated gently on a steam bath then cooled to room temperature. Excess water was added and the title compound 464A was collected by filtration.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[CH:10][CH:11]=1.C(N(CC)CC)C>C(OCC)C.C(OCC)(=O)C>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc(N)ccc1-c1ccccc1Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(C)=O)ccc1-c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Acetyl chloride (70 mg, 63 μl, 0.89 mmol) was added to a solution of methyl 4-amino-2′-bromo-2-biphenylcarboxylate (227 mg, 0.74 mmol) and triethylamine (90 mg, 123 ul, 0.89 mmol) in diethyl ether (3 ml) and stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate(10 ml) and washed with 2M HCl, 5% NaHCO3, water and brine the organic phase was dried and evaporated to leave the title compound as a yellow oil (226 mg, 88%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH3:16])[C@H:14]([CH:17]=[O:18])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O-])(O)=[O:34].[Na+].BrBr.[O-]S([O-])(=S)=O.[Na+].[Na+]>CO.O>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH3:16])[C@H:14]([C:17]([O:34][CH3:33])=[O:18])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:12]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: C[C@@H]1[C@H](C=O)[C@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Agent: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H]1[C@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)[C@@H]1C
Yield: 107.1 %

Procedure:
To a stirred and ice-cooled mixture of crude (2S*,3S*,4R*,5R*)-1-benzyloxycarbonyl-3-[N-(t-butoxycarbonyl)amino]-4-formyl-5-methyl-2-phenylpyrrolidine (3.66 g, 5.90 mmol) and NaHCO3 (19.8 g, 0.24mol) in MeOH--H2O (9:1 by volume; 30 ml) was added a 2.0 M solution of Br2 in MeOH--H2O (9:1; 30 ml, 60 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours, during which the color changed from deep red to orange. Sat. Na2S2O3 (hypo) aq. solution was added dropwise to the mixture with ice-cooling, until the orange color due to the excess Br2 was discharged. The mixture was filtered through a pad of Celite, and the filter cake was washed with CH2Cl2. The combined filtrate and washings were concentrated in vacuo. The syrupy residue was diluted with AcOEt--PhMe (2:1, 120 ml), washed with sat. Na2S2O3 aq. solution (×2), sat. NaHCO3 aq. solution (×1), and sat. NaCl aq. solution, dried (MgSO4), and concentrated in vacuo to give a white solid (2.96 g). This was recrystallized from AcOEt-n-hexane to give title compound (2.44 g, 88% in 2 steps from (2S*,3S*,4R*,5R*)-1-benzyloxycarbonyl-3-[N-(t-butoxycarbonyl)amino]-4-hydroxymethyl-5-methyl-2-phenylpyrrolidine) as white powders. mp 147-148 C.; IRmax (nujol): 3310(s), 1728(s), 1701(s, shoulder), 1690(vs), 1537(s), 1535(s), 1280(m), 1165(m), 750(m), 700(s) cm-1 ; 1H-NMR δ: 7.52-7.15(m, 9H), 7.05(br.s, 1H), 5.28(br.d, J=8.1 Hz, 1H), 5.05(br.s, 2H), 4.60(ddd, J=11.7, 8.8, 8.1 Hz, 1H), 4.35-4.17(m, 1H), 4.02(br.d, J=8.8 Hz, 1H), 3.71(s, 3H), 2.58(dd, J=11.7, 9.9 Hz, 1H), 1.62(br.d, J=5.5 Hz, 3H), 1.39(s, 9H) ppm.
Reaction SMILES: S([O-])([O-])(=O)=O.[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:35][O:36][CH2:37][CH:38]=[CH2:39])[C:13]([NH:15][CH:16]2[C:33](=[O:34])[N:18]3[C:19]([C:30]([OH:32])=[O:31])=[C:20]([CH2:23][N+:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21][S:22][C@H:17]23)=[O:14])[N:8]=1.NC1SN=C(C(=NOCC=C)C(NC2C(=O)N3C([C:64]([OH:66])=[O:65])=C(C[N+]4C=CC=CC=4)CS[C@H]23)=O)N=1.C(=O)([O-])O.[Na+:78]>>[C:64]([NH:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:35][O:36][CH2:37][CH:38]=[CH2:39])[C:13]([NH:15][CH:16]2[C:33](=[O:34])[N:18]3[C:19]([C:30]([O-:32])=[O:31])=[C:20]([CH2:23][N+:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:21][S:22][C@H:17]23)=[O:14])[N:8]=1)([O-:66])=[O:65].[Na+:78]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NC(=O)[O-])n1

Procedure:
Sodium 7-[2-(5-carboxylatoamino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) was prepared by reacting 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate hemisulfate (syn isomer((50 mg) and sodium hydrogencarbonate (15.3 mg) and detected according to a similar manner to that of Example 17.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.Cl>O1CCCC1CO>[C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCC1CCCO1
Product: O=C(O)Cc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of methyl 3-[2-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-4-pyridyl]methoxy]phenylacetate (521 mg) in tetrahydrofuran-methanol (1:1, 12 mL) was dropwise added a 1N aqueous sodium hydroxide solution (3 mL) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was poured into water, and the reaction mixture was neutralized with 1N hydrochloric acid (3 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 3-[2-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-4-pyridyl]methoxy]phenylacetic acid. Recrystallization from ethanol-hexane gave colorless needle crystals (473 mg, 94%). melting point: 136-137° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]Cl.[CH:10]([O:13][C:14](=[O:30])[NH:15][C@@H:16]1[CH2:29][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][C:26]=3[C:18]=2[CH2:17]1)([CH3:12])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C.ClCCl.O>[CH:10]([O:13][C:14](=[O:30])[NH:15][C@@H:16]1[CH2:29][C:19]2[N:20]([CH2:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[Br:1])[C:21]3[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][C:26]=3[C:18]=2[CH2:17]1)([CH3:12])[CH3:11]
Reactant: ClCc1ccncc1Br
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3ccncc3Br)c3ccc(C#N)cc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.8 %

Procedure:
A mixture of 3-bromo-4-(chloromethyl)pyridine (3.16 g, 11.5 mmol), ((S)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (2.50 g, 8.82 mmol) and cesium carbonate (4.31 g, 13.2 mmol) in dimethylformamide (20 mL) is stirred at room temperature under nitrogen overnight. The reaction mixture is then diluted with ethyl acetate, dichloromethane, and water. The organic phase is separated, washed with water twice, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a brown oil (˜4.75 g). The oil is triturated with hexanes twice, then with ether twice. It is then purified by flash chromatography eluting with 30 to 60% ethyl acetate/hexanes to obtain an off-white solid (3.23 g, 81%). LC-ES/MS m/z (79Br/81Br) 453.0/455.0 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+]([O-])=O)[CH:11]=2)[N:6]2[C:16]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:17][C:18]([CH3:21])=[C:19]([CH3:20])[C:5]=12.[Cl:28]CCC1C2C(=CC=CC=2C(F)(F)F)N2C(C3CCCCC3)=NC(C)=C(C)C=12>>[Cl:28][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]1[C:16]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17][C:18]([CH3:21])=[C:19]([CH3:20])[C:5]1=[C:4]2[CH2:3][CH2:2][Cl:1]
Reactant: Cc1nc(C2CCCCC2)n2c(c1C)c(CCCl)c1c(C(F)(F)F)cccc12
Reactant: Cc1nc(C2CCCCC2)n2c(c1C)c(CCCl)c1cc([N+](=O)[O-])ccc12
Product: Cc1nc(C2CCCCC2)n2c(c1C)c(CCCl)c1cc(Cl)ccc12

Procedure:
5-(2-chloroethyl)-1-cyclohexyl-3,4-dimethyl-7-nitropyrimido[1,6-a]indole and 5-(2-chloroethyl)-1-cyclohexyl-3,4-dimethyl-6-trifluoromethylpyrimido[1,6-a]indole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[O:8][CH2:9][O:10][C:3]=12.C([Li])CCC.C[O:17][B:18](OC)[O:19]C>C1COCC1>[F:1][C:2]1([B:18]([OH:19])[OH:17])[CH:7]=[CH:6][CH:5]=[C:4]2[O:8][CH2:9][O:10][CH:3]12
Reactant: Fc1cccc2c1OCO2
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)C1(F)C=CC=C2OCOC21
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 21.3 %

Procedure:
1-Fluoro-2,3-methylenedioxybenzene (5.0 g, 35.7 mmol) was dissolved in THF (70 mL) and the solution was cooled to −65° C. in a dry ice acetone bath. n-Butyl lithium (2.5 g, 15.7 mL, 39.3 mmol) was added to the solution via syringe with stiffing. The reaction was allowed to warm to −35° C. over 1 hour, then cooled to −65° C. and treated with trimethylborate (4.1 g, 39.3 mmol) via syringe. The reaction was allowed to warm slowly to room temperature, quenched with 1N HCl (50 mL), stirred for 15 minutes, and then extracted with ether. The organic phase was then extracted with 1N sodium hydroxide and this aqueous extract was then acidified with 1N hydrochloric acid. The acidic aqueous solution was then extracted with two portions of ether and these combined ether extracts were dried and concentrated to an oily solid that was triturated with methylene chloride. The resulting solid was collected by filtration, washed with methylene chloride, and dried to give 1-fluoro-2,3-methylenedioxyphenylboronic acid (1.4 g, 7.6 mmol) as a tan solid: 1H NMR (DMSO-d6): δ 8.05 (br s, 2H), 7.08 (dd, 1H, J=7.8, 5.1 Hz), 6.76 (d, 1H, J=7.8 Hz), 6.08 (s, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:9]=1[C:10](OC)=[O:11].O.[OH-].[Na+]>C(OCC)C.C(OCC)(=O)C>[Cl:7][C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1cc(Cl)cc(OC)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: COc1cc(Cl)cc(CO)c1Cl
Yield: 94.1 %

Procedure:
To a suspension of 3.62 grams (0.095 mole) of lithium aluminum hydride in 200 mL of diethyl ether was added dropwise at a rate to maintain a gentle reflux a solution of 17.26 grams (0.073 mole) of methyl 2,5-dichloro-3-methoxybenzoate in 70 mL of diethyl ether. Upon completion of addition, the reaction mixture was refluxed for an additional three hours after which it was cooled in an ice-water bath. Very carefully, 5.5 mL of water, 4.5 mL of a 20% aqueous solution of sodium hydroxide, and 12 mL of water were added sequentially to the vigorously stirred reaction mixture. The reaction mixture was filtered through Celite® filter aid, which removed the finely divided precipitate. The solvent was then evaporated from the filtrate under reduced pressure, leaving an oil as the residue. The oil was dissolved in ethyl acetate, and this solution was washed twice with water and once with a saturated aqueous solution of sodium chloride. After being dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, leaving 14.22 grams of 2,5-dichloro-3-methoxyphenylmethanol as a yellow oil. This oil solidified on standing, yielding solid 2,5-dichloro-3-methoxyphenylmethanol, m.p. 58°-64° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:25]=[CH:24][C:10]2[O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Cl)=[CH:14][C:13]=3[C:9]=2[CH:8]=1)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+]>CC(=O)CC>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:25]=[CH:24][C:10]3[O:11][C:12]4[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:14][C:13]=4[C:9]=3[CH:8]=2)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(CCCCl)c1ccc2oc3ccc(C(=O)CCCCl)cc3c2c1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(CCCN1CCCCC1)c1ccc2oc3ccc(C(=O)CCCN4CCCCC4)cc3c2c1

Procedure:
A mixture of 17.0 g (0.045 mole) of 2,8-bis(4-chlorobutyryl)dibenzofuran, 68.0 g (0.8 mole) of piperidine and 2.0 g of potassium iodide in 500 ml of butanone was heated at reflux for 72 hours then filtered. The filtrate was concentrated to one-half its original volume then diluted with 600 ml of water. The resulting semi-solid was purified by chromatography on neutral alumina using methylenechloride as the eluant. The solvent was removed from the fraction collected leaving a solid residue which was recrystallized from pentane to give the desired product. M.P. 70°-71° C., λmaxEtOH 251, E1cm1% 1520.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:19][CH3:20])[C:10]2[CH:11]=[C:12]([S:15]([NH2:18])(=[O:17])=[O:16])[S:13][CH:14]=2)=[CH:5][CH:4]=1.[NH4+].[OH-]>Br>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:19][CH3:20])[C:10]2[CH:11]=[C:12]([S:15]([NH2:18])(=[O:17])=[O:16])[S:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CNC(c1ccc(OC)cc1)c1csc(S(N)(=O)=O)c1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Product: CNC(c1ccc(O)cc1)c1csc(S(N)(=O)=O)c1

Procedure:
A solution of 1.0 g (0.0032 mol) product from Step B in 30 ml 48% aqueous hydrobromic acid was heated at 85° C. for 4.0 hours. The cooled reaction mixture was made alkaline with concentrated NH4OH solution and was extracted with ether. The organic extract was dried, the solvent evaporated and the resulting residue was purified by flash chromatography on silican gel eluting with 2l % methanol/chloroform to give pure product as a tan solid, m.p. 127°-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=O)=[CH:17]1.N1CCCCC1>C(O)C>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](/[CH:25]=[CH:14]/[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:15])=[CH:17]1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Yield: 65.9 %

Procedure:
3',4',5'-Trimethoxyacetophenone (42.0 g) and indole-3-carboxaldehyde (29.0 g) were dissolved in ethanol (200 ml), and piperidine (17.0 g) was added thereto, followed by heating under reflux for 48 hours. The reaction solution was ice-cooled, and the precipitated crystals were collected by filtration to give Compound 1 (44.4 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+:7]([CH2:9]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:8].[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>CO>[F:20][C:21]([F:31])([F:32])[O:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]2[O:28][CH:9]=[N:7][CH:8]=2)=[CH:25][CH:24]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: FC(F)(F)Oc1ccc(-c2cnco2)cc1
Yield: 82.9 %

Procedure:
To a round bottom flask was added K2CO3 (5.09 g, 36.8 mmol), 1-(isocyanomethylsulfonyl)-4-methylbenzene (3.95 g, 20.25 mmol), MeOH (30 mL) and 4-(trifluoromethoxy)benzaldehyde (2.63 mL, 18.41 mmol). The reaction was refluxed for 2 hrs. After this time, the reaction mixture was concentrated under reduced pressure. The remaining residue was dissolved in water (50 ml). The aqueous solution was extract with EtOAc (50 ml). The EtOAc layer was washed with saturated aqueous NaCl (30 ml), dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give the product, 5-(4-(trifluoromethoxy)phenyl)oxazole, (3.5 g, 15.27 mmol, 83% yield) as an off white solid. Anal. Calcd. for C10H6F3NO2 m/z 229.1, found: 230.1 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.94 (s, 1H), 7.70 (d, J=8.80 Hz, 2H), 7.37 (s, 1H), 7.29 (d, J=8.25 Hz, 2H).
Reaction SMILES: [C:1]1([C@@H:7]([C@H:9]2[O:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10]2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:22].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[Br:22][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:9]1[O:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10]1
Reactant: [Br-]
Reactant: O[C@@H](c1ccccc1)[C@@H]1CN(Cc2ccccc2)CCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: Br[C@H](c1ccccc1)[C@@H]1CN(Cc2ccccc2)CCO1
Temperature: 60 °C
Yield: 80.6 %

Procedure:
To a solution of 4a (4.71 g, 16.6 mmol) in anhydrous chloroform (200 ml) under nitrogen was added triphenylphosphine dibromide (14.04 g, 33.26 mmol). The reaction mixture was heated at 60° C. overnight. The mixture was allowed to cool to room temperature then washed with saturated aqueous sodium carbonate solution, dried over sodium sulphate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica (eluent: ethyl acetate/isohexane gradient 10/90 to 30/70 [v/v]) to give 5a as a white solid (4.63 g, 81%); MW 346.27; C18H20BrNO; 1H NMR (CDCl3): 7.14-7.39 (10H, m), 4.83 (1H, d, 7 Hz), 4.01 (1H, br, t, 8 Hz), 3.73 (1H, br, d, 11 Hz), 3.60-3.48 (2H, m), 3.39 (1H, d, 12 Hz), 3.20 (1H, d, 11 Hz), 2.50 (1H, d, 10 Hz), 2.07 (2H, t, 10 Hz); LCMS: (6 min method) m/z 346 [M]+ @ Rt 2.51 min.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Si:10]([O:27][CH2:28][C@H:29]1[O:33][C:32](=[O:34])[C@H:31]([C:35](O)([CH3:37])[CH3:36])[CH2:30]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[Si:10]([O:27][CH2:28][C@H:29]1[O:33][C:32](=[O:34])[C@H:31]([C:35]([F:7])([CH3:37])[CH3:36])[CH2:30]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)OC1=O
Solvent: ClCCl
Product: CC(C)(F)[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of diethylaminosulfur trifluoride (414 μL, 3.0 mmol) in DCM (10 mL) at −78° C. was added a solution of (3S,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(1-hydroxy-1-methyl-ethyl)tetrahydrofuran-2-one (compound 40e, 1.03 g, 2.5 mmol) in DCM (10 mL) dropwise. The resulting mixture was warmed up to room temperature and stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 0-20% EtOAc in petroleum ether) to afford 820 mg of (3R,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(1-fluoro-1-methyl-ethyl)tetrahydrofuran-2-one (compound 40f) as a viscous oil. MS obsd. (ESI+) [(M+H)+]: 415.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1)=[O:6].[H-].[Na+].[CH3:21]I>O1CCCC1>[CH3:21][N:4]([CH2:3][C:2]([F:1])([F:17])[F:18])[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1)=[O:6]
Reactant: CI
Reactant: COC(=O)c1ccc(C(=O)NCC(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)N(C)CC(F)(F)F)nc1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of methyl 6-[(2,2,2-trifluoroethyl)carbamoyl]nicotinate (3.0 g, 11.5 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (60% suspension in mineral oil) (1.4 g) at ambient temperature. The reaction mixture was stirred for 1 h and methyl iodide (1.5 mL) was added. The reaction mixture was stirred over night and then quenched with water (20 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 1.72 g (61%) of the title compound; 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (d, 1 H), 4.50 (q, 1 H), 4.23 (q, 1 H), 3.99 (s, 3 H), 3.24 (d, 3 H); MS (ESI) m/z 277[M+H+].