Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[CH2:14][CH2:13]2)[N:3]=1.[Cl:29]C1C=C2C(C=CC(C)=N2)=C(N2CCNCC2)C=1.[N+](C1C=CC(S(OCCC2C=CC=C([N+]([O-])=O)C=2)(=O)=O)=CC=1)([O-])=O>>[Cl:29][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[C:8]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[CH2:14][CH2:13]2)[CH:7]=1
Reactant: Cc1ccc2c(N3CCNCC3)cc(Cl)cc2n1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cccc2n1
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)OCCc2cccc([N+](=O)[O-])c2)cc1
Product: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cc(Cl)cc2n1
Yield: 92 %

Procedure:
The title compound was prepared in 92% yield using a similar procedure to description D5 starting from 7-chloro-2-methyl-5-(1-piperazinyl)quinoline (D16) and 2-(3-Nitrophenyl)ethyl 4-nitrobenzenesulfonate (D15).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:22][CH2:23][CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:22][CH2:23][CH3:24])[N:10]=2)=[CH:7][CH:8]=1
Reactant: CCCI
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(C)c21
Yield: 49.9 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.115 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.098 mL, 1.0 mmol) to give the title compound (0.070 g) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1.N1C=CC=CC=1>O>[C:20](/[CH:19]=[CH:1]/[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])([OH:22])=[O:21]
Reactant: O=C(O)CC(=O)O
Reactant: COC(=O)c1cc(C=O)cc(-n2cccc2)c1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: COC(=O)c1cc(/C=C/C(=O)O)cc(-n2cccc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A mixture of methyl 3-formyl-5-(pyrrol-1-yl)benzoate (3.0 g), malonic acid (2.73 g), piperidine (0.3 ml) and pyridine (30 ml) was stirred for 1 hour at 80° C. After being cooled to room temperature, the reaction mixture was poured into water. The solution was acidified to pH 1 and extracted with ethyl acetate. The extract was washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with the mixture of chloroform and methanol (15:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-((E)-2-carboxyethenyl)-5-(pyrrol-1-yl)benzoate (2.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]=2[CH:22]=O)=[C:4]([F:24])[CH:3]=1.[CH3:25][NH2:26]>C(O)C>[F-:24].[C:17]([O:16][C:15]([NH:14][C:10]1[N:11]=[CH:12][CH:13]=[C:8]2[C:9]=1[CH:22]=[N+:26]([CH3:25])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]2=1)=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1nccc(-c2ccc(Cl)cc2F)c1C=O
Reactant: CN
Solvent: CCO
Product: C[n+]1cc2c(NC(=O)OC(C)(C)C)nccc2c2ccc(Cl)cc21
Product: [F-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
To a stirred solution of tert-butyl (4-(4-chloro-2-fluorophenyl)-3-formylpyridin-2-yl)carbamate (700 mg, 1.996 mmol) in ethanol (10 mL) at 0° C. was added methylamine (8M in EtOH) (620 mg, 2.49 mL, 19.96 mmol) and the reaction was stirred at rt for 5 h. After the consumption of starting material, solvent was removed under reduced pressure. The residue was washed with hexane (50 mL) and the solid so obtained was dried under vacuum to yield the fluoride salt of 4-((tert-butoxycarbonyl)amino)-8-chloro-6-methylbenzo[c][2,7]naphthyridin-6-ium fluoride (900 mg, 1.69 mmol, 84% yield) as a yellow solid. LC/MS (ESI) m/e 344.2 [(M)+, calcd for C18H19ClN3O2 344.1]; LC/MS retention time (method C): tR=1.90 min.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH:34]([CH3:36])[CH3:35])[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:38].[Na]>O1CCOCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH:34]([CH3:36])[CH3:35])[C:27]([O-:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:38]
Reactant: CCOC(=O)C(=NOC(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)ON=C(C(=O)[O-])c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A mixture of 27.7 g of the product of Step D, 150 ml of dioxane and 65 ml of 2 N sodium hydroxide was refluxed for 2 hours and the mixture was cooled for crystallization of a sodium salt. The mixture was vacuum filtered and the recovered product was rinsed with a 1--1 ether-dioxane mixture and dried to obtain 16.85 g of raw sodium 2-(2-tritylamino-4-thiazolyl)-2-(1-methylethoxyimino)-acetate.
Reaction SMILES: [Cl-:1].Br[C:3]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[S:5][CH:4]=1>CN(C)C=O.[Cu]>[Cl:1][C:3]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[S:5][CH:4]=1
Reactant: CN1CCc2c(Br)csc2C(c2ccccc2)C1
Reactant: [Cl-]
Agent: [Cu]
Solvent: CN(C)C=O
Product: CN1CCc2c(Cl)csc2C(c2ccccc2)C1

Procedure:
Anhydrous copper I chloride (0.68 g) was added to a stirred solution of 3-bromo-6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (1.0 g) in dry dimethylformamide under nitrogen. The mixture was heated to 120° for 5 hours, evaporated, water added and extracted with dichloromethane. The extracts were dried, filtered and evaporated and the residue chromatographed on silica, eluting with 1% methanol in dichloromethane, to give a crude product which contained 10% of the starting bromo- compound. Further purification using preparative reverse phase high pressure liquid chromatographed gave the pure title product, m.p. 67° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:13]=[C:14]([C:31](=[O:33])[CH3:32])[CH:15]=[C:16]([N:20]2[CH2:24][C@@H:23]([O:25][CH2:26][O:27][CH3:28])[C@H:22]([O:29][CH3:30])[CH2:21]2)[C:17]=1[O:18][CH3:19])([CH3:11])([CH3:10])[CH3:9].[Br:34]N1C(=O)CCC1=O>O1CCCC1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Br:34][CH2:32][C:31]([C:14]1[CH:15]=[C:16]([N:20]2[CH2:24][C@@H:23]([O:25][CH2:26][O:27][CH3:28])[C@H:22]([O:29][CH3:30])[CH2:21]2)[C:17]([O:18][CH3:19])=[C:12]([C:8]([CH3:11])([CH3:9])[CH3:10])[CH:13]=1)=[O:33]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCO[C@@H]1CN(c2cc(C(C)=O)cc(C(C)(C)C)c2OC)C[C@H]1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCO[C@@H]1CN(c2cc(C(=O)CBr)cc(C(C)(C)C)c2OC)C[C@H]1OC
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
Triethylamine (0.46 ml, 3.3 mmol) and tert-butyl dimethylsilyltrifluoromethanesulfonate (0.37 ml, 1.6 mmol) were added dropwise in that order to a solution of 1-{3-(tert-butyl)-4-methoxy-5-[(3R,4R)-3-methoxy-4-(methoxymethoxy)tetrahydro-1H-1-pyrrolyl]phenyl}-1-ethanone (397 mg, 1.09 mmol) in tetrahydrofuran (4 ml) while cooling on ice, and the mixture was stirred at the same temperature for 20 minutes. N-Bromosuccinimide (290 mg, 1.63 mmol) was then added and stirring was continued at the same temperature for 15 minutes. After completion of the reaction, the mixture was diluted with saturated aqueous sodium hydrogencarbonate and ethyl acetate and the organic layer was separated. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (434 mg, 90%) as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:10]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N[C@H](C(O)=O)C[SeH].[Li]CCCC.[CH3:49][S:50]C.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:10]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:9]1[S:50][CH3:49])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(Cc4ccccc4)cn(C(=O)OC(C)(C)C)c23)CC1
Reactant: CSC
Agent: N[C@@H](C[SeH])C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1c(Cc2ccccc2)c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c2n1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester (186 mg, 0.38 mmol) in THF (5 ml) was cooled to −78° C., and Sec-BuLi (1.4 ml, 1.4 M in cyclohexane) was added. After stirring at −78° C. for 20 minutes, 1 ml of dimethyl sulfide was added and the reaction was allowed to warm up to room temperature for 30 minutes. H2O was slowly added, followed by EtOAC. The organic layer was separated and washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo to give crude 3-benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-methylsulfanyl-indole-1-carboxylic acid tert-butyl ester as an oil (277 mg), which was used without further purification.
Reaction SMILES: C([Al](CC(C)C)CC(C)C)C(C)C.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:32])(=[O:31])=O)=[CH:25][CH:24]=1.[NH:33]1[C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([C:42](OC)=[O:43])[C:36]=2[CH:35]=[CH:34]1.Cl>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:42]([C:37]2[C:36]3[CH:35]=[CH:34][NH:33][C:41]=3[CH:40]=[CH:39][CH:38]=2)=[O:43])(=[O:31])=[O:32])=[CH:27][CH:28]=1
Reactant: Nc1ccccc1O
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)Oc2ccccc2NC(=O)c2cccc3[nH]ccc23)cc1
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
140 ml of triisobutylaluminum in solution in toluene at 1.1 mole/l were added to a solution of 18 g of 2-aminophenol-4-methylbenzenesulfonate in 300 ml of chloroform, and after stirring for 15 minutes, a solution of 12.15 g of methyl indol-4-carboxylate in 120 ml of chloroform was added. The mixture was refluxed for 20 hours and was then cooled to 0° to -10° C. and 500 ml of an N aqueous solution of hydrochloric acid were added with stirring over 15 minutes. The chloroform phase was then purified by chromatography over silica (eluent:methylene chloride) to obtain 25 g of N-[2-[(4-methylphenyl)sulfonyloxy]phenyl]-1H-indol-4-carboxamide melting at 135° C.
Reaction SMILES: C([Li])(C)(C)C.[Cl:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][CH:8]=1.CN(C)[CH:17]=[O:18].C(O)(=O)C>C1COCC1.CCOCC>[Cl:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[C:10]([CH:17]=[O:18])=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: COc1cccc(Cl)n1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1nc(Cl)ccc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of tert-butyllithium (1.7M in pentane, 48.5 mL, 83.0 mmol) in 150 mL of THF at -78° C. was added 6-chloro-2-methoxypyridine (8.94 mL, 75.0 mmol) over 5 min. The reaction mixture was stirred at -78° C. for 1 h, then dimethylformamide (7.55 mL, 97 mmol) was added and the mixture was stirred at this temperature for 1.5 h. After the addition of glacial acetic acid (8.6 mL, 150 mmol), the reaction mixture was allowed to warm to room temperature over a 30-min period, then diluted with ether (200 mL). The organic phase was washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), and was dried over MgSO4. Concentration afforded the crude product as a light yellow solid which was recrystallized from hexanes to give 9.6 g (75%) of 6-chloro-2-methoxy-3-pyridinecarboxaldehyde as a white solid: mp 80°-81° C. (mp 62°-64° C.) (See Dainter, R. S.; Suschitzky, H.; Wakefield, B. J. Tetrahedron Lett. 1984, 25, 5693.) 1H NMR (300 MHz, CDCl3) δ10.31 (s, 1H), 8.07 (d, 1H, J=9 Hz), 7.03 (d, 1H, J=9 Hz), 4.09 (s, 3H); IR (nujol) 1685, 1580, 1565, 1270, 1140, 1090, 1005, 905, 820, 755 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:39]>>[ClH:39].[NH2:23][C@@H:20]1[CH2:21][CH2:22][N:18]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:17])[C@@H:13]([O:15][CH3:16])[CH3:14])[C:4]=23)[CH2:19]1
Reactant: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
tert-Butyl (R)-1-(5-bromo-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.41 g, 0.85 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-50% CH3CN/water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (S)-N-(4-((R)-3-aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide hydrochloride (0.35 g, 90% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.17 (s, 1H), 7.39 (s, 1H), 4.03-3.96 (m, 3H), 3.95-3.79 (m, 1H), 3.73-3.69 (m, 1H), 3.60-3.53 (m, 1H), 3.36 (s, 3H), 2.40-2.35 (m, 1H), 2.07-2.02 (m, 1H), 1.31-1.29 (d, 3H). LCMS (APCI+) m/z 382, 384 (M+H)+.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([F:37])[CH:28]=2)=[N:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=[N:17][CH:18]=1>CCOCC>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C@:19]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([F:37])[CH:28]=2)[CH2:2][C:1]#[N:3])=[N:17][CH:18]=1
Reactant: CC(C)(C)[S@](=O)N=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: CC#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)[S@](=O)N[C@](CC#N)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
At −78° C. in a 3 neck flask under argon atmosphere, anhydrous acetonitrile (0.150 g, 3.68 mmol) was added to dry ether (2 mL) followed by dropwise addition of LDA (1.84 mL, 3.68 mmol, 2.0M solution in cyclohexanes). The solution was stirred at −78° C. for 20 min. In a separate flask at 0° C. under argon, BF3Et2O (0.260 g, 0.19 mmol) was added to a solution of (S)-N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-2-methylpropane-2-sulfinamide (0.750 g, 1.84 mmol) in dry ether (10 mL). The pre-complexed sulfinylimine solution was transferred to the anion solution via syringe dropwise at −78° C. After 30 min the orange solution was quenched by the addition of 1.0M HCl (ca. 10 mL) and the reaction mixture transferred to a separation funnel and extracted with EtOAc (3×20 mL). The combined organic portions were dried over Na2SO4, decanted, concentrated and the diastereomers purified by silica gel ISCO chromatography on 120 g column, 0-90% EtOAc/hexanes. (S)-N-((R)-1-(5-chloropyridin-2-yl)-2-cyano-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide eluted next and was isolated as the major product (0.23 mg, 28% yield). Rf0.8 (Hexane:EtOAc 1:1) LCMS: 1.84 min [M+1] 448.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.58 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 99%; NMR: 400 MHz 1H (CDCl3) 8.62 ppm, d, J=2.6 Hz; 7.73 ppm, dd, J=2.6 and J=8.8 Hz; 7.38, 1H, s; 7.32 ppm, 1H, d, J=7.9 Hz; 7.20 ppm, 2H, d, J=8.8 Hz; 5.87 ppm, 1H, s; 3.76 ppm, 1H, d, J=16.7 Hz; 3.67 ppm, 1H, d, J=16.7 Hz; 1.36 ppm, 3H, s. (S)-N-((S)-1-(5-chloropyridin-2-yl)-2-cyano-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide eluted last and was isolated as the a pale yellow oil (0.088 mg, 11% yield). Rf0.7 (Hexane:EtOAc 1:1) LCMS: 1.90 min [M+1] 448.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.65 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 99%.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[NH2:10][C:11](N)=[O:12].O>CN1CCCC1=O>[OH:3][C:2]1[N:4]=[C:5]([OH:6])[C:7]([C:11]([NH2:10])=[O:12])=[C:8]([OH:9])[N:1]=1
Reactant: NC(N)=O
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1c(O)nc(O)nc1O
Yield: 96.5 %

Procedure:
A mixture of 128 grams of barbituric acid and 120 grams of urea in 200 ml of 1-methyl-2-pyrrolidone was heated at 145° for 15 minutes. Hot water was then added to the reaction mixture; a white solid precipitated and was collected by filtration. The precipitate was washed with hot dimethylformamide and dried to give 165 grams of 2,4,6-trihydroxy-5-pyrimidinecarboxamide; mp, >270°. The mass spectrum of the product was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH:22]([OH:24])[CH3:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C.Cl>CS(C)=O>[C:22]([C:19]1[O:18][C:17]([S:14]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:4]2)(=[O:15])=[O:16])=[CH:21][CH:20]=1)(=[O:24])[CH3:23]
Reactant: CC(O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Temperature: 60 °C
Reaction time: 72 h
Yield: 77.2 %

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[5-(1-hydroxyethyl)-2-furyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (234 mg) in dimethyl sulfoxide (3 mL) were added triethylamine (3 mL) and sulfur trioxide pyridine complex (449 mg), and the mixture was stirred at 60° C. for 3 days. 1 mol/L Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:2) to give the title compound as a pale-yellow oil (yield 180 mg, 77%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[O:19]1[CH2:23][CH2:22][C:21](=O)[CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[O:19]1[CH2:23][CH2:22][CH:21]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:4][CH2:3]2)[CH2:20]1
Reactant: N[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Reactant: O=C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](NC2CCOC2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of benzyl trans-4-aminocyclohexylcarbamate (396 mg, 1.595 mmol) in CH2Cl2 (9 ml) was added dihydrofuran-3(2H)-one (151 mg, 1.754 mmol) followed by acetic acid (150 μL, 2.62 mmol) and sodium triacetoxyborohydride (439 mg, 2.073 mmol) under Argon. Stirred at 25° C. for 16 h, then concentrated in vacuo. The resulting residue was partitioned between EtOAc and 1M NaOH. The organics were combined, then washed with 1M NaOH (×2), water (×2), saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure to give racemic benzyl trans-4-(tetrahydrofuran-3-yl-amino)cyclohexylcarbamate (495 mg). The resulting residue was used in next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19][C:20]1[N:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Br:19][C:20]1[N:25]=[CH:24][C:23]([NH:26][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:22][CH:21]=1
Reactant: Nc1ccc(Br)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3.0 g, 11.7 mmol), 6-bromo-pyridin-3-ylamine (2.0 g, 11.7 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (2.4 g, 17.5 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.4 g, 17.5 mmol) in anhydrous dichloromethane (100 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a solid. Recrystallization of the crude solid from ethyl acetate/hexane/methanol gave 4.04 g of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide. The mother liquor was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to give an additional 200 mg of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide (4.24 g in total, 88%) as a light brown solid. LCMS calcd for C16H9BrF3N3O2 (m/e) 412, obsd 413 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:13]O.S(=O)(=O)(O)O>O>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1ccc(O)c(F)c1

Procedure:
A mixture of 2.0 g of 3-fluoro-4-hydroxybenzeneacetic acid, 10 ml of methyl alcohol and 1 ml of concentrated sulfuric acid is heated at reflux temperature for 23.5 hours. The cooled solution is diluted with water and extracted with methylene chloride. The organic layer is washed with water, saturated sodium bicarbonate, water and saturated sodium chloride; dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:25% ethyl acetate/hexane) to give 1.9 g of the desired product.