Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]2[O:18][C:17](=O)[CH:16]([CH2:20][CH2:21][CH3:22])[CH2:15][CH2:14]2)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:20][CH2:21][CH3:22])[CH2:17][O:18]2)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: CCCC1CCC(c2cc(F)c(C(F)(F)F)c(Cl)c2)OC1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCC[C@H]1CC[C@H](c2cc(F)c(C(F)(F)F)c(Cl)c2)OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A mixture of 7.7 g (22.7 mmol) of the 6-(3-chloro-5-fluoro-4-trifluoromethylphenyl)-3-propyltetrahydro-2-pyrone, 13.2 g (113.6 mmol) of triethylsilane, and 50 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. After termination of the reaction, 30 ml of water was added to the reaction solution and extracted with 50 ml of toluene. The organic layer thus obtained was washed with a diluted aqueous sodium bicarbonate solution thrice and water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: heptane/toluene=9/1) to obtain 6.6 g of a crude trans-2-(3-chloro-5-fluoro-4-trifluoromethylphenyl)-5-propyltetrahydropyran.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:3]=1.O.C([OH:19])C.[OH-].[Na+].OO>C1COCC1>[OH:19][CH:3]1[CH:2]([CH3:1])[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]1
Reactant: CCO
Reactant: CC1=CCC(NC(=O)OC(C)(C)C)CC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCC(NC(=O)OC(C)(C)C)CC1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a stirring solution of tert-butyl 4-methylcyclohex-3-enylcarbamate (1.5844 g, 7.50 mmol) in THF (94 mL) at 0° C. was added 1M borane THF complex (33.7 mL, 33.7 mmol). The solution was stirred at 0° C. for 1 h and then at room temperature for 2 h. The reaction was quenched very slowly with water (40.5 mL, 2249 mmol), diluted with ethanol (39.8 mL, 682 mmol) and basified with aqueous sodium hydroxide solution (5 N, 37.5 mL, 187 mmol). To the stirring biphasic mixture was slowly added hydrogen peroxide (38.3 mL, 375 mmol) and the resulting mixture was heated to 45° C. for 20 h. The crude reaction was quenched with saturated aqueous sodium sulfite solution (70 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate in hexanes). The product fractions were combined and concentrated to afford a mixture of four isomers of tert-butyl 3-hydroxy-4-methylcyclohexylcarbamate (trans relationship between 3-hydroxy and 4-methyl moieties) (0.9608 g, 4.19 mmol, 55.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.60-6.85 (m, 1H), 4.29-4.58 (m, 1H), 3.35-3.80 (m, 1H), 2.81-3.28 (m, 1H), 1.20-1.96 (m, 14H), 0.79-1.14 (m, 5H; MS (ESI) m/z 230.5 [M+1]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12](I)([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:12]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:14])[CH3:13]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(=NOC(C)C)C(C)=O
Yield: 93.3 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 30 g.), iso-propyl iodide (32.5 g.), potassium carbonate (39.5 g.) and acetone (150 ml.) were treated in a similar manner to that of Example D-(1) to give ethyl 2-iso-propoxyimino-3-oxobutyrate (syn isomer, 35.4 g.), oil.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[CH:11]=[C:12]([CH3:25])[N:13]=[C:14]([C:19](N(OC)C)=[O:20])[C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][Mg+].[Br-]>C1COCC1>[C:19]([C:14]1[N:13]=[C:12]([CH3:25])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:18])[CH:17]=[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[N:9]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:20])[CH3:32]
Reactant: CON(C)C(=O)c1nc(C)cc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1nc(C)cc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.7 %

Procedure:
2-Anilino-N-methoxy-N,7-dimethyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxamide (60 mg, 0.14 mmol) was suspended in THF (5 mL). To this stirring suspension at 0° C. was added MeMgBr (0.19 mL, 0.56 mmol, 3M in Et2O). The reaction was stirred at room temperature for 6 h and quenched with saturated aqueous NH4Cl, diluted with EtOAc, and washed with brine. The organic layer was collected, dried over Na2SO4, and concentrated in vacuo. The residue was purified by Biotage silica gel chromatography using EtOAc as the eluent to provide 5-acetyl-2-anilino-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one as a light yellow solid (34 mg, 66%): LCMS RT: 2.20 min, MH+: 370.4.
Reaction SMILES: [O:1]=[C:2]([O-:13])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Ca+2:14].[O:15]=[C:16]([O-:27])[C@@H:17]([C@H:19]([C@@H:21]([C@@H:23]([CH2:25][OH:26])[OH:24])[OH:22])[OH:20])[OH:18].[B:28](O)(O)[OH:29]>O>[B:28]1([OH:29])[O:8][CH:7]([CH:5]([OH:6])[CH:3]([OH:4])[C:2]([O-:13])=[O:1])[CH:9]([CH2:11][OH:12])[O:10]1.[B:28]1([OH:29])[O:22][CH:21]([CH:19]([OH:20])[CH:17]([OH:18])[C:16]([O-:27])=[O:15])[CH:23]([CH2:25][OH:26])[O:24]1.[Ca+2:14]
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: OB(O)O
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])C(O)C(O)C1OB(O)OC1CO
Temperature: 50 °C

Procedure:
860.5 grams of calcium gluconate monohydydrate and 244 grams of technical grade boric acid were added to 1100 grams of water at room temperature. The resultant mixture was stirred and warmed to a temperature of about 50° C. until a dark brown solution was obtained. The solution was allowed to cool to room temperature. The solution can be used as is or the water can be evaporated to provide the calcium borogluconate as a brownish solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:22])[CH2:9][NH:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:13])[CH:5]=[CH:6][CH:7]=1.[O:23](C(OC(C)(C)C)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=O.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C1COCC1.CN(C1C=CN=CC=1)C>[C:27]([O:26][C:24](=[O:23])[N:10]([CH2:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:22])[CH2:11][C:12](=[O:13])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1ccccc1NC(=O)CNCC(O)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1NC(=O)CN(CC(O)c1cccc(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.2 %

Procedure:
To 2-[2-(3-bromo-phenyl)-2-hydroxy-ethylamino]-N-o-tolyl-acetamide (4 g) in THF (100 mL) was added DMAP (134 mg) and (BOC)2O (2.89 g) in THF (100 mL) at 0° C. The mixture was stirred at room temperature for 2 h. An aqueous solution of NaHCO3 and ethyl acetate was added, the phases were separated and the inorganic one was extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2, n-heptane/ethyl acetate 1:1,) yielded [2-(3-bromo-phenyl)-2-hydroxy-ethyl]-(o-tolylcarbamoyl-methyl)-carbamic acid tert-butyl ester (0.88 g, 88%) as a colorless oil, MS: 463.1 (M+H, 1Br)+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]([CH:7]([C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[CH3:8])CO.[CH:14]([Cl:17])(Cl)[Cl:15]>C1S(=O)(=O)CCC1.S(Cl)(Cl)=O>[ClH:15].[ClH:1].[NH2:3][CH:4]([CH:7]([C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[CH3:8])[CH2:14][Cl:17]
Reactant: CC(c1c[nH]cn1)C(N)CO
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: CC(c1c[nH]cn1)C(N)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3 g (13.2 mmol) 2-amino-3-(1H-imidazol-4-yl)butanol dihydrochloride are solved in a mixture of 25 ml tetramethylenesulfone and 10 ml thionyl chloride and stirred 12 hours at room temperature. Dropwise addition of 200 ml chloroform affords 2-amino-1-chloro-3-(1H-imidazol-4-yl)butane dihydrochloride. Yield: 2.87 g (88.2%) of a hygroscopic precipitate.
Reaction SMILES: [O:1]=[CH:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.C[Si](C)(C)[C:23]([F:26])([F:25])[F:24].C1COCC1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:24][C:23]([F:26])([F:25])[CH:2]([OH:1])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CCOC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(OCC(O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
A mixture of benzyl 4-(2-oxoethoxy)piperidine-1-carboxylate (2.00 g), trimethyl(trifluoromethyl)silane (1.23 g), tetrabutylammonium fluoride (1 M THF solution, 1 drop) and THF (20 mL) was stirred at 0° C. for 1 hr, and then at room temperature for 3 days. Water was added thereto, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in THF (20 mL). Tetrabutylammonium fluoride (1 M THF solution, 8.65 mL) was added thereto at 0° C., and the obtained mixture was stirred at 0° C. for 2 hr. 1M Hydrochloric acid was added, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.60 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Cl:12])[CH:6]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[C:7]([Cl:12])[CH:6]=1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)OC)cc1Cl
Yield: 86.2 %

Procedure:
A mixture of 45 g of product from Example 62, 62.2 g Of 1-bromotetradecane, 58.9 g of powdered potassium carbonate and 500 ml of acetone is heated at reflux temperature for 51 hours. The cooled solution is filtered and concentrated in vacuo. The residue is dissolved in methylene chloride, washed with 2% sodium bicarbonate and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:5% ethyl acetate) and recrystallized from hexane to give 76.8 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])[CH2:20][CH2:19]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[O:17][CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N+:34]([O-:36])=[O:35])[CH2:22][CH2:23]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
The procedure of Example 1 (a) was repeated except for using di(4-fluorophenyl)methyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-di(4-fluorophenyl)methoxy-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[N:12]1[CH:22]=[C:15]2[CH:16]=[N+:17]([O-])[CH:18]=[C:19]([F:20])[C:14]2=[N:13]1.P(Cl)(Cl)([Cl:25])=O>ClCCCl>[Cl:25][C:16]1[C:15]2=[CH:22][N:12]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=3[Cl:11])[N:13]=[C:14]2[C:19]([F:20])=[CH:18][N:17]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(-n2cc3c[n+]([O-])cc(F)c3n2)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=[N+]([O-])c1cc(Cl)c(-n2cc3c(Cl)ncc(F)c3n2)c(Cl)c1
Temperature: 70 °C
Yield: 40.2 %

Procedure:
2-(2,6-Dichloro-4-nitrophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine 5-oxide (4.20 g, 12.24 mmol) was suspended in DCE (60 mL), under an atmosphere of nitrogen and phosphorus oxychloride (3.61 mL, 39.2 mmol) was added. The reaction mixture was heated at 70° C. for 95 minutes. The resultant mixture was cooled to room temperature and was carefully quenched by the addition of 10% aqueous sodium carbonate solution. The layers were separated and the aqueous layer was extracted with DCM (×4). The combined organic layers were filtered to remove insoluble solids, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in cyclohexane) to afford the title compound as a pale yellow solid (1.78 g, 40% yield). 1H NMR (300 MHz, CDCl3): δ 8.43 (s, 2H), 8.37 (d, J=2.2 Hz, 1H), 8.03 (d, J=3.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17](=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12](/[CH:19]=[CH:18]/[C:17](=[O:20])[CH3:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(C)=O
Reactant: Brc1ccc(OCc2ccccc2)nc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)/C=C/c1ccc(OCc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 38.2 %

Procedure:
To a solution of 2-(benzyloxy)-5-bromopyridine (600 mg) in DMF (12 mL) were added 3-buten-2-one (400 mg), tris(dibenzylidene acetone) dipalladium(0) (74 mg), triethylamine (460 mg), and tris(o-tolyl)phosphine (70 mg) at room temperature under nitrogen flow, and the mixture was stirred at 100° C. for 24 hours. The reaction liquid was allowed to cool, and insolubles were filtered through Celite. Water was added to the filtrate, followed by three times extractions with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1-3/2) to obtain (3E)-4-[6-(benzyloxy)pyridin-3-yl]but-3-en-2-one (220 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[O:34]1[CH2:38][CH2:37][O:36][CH:35]1[C:39]1[S:40][CH:41]=[C:42]([Sn](C)(C)C)[N:43]=1.N#N>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:34]1[CH2:38][CH2:37][O:36][CH:35]1[C:39]1[S:40][CH:41]=[C:42]([C:2]2[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]3[C:10]([C:11](=[O:31])[C:12]([N:14]4[CH2:19][CH2:18][N:17]([C:20]5[N:24]([C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[N:23]=[N:22][N:21]=5)[CH2:16][CH2:15]4)=[O:13])=[CH:9][NH:8][C:7]=23)[N:43]=1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Reactant: C[Sn](C)(C)c1csc(C2OCCO2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1COCCO1
Product: COc1cnc(-c2csc(C3OCCO3)n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 100 °C

Procedure:
To a sealable 75 mL flask containing 1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.3 g, 0.643 mmol) was added a solution of 2-(1,3-dioxolan-2-yl)-4-(trimethylstannyl)thiazole (0.210 g, 0.655 mmol) in 1,4-Dioxane (10 ml). The mixture was flushed with N2 and Pd(PPh3)4 (0.149 g, 0.129 mmol) was added. The mixture was again flushed with N2, and the flask was sealed and heated in an oil bath to 100° C. After 20 h of heating, the mixture was cooled to rt. The mixture was transferred to a rb flask using MeOH as the transfer solvent. The solvent was removed under reduced pressure. The residue was re-dissolved in DMF, and was passed through a pad of celite to remove any remaining solids. The DMF solution was purified by prep HPLC. After the prep HPLC, a mostly-pure sample was collected as an off-white solid. A small portion of this material was removed and re-purified by flash chromatography (0-5% MeOH in dichloromethane gradient) [20 mg after the purification]. The remainder of the product was carried forward to the next step with no additional purification (0.305 g). LCMS: m/e 588.1 (M+H)+, ret time 1.30 min (method 3). 1H NMR (500 MHz, DMSO-D6) δ ppm 12.20 (s, 1H) 8.38 (s, 1H) 8.22 (s, 1H) 8.11 (s, 1H) 7.68-7.72 (m, 2H) 7.57-7.66 (m, 3H) 6.29 (s, 1H) 4.16-4.20 (m, 2H) 4.07-4.10 (m, 2H) 3.99 (s, 3H) 3.67-3.71 (m, 2H) 3.41-3.45 (m, 2H) 3.30-3.32 (m, 2H) 3.15-3.19 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)(O)[O-].[Na+].CI>CN(C)C=O>[CH3:22][O:20][C:19](=[O:21])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a solution of t-butyloxycarbonyl-O-benzyl-D-serine (25.0 g, 84.7 mmol) stirring in dimethylformamide (500 mL) at room temperature was added sodium bicarbonate (14.2 g, 169 mmol) followed by methyl iodide (26.4 mL, 424 mmol). After 18 h, the reaction mixture was concentrated to approximately 100 mL. Ethyl acetate was added and the mixture washed with aqueous sodium bicarbonate and brine. The organic extract was dried and concentrated to give the desired compound (25 g, 96%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) d 1.45 (s, 9H), 3.70 (m, 1H), 3.75 (s, 3H), 3.85 (m, 1H), 4.50 (m, 3H), 7.30 (m, 5H); MS (FD) m/e 310; Anal. calce'd for C16H23NO5: C, 62.12; H, 7.49; N, 4.53. Found: C, 62.31; H, 7.49; N, 4.43.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][NH:30][N:29]=1)[CH3:26].O>CN(C)C=O>[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][N:30]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:16][C:17]=3[CH3:18])=[CH:7][CH:6]=2)[N:29]=1)[CH3:26]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)Cc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (551 mg), ethyl 3-ethoxy-1H-pyrazol-4-ylacetate (347 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-ylacetate (608 mg, yield: 73%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:16]([C:28]1[O:32][CH:31]=[N:30][CH:29]=1)=[CH:15]2.[Cl:33]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:33][C:31]1[O:32][C:28]([C:16]2[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)=[CH:29][N:30]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnco2)cc2cc(F)ccc21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2cc(F)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
LiHMDS (1.06 M in THF, 3.44 mL, 3.43 mmol) was added to a solution of tert-butyl 5-fluoro-2-(oxazol-5-yl)-1H-indole-1-carboxylate 49 (0.865 g, 2.86 mmol) in THF (20 mL) at −78° C., and the mixture was stirred at −78° C. for 1 h. A solution of hexachloroethane (1.01 g, 4.29 mmol) in THF (5 mL) was added at −78° C., and the mixture was stirred at −78° C. for 2 h and allowed to warm to room temperature and stirred for 14 h. The reaction was quenched by adding EtOAC: H2O (50 mL:15 mL), and then extracted with Ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. The product was purified by column chromatography (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-chlorooxazol-5-yl)-5-fluoro-1H-indole-1-carboxylate 50 (0.74 g, 77% yield) as white solid. MS (ES) m/z 337 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:29]=1.CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C@@:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:28])[C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:29]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(CCCNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Solvent: CC(C)O
Solvent: CCCCCC
Product: O=C1Nc2ccc(Cl)cc2[C@](CCCNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1

Procedure:
N-{3-[6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]propyl}-4-fluorobenzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:2-propanol=3:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.