Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:38])(C[Si](OC(C)C)(C)C)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:18][CH:17]=2)[C:12]1=[O:29])[CH3:10].[C:39](=O)([O-])[OH:40].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:38])([CH2:39][OH:40])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:20][CH:21]=2)[C:12]1=[O:29])[CH3:10]
Reactant: O=C([O-])O
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccccc1F)[C@@H](C)n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccccc1F
Yield: 60.3 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-(isopropoxydimethylsilyl)-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (5.5 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 50 ml), to which 10 ml of 30% aqueous hydrogen peroxide and 0.82 g of sodium hydrogencarbonate were added. The mixture was heated at 80° to 85° C. for 2 hours. The reaction solution was cooled and extracted with 200 ml of ethyl acetate. The extract was washed with 100 ml of water, an aqueous solution of Na2S2O3 (100 ml×2) and 100 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate=1:1) and recrystallized from a mixture of methanol and diisopropyl ether to give 2.7 g of 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (yield: 60%) as colorless powdery crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24]Cl)[CH3:21]>>[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH2:10][C:11]2[CH:12]=[C:13]([C:17]#[N:18])[CH:14]=[CH:15][C:16]1=2)[CH3:21]
Reactant: CN(C)CCCCl
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21

Procedure:
According to the present invention, the alkylation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (5-cyanophthalane) with N,N-dimethylaminopropylchloride may be carried out following prior art procedure, and preferably as described in U.S. Pat. No. 4,136,193. However, according to the process described in U.S. Pat. No. 4,136,193, after the completion of the alkylating reaction, the reaction mass is diluted with ice cold water and the aqueous layer is extracted into ether. The ether layer is then extracted with 20% aqueous acetic acid. The pH of the aqueous acidic layer is then adjusted to alkaline, e.g. pH 10-11, with sodium hydroxide and the citalopram base extracted into ether. The ether layer is then concentrated under reduced pressure to obtain citalopram base oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[Br:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.O>CCCCCC.C1COCC1>[Br:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)([C:7]2[CH:8]=[N:9][CH:10]=[N:11][CH:12]=2)[OH:19])=[CH:16][CH:15]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Brc1cncnc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(Br)cc1)(c1ccc(Br)cc1)c1cncnc1
Reaction time: 16 h

Procedure:
With stirring and with the exclusion of moisture, a solution of 20 ml of 1.6N n-butyllithium in hexane is added dropwise in the course of 30 minutes to a solution, cooled to -75°, of 5.2 g (33 mmol) of 5-bromopyrimidine and 10.7 g (31.2 mmol) of 4,4'-dibromobenzophenone in 130 ml of THF. The reaction mixture is stirred for a further 0.5 hours at -75° and then for 16 hours at room temperature; then, while cooling with ice, it is hydrolysed by the addition of 20 ml of water. The organic phase is separated off and diluted with ethyl acetate. The solution is washed with 2N HCl and a semi-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation. The residue is purified by column chromatography (400 g of silica gel, methylene chloride/ethyl acetate 85:15) and recrystallised from ethyl acetate, m.p. 89°-90°, Rf value=0.11 (silica gel, methylene chloride/ethyl acetate 85:15).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].Br[C:20]1[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][N:32]3[CH:35]=[CH:36][N:37]=[C:31]3[CH:30]=2)=[O:26])=[CH:22][CH:21]=1.Br[C:39]1C=CC(N)=CC=1>>[CH3:39][C:2]([CH3:3])([CH3:4])[CH2:1][N:5]1[CH:9]=[C:8]([C:20]2[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][N:32]4[CH:35]=[CH:36][N:37]=[C:31]4[CH:30]=3)=[O:26])=[CH:22][CH:21]=2)[CH:7]=[N:6]1
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)o1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(C)Cn1cc(-c2ccc(C(=O)NCc3ccn4ccnc4c3)o2)cn1

Procedure:
The title compound was prepared as described in Example 51A, substituting 1-neopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)furan-2-carboxamide for 4-bromoaniline. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.89 (t, J=6.1 Hz, 1H), 8.49 (dd, J=7.0, 0.9 Hz, 1H), 8.11 (d, J=0.5 Hz, 1H), 7.95-7.83 (m, 2H), 7.52 (d, J=1.2 Hz, 1H), 7.46-7.34 (m, 1H), 7.17 (d, J=3.4 Hz, 1H), 6.85 (dd, J=7.0, 1.7 Hz, 1H), 6.66 (d, J=3.5 Hz, 1H), 4.49 (d, J=6.0 Hz, 2H), 3.95 (s, 2H), 0.92 (s, 9H); MS (ESI(+)) m/e 378 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:25][NH:26][C:27](=[O:35])[CH:28]([CH:32]([CH3:34])[CH3:33])[C:29](O)=[O:30]>>[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:25][NH:26][C:27](=[O:35])[CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:30]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C)C(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CC(C)C(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=519.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-isopropyl-malonamic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:26][CH:27]1CC[CH2:28]1.[C-]#N.[K+]>C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]3[CH2:28][CH2:27][CH2:26]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Product: O=C(OCC1CCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
10.35 g (0.03 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 25 ml of hydroxymethylcyclobutane and 0.5 g of powdered potassium cyanide are heated to 165° for 2 hours, the ethanol formed being distilled off continuously. The mixture is subsequently evaporated in vacuo, the residue is taken up in chloroform, the chloroform solution is washed three times with water, dried over magnesium sulphate and evaporated. By recrystallization of the resulting material from ethyl acetate there is obtained cyclobutylmethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 204°-205°.
Reaction SMILES: C([NH:8][CH:9]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[NH:20][C:16]([CH:9]([NH2:8])[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:17][C:18]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)NC(c1cccnc1)c1nc2cc(Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(c1cccnc1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1g from N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine and trifluoroacetic acid in dichloromethane.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].C(OCC)(=O)C.[ClH:25]>C(O)(=O)C.[Cu](Cl)Cl>[Cl:25][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: Cl
Reactant: COC(=O)c1ccc(C(=O)O)cc1N
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)O)cc1Cl
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To 3-amino-4-methoxycarbonylbenzoic acid (0.98 g, 5 mmol) suspended in 12 M hydrochloric acid (25 mL) and acetic acid (25 mL), an aqueous solution (10 mL) sodium nitrite (0.35 g, 5 mmol) was added at −10° C., and the resulting solution was stirred for 30 minutes. The solution was added to copper chloride (I) (0.99 g, 10 mmol) in 12 M hydrochloric acid (25 mL) at −10° C., and the resulting reaction mixture was stirred at room temperature for 1 hour. After addition of ethyl acetate, the reaction mixture was washed with water, dried over magnesium sulfate, filtered through celite and purified by silica gel column chromatography to give 0.44 g of the desired product as a colorless solid (yield 39%).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[N:22]#[C:23]Cl>C(Cl)Cl>[C:23]([N:13]1[C:14]([CH3:17])([CH3:16])[CH2:15][CH:10]([O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][C:12]1([CH3:19])[CH3:18])#[N:22]
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1
Reactant: N#CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1C#N

Procedure:
104.5 g (0.4 mole) of 4-benzoyloxy-2,2,6,6-tetramethyl piperidine are dissolved in 400 ml of methylene chloride, 400 ml of 1N sodium hydroxide are introduced and 21 ml of cyanogen chloride are added dropwise over a period of 30 minutes with cooling at -5° to -5° C. The cooling is then removed and the mixture is stirred until it reaches room temperature. The organic phase is separated off, dried with sodium sulphate, filtered and the methylene chloride distilled off. Recrystallisation from acetonitrile gives 94 g (82% of the theoretical) of 1-cyano-4-benzoyloxy-2,2,6,6-tetramethyl piperidine melting at 150° to 152° C. The IR-spectrum no longer shows an NH-band, but instead a nitrile band at 2170 cm-1 and a carbonyl band at 1700 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]2=[O:18])([O-])=O.[H][H]>[Pd].COCCO>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: COCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
1.4 Grams of a palladium on carbon catalyst was added to a mixture of 154 grams of 5-nitrotetrahydroanthraquinone and 3000 grams of methyl cellosolve, into which was fed hydrogen at room temperature under normal pressure for hydrogenation. After hydrogen was absorbed in an amount of 2 mols per mol of the 5-nitro compound, the catalyst was separated by filtration. To the resultant filtrate was added 60 grams of triethylamine, followed by agitating at 100° C. for 3 hours and feeding air at 100° C. for 1 hour. Then, methyl cellosolve was removed by distillation until crystals began to precipitate. The solution was allowed to cool and the crystals were separated by filtration, washed with water and dried to obtain 118 grams of 1-aminoanthraquinone having a purity of 98.0%.
Reaction SMILES: N[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:15]([NH:20][C:21]([C:23]1[N:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=1)=[O:22])[CH2:16][CH2:17][CH2:18][CH3:19].[N:30]12CCCN=C1CCCCC2>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(OCC)(=O)C>[CH2:15]([NH:20][C:21]([C:23]1[N:24]=[N:25][C:26]([NH:30][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:13]=[CH:14][CH:2]=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[CH:27][CH:28]=1)=[O:22])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCNC(=O)c1ccc(Cl)nn1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCNC(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)nn1
Temperature: 80 °C
Yield: 27 %

Procedure:
To a mixture of 4-aminobenzylpiperidine (0.460 g, 2.42 mmol), 6-chloropyridazine-3-carboxylic acid pentylamide (0.500 g, 2.20 mmol) and tetrabutylammonium bromide (0.071 g, 10 mole %) in DMF (5 mL) was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.66 mL, 4.40 mmol). The brown reaction mixture was heated at 80° C. for 24 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water, dried over Na2SO4, filtered, and concentrated. The crude material was subjected to column chromatography to afford the title compound as a brown solid in 27% yield (0.238 g). 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J=9.3 Hz, 1H), 7.87 (t, J=5.7 Hz, 1H), 7.31-7.20 (m, 6H), 6.65 (d, J=9.3 Hz, 1H), 4.91 (d, J=7.5 Hz, 1H), 3.91 (m, 1H), 3.51 (s, 2H), 3.42 (q, J=7.2 Hz, 2H), 2.86 (m, 2H), 2.21-2.06 (m, 4H), 1.64-1.54 (m, 4H), 1.37-1.28 (m, 4H), 0.91-0.85 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 163.3, 159.1, 145.2, 138.3, 129.1, 128.3, 127.1, 126.8, 113.7, 63.1, 52.2, 48.8, 39.4, 32.2, 29.3, 29.1, 22.4, 14.0. MS (ES+) m/z 380 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)CC)C.[CH3:28][O:29][C@:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:34]([F:37])([F:36])[F:35])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:28][O:29][C@@:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:34]([F:37])([F:36])[F:35])[C:31]([NH:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)[CH2:3][OH:4])=[O:32]
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Reactant: CCCCCCCCc1ccc(CCC(N)CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(CCC(CO)NC(=O)[C@](OC)(c2ccccc2)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
2-Amino-4-(4-octylphenyl)butanol (10 mg), N,N-dimethyl-p-aminopyridine (17.5 mg), anhydrous triethylamine (11.4 μl) and anhydrous methylene chloride (1 ml) were mixed and the mixture was stirred under a nitrogen atmosphere at room temperature. Thereto was added (R)-α-methoxy-α-trifluoromethylphenylacetyl chloride (16.8 μl) and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer chromatography (eluent; chloroform:methanol=9:1) to give the two diastereomer mixtures. Moreover, the mixture was purified by high performance liquid chromatography (eluent; methanol:water=88:12, flow rate; 8.0 ml /minute) to give the subject oily substance (9.8 mg) of 67.8 minutes at retention time and the subject oily substance (9.6 mg) of 71.6 minutes at retention time.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([S:12]([O-:14])=[O:13])[CH:8]=[C:9]([Cl:11])[CH:10]=1)(=O)C.[Na+].[C:16]([O-])(=[O:18])[CH3:17].[K+].Cl[CH:22]([CH2:26]Cl)[C:23](N)=[O:24].Cl>C(O)C>[NH2:4][C:5]1[CH:6]=[C:7]([S:12]([CH:26]=[CH:22][C:23]([O:18][CH2:16][CH3:17])=[O:24])(=[O:13])=[O:14])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: CC(=O)Nc1cc(Cl)cc(S(=O)[O-])c1
Reactant: CC(=O)[O-]
Reactant: NC(=O)C(Cl)CCl
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C=CS(=O)(=O)c1cc(N)cc(Cl)c1

Procedure:
2-carbethoxyvinyl 3-amino-5-chlorophenyl sulfone is prepared by reacting sodium 3acetamido-5-chlorobenzenesulfinate in aqueous ethanol solution, in the presence of potassium acetate, with 2,3-dichloropropionamide. The resulting 2-carboxyamidovinyl 3-acetamido-5-chlorophenyl sulfone is hydrolyzed with dilute hydrochloric acid to give 2carboxyamidovinyl 3-amino-5-chlorophenyl sulfone. The dried solid is boiled with ethanol under reflux for 2 hours in the presence of concentrated sulfuric acid. After drowning in water and neutralization 2-carbethoxyvinyl 3-amino-5-chlorophenyl sulfone is obtained.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[S:24]([NH:27][CH:28]1[CH2:30][CH2:29]1)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:15]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[S:24](=[O:26])(=[O:25])[NH:27][CH:28]2[CH2:29][CH2:30]2)[CH:10]=1
Reactant: NCc1cc(F)ccc1S(=O)(=O)NC1CC1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(=O)(=O)NC1CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
(Step 3) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.48 g), 2-(aminomethyl)-N-cyclopropyl-4-fluorobenzenesulfonamide obtained in Step 2 (0.60 g) and potassium carbonate (0.85 g) in ethanol (20 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.06 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([CH:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[OH:26])[CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[S:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:25]([CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:20][CH2:21]1)=[O:26]
Reactant: OC(c1cccs1)C1CCN(CCc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1cccs1)C1CCN(CCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve oxalyl chloride (1.23 g, 9.67 mmol) in methylene chloride (100 mL), place under an argon atmosphere and cool to -78° C. Add dimethylsulfoxide (1.43 mL) and stir for 15 minutes. Add, by dropwise addition, a solution of α-[1-(2-phenylethy)-4-piperidinyl]-2-thiophenemethanol (2.43 g, 8.06 mmol) in methylene chloride (100 mL). Stir at -78° C. for 30 minutes, then add triethylamine (6.07 mL). Stir at -78° C. for 30 minutes, remove the ice bath and allow to warm to room temperature. Evaporate the solvent in vacuo and partition between methylene chloride and water. Separate the organic phase and extract the aqueous phase with methylene chloride. Combine the organic phases, wash with water and dry (MgSO4). Evaporate the solvent in vacuo and recrystallize (isopropanol) to give the title compound as a white crystalline solid; mp 77°-79° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:10]O>>[CH3:10][O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[OH:1]
Reactant: CO
Reactant: OCc1ccccc1O
Product: COCc1ccccc1O
Yield: 58 %

Procedure:
A solution of 2-hydroxybenzyl alcohol (5 g, 40 mmol) in methanol (25 mL) was heated in a sealed vessel at 150° C. for 4 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by fractional distillation (90° C./10 mm Hg) to afford the title compound as a colourless liquid in 58% yield, 3.22 g. LRMS APCI m/z 137 [M−H]−
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:9])[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C2CO2)c1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCC(O)c2cccc(Cl)c2)cc1
Temperature: 78 °C
Yield: 9.8 %

Procedure:
To a stirring solution of 2-(3-chlorophenyl)oxirane (6.20 g, 40.0 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (7.30 g, 60.0 mmol), 1M NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. for three hours. The reaction was allowed to cool to RT and then extracted with EtOAc (2×150 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was adsorbed onto silica gel and chromatographed eluting with 25-40% EtOAc/hexanes. There are 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.08 g (10%) of the desired product as a colorless oil. Fractions containing the lower Rf spot were combined and evaporated in vauo to give 0.95 g (8%) of the regioisomer as a colorless oil, 44B. Some starting epoxide (2.85 g) was also recovered.