Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:64][C@H:65]([C:70](O)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:64][C@@H:65]([CH2:66][CH:67]([CH3:69])[CH3:68])[C:70]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:71]
Reactant: CCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a solution of ethyl 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoate (11, 200 mg, 0.48 mmol), DCC (120 mg, 0.58 mmol) and DMAP (6 mg, 0.048 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (168 mg, 0.48 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 30% ethyl acetate in petroleum ether as an eluent to yield 150 mg (60%) of the title compound as a colorless semi solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])[N:6]=1.[ClH:13].[CH3:14]O>>[ClH:13].[ClH:13].[CH3:14][O:11][C:10](=[O:12])[C@H:8]([CH2:7][C:5]1[N:6]=[C:2]([NH2:1])[S:3][CH:4]=1)[NH2:9]
Reactant: Nc1nc(C[C@H](N)C(=O)O)cs1
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1csc(N)n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
3-(2-Amino-4-thiazolyl)-L-alanine containing methanol, 26.3 kg (76 mol) and 72 L of methanol are charged into a reactor and stirred at 5° C., followed by 16.9 kg of anhydrous hydrogen chloride gas and stirred at 25° C. for 5 hours. The solution is heated to reflux and then cooled to 5° C. and held for 1 hour. The product is filtered and dried under vacuum at 50° C. to give 17.7 kg of 3-(2-amino-4-thiazolyl)-L-alanine methyl ester dihydrochloride as an off-white solid, 99% pure by HPLC; IR (mineral oil): 3410 (sh), 1749 (sh), 1631 (sh), 1225 (m) cm-1.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[CH:16][C:17]([CH:19]([CH3:23])[C:20](N)=[O:21])=[CH:18][C:12]=3[C:11](=[O:24])[CH2:10][C:9]=2[CH:25]=1)([O-:4])=[O:3].C(O)(=[O:28])C>>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[CH:16][C:17]([CH:19]([CH3:23])[C:20]([OH:28])=[O:21])=[CH:18][C:12]=3[C:11](=[O:24])[CH2:10][C:9]=2[CH:25]=1)([O-:4])=[O:3]
Reactant: CC(=O)O
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1cc([N+](=O)[O-])ccc1S2
Agent: Cl
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc([N+](=O)[O-])ccc1S2
Reaction time: 3.5 h
Yield: 43 %

Procedure:
A mixture of 3 ml of conc. hydrochloric acid, 3 ml of acetic acid and 0.33 g of 2-(10,11-dihydro-8-nitro-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide was refluxed with stirring for 3.5 hours. The reaction mixture was concentrated, and to this was added water. Threafter, the resulting mixture was extracted with ethyl acetate, and the extract was reextracted with a saturated sodium hydrogen carbonate solution. The extract was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a brown solid substance, which was chromatographed over 6 g of silica gel and eluted with chloroform, and there were obtained light yellow crystals. The thus obtained crystals were recrystallized from chloroform to give 0.14 g (yield: 43%) of 2-(10,11-dihydro-8-nitro-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a light yellow powder having a melting point of 209.5°-211° C.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:12][C:5]=2[C:6](=[O:11])[C:7]=1[NH:8][CH:9]=[O:10].[OH-:28].[Na+]>>[CH:9]([NH:8][C:7]1[C:6](=[O:11])[C:5]2[CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:4]=2[O:3][C:2]=1[OH:28])=[O:10]
Reactant: CS(=O)(=O)Nc1cc2oc(Br)c(NC=O)c(=O)c2cc1Oc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Product: CS(=O)(=O)Nc1cc2oc(O)c(NC=O)c(=O)c2cc1Oc1ccccc1

Procedure:
2-Bromo-3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with 1N aqueous sodium hydroxide solution to obtain 3-formylamino-2-hydroxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[NH:21]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[N:21][NH:22][CH:23]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3cn[nH]c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 1H-pyrazole-4-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(1H-pyrazol-4-yl)-6-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 221(MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:40](=[O:41])[N:13]3[C:14]([C:37]([OH:39])=[O:38])=[C:15]([CH2:18]OC(=O)C4C=CC=CC=4S(=O)(=O)NC(OCC)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:42][C:43]1[N:47]([CH3:48])[N:46]=[N:45][N:44]=1.C(=O)([O-])O.[Na+].P(=O)(O)(O)O>O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:40](=[O:41])[N:13]3[C:14]([C:37]([OH:39])=[O:38])=[C:15]([CH2:18][S:42][C:43]4[N:47]([CH3:48])[N:46]=[N:45][N:44]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: Cn1nnnc1S
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 81.1 %

Procedure:
In water (50 ml) is suspended 7β-phenylacetamido-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (3.0 g) together with 5-mercapto-1-methyl-1H-tetrazole (1.0 g). The mixture is adjusted to pH 5.5 with sodium hydrogen carbonate and the resultant solution is heated at 60° C. for 50 minutes. The solution is brought to pH 2.0 with dilute phosphoric acid and extracted with ethyl acetate (100 ml). The extract is rinsed with a saturated aqueous solution of sodium chloride, dried and concentrated. Then, following the addition of ether, the precipitate is recovered by filtration. By the above procedure is obtained 7β-phenylacetamido-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:27][CH2:26][C@:25]([CH:31]([CH3:33])[CH3:32])([C:28](O)=[O:29])[CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:31]([C@:25]1([C:28]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][CH:5]=3)[CH2:10]2)=[O:29])[CH2:26][CH2:27][C@@H:23]([NH:22][C:20](=[O:21])[O:19][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:24]1)([CH3:33])[CH3:32]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 36 h
Yield: 54.7 %

Procedure:
To a solution of 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline (1.7 g, 8.45 mmol) of Step B-4, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (2.75 g, 10.14 mmol) of Step A-4,4-dimethylaminopyridine (0.70 g, 5.73 mmol), and N,N-diisopropylethylamine (7.0 mL, 40.2 mmol) in methylene chloride (30.0 mL) was added bromotris(pyrrolydino)phophonium hexafluorophosphate (5.119 g, 10.98 mmol). After being stirred for 36 h at room temperature, the solution was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 20% ethyl acetate/hexanes to give 2.1 g (55%) of desired product. MS calculated for C24H33F3N2O3: (M+H)+455; found 355 (M−Boc+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:5]([C:7]1[N:8]=[CH:9][N:10]([CH3:12])[CH:11]=1)=[O:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O.O1CCCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:1][CH2:2][CH2:3][N:4]([CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]([C:7]2[N:8]=[CH:9][N:10]([CH3:12])[CH:11]=2)=[O:6])=[CH:22][CH:21]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Cn1cnc(C(=O)N(CCO)C2CCOCC2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cnc(C(=O)N(CCOc2ccc(Cl)cc2)C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.8 %

Procedure:
To a mixture of N-(2-hydroxyethyl)-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-4-carboxamide (150 mg), p-chlorophenol (114 mg), triphenylphosphine (217 mg) and tetrahydrofuran (3.8 mL), DIAD (172 μL) was added under cooling with ice and the resulting mixture was stirred at room temperature for 3 days. To the reaction mixture, water was added and extraction was conducted with diethyl ether. The diethyl ether layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvents were distilled off under reduced pressure and the resulting residue was purified by column chromatography (silica gel cartridge; chloroform/methanol=99:1 and NH silica gel cartridge; hexane/ethyl acetate=1:3 to 1:9) to give the titled compound (103 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.ClC1C=C(C=CC=1)C(OO)=[O:15]>C(OCC)(=O)C>[N+:1]1([O-:15])[CH:2]=[CH:3][C:4]2[C:9]=1[NH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: CCOC(C)=O
Product: [O-][n+]1ccc2ccc[nH]c1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
To a solution of 7-azaindole (84.8 g, 0.72 mol) in ethyl acetate (700 mL) at 0° C. was added a solution of m-chloroperoxybenzoic acid (19.6 g, 1.14 mol) in ethyl acetate (600 mL) over 1.5 h. The resulting solution was stirred at room temperature for 4 h. After cooling to 0° C., the resulting slurry was filtered and the solid was washed with ethyl acetate (3×30 mL), and the filtrate concentrated in vacuo. The residue was treated at 0° C. with an aqueous 30% potassium carbonate solution to pH 9.5˜10.5. This mixture was stirred for 2 h at 0° C., filtered to collect the precipitate and the precipitate washed with water (2×20 mL) and dried in vacuo to afford 7-azaindole N-oxide (77 g, 80%); LC/MS m/e calcd for C7H6N2O [M+H]+ 135.15, observed 134.9.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[I:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1I
Temperature: 25 °C

Procedure:
A stirred solution of 2-iodo-5-methylbenzoic acid (17.3 g, 66.0 mmol) and concentrated H2SO4 (3 mL) in MeOH (200 mL) was heated at reflux for 18 h. After this time, the reaction mixture was cooled to rt, concentrated to one third volume, diluted with EtOAc (300 mL), washed with saturated NaHCO3 (2×200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dried under high vacuum to afford methyl 2-iodo-5-methylbenzoate as a colorless oil (18.2 g, quant.). 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=8.1 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 6.99-6.96 (m, 1H), 3.92 (s, 3H), 2.33 (s, 3H). A stirred suspension of methyl 2-iodo-5-methylbenzoate (18.2 g, 66.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.2 g, 73.3 mmol), K2CO3 (27.5 g, 200 mmol), and Pd(PPh3)4 (11.5 g, 9.99 mmol) in 1,4-dioxane (150 mL) and H2O (50 mL) was heated at 100° C. for 18 h under nitrogen. After this time, the reaction mixture was cooled to rt, diluted with EtOAc (400 mL), washed with saturated NaHCO3 (2×300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0% to 80% EtOAc/hexanes to afford methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate as a colorless oil (13.3 g, 87%). 1H NMR (300 MHz, CDCl3) δ 7.55-7.25 (m, 5H), 3.94 (s, 3H), 3.80 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([OH:15])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].F[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH2:1]([C:5]1[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([O:15][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2c(O)c1-c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCCCc1cc2ccccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 67 %

Procedure:
3-Butyl-2-phenyl-1-naphthalenol (172) (0.30 g, 1.09 mmol) and 4-fluorobenzaldehyde was heated with Cs2CO3 in DMSO at 100° C. to give 0.28 g (67%) of the title compound (173) as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.77 (t, J=7.3 Hz, 3H), 1.15-1.30 (m, 2H), 1.40-1.55 (m, 2H), 2.58 (t, J=7.8 Hz, 2H), 6.68 (d, J=8.6 Hz, 2H), 7.08-7.14 (m, 2H), 7.19-7.26 (m, 3H), 7.39 (t, J=7.4 Hz, 1H), 7.50 (1, J=7.3 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.71 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 9.79 (s, 1H). LCMS (APCI): m/z 381 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:18][CH3:19])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)[CH3:3].[H][H]>CO.[Pd]>[ClH:1].[ClH:1].[CH2:18]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)[CH3:19]
Reactant: [H][H]
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN(CC)CCCOc1ccc(N)cc1

Procedure:
Hydrogenate a solution of 8.5 g (29.4 mmol) of N,N-diethyl-3-(4-nitrophenoxy)propanamine hydrochloride in 100 mL of methanol over 0.92 g of 10% palladium on carbon catalyst at 40-45 psi at room temperature. When hydrogen uptake ceases remove the catalyst by filtration and add 5 mL of concentrated hydrochloric acid. Remove the solvent in vacuo. Recrystallize the residue from ethanol to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[K+].[CH3:11][O:12][CH2:13]Cl>N1C=CC=CC=1>[F:1][CH:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1([CH2:11][O:12][CH3:13])[OH:8]
Reactant: COCCl
Reactant: Oc1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COCC1(O)C=CC=CC1F
Yield: 62 %

Procedure:
To a reaction mixture containing 2-fluorophenol (20, 2 g, 17.84 mmol) in 30 mL of dry pyridine was added powdered KOH (1 g, 17.71 mmol) and methoxymethyl chloride (1.8 g, 22.49 mmol) and this reaction mixture was heated under reflux for 3.5 hours (FIG. 2D). The reaction was cooled and partitioned between 1 M NaOH and ethyl ether (2×30 mL). The organic solution was washed with 1 M HCl (2×20 mL), water, and then dried (MgSO4), filtered, and the solvent removed under vacuo to afford a oily residue. The crude product was purified by column chromatography (EtOAc:hexanes; 5:95) to afford the desired product as a pale yellow oil in 62% yield. 1H NMR (CDCl3) δ 6.95-7.22 (m, 4H, ArH), 5.21 (s, 2H, CH2), 3.52 (s, 3 H, CH3).
Reaction SMILES: C[O:2][CH:3]1[NH:7][C:6](=O)[CH2:5][CH2:4]1.[CH2:9]([Si](C)(C)C)[C:10]#[CH:11]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:9]([CH:6]1[NH:7][C:3](=[O:2])[CH2:4][CH2:5]1)=[C:10]=[CH2:11]
Reactant: C#CC[Si](C)(C)C
Reactant: COC1CCC(=O)N1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C=CC1CCC(=O)N1
Reaction time: 0.5 h

Procedure:
A solution of 5-methoxypyrrolidin-2-one (34) (2.55 g, 33.3 mmol), propargyl trimethylsilane (3.77 g, 33.7 mmol) and CH2Cl2 (100 mL) was cooled to 0° C. To this solution was added TiCl4 (4.9 mL, 44.4 mmol) in CH2Cl2 (20 mL) over a 15 min period at ≤3° C. After stirring for 30 min, the reaction was poured through silica gel (30 g), rinsed with CH2Cl2 (100 mL), and this initial filtrate (120 mL) discarded. The silica gel was then washed with 5% MeOH/CH2Cl2 (100 mL) followed by 10% MeOH/CH2Cl2 (100 mL), and the combined filtrates were washed with water (50 mL). The aqueous layer was back extracted with CH2Cl2 (4×30 mL), and the combined organic layers dried over MgSO4 and rotary evaporated (≤30° C.) to give 5-(1,2-propadienyl)-2-pyrrolidinone (35) as a brown oil: TLC (Eluant A) Rf =0.45; 1H NMR: δ6.6 (br s, 1 H, NH); 5.17 (ddd, 3J64 ≃4J68 ≃4J68 ≃6.6 Hz, 1 H, H6); 4.88 (d, 4J68' =6.4, 1 H, H8'); 4.21 (m, 1 H, H5); 2.35 (m, 3 H, H3, H4, H4'); 1.93 (m, 1 H, H3'); Cl Mass spec: m/z 124 (MH+), 84 (MH+ --C3H4).
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([C:20](OCC)=[O:21])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:20][OH:21])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2cccs2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1cccs1)n1cc(CO)cc1-c1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A solution (20 mL) of ethyl 5-phenyl-1-(2-thienylsulfonyl)-1H-pyrrole-3-carboxylate (650 mg) in tetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (5 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/L hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 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=7:3→1:1) to give the title compound as a pale-red oil (yield 480 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=O)[CH:3]=1.Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][NH2:33])=[CH:28][CH:27]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:33][O:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:3]=1
Reactant: NOc1ccc(F)cc1
Reactant: O=C(c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F)C1CCCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C(=NOc1ccc(F)cc1)C1CCCCC1)C(F)(F)F
Yield: 37.6 %

Procedure:
A solution of N-(4-chloro-2-cyclohexanecarbonylphenyl)trifluoromethanesulfonamide 29E (410 mg, 1.11 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (200 mg, 1.22 mmol) and anhydrous NaOAc (100 mg, 1.22 mmol) in EtOH (20 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue purified by column chromatography (eluting with CH2Cl2/PE, 3:7 to CH2Cl2) to afford N-{4-chloro-2-[(4-fluorophenoxyimino)cyclohexylmethyl]phenyl}trifluoromethanesulfonamide 169 (200 mg, 38%), as a white solid. 1H n.m.r. (200 MHz, CDCl3) δ 7.54, d, J=8.8 Hz, 1H, 7.43, dd, J=2.2 and 8.8 Hz, 1H; 7.24, d, J=2.2 Hz, 1H, 7.12-6.95, m, 5H, 2.56, m, 1H, 2.14, m, 1H, 1.93-1.65, m, 5H, 1.29, m, 4H.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C(#N)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH:27]([CH3:29])[CH3:28])[N:20]=[C:19](OS(C3C=CC(C)=CC=3)(=O)=O)[N:18]=2)=[CH:13][CH:12]=1>O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH:27]([CH3:29])[CH3:28])[N:20]=[C:19]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[N:18]=2)=[CH:15][CH:16]=1
Reactant: CNS(C)(=O)=O
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(OS(=O)(=O)c2ccc(C)cc2)nc1C(C)C
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 81.5 °C
Yield: 74.8 %

Procedure:
In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 196 mg (1.8 mmol.) of N-methylmethanesulfonamide, 198 mg (1.8 mmol.) of sodium t-pentoxide, 7.5 mL of acetonitrile, and 667 mg (1.5 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine. The mixture was heated to 81-82° C. for 1.5 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the cooled mixture was added 10 mL of water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (2:1, volume ratio)). There was obtained 428 mg of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesul-fonylamino)-pyrimidine. The yield was 75% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine).