Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]2[NH:8][N:9]([OH:11])[CH:10]=[C:6]2[CH:5]=[C:4]([S:12][CH3:13])[N:3]=1.[CH3:14]I.C[O-].[Na+]>CO>[Cl:1][C:2]1[N:7]2[NH:8][N:9]([O:11][CH3:14])[CH:10]=[C:6]2[CH:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSC1=CC2=CN(O)NN2C(Cl)=N1
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CON1C=C2C=C(SC)N=C(Cl)N2N1

Procedure:
A mixture of 1.2 g (5 mmole) of 7-chloro-2-hydroxy-5-methylthiotriazolo[1,5-c]pyrimidine (from Example 7), 2 g (14 mmole) of methyl iodide, 1.2 g (5 mmole) of sodium methoxide (as a 25% methanolic solution), and 50 ml of methanol was heated at its reflux temperature for two hours and then cooled. The solid was collected by filtration and recrystallized from a 50:50 mixture of glyme and hexane to provide yellow crystals of 7-chloro-2-methoxy-5-methylthiotriazolo[1,5-c]pyrimidine, m.p. 243°-244° C. Analysis: Calculated for C7H7ClN4OS: %C, 36.4; %H, 3.1; %N, 24.3; Found: %C, 36.3; %H, 2.9; %N, 24.2.
Reaction SMILES: O=[O+][O-].[CH2:4]([O:11][C:12](=[O:47])[CH2:13][CH:14]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:15](=[O:38])C(C#N)=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:48]([NH2:56])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(Cl)Cl>[NH:39]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[C@H:14]([C:15]([NH:56][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:38])[CH2:13][C:12](=[O:47])[O:11][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)OCc1ccccc1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[O+][O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Ozone gas was bubbled through a solution of 5 (606 mg, 1 mmol) in CH2Cl2 (20 mL) cooled to −78° C. until its blue color persists within the solution. The excess ozone was purged using argon and phenethylamine (181 mg, 189 μL, 1.5 mmol) was added. The resulting solution was stirred at −78° C. for 1 h and then allowed to warm to r.t. The solvent was removed under reduced pressure and the residue chromatographed on silica gel (0-30% ethyl acetate in hexane) to yield the product as a clear oil which was then recrystallized from ether/hexane (145 mg, 32%): mp 132-134° C.; 1H NMR (CDCl3) δ1.43 (s, 9H, Boc CH3's), 2.81 (t, 2H, NHCH2—CH2—Ph), 3.12 (dd, 1H, 1 of CH2—CO2Bzl), 3.44 (dd, 1H, 1 of CH2—CO2Bzl), 3.55 (t, 2H, NH—CH2—CH2Ph), 5.10 (s, 2H, benzyl CH2), 5.13 (m, 1H, α-CH), 5.51 (d, 1H, urethane NH), 6.92 (br, 1H, amide NH), 7.20 (m, 5H, phenethyl aromatic CH's), 7.30 (m, 5H, benzyl aromatic CH's); FABMS (calculated for C25H31N2O6, 455.2182) m/e 455.2146 (M++1).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9]([O:11][C:12](=[O:22])[CH2:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:10].N1C=CC=CC=1>O>[CH2:9]([O:11][C:12](=[O:22])[CH2:13][C:14](=[N:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:10]
Reactant: NN1CCCC1=O
Reactant: CCOC(=O)CC(=O)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CC(=NN1CCCC1=O)c1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
Place 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem., 1969, 9(2), 58; 155.6 g, 1.14 mol) in a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-oxo-3-pyridin-2-yl-propionic acid ethyl ester (Preparation 2, Part A; 200 g, 1.04 mol) and pyridine (400 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (500 mL) and extract with toluene (2×500 mL). Combine the organic layers, dry (sodium sulfate), filter, and concentrate in vacuo to yield 280 g (98%) of the subtitled compound as a dark oil. MS (ES) m/z=276 (M+H).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CC([O-])(C)C.[K+]>CC(O)C>[C@@H:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a 100 mL autoclave with a stirrer, trans-RuCl2[(R)-dm-segphos][(S)-daiPen] (3.6 mg, 0.003 mol, 1/1,000 molar fold of 1-tetralone) was added. After purging with nitrogen, 2-propanol (3 mL), 1-tetralone (439 mg, 3 mmol) and 2-propanol solution of t-BuOK (0.1 mol/L, 0.3 mL, 0.03 mmol) were added. Subsequently, purging with hydrogen, the mixture was stirred at 25° C. for 15 hours under hydrogen pressure of 1 MPa. As a result of analysis of the reaction solution by using gas chromatography (Chirasil-DEX CB), it was found that the conversion rate is 42% and the optical purity is 90% ee.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([C:15]([O:17]CC)=[O:16])=[CH:8]2.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([C:15]([OH:17])=[O:16])=[CH:8]2
Reactant: CCOC(=O)C1=Cc2c(OC)ccc(OC)c2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(OC)c2c1C=C(C(=O)O)CC2

Procedure:
Ethyl 3,4-dihydro-5,8-dimethoxy-2-naphthoate (7.50 g, 28.6 mmole) is added to a mixture of ethanol (50 ml) and a 2 N aqueous solution of sodium hydroxide (25 ml), and the resultant mixture is boiled for 5 hours. After completion of the reaction, the reaction mixture is concentrated to the one-fourth of the amount, diluted with water (50 ml) and washed with ether (100 ml×2). The aqueous layer is made acidic with conc. hydrochloric acid, and the precipitated white solid is collected by filtration and then dried (6.50 g, 97%). M.P.<220° C. Recrystallization from ethanol affords an analytical sample of 9b as colorless needles. M.P.<220° C. IRνmaxNujol cm-1 : 1660 (COOH), NMR (in CDCl3 - DMSO-d6): 2.20-3.00 (4H, m, CH2CH2C=), 3.80 (3H, s, OCH3), 3.82 (3H, s, OCH3), 6.75 (1H, d, J=10.7Hz, one of aromatic protons), 6.93 (1H, d, J=10.7Hz, one of aromatic protons), 7.82 (1H, broad s, CH=).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH:19]1([C:22]2[C:23]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[C:23]([N:29]3[CH2:34][CH2:33][N:32]([C:11]([C:10]4[CH:9]=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:13])[CH2:31][CH2:30]3)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=2)[CH2:20][CH2:21]1
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)c(C2CC2)c1
Yield: 45.9 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (300 mg) described in Preparation Example 25 and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine (241 mg) described in Preparation Example 86 and by the reaction and treatment in the same manner as in Example 109, the title compound (225 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:13][O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-5-fluoro-2-nitrophenol (2.29 g, 12.0 mmol) was dissolved in DMF (25 mL). K2CO3 (2.5 g, 18 mmol) and iodomethane (0.893 mL, 14.3 mmol) were added and the mixture was stirred at rt overnight. The mixture was then poured into H2O and extracted with EtOAc (2×) and then the combined organics were extracted with H2O (5×). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to give the title compound of step B without further purification (2.19 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.54 (d, J=11.4 Hz, 1H), 3.90 (d, J=1.1 Hz, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1.O[C:28]1[CH:29]=[CH:30][C:31]2[CH2:37][CH2:36][CH2:35][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:33][C:32]=2[CH:42]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:20]1[CH2:25][CH2:24][CH:23]([O:26][C:28]2[CH:29]=[CH:30][C:31]3[CH2:37][CH2:36][CH2:35][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:33][C:32]=3[CH:42]=2)[CH2:22][CH2:21]1
Reactant: OC1CCOCC1
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(OC3CCOCC3)ccc2CCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94 %

Procedure:
To triphenylphosphine (1.18 g, 4.50 mmol), tetrahydropyran-4-ol (0.429 g, 4.50 mmol) and methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) dissolved in THF (10 ml) was added at 0° C. a solution of diisopropyl azodicarboxylate (0.886 ml, 4.50 mmol) in THF (2 ml), and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography (silica gel: 45 g, ethyl acetate/hexane=1/25). The objective fractions were concentrated under reduced pressure to obtain methyl 2-[(tetrahydropyran-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (427 mg, 1.41 mmol, 94%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[N:20]=[N:19][N:18]=2)[CH:9]=[CH:8][C:7]=1[N+:28]([O-])=O>[Pd].C(O)C>[CH:22]1([N:21]2[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:10]3[CH:11]=[C:6]4[C:7](=[CH:8][CH:9]=3)[NH:28][C:3](=[O:2])[CH2:4][NH:5]4)=[N:18][N:19]=[N:20]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)CNc1cc(OCCCCc2nnnn2C2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: O=C1CNc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1

Procedure:
N-[5-{4-(1-cyclohexyl tetrazole-5-yl) butoxy}-2-nitropheny] amino acetic acid methyl ester 1.9 g (4.4 mM) and 10% Pd/C catalyst 1.9 g were added to ethanol 500 ml.
Reaction SMILES: [OH-].[K+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[C:11]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].Cl>O.[Cu]>[CH3:20][C:17]1[CH:16]=[C:12]([C:11]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14]
Reactant: Sc1ccccc1
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: [Cu]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1ccc(Sc2ccccc2)c(C(=O)O)c1

Procedure:
To a solution of 855 g of potassium hydroxide in 7 litres of water are added, at 50° C under argon, 420 g of thiophenol and the mixture is stirred for 15 minutes. There are then added thereto 22.1 g of copper powder and 1 kg of 2-iodo-5-methyl-benzoic acid and the mixture is heated for 7 hours under reflux. After cooling, the mixture is adjusted to pH 3 with 600 ml of concentrated hydrochloric acid and extracted with methylene chloride, washed with water, dried over sodium sulphate and concentrated to a thick crystal mash. This is filtered under suction, washed with cold ethanol and low-boiling petroleum ether and dried. There is obtained 3-methyl-6-(phenylthio)-benzoic acid of melting point 156°-157° C.
Reaction SMILES: Cl.O1CCOCC1.[CH:8]([C:11]1[C:12]([O:41]COC)=[CH:13][C:14]([O:37]COC)=[C:15]([C:17]2[N:18]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[C:19](=[O:22])[NH:20][N:21]=2)[CH:16]=1)([CH3:10])[CH3:9]>CO>[OH:37][C:14]1[CH:13]=[C:12]([OH:41])[C:11]([CH:8]([CH3:10])[CH3:9])=[CH:16][C:15]=1[C:17]1[N:18]([C:23]2[CH:24]=[CH:25][C:26]([CH2:29][N:30]3[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]3)=[CH:27][CH:28]=2)[C:19](=[O:22])[NH:20][N:21]=1
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=O)n1-c1ccc(CN2CCN(C)CC2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)c1cc(-c2n[nH]c(=O)n2-c2ccc(CN3CCN(C)CC3)cc2)c(O)cc1O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
At room temperature, 4 N hydrochloric acid/1,4-dioxane solution (5 mL) was added to a methanol (5 mL) solution of 5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-[4-(4-methyl piperazin-1-ylmethyl)phenyl]-2,4-dihydro-[1,2,4]triazol-3-one (F652-09, 644 mg, 1.26 mmol). After stirring at 40° C. for 1 hour, the solvent was distilled off under reduced pressure. Methanol was added to the crude product thus obtained, and the resulting suspension was stirred at room temperature. The precipitated solid was collected by filtration to obtain 5-(2,4-dihydroxy-5-isopropylphenyl)-4-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-2,4-dihydro-[1,2,4]triazol-3-one (OH-a13) dihydrochloride (white solids).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].[NH2:13][OH:14].Cl.C([O-])([O-])=O.[K+].[K+]>CCO.O>[F:12][C:5]1[CH:4]=[C:3]([C:1](=[NH:2])[NH:13][OH:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc(C(=O)O)c(F)c1
Yield: 64.2 %

Procedure:
To a solution of 4-Cyano-2-fluorobenzoic acid (1 g, 6.06 mmol) in EtOH (10.09 mL) was added NH2OH.HCl (0.884 g, 12.72 mmol) previously dissolved in water (5 mL) and aqueous solution K2CO3 (1.339 g, 9.69 mmol) in water (15 mL). Then 8-hydroxyquinone (0.011 g, 0.079 mmol) was added. The resulting solution was stirred at reflux for 4 h. EtOH was evaporated from the reaction mixture, then acidified to pH 3 with aqueous HCl (2 N) solution. The precipitate was filtered, washed with water and dried to yield 2-fluoro-4-(N-hydroxycarbamimidoyl)-benzoic acid (786.3 mg, 3.89 mmol, 64.2% yield) as yellowish solid. The crude was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm: 13.21 (m, 1 H), 10.01 (s, 1 H), 7.85 (t, J=7.95 Hz, 1 H), 7.44-7.69 (m, 2 H), 5.99 (br. s., 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([N+:15]([O-:17])=[O:16])=[C:5]2[C:6]=1[C:12](=[O:14])[CH2:11][CH2:10][NH:9]2
Reactant: O=C(O)CCNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: O=C1CCNc2c([N+](=O)[O-])cc(Cl)c(Cl)c21
Yield: 26.7 %

Procedure:
Starting from 3-(4,5-dichloro-2-nitrophenylamino)propionic acid (40.0 g), phosphorus pentoxide (70.0 g) and toluene (300 ml), 5,6-dichloro-2,3-dihydro-8-nitro-4(1H)-quinolinone (10.0 g) was obtained in a manner similar to Step 1 of Example 1.
Reaction SMILES: [CH2:1]([C:3]([C:7]1[C:15]2[NH:14][C:13](=[O:16])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(O)[CH2:4][CH3:5])[CH3:2].Cl>[Pd].C(O)(=O)C>[CH2:1]([CH:3]([C:7]1[C:15]2[NH:14][C:13](=[O:16])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(O)(CC)c1cccc2[nH]c(=O)[nH]c12
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CCC(CC)c1cccc2[nH]c(=O)[nH]c12
Temperature: 80 °C
Reaction time: 6 h
Yield: 80.5 %

Procedure:
A mixture of 4-(1-ethyl-1-hydroxypropyl)-1,3-dihydro-2H-benzimidazol-2-one (32.9 g, 149 mmol), 10% palladium on carbon (50% wet; 3.3 g), concentrated hydrochloric acid (3 mL) and acetic acid (300 mL) was purged with hydrogen and stirred under balloon pressure hydrogen at 80° C. for 6 hr. The catalyst was removed by filtration, and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo. The residue was suspended in diisopropyl ether (25 ml), and the suspension was stirred at 70° C. for 30 min. n-Hexane (25 mL) was added to the suspension, cooled to room temperature and stirred for 30 min. The resulting solid was collected by filtration and washed with n-hexane to give the title compound (24.6 g, 120 mmol, 81%) as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([CH2:20][CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([O:8]CC)=[O:7])C.[OH-].[Li+]>C(O)C.O>[C:23]1([S:22][CH2:21][CH2:20][C:5]([CH2:11][CH2:12][S:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:4]([OH:29])=[O:3])[C:6]([OH:8])=[O:7])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(CCSc1ccccc1)(CCSc1ccccc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CCSc1ccccc1)(CCSc1ccccc1)C(=O)O
Temperature: 49 °C
Reaction time: 2 h
Yield: 115.2 %

Procedure:
A solution of 2,2-bis-(2-phenylsulfanyl-ethyl)-malonic acid diethyl ester (5.614 g) in ethanol (100 mL) was treated with lithium hydroxide (2.84 g) in water (10 mL). The reaction mixture was heated at 49° C. for 17 hours followed by 85° C. for 2 hours. The solvents were evaporated at reduced pressure to give a residue that was treated with water (100 mL) and washed with ether. The aqueous layer was cooled on ice, acidified and the product extracted with ethyl acetate. The extracts were dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure to give acid 2,2-bis-(2-phenylsulfanyl-ethyl)-malonic acid (5.628 g).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:38])[C:21]([CH3:37])=[C:22]([C:24]3[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])=[CH:26][N:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:38])[C:21]([CH3:37])=[C:22]([C:24]3[N+:25]([O-:9])=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])=[CH:35][CH:36]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)C)cn1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2-methylpropyl)-nicotinamide (Intermediate 30, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2-methylpropyl)-3-pyridinecarboxamide 1 oxide as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][OH:5])[CH3:2].[C:8](Cl)([Cl:10])=[O:9].ClC([O-])=O>C1C=CC=CC=1>[Cl:10][C:8]([O:5][CH2:4][CH:3]([CH2:6][CH3:7])[CH2:1][CH3:2])=[O:9]
Reactant: CCC(CC)CO
Reactant: O=C(Cl)Cl
Agent: O=C([O-])Cl
Solvent: c1ccccc1
Product: CCC(CC)COC(=O)Cl
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
20.4 G. (0.2 moles) of 2-ethyl-1-butanol is added dropwise under anhydrous conditions to 250 ml. (0.4 moles) of 17.2% phosgene solution in benzene with stirring in an ice bath. The addition is complete in 70 minutes and the solution is allowed to gradually warm to room temperature and stirred for 16 hours. The excess phosgene and hydrogen chloride are removed with a stream of nitrogen and the residual solution evaporated to dryness in vacuo affording 17.9 g. (54%) of a light yellow oil which IR demonstrates having a strong chloroformate band and no hydroxy. The oil is used as is in further reactions.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH:11]=[CH:12][CH2:13]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:28]=2[N:29]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][N:25]([CH2:13][CH:12]=[CH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:26][CH2:27][C:28]=2[N:29]=1
Reactant: ClCC=Cc1ccccc1OCc1ccccc1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1OCc1ccccc1)CC2
Yield: 36 %

Procedure:
Prepared from 2-benzyloxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6 H-thiazolo[5,4-d]azepine in chloroform for 5 hours at 50° C. Yield: 36% of theory, Melting point: 103°-107° C. (ether).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:25][C:26]1[O:30][C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[N:28][C:27]=1[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:37][CH2:36][C:27]2[N:28]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[O:30][C:26]=2[CH3:25])=[CH:11][CH:12]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(OC)cc1
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)Oc1ccc(OC)cc1
Yield: 86 %

Procedure:
Prepared from 3-(4-hydroxyphenyl)-2-methyl-2-(4-methoxyphenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester to produce a colorless oil (86%). 1H NMR (300 MHz, CDCl3): δ 7.57 (d, 1H, J=3.5), 7.36 (d, 1H, J=5.1), 7.15 (d, 2H, J=8.6), 7.07 (dd, 1H, J=5.1, 3.5), 6.81 (d, 2H, J=6.6), 6.78 (d, 2H, J=8.6), 6.71 (d, 2H, J=6.6), 4.21 (q, 2H, J=7.2), 4.20 (t, 2H, J=6.4), 3.74 (s, 3H), 3.21 (d, 1H, J=13.7), 3.08 (d, 1H, J=13.7), 2.95 (t, 2H, J=6.4), 2.35 (s, 3H), 1.28 (s, 3H), 1.25 (t, 3H, J=7.2). MS [EI+] 522 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[C:10]([CH:15]3[C:19](=[O:20])[CH:18]=[CH:17][CH:16]3[OH:21])[CH:9]=2)=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[C:10]([CH:15]3[C:16](=[O:21])[CH:17]=[CH:18][C:19]3=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C=CC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C=CC1=O
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of 5-[5-(4-chloro-phenyl)-2-ethyl-thiophen-3-yl]-4-hydroxy-cyclopent-2-enone (300 mg, 0.95 mmol) in acetone (5 ml) at 0° C. is added, dropwise, Jones' reagent and the resulting yellow solution stirred at 0° C. for 80 minutes. Reaction is quenched by the addition of propan-2-ol (1 ml) and stirred for a further 2 hours. Brine (50 ml) is added and the reaction is extracted with ethyl acetate (2×50 ml). The combined organics are then washed with brine, dried over magnesium sulphate and concentrated in vacuo to give 2-[5-(4-chloro-phenyl)-2-ethyl-thiophen-3-yl]-cyclopent-4-ene-1,3-dione as an orange solid (248 mg).
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].Cl[C:6]1[C:7]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:8]=2[S:9][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=[O:12].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:28][C:26]1[CH:25]=[CH:24][C:8]2[S:9][C:10]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)=[O:12])=[C:6]([S:4][CH:2]([CH3:3])[CH3:1])[C:7]=2[CH:27]=1
Reactant: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2Cl)cc1
Reactant: CC(C)S
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2SC(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
2-Propanethiol (32 μL, 0.35 mmol) is added to a solution of methyl 4-[[[3-chloro-5-methoxybenzo[b]thien-2yl]carbonyl]amino]benzoate (100 mg, 0.27 mmol) in 1 mL of DMF. Diazabicycloundecene (DBU) (52 μL, 0.35 mmol) is added and the mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives methyl 4-[[[5-methoxy-3-[(1-methylethyl)thio]benzo[b]thien-2yl]carbonyl]amino]benzoate in 72% yield; mp=157.5°-158.5° C.