Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].B(F)(F)F.CCOCC.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:34])[C:5]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=1)([CH3:22])[CH2:6][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccc(C(F)(F)F)cc1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4-Benzyloxyphenyl)-3-hydroxy-2-(4-trifluoromethylphenoxy)-2-methylpropionic acid ethyl ester (9.5 mmol) in anhydrous CH2Cl2 (30 mL) was cooled to 0° C. and treated with BF3-Et2O (1.16 mL, 9.5 mmol) and triethylsilane (1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and gradually warmed to ambient temperature. Saturated aqueous Na2CO3 (15 mL) was added and the mixture was stirred vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 3-(4-benzyloxyphenyl)-2-(4-trifluoromethylphenoxy)-2-methylpropionic acid ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[C:18]3Cl)([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1.[CH:26](/B(O)O)=[CH:27]\[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[C:18]3/[CH:26]=[CH:27]\[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc2nccc(Cl)c2c1)c1cscn1
Reactant: OB(O)/C=C/c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1ccc2nccc(/C=C\c3ccccc3)c2c1)c1cscn1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A mixture of (4-chlorophenyl)(4-chloroquinolin-6-yl)(thiazol-4-yl)methanol (65 mg, 0.168 mmol), (E)-styrylboronic acid (39.74 mg, 0.269 mmol), Pd(OAc)2 (3.77 mg, 0.0168 mmol), SPhos (13.8 mg, 0.0336 mmol), and K3PO4.H2O (71.25 mg, 0.336 mmol) in anhydrous THF (1.5 mL) was stirred at 30° C. overnight. The reaction was diluted with EtOAc and water. The organics were concentrated and purified by REDSEP GOLD silica column (40% EtOAc/heptanes) to yield (Z)-(4-chlorophenyl)(4-styrylquinolin-6-yl)(thiazol-4-yl)methanol
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[K+]>C1COCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C=O)cc2)cc1
Yield: 95.2 %

Procedure:
4-Chlorobenzaldehyde (141 mg, 1.00 mmol) reacted with 4-methoxyphenylboronic acid (200 mg, 1.32 mmol) using 1/2 mol % of Pd(OAc)2/Ph5FcP(t-Bu)2 and KF (180 mg, 3.10 mmol) in THF (2 ml) at 50° C. to give the title compound (202 mg, 94%) as a solid: 1H-NMR (400 MHz, CDCl3): δ. 13C{1H}-NMR (100 MHz, CDCl3): δ 191.90, 160.78, 146.77, 134.63, 132.03, 130.31, 128.48, 127.04, 114.45, 55.38.: GC/MS (EI): m/z 212 (M+).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH:20]=[C:19]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:18]=[N:17]1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH2:13][C:14]#[N:15])([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC=C1CC(OCc2ccccc2)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(OCc5ccccc5)C4)c3)ncnc21
Temperature: 50 °C

Procedure:
To a mixture of [3-(benzyloxy)cyclobutylidene]acetonitrile (0.1 g, 0.0005 mol) and 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.1 g, 0.0003 mol) in acetonitrile (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL, 0.0003 mol) under nitrogen. The mixture was heated at 50° C. overnight, then concentrated under reduced pressure. The residue was purified with combiflash (silica gel, 0-55% EtOAc/Hex) to give the desired product as cis- and trans-isomer mixture. LCMS calculated for C28H35N6O2Si(M+H)+: 515.3; Found: 515.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[S:19])[NH2:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CCO>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[S:19][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C(N)=S)ccc21
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)n1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-thiocarbamoyl-indole-1-carboxylic acid tert-butyl ester (13.16 g, 47.6 mmol) and 250 mL of EtOH was added ethyl bromopyruvate (6.05 mL, 48.2 mmol). The resulting solution was stirred at 60° C. for 1.5 h, then concentrated in vacuo. The resulting solid was purified by flash chromatography on silica gel using 5% EtOAc/hexane→80% EtOAc/hexane→CH2Cl2 as the eluant to give a white solid. MS m/z: 373 (M+1). Calc'd for C19H20N2O4S-372.44.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH2:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:20])=[O:21])=[CH:23][CH:24]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccncc3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid ethyl ester (3.0 g, 6.5 mmol) dissolved in TBF:Methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.2 g (42%); off white solid; MS: 433.0 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21]N(CCN(C)C)C.C([Li])CCC.IC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[N:16]=[C:10]2[CH:9]1[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: Cc1ccccc1
Product: CC1c2nc(C(F)(F)F)nn2CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-N-(tert-butoxycarbonyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine (1.85 g, 6.35 mmol) in 25 mL of toluene at −78° C. was added N,N,N,N-tetramethylethylenediamine (1.01 mL, 6.67 mmol) followed by n-butyllithium (4.17 mL of a 1.6 M solution in hexanes, 6.67 mmol). The mixture was stirred at −78° C. for 10 min and then iodomethane (0.415 mL, 6.67 mmol) was added dropwise. The mixture was allowed to stir at −78° C. for 10 min, and then it was warmed to ambient temperature. The reaction was quenched with aqueous ammonium chloride and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography (silica gel, 10% ethyl acetate/hexane) yielded the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]([CH2:10][C:11]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13][CH2:12]1)[C:7]([OH:9])=O.[O:25]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[CH:28][N:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[O:25]1[C:29]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:7](=[O:9])[C:6](=[O:5])[CH2:10][C:11]3([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]([F:22])([F:23])[F:24])[CH2:14][CH2:13][CH2:12]3)=[CH:34][CH:35]=2)=[CH:28][N:27]=[CH:26]1
Reactant: Nc1ccc(-c2cnco2)cc1
Reactant: O=C(O)C(=O)CC1(c2ccccc2C(F)(F)F)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: O=C(CC1(c2ccccc2C(F)(F)F)CCC1)C(=O)Nc1ccc(-c2cnco2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
0.052 ml of thionyl chloride was added to a solution of 0.1 g of 2-Oxo-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-propionic acid in 2 ml of dimethyl acetamide at −5° C., and stirred for 30 min at −5° C. Then 56 mg of 4-oxazol-5-yl-phenylamine was added in solid form and stirred for 1 hour at room temperature. Potassium carbonate was added and stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined ethyl acetate extracts were washed twice with water, dried and concentrated by evaporation. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 10%-20%) to yield 63 mg of product.
Reaction SMILES: C=O.C(O[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:39])[C@@H:26]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=O)C1C=CC=CC=1>CO.C(OCC)(=O)C>[C:35]([O:34][C:32](=[O:33])[NH:31][C@H:26]([C:25](=[O:39])[C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:11])[CH2:18][CH2:17]2)=[CH:24][CH:23]=1)[C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:36])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1)C(C)(C)C
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)cc2)CC1
Reaction time: 18 h

Procedure:
Formaldehyde (37% wt. % solution in H2O, 0.5 mL) was added to a solution of 4-[4-(2(S)-tert-Butoxycarbonylamino-3,3-dimethylbutyryl)-phenyl]-piperazine-1-carboxylic acid benzyl ester in methanol (3 mL) and ethyl acetate (1 mL). The mixture was degassed and 10% palladium on charcoal (20 mg) was added. Hydrogen gas was bubbled through the suspension for 15 minutes when a balloon containing hydrogen was introduced to the reaction. After 18 hours, the catalyst was removed by filtration and the solvents were removed in vacuo to give a yellow oil which was used without further purification (0.15 g, 100% crude).
Reaction SMILES: [CH3:1][C:2]([S:16][C@@H:17]1[CH2:22][O:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:19][CH2:18]1)([CH3:15])[C:3]([C:5]1C=CC(C(F)(F)F)=CC=1)=[O:4].[I-].C[S+](C)(C)=O.[OH-].[K+].[NH:37]1[CH:41]=[N:40][CH:39]=[N:38]1>C(O)(C)(C)C.O.C(Cl)(Cl)Cl>[CH3:1][C:2]([S:16][C@@H:17]1[CH2:22][O:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:19][CH2:18]1)([CH3:15])[CH:3]([OH:4])[CH2:5][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1
Reactant: CC(C)(S[C@H]1CO[C@H](c2ccccc2)OC1)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: c1nc[nH]n1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(S[C@H]1CO[C@H](c2ccccc2)OC1)C(O)Cn1cncn1

Procedure:
680 mg (1.66 mmol) of 2-methyl-2-[(trans-2-phenyl-1,3-dioxan-5-yl)thio]-4'-(trifluoromethyl)propiophenone, 547 mg (2.49 mmol) of trimethylsulfoxonium iodide, 381 mg (6.79 mmol) of potassium hydroxide and 264 mg (3.82 mmol) of 1,2,4-triazole were heated with stirring in 5.7 ml of t-butanol at 80° C. for 6 hours. After cooling, the reaction mixture was distributed between chloroform and water and the chloroform layer was separated and dried, followed by evaporation of the solvent. The thus obtained oil was subjected to column chromatography using silica gel and eluted with a mixed solvent of ethyl acetate-hexane (1:1) to obtain 605 mg (yield: 74%) of the title compound as a foam.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](N)=[O:7])#[N:2].N([N+]([O-])=O)=[O:13].CC1OC(OC2C(O)CC(OC3C(O)CC(OC4CC5CCC6C7(O)CC(OC(C)=O)C(C8COC(=O)C=8)C7(C)CCC6C5(C)CC4)OC3C)OC2C)CC(O)C1O>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:13])=[O:7])#[N:2]
Reactant: O=N[N+](=O)[O-]
Reactant: N#Cc1cccc(C(N)=O)c1
Agent: CC(=O)OC1CC2(O)C3CCC4CC(OC5CC(O)C(OC6CC(O)C(OC7CC(O)C(O)C(C)O7)C(C)O6)C(C)O5)CCC4(C)C3CCC2(C)C1C1=CC(=O)OC1
Agent: O=S(=O)(O)O
Product: N#Cc1cccc(C(=O)O)c1
Yield: 92 %

Procedure:
m-Cyanobenzamide (2.92 g) was added to a 70 wt. % aqueous sulfuric acid solution (100 ml), and the mixture was stirred under cooling with ice. The mixture was allowed to react while dinitrogen trioxide gas was introduced thereto at 336 N ml/hour for two hours. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 2.68 g of m-cyanobenzoic acid (yield 92%, based on m-cyanobenzamide). The m-cyanobenzoic acid obtained had a purity of 99% or more.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[OH-].[Na+].Br[CH2:10][CH2:11][Cl:12]>C(OCC)C>[Cl:12][CH2:11][CH2:10][S:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1cccs1
Reactant: ClCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: ClCCSc1cccs1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
4.72 cm3 of thiophene-2-thiol were run, with stirring at a temperature in the region of 20° C., into a stirred solution of 8.25 cm3 of 20% aqueous sodium hydroxide solution and 14.6 cm3 of 1-bromo-2-chloroethane. The mixture was subsequently stirred for 6 hours at a temperature in the region of 20° C. 40 cm3 of ethyl ether were subsequently added and the organic phase was washed with water and then dried over magnesium sulfate. After filtering through paper, the organic solution was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography, under a pressure reduced to 50 kPa of nitrogen, on a column of silica gel (particle size 20-45 μm; diameter 4.5 cm; weight of silica 250 g), elution was carried out with a cyclohexane/ethyl acetate (95/5 by volume) mixture. 7.27 g of 2-(2-chloroethylthio)thiophene were obtained in the form of a mobile oil with a yellow color.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][F:12])(=O)=O)=CC=1.[OH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[N:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[F:12][CH2:11][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCF)cn1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A solution containing fluoromethyl toluene-4-sulfonate (233 mg) in DMF was added to a solution containing methyl 5-hydroxypyridine-2-carboxylate (100 mg) and cesium carbonate (532 mg) in DMF (5 mL). The reaction solution was stirred at 70° C. for 3 h. The reaction solution was cooled to RT. EtOAc and saturated aqueous NH4Cl were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous MgSO4, and the insoluble matter was separated by filtration.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)#[N:2].C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O.O>[C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)(=[O:22])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(c1)-c1nc(C#N)cn1CCO2
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
Methyl 2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate (220 mg, 0.82 mmol) was dissolved in 4.0 ml of dimethyl sulfoxide and treated with a solution of potassium carbonate (136 mg, 0.980 mmol) in water (1.60 mL, 88.8 mmol). After cooling at 0° C., hydrogen peroxide (0.751 mL, 9.80 mmol) was added slowly. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with 20 ml of water and extracted with ethyl acetate (3×20 ml). The oprganic extracts were washed with 5% sodium thiosufate, sat. NaHCO3, brine, dried over sodium sulfate and concentrated to give 180 mg (77%) of crude methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate. MS (ESI+): 288.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]([F:32])([F:31])[CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27][C:28](=[O:30])[CH3:29])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].[OH-].[K+].CO.[N+](=C)=[N-].O1C=C[CH2:44][CH2:43][CH2:42]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCOCC.O1CCOCC1>[CH3:1][O:2][C:3](=[O:33])[C:4]([F:31])([F:32])[CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27][CH:28]4[CH2:29][CH2:44][CH2:43][CH2:42][O:30]4)[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: C1=COCCC1
Reactant: COC(=O)C(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 95 %

Procedure:
The difluoroester (5) (880 mg, 1.9 mmol) was treated with 2% KOH-MeOH (30 ml) at room temperature for 2 hr. The usual work-up (ether for extraction) gave a crude acid. This in ether (10 ml) was treated with etheral solution of diazomethane until the gas evolution was ceased. This solution was concentrated under reduced pressure to leave the residue. This in dioxane (10 ml) was treated with 2,3-dihydropyran (516 μl) and TsOH (10 mg) at room temperature for 3 hr. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (200 g). Elution with n-hexane-ether (15:1) provided the THP-ester (6) (907 mg, 95%), amorphous. 1H-NMR δ: 0.70 (3H, s, 18-H3), 1.03 (3H, s, 19-H3), 1.10 (3H, d, J=6 Hz, 21-H3), 3.53 (2H, m, THP), 3.86 (3H, s, --CO2CH3), 3.93 (1H, m, 3-H), 4.73 (1H, m, THP), 5.36 (1H, m, 6-H). 19F-NMR δ: +40.0. MS m/z: 424 (M+ -DHP), 406, 391.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[O:5]
Reactant: CCNCC
Reactant: O=C(Cl)c1cc(F)c(F)cc1Br
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.05 g of 2-bromo-4,5-difluorobenzoyl chloride in 5 ml of DCM are added dropwise with stirring to a solution of 846.9 μl of diethylamine in 5 ml of DCM. The mixture is subsequently stirred at RT for 1 h. The mixture is then extracted a number of times against water (pH 9), the organic phase is dried and purified by column chromatography.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O)[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)C(OC6[C@H](O)[C@@H](O)C(C7[C@H](O)[C@@H](O)C(O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]9[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]9CO)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO>>[C:4]1([CH:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: OC[C@H]1OC2C3[C@@H](CO)OC(O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]9[C@H](O)[C@@H](O)C(OC1[C@H](O)[C@H]2O)O[C@@H]9CO)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)[C@H](O)[C@H]3O
Product: CC(O)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of (S)-(-)-α,-α-diphenyl-2-pyrrolidinemethanol (DPP) (Aldrich) (1.02 g, 4.03 mmol) in carefully dried THF (4 mL) was added to a solution of sodium aluminum hydride in THF (4.85 mL of 0.252M solution, 1.25 mmol) with stirring under argon at r.t. for 5 min, 45.5 cm3H2 being evolved (calcld. 56 mL for AlH2 complex formation). 1.2 mL of the solution thus obtained was placed by syringe in another flask, and was allowed to stand at r.t. for 1 h. The solution was cooled to +70° C. and acetophenone (0.6 mL of 0.133M solution in THF, 0.083 mmol) was added. Within 24 h (-70° C.) the first probe of reaction mixture was taken and analyzed by GC (30 m capillary column, stationary phase was pentylated and trifluoroacetylated γ-cyclodextrine). GC analysis gave 86% conversion of AP into 1-phenylethanol, e.e. 69% (R). After an additional 24 h, the reaction mixture was warmed to -20° C. and was allowed to stand at this temperature for 4 days. GC analysis of the reaction mixture gave conversion of AP 88% and e.e. value 70% (R). After an additional 3 days, the reaction mixture was hydrolyzed using MeOH-ether (1:10) until evolution of H2 ceased. The mixture was diluted by 4-fold volume of ether and extracted by 10% HCl to remove the aluminum compounds and the ligand. The ether layer was separated and analyzed by GC: conversion of AP 91%., e.e. 67% (R).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[CH:17]1([NH:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28](=[O:44])[C:29]([O:39][CH2:40][C:41](=O)[CH3:42])=[CH:30][N:31]3[CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:26][C:25]=2[F:45])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl-].[NH4+]>C1COCC1>[CH:17]1([NH:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28](=[O:44])[C:29]([O:39][CH2:40]/[C:41](/[CH3:42])=[CH:7]/[C:6]([O:5][CH2:3][CH3:4])=[O:16])=[CH:30][N:31]3[CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:26][C:25]=2[F:45])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)COc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)COc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reaction time: 0.5 h

Procedure:
To a 5 ml THF solution of 119 mg of 60% sodium hydride was added 598 μl of ethyl(diethoxyphosphoryl)acetate at 0° C., followed by stirring for 30 minutes. A 5 ml THF solution of 400 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(2-oxopropoxy)quinolin-4(1H)-one was added thereto at the same temperature, followed by stirring at room temperature for 2 hours. To the reaction mixture was added aqueous saturated ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 200 mg of ethyl (2E)-4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}-3-methylbut-2-enoate.