Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(=O)[N:7]([CH2:11][CH2:12][NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([N+:25]([O-])=O)=[CH:20][CH:19]=2)=[O:15])[CH2:8][CH2:9][CH3:10])(C)C.C([NH:31][CH2:32][CH2:33][NH:34][C:35]([C:37]1[NH:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([NH:46][C:47]([C:49]1[NH:50][C:51]3[C:56]([CH:57]=1)=[CH:55][C:54]([C:58](NC1C=C4C(=CC=1)NC(C(=O)NCCNCC)=C4)=[O:59])=[CH:53][CH:52]=3)=[O:48])=[CH:41][CH:40]=2)=[O:36])C.F[C:79]1[C:84](NC(C2NC3C(C=2)=CC(C(NC2C(F)=C(F)C(F)=C(F)C=2F)=O)=CC=3)=O)=C(F)C(F)=C(F)[C:80]=1F>>[CH2:80]([NH:31][CH2:32][CH2:33][NH:34][C:35]([C:37]1[NH:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([NH:46][C:47]([C:49]1[NH:50][C:51]3[C:56]([CH:57]=1)=[CH:55][C:54]([C:58]([NH:25][C:21]1[CH:22]=[C:23]4[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:14](=[O:15])[NH:13][CH2:12][CH2:11][NH:7][CH2:8][CH2:9][CH3:10])=[CH:24]4)=[O:59])=[CH:53][CH:52]=3)=[O:48])=[CH:41][CH:40]=2)=[O:36])[CH2:79][CH3:84]
Reactant: CCNCCNC(=O)c1cc2cc(NC(=O)c3ccc4[nH]c(C(=O)Nc5ccc6[nH]c(C(=O)NCCNCC)cc6c5)cc4c3)ccc2[nH]1
Reactant: O=C(Nc1c(F)c(F)c(F)c(F)c1F)c1ccc2[nH]c(C(=O)Nc3c(F)c(F)c(F)c(F)c3F)cc2c1
Reactant: CCCN(CCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1)C(=O)OC(C)(C)C
Product: CCCNCCNC(=O)c1cc2cc(NC(=O)c3ccc4[nH]c(C(=O)Nc5ccc6[nH]c(C(=O)NCCNCCC)cc6c5)cc4c3)ccc2[nH]1

Procedure:
Compound 82 (131.2 mg, 0.336 mmol) was reduced to 83 by hydrogenation according to general procedure A in example 10. Similar procedure as described for the preparation of 76 from condensation of compound 83 with 1H-indole-2,5-dicarboxylic acid bis-(pentafluorophenyl-amide) 74 (45 mg, 0.084 mmol) followed deprotection of Boc group and purification by HPLC gave GL496564 (39.4 mg, 63%). ESI MS: 690.31 (M+H+), 345.66 (M/2+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[CH:17]=O.[C:24](#[N:28])[CH2:25][C:26]#[N:27]>>[NH2:28][C:24]1[O:1][C:2]2[C:10]([CH:17]([C:16]3[CH:15]=[C:14]([O:13][CH3:12])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=3)[C:25]=1[C:26]#[N:27])=[CH:9][CH:8]=[C:7]1[N:6]([CH3:11])[CH:5]=[CH:4][C:3]=21
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: N#CCC#N
Reactant: Cn1ccc2c(O)cccc21
Product: COc1cc(OC)cc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2C)c1

Procedure:
The title compound was prepared from 4-hydroxy-1-methylindole (40 mg, 0.27 mmol), 3,5-dimethoxybenzaldehyde (45 mg, 0.27 mmol) and malononitrile (18 mg, 0.27 mmol) similar to Example 24 to yield 62 mg (60%) of white solids. 1H NMR (CDCl3): 7.04-7.00 (m, 2H), 6.81 (d, J=8.4 Hz, 1H), 6.55 (d, J=3.0 Hz, 1H), 6.37-6.31 (m, 3H), 4.77 (s, 1H), 4.64 (brs, 2H), 3.77-3.74 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]3=[O:22])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[N:13]([CH3:23])[C:12]3=[O:22])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc2snc(Cl)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(Cl)c3c2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-(3-chloro-1,2-benzisothiazol-5-yl)-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.06 g), potassium carbonate (0.470 g) and iodomethane (0.500 mL) in N,N-dimethylformamide is stirred at room temperature for 90 minutes, treated with additional iodomethane (0.500 mL), stirred at room temperature for 15 minutes, and diluted with water. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven at room temperature to give the title product as a solid which is identified by NMR spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[H-].[Na+].[Cl:16][C:17]1[N:18]=[N:19][CH:20]=[C:21](Cl)[CH:22]=1>CN(C)C=O>[Cl:16][C:17]1[N:18]=[N:19][CH:20]=[C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:22]=1
Reactant: Clc1cnnc(Cl)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1cnnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (350 mg, 1.6 mmol) in 4 mL of N,N-Dimethyl formamide at 0 degree, is added Sodium hydride (100 mg) and the reaction mixture is allowed to stirred at 0 degree for 20 minutes. 3,5-dichloropyridazine (1.6 mmol) is added and the reaction mixture is warmed to room temperature. The reaction mixture is stirred at room temperature until formation of the desired compound. The reaction mixture is quenched with water and extracted with Ethyl acetate. The combined Ethyl acetate layers are dried over Sodium Sulfate and solvent is removed under reduced pressure. The residue can be purified by Prep-HPLC.
Reaction SMILES: [CH3:1][S:2]([CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH3:1][S:2][CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12]
Reactant: CS(=O)C=C1C(C)(C)CCC1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSC=C1C(C)(C)CCC1(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 75 %

Procedure:
20 g of 2,2,5,5-tetramethylcyclopentylidenemethyl methyl sulfoxide was dissolved in 200 ml of tetrahydrofuran, and 4.0 g of lithium aluminum hydride was added thereto in small portions. The mixture was stirred at room temperature for 10 hours, and then 100 ml of ethyl acetate was added dropwise thereto. After the mixture was subjected to filtration, the filtrate was concentrated under reduced pressure. The oily substance was subjected to silica gel column chromatography using ethyl acetate-n-hexane as an eluent, whereby 13.8 g of 2,2,5,5-tetramethylcyclopentylidenemethyl methyl sulfide was obtained as an oily substance.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[S:16][C:15]([CH2:17][C:18]2([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:11][C:12]1[S:16][C:15]([CH2:17][C:18]2([CH:22]=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1
Reactant: OCC1(Cc2ccc(Cl)s2)CCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1(Cc2ccc(Cl)s2)CCC1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (12 mL, 24 mmol) was added to CH2Cl2 (250 mL) at −78° C. DMSO (3.75 g, 48 mmol) was added dropwise to the mixture and stirring was continued for 15 min. A solution of alcohol 20 (2.57 g, 12 mmol) in CH2Cl2 (20mL) was then added dropwise. After 1 hr at −78° C., Et3N (9.72 g, 96 mmol) was added and the mixture was warmed to 23° C. After 1 h, the mixture was poured into NaHCO3 (sat) and the organic layer was seperated. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layer was washed with brine, dried (Na2SO4), concentrated and purified by FCC (silica gel, 100% hexane; 2:1, hexane/CH2Cl2) to afford the above named aldehyde 21.
Reaction SMILES: [C:1](=[O:3])=[O:2].[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O-:14].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[OH:14][C:5]1[C:6]([C:1]([OH:3])=[O:2])=[CH:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1
Reactant: O=C=O
Reactant: [O-]c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 240 °C
Yield: 69 %

Procedure:
A stainless steel pressure autoclave is charged with 50 parts of kerosene and heated to 240° C. It is then pressurized with 10 bar of carbon dioxide. Over the course of 8 hours, a mixture of 50 parts of sodium β-naphtholate and 32 parts of sodium carbonate are metered in as a suspension in kerosene via a metering pump, part of the kerosene being distilled off, condensed and transferred out of the reaction vessel at reduced pressure. After the usual workup, the 2-hydroxynaphthalene-3-carboxylic acid is obtained in a yield of 69% based on sodium β-naphtholate used. In addition, 20% of unreacted β-naphthol and small amounts of 2-hydroxynaphthalene-6-carboxylic acid and 2-hydroxynaphthalene-3,6-dicarboxylic acid are obtained.
Reaction SMILES: C([O:8][C:9](=[O:22])[CH:10]=[CH:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[CH2:12][CH2:11][CH2:10][C:9]([OH:22])=[O:8]
Reactant: [H][H]
Reactant: O=C(C=CCC1Cc2ccccc2C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCCC1Cc2ccccc2C1
Yield: 85.1 %

Procedure:
6.45 g (22.1 mmol) of benzyl-4-(indan-2-yl)-2-butenoate was dissolved in 120 ml of methanol, to which 0.6 g of 10% palladium on carbon was added and stirred vigorously for 2.5 hours in the stream of hydrogen. The catalyst was removed by filtration, the filtrate was condensed to obtain 3.84 g of crystalline 4-(indan-2-yl)butanoic acid. Yield: 85%
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:19][C:20]3([C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37].COC(C)(C)C>C(O)C>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:19][C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:27]([O-:29])=[O:28])=[CH:30][CH:31]=4)[CH2:21][CH2:22]3)=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.[CH2:36]([NH2+:38][CH2:39][CH3:40])[CH3:37]
Reactant: O=C(O)c1ccc(C2(NC(=O)c3cccc4ccn(Cc5ccc(C(F)(F)F)cc5)c34)CC2)cc1
Reactant: CCNCC
Solvent: CCO
Solvent: COC(C)(C)C
Product: CC[NH2+]CC
Product: O=C([O-])c1ccc(C2(NC(=O)c3cccc4ccn(Cc5ccc(C(F)(F)F)cc5)c34)CC2)cc1
Reaction time: 0.5 h

Procedure:
4-{1-[({1-[4-(trifluoromethyl)benzyl]-1H-indol-7-yl}carbonyl)amino]cyclopropyl}benzoic acid (13 g, 27.2 mmol) was dissolved in 146 ml ethanol. Diethylamine (3.4 ml, 33 mmol) was added and the mixture was stirred 30 min (formation of precipitate observed). 260 ml of methyl tert-butylether was added and the mixture aged one hour. The solid was collected by filtration, washed with methyl tert-butylether and dried under vacuum at 85° C. for 24 h. 1H NMR 6 Acetone-d6: 8.30 (1H, s), 7.90 (2H, d), 7.80 (1H, d), 7.55 (2H, d), 7.45-7.35 (4H, m), 7.15 (1H, d), 7.00 (2H, d), 6.70 (1H, d), 5.80 (2H, s), 2.60 (4H, q), 1.25-1.20 (2H, m), 1.10-1.05 (8H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7](SC)[N:6]3[N:14]=[C:15]([C:17]4[O:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:5]3[C:4]=2[CH:3]=1>C1(N)CCCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH:8][CH:9]3[CH2:10][CH2:11][CH2:2][CH2:3][CH2:4]3)[N:6]3[N:14]=[C:15]([C:17]4[O:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:5]3[C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(Cl)cc2c2nc(-c3ccco3)nn12
Solvent: NC1CCCCC1
Product: Clc1ccc2nc(NC3CCCCC3)n3nc(-c4ccco4)nc3c2c1

Procedure:
A mixture of 9-chloro-2-(2-furyl)-5-methylthio(1,2,4]triazolo[1,5-c]quinazoline (5.7 g) is refluxed with cyclohexylamine (40 ml) under nitrogen for 6 hours. The mixture is cooled and the insoluble solid collected and recrystallized from ethanol to afford pure 9-chloro-5-cyclohexylamino-2-(2-furyl)-[1,2,4]triazolo[1,5-c]quinazoline, mp 158°-160°.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:13][O:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[CH:17]=[N+:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:13][O:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[CH:17]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccccc1C=[N+]1CCCC1
Reactant: c1ccc(-n2cccc2)cc1
Agent: [Cl-]
Product: COc1ccccc1C(c1cccn1-c1ccccc1)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-phenyl-1H-pyrrole and 1-(2-methoxy-benzylidene)pyrrolidinium chloride.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])=[C:7]([CH3:13])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:17]([C:20]1[CH:27]=[CH:26][C:23](CCl)=[CH:22][CH:21]=1)([CH3:19])[CH3:18].CN(C)[CH:30]=[O:31]>>[CH3:13][C:7]1[C:8](=[O:12])[O:9][C:10]2[C:5]([C:6]=1[CH3:14])=[C:4]([O:31][CH3:30])[CH:3]=[C:2]([C:23]1[CH:26]=[CH:27][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=1)[CH:11]=2
Reactant: Cc1c(C)c2ccc(O)cc2oc1=O
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1cc(-c2ccc(C(C)C)cc2)cc2oc(=O)c(C)c(C)c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5.7 g of 7-hydroxy-3,4-dimethylcoumarin in 25 ml of dimethylformamide were added dropwise to a suspension of 1.05 g of NaH (80%) in 15 ml of dimethylformamide at room temperature. After 45 minutes, 5.05 g of 4-isopropylbenzyl chloride, dissolved in 20 ml of dimethylformamide, were added and the mixture was stirred overnight at room temperature. The reaction mixture was hydrolyzed with ice water, and the precipitated solid was filtered off under suction and recrystallized from methanol.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH2:19]1[CH:24]2[CH2:25][C:26]3([C:28]([O-])=[CH:29][N+]#N)[CH2:27][CH:20]1[CH2:21][CH:22]3[CH2:23]2.CN1CCCC1=[O:39]>ClCCCl.CCOC(C)=O>[CH2:23]1[CH:22]2[C:26]3([CH2:28][C:29]([NH:1][N:2]4[N:11]=[C:10]([N:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[C:3]4=[O:18])=[O:39])[CH2:27][CH:20]([CH2:19][CH:24]1[CH2:25]3)[CH2:21]2
Reactant: CN1CCCC1=O
Reactant: N#[N+]C=C([O-])C12CC3CC(CC1C3)C2
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(CC12CC3CC(CC1C3)C2)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
A solution of the product from Example 1B (48.5 mg, 0.197 mmol) and the product from Example 210A (0.0384 g, 0.202 mmol) in 1,2-dichloroethane (0.6 mL) and 1-methyl-2-pyrrolidinone (0.20 mL) was microwaved at 180° C. for 20 minutes, diluted with EtOAc, washed with sat NaHCO3 and brine, dried (Na2SO4), filtered, and chromatographed (12% EtOAc/DCM) to give 31.2 mg of the title compound as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.34-8.27 (m, 1H), 8.06-7.93 (m, 2H), 7.93-7.84 (m, 1H), 3.85-3.78 (m, 4H), 3.12-3.04 (m, 4H), 2.44 (s, 2H), 2.33 (t, J=6.6, 1H), 2.17 (s, 2H), 1.83-1.46 (m, 10H); MS (ESI+) M/Z 409 (M+H)+.
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH2:7][S:6][CH2:5][S:4]1.[Cl:8][CH2:9][CH2:10][C:11](Cl)=[O:12]>C1(C)C=CC=CC=1>[Cl:8][CH2:9][CH2:10][C:11]([S:1][CH2:2][CH:3]1[CH2:7][S:6][CH2:5][S:4]1)=[O:12]
Reactant: SCC1CSCS1
Reactant: O=C(Cl)CCCl
Solvent: Cc1ccccc1
Product: O=C(CCCl)SCC1CSCS1
Yield: 81.7 %

Procedure:
Into 500 ml glass reactor equipped with a stirrer and a cooling pipe, 91.2 g (0.60 moles) of 4-mercaptomethyl-1,3-dithiolane (2-1) produced in Example 1 was weighed and poured, and 80.0 g (0.63 moles) of 3-chloropropionic chloride was added dropwise into the reactor at 40° C. over 15 minutes. After reacted at 40° C. for eight hours with stirring, 200 g of toluene was added to the reaction mixture to dissolve the mixture. The mixture then was moved into a separating funnel to be rinsed three times with 300 g of 3 wt. % sodium hydrogen carbonate aqueous solution. Then, after the mixture was rinsed with 300 g of pure water until the water layer became neutral, the organic layer (toluene solution) was taken out. Toluene was evaporated off under reduced pressure, and 119 g of 4-(3-chloropropionylthiomethyl)-1,3-dithiolane was obtained as a transparent and colorless liquid.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C:6]1C=C[CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][C:12]([CH2:16][O:17][CH3:18])=[CH:11]2.C(#N)C.[OH2:22]>>[CH:9]([C:10]1[C:15]([C:6]([O:5][CH3:4])=[O:1])=[N:14][CH:13]=[C:12]([CH2:16][O:17][CH3:18])[CH:11]=1)=[O:22]
Reactant: COCc1cnc2c(OC)cccc2c1
Reactant: O=[O+][O-]
Reactant: O
Solvent: CC#N
Product: COCc1cnc(C(=O)OC)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ozone is bubbled through a solution of 8-methoxy-3-(methoxymethyl)quinoline (0.134 g, 0.66 mmol) in a 9:1 acetonitrile/water mixture at 0° C. After 10 minutes, the reaction mixture is concentrated in vacuo and the resulting oil is dissolved in methanol and treated with excess diazomethane. After stirring for 14 hours at room temperature, the reaction mixture is treated with acetic acid and concentrated in vacuo to obtain a red oil. Flash chromatography of the oil using silica gel and a 3:1 hexanes/ethyl acetate mixture gives the title product as a colorless oil which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[H-].[Na+].Br[C:13]1[CH:14]=[C:15]([N+]([O-])=O)[C:16]([C:19]#[N:20])=[N:17][CH:18]=1.[NH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=[S:30]>CN(C=O)C>[CH2:1]([C:3]1[C:8]([O:9][C:15]2[C:16]([C:19]#[N:20])=[N:17][CH:18]=[C:13]([S:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: S=c1cccc[nH]1
Reactant: CCc1ncccc1O
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.5 %

Procedure:
2-Ethylpyridin-3-ol (27.5 g, 223 mmol) was dissolved in DMF (900 mL) and cooled in an ice bath. 60% Sodium hydride (8.93 g, 223 mmol) was added portionwise and stirred in an ice bath for 30 minutes. 5-Bromo-3-nitropicolinonitrile (50.9 g, 223 mmol) was added in one portion and the reaction was stirred in an ice bath for 1 hour. Pyridine-2(1H)-thione (24.8 g, 223 mmol) was added, followed by 60% sodium hydride (8.93 g, 223 mmol) and reaction was stirred in an ice bath slowly warming to ambient temperature overnight. The reaction was concentrated in vacuo to about 300 mL and poured into 3 L water with vigorous stirring. The mixture was extracted with EtOAc, washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford 3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (81 g, 242 mmol, 108% yield) as a dark oil.
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:10])[CH3:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].O=[C:12](CC)[CH2:13]CCC(O)=O.C(OCC)(=O)C=C>C(C(C)=O)C>[CH2:12]([O:6][C:5]([CH2:4][CH2:3][CH:2]([CH3:1])[C:8](=[O:10])[CH3:9])=[O:7])[CH3:13]
Reactant: CC(=O)C(C)CCC(=O)O
Reactant: CCC(=O)CCCC(=O)O
Agent: C=CC(=O)OCC
Solvent: CCC(C)=O
Product: CCOC(=O)CCC(C)C(C)=O

Procedure:
Fraction (b) contains 95% by weight of ethyl ester of 3-methyl-4-oxopentane-1-carboxylic acid and 2% by weight of ethyl ester of 4-oxo-hexane-1-carboxylic acid. 41% of the total amount of ethyl acrylate has been converted. The efficiency in ethyl ester of 3-methyl-4-oxo-pentane-1-carboxylic acid amounts to 56% referred to the quantity of converted methyl ethyl ketone, and to 58% referred to the quantity of converted ethyl acrylate.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In 50 ml of ethanol was dissolved 1.6 g of p-(1-imidazolyl)phenol and 1.4 g of anhydrous potassium carbonate was added to the solution. While stirring, 2.1 g of ethyl α-bromoisobutyrate was dropwise added to the mixture. Thereafter stirring was continued for 20 hours under reflux. After cooling to room temperature, the solvent was removed from the reaction mixture in vaccuo. The residue was dissolved in methylene chloride. After the solution was successively washed with a 5% aqueous hydrogen sodium carbonate solution, water and a saturated aqueous sodium chloride solution, the solution was dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation under reduced pressure and the residue was subjected to silica gel column chromatography. The product was eluted out using chloroform-methanol (9:1) as an eluant. The solvent was removed from the under reduced pressure to give the desired product, ethyl 2-[p-(1-imidazolyl)phenoxy]-2-methylpropionate, as an oily substance. ##STR82##
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:16](/[CH:19]=[CH:14]/[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:13][CH:12]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Oc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 6-phenoxy-pyridine-3-carbaldehyde described in Manufacturing Example 232-1-2 (4.75 g, 23.8 mmol), nitromethane (6.45 mL, 119 mmol), ammonium acetate (3.67 g, 47.6 mmol) and acetic acid (20 mL) was stirred for 3 hours at 100° C. This mixture was cooled to room temperature, and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (5.97 g) as a crude product.
Reaction SMILES: N1CCOCC1.[C:7]([C:9]1[C:14]([CH:15]2[CH2:17][CH2:16]2)=[CH:13][C:12](=[O:18])[NH:11][C:10]=1[SH:19])#[N:8].Br[CH2:21][C:22]([NH2:24])=[O:23]>CN(C=O)C>[C:7]([C:9]1[C:14]([CH:15]2[CH2:16][CH2:17]2)=[CH:13][C:12](=[O:18])[NH:11][C:10]=1[S:19][CH2:21][C:22]([NH2:24])=[O:23])#[N:8]
Reactant: N#Cc1c(C2CC2)cc(=O)[nH]c1S
Reactant: NC(=O)CBr
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: N#Cc1c(C2CC2)cc(=O)[nH]c1SCC(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
3-Cyano-4-cyclopropyl-6-oxo-1,6-dihydro-pyridine-2-thiol morpholine salt (15.00 g, 53.69 mmol) was suspended in 15 mL of dry DMF. 2-Bromoacetamide (7.74 g, 55.0 mmol) was added. This mixture was stirred at room temperature for 30 min and quenched with water. The resultant solid was collected by filtration, washed with water and dried under high vacuum for 24 h to give 2-(3-cyano-4-cyclopropyl-6-oxo-1,6-dihydro-pyridin-2-ylsulfanyl)-acetamide as a pale colored solid (13.22 g, 99%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: Cc1ccccc1B(O)O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4C)c3O2)cc1
Yield: 69.5 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 2-methylphenyl boronic acid (0.266 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.358 g (70%) of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:3); mp 98-100° C.; Anal. calcd. for C23H22O4S: C, 70.03; H, 5.62. Found: C, 69.83; H, 5.61.