Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>CN(C=O)C>[OH:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[C:11]([C:13]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:15])[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1csc(-c2ncccc2O)n1
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1csc(-c2ncccc2O)n1
Temperature: 80 °C
Yield: 53.8 %

Procedure:
A suspension of 2-(3-hydroxy-2-pyridyl)-4-thiazolecarboxylic acid (200 mg) and N,N'-carbonyldiimidazole (hereinafter, referred to as CDI) (291.9 mg) in dry DMF (7 ml), prepared under argon atmosphere, was heated at 80° C. for 1.5 hours. A solution of 5-aminotetrazole (91.9 mg) in dry DMF (3 ml) was added dropwise thereto and allowed to react at 85° C. for 3.5 hours. Then the reaction mixture was cooled to room temperature. The produced solids were filtered with suction, washed with DMF and THF and dried to give white solids of 2-(3-hydroxy-2-pyridyl)-N-(1H-tetrazole-5-yl)-4-thiazolecarboxamide (140 mg, 54%), m.p. above 300° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:14][O:13][C:9]1[CH:10]=[CH:11][C:12]2[CH:4]=[CH:5][S:6][C:7]=2[CH:8]=1
Reactant: CCOC(CSc1cccc(OC)c1)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2ccsc2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 65.9 %

Procedure:
The title compound was synthesized by referring to J. Med. Chem., 1989, 32, 2548. To a solution of 3-methoxybenzenethiol (26.9 g) in acetone (100 ml) was added potassium carbonate (27 g), then 2-bromo-1,1-diethoxyethane (29 ml) was added dropwise thereto followed by stirring overnight at room temperature. To the reaction solution was added acetone, the solution was filtered, the solvent was evaporated in vacuo, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene (39.1 g). To dichloromethane (2 1) was added boron trifluoride diethyl ether complex (12.7 ml) under a nitrogen atmosphere, then a solution of 1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene (25.6 g) in dichloromethane (200 ml) was added dropwise over 1.5 hours, the solution was stirred for 40 minutes at room temperature, then a saturated aqueous solution of sodium carbonate (1 1) was added thereto followed by stirring for 1 hour at room temperature. The solution was extracted with dichloromethane, then dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (10.8 g).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14](S(C)(=O)=O)[N:13]=1.[ClH:26]>C1COCC1.O>[ClH:26].[C:3]([CH:5]([C:14]1[N:13]=[C:12]([CH3:11])[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: Cc1cc(C(F)(F)F)nc(S(C)(=O)=O)n1
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C#N)c1nc(C)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1,1,1-trifluoro-2,4-pentanedione (5.00 g; 32.4 mmol) and S-methylisothiourea hemisulfate (4.06 g; 29.2 mmol) in pyridine (3.75 mL) and water (62 mL) was heated at reflux for 1 day. The mixture was cooled to room temperature, extracted with chloroform, and the chloroform extract washed with water to give 4-methyl-2-(methylthio)-6-(trifluoromethyl)pyrimidine as an off-white solid (4.60 g, 22.1 mmol). This was dissolved in MeOH (60 mL), and a solution of OXONE® (27.1 g, 44.2 mmol) in water (100 mL) was added over 10 min. The mixture was stirred at room temperature for 4 hr and then extracted with EA. The EA was washed with water, dried, and concentrated to give 4-methyl-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (4.8 g) as a white solid. Sodium hydride (0.16 g of a 60% dispersion in mineral oil; 4.0 mmol) was added to a stirred solution of ethyl cyanoacetate (0.21 mL; 2.0 mmol) in THF (8 mL), and the resulting suspension stirred at room temperature for 15 min. 4-Methyl-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (0.48 g; 2.0 mmol) was then added, and the mixture stirred overnight. Water was added, followed by 1M hydrochloric acid to adjust to pH 3-4. The solid that formed solid was filtered, washed with water, and dried under high vacuum to give ethyl 2-cyano-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetate hydrochloride salt (0.43 g) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[OH:22][CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:20][C:16]1[N:15]=[C:14]([N:7]2[C:6]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:22][CH:23]2[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]2)[CH:19]=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (1 g, 2.45 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (2 g, 11.55 mmol) and cesium carbonate (4 g, 12.28 mmol) in N,N-dimethylformamide (15 mL) was stirred under nitrogen overnight at room temperature. The resulting solution was quenched with 200 mL of water. The precipitate was collected by filtration, washed with 200 mL of water and dried in a vacuum oven to give 750 mg (60%) of tert-butyl 3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidine-1-carboxylate as a yellow solid: LC-MS: m/z=+461 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH3:16][N:17]([CH3:35])[C:18]1[N:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[N:23]=[CH:22][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:20][CH:19]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)nc2)cc1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)nc1)c1ccc(C(C)C)cc1)CCC2

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and [(6-dimethylaminopyridin-3-yl)methyl](4-isopropylphenyl)amine (0.24 g) as starting materials, N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide was obtained. This was dissolved in ether, and 4 mol/L-hydrochloric acid/dioxane (0.30 mL) was added. The solvent was evaporated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride ½ hydrate (0.43 g). melting point: 158-160° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15]C)[CH:10]=3.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3
Reactant: COc1cc2c(=O)c(Cc3cccnc3)cn3c4cc(Br)ccc4c(c1)c23
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.5 %

Procedure:
9-bromo-2-methoxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (700 mg) obtained in Example 101 was suspended in anhydrous methylene chloride (70 ml), and to the suspension was added dropwise a solution of boron tribromide in methylene chloride (1M; 10 ml) at room temperature. The reaction mixture was stirred at room temperature for 12 hours, and poured into ice water (100 ml). To this mixture was added saturated aqueous solution of sodium carbonate until the termination of foaming. The crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with ethanol and ether in succession to obtain the title compound (450 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13](O)[C:12]([C:16]#[C:17][CH2:18][CH2:19][CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:34])=O>C(OCC)(=O)C>[Cl:34][C:13]1[C:12]([C:16]#[C:17][CH2:18][CH2:19][CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[CH:11][N:10]=[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:14]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCC#Cc1cnc(Nc2cccc(F)c2)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCC#Cc1cnc(Nc2cccc(F)c2)nc1Cl
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
To 2-(5-(2-((3-fluorophenyl)amino)-4-hydroxypyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (J4, 36 mg), phosphorus oxychloride (1 mL) was added at room temperature, and the mixture was stirred at 80° C. for 45 minutes. The reaction mixture was cooled to room temperature, and then poured into ice, and then ethyl acetate was added to the mixture. The organic layer was separated, washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid matter was washed with diisopropyl ether, and then dried under reduced pressure to obtain 2-(5-(4-chloro-2-((3-fluorophenyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (J5, 21 mg) as pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:24][C:35]([C:31]2[CH:30]=[C:29]3[C:34]([C:26]([Cl:25])=[CH:27][NH:28]3)=[CH:33][CH:32]=2)=[O:36])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccn2)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-pyridinyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (730 mg, 2.2 mmol) and 3-chloroindole-6-carboxylic acid (468 mg, 2.4 mmol) afforded, after purification (SiO2: 10 DCM:2 EtOAc:2 Hexane:0 to 1.5 isopropyl amine), 835 mg (64%) of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[NH4+:15].[OH-]>O1CCCC1>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH2:15])(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc2cnccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Isoquinoline-5-sulfonyl chloride (528 mg) was dissolved in tetrahydrofuran (8 mL), cooled to 0° C., then concentrated NH4OH (0.7 mL) was added and the reaction was allowed to come to room temperature overnight. The product was filtered off, washed with water, and dried under vacuum.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[C:11](N1C=CN=C1)([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[O:12]>[OH-].[Na+]>[N:13]1([C:11]([NH:10][C:8]([S:7][CH3:6])=[NH:9])=[O:12])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CSC(=N)N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CSC(=N)NC(=O)n1ccnc1
Yield: 142.8 %

Procedure:
To S-methylisothiourea sulfate (8.35 g, 30.0 mmol), 1 M sodium hydroxide aqueous solution (60 mL) was added and then 1,1′-carbonyldiimidazole (9.73 g, 60.0 mmol) was slowly added at 0° C. with stirring, followed by stirring the resultant mixture at 0° C. for 30 minutes. After completion of the reaction, the precipitated solid was collected by filtration and the obtained solid was washed with ice water and dried to obtain the title compound (7.89 g, yield 72%).
Reaction SMILES: Cl[C:2]1[C:10]2[N:9]=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].CC1C=C(C)C=C(C)N=1.Cl>CO>[CH3:17][O:18][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2c1nnn2C1CCCCC1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cccc2c1nnn2C1CCCCC1

Procedure:
A slurry of 1.5 g. of 4-chloro-1-cyclohexylbenzotriazole, 15 g. of sodium methoxide, 10 g. cuprous iodide in 50 ml. of 2,4,6-trimethyl pyridine and 10 ml. of methanol is heated to the reflux temperature for 26 hours. The reaction is cooled and poured into 150 ml. of 10% hydrochloric acid. The product is extracted with ethyl ether and on evaporation of the solvent, 0.5 g. of an oil was obtained which solidified on standing. Recrystallized the crude product from ethyl ether, m.p. 118°-120° C. The analytical sample has a m.p. 133°-134° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[CH2:17]([N:20]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26]O)[C:21]1=[O:28])[C:18]#[CH:19]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][CH2:26][N:22]1[C:23](=[O:25])[CH2:24][N:20]([CH2:17][C:18]#[CH:19])[C:21]1=[O:28])=[O:14]
Reactant: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: C#CCN1CC(=O)N(CO)C1=O
Solvent: ClC(Cl)Cl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@H](/C=C(/F)C(=O)OCC)C2(C)C)C1=O

Procedure:
Using the procedure of Example 1, (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylic acid and 3-(2-propynyl)-2,5-dioxoimidazolidinyl-methanol were reacted to obtain 3-(2-propynyl)-2,5-dioxoimidazolidinyl-methyl (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+12°±2° (c=0.5% in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:34]=1.[CH3:35][N:36]([CH3:44])[C@@H:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C@H:38]1[OH:43]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:43][C@@H:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C@H:37]4[N:36]([CH3:44])[CH3:35])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:34]=1
Reactant: CN(C)[C@@H]1CCCC[C@H]1O
Reactant: COc1ccc2c(C(=O)c3ccc(F)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Product: COc1ccc2c(C(=O)c3ccc(O[C@@H]4CCCC[C@H]4N(C)C)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 77 %

Procedure:
The title compound was prepared in 77% yield by essentially following the procedures outlined in Example 72, Part E, from 4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (Example 59, Part A) and (±)-trans-2-(dimethylamino)cyclohexanol (Part A).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH:18]=[C:17]([C:29]([OH:32])([CH3:31])[CH3:30])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:19]2[N:20]=[C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]=[C:17]([C:29]([OH:32])([CH3:31])[CH3:30])[CH:18]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cc3ccc(Cl)cc3)cc(C(C)(C)O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(NC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 119 %

Procedure:
To a solution of 4-[4-(4-chloro-benzyl)-6-(1-hydroxy-1-methyl-ethyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (220 mg, 0.447 mmol) in dichloromethane (5 mL) was added at 0° C. trifluoroacetic acid (365 μL, 4.77 mmol) and the mixture was stirred for 18 hours while allowing to warm to ambient temperature. It was basified by addition of 1 M aqueous sodium carbonate solution (5 mL) and extracted with dichloromethane (15 mL). The organic layers were washed with 1 M aqueous sodium carbonate solution (15 mL) and dried over sodium sulfate. Concentration afforded the title compound (192 mg, 99%) as a brown semi-solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:10]=1)[CH3:2].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(#N)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]([C:30](=[O:31])[NH:29][C:26]2[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=2)[N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:10]=1)[CH3:2]
Reactant: CCc1ccccc1-c1nc(-c2cccc(OC)c2)n[nH]1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CC#N
Product: CCc1ccccc1-c1nc(-c2cccc(OC)c2)nn1C(=O)Nc1ccc(C)cc1
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 5 g (0.018 mole) of 5-(2-ethylphenyl)-3-(3-methoxyphenyl)-1H-1,2,4-triazole in 50 ml of anhydrous acetonitrile, 2,25 ml (0.018 mole) of 4-methylphenyl isocyanate were added. The resulting mixture was kept in the darkness for 18 hours, then the solid which formed was recovered by filtration and the mother liquors were brought to dryness under vacuum at room temperature. The obtained residue was taken up with 20 ml of diethyl ether, the mixture was filtered and the solid on the filter was collected with the solid deriving from the first filtration. 5.9 Grams (80%) of 5-(2-ethylphenyl)-3-(3-methoxyphenyl)-1-(4-methylphenylcarbamoyl)-1H-1,2,4-triazole were obtained. M.p. 141°-42° C. (from acetonitrile). Δδ=-0.24.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[CH:21]1([C:24](=N)OCC)[CH2:23][CH2:22]1>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]2[O:15][C:24]([CH:21]3[CH2:23][CH2:22]3)=[N:17][N:16]=2)=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=N)C1CC1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)NN)cc1
Agent: Cl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2nnc(C3CC3)o2)cc1
Yield: 40 %

Procedure:
4-(((Tert-butyldimethylsilyl)oxy)methyl)benzohydrazide was reacted with ethyl cyclopropanecarbimidate hydrochloride according to the procedure used for the synthesis of Example 18. Purification by chromatography (EtOAc-hexanes) gave 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-cyclopropyl-1,3,4-oxadiazole as a brown oil (3.7 g, 40% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])[CH3:2].[OH-].[Na+].[S:24](=[O:28])(=O)(O)[OH:25]>>[CH2:20]([O:19][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])[S:24]([C:11]1[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=1)(=[O:28])=[O:25])[CH3:21]
Reactant: O=S(=O)(O)O
Reactant: CCOC(CNCc1ccc2c(c1OC)OCO2)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
62.29 g (0.2 mol) of N-(2-methoxy-3,4-methylenedioxybenzyl)-N-methylaminoacetaldehyde dimethylacetal (1) obtained in Example 2 was dissolved in 400 ml of 6N sulfuric acid. After stirring at 76°-78° C. for 1.5 hours, the reaction mixture was cooled and pH was adjusted to about 11 by adding 25% aqueous solution of sodium hydroxide at temperature lower than 30° C. It was extracted with 200 ml and then 100 ml of methylene chloride successively, which were combined and washed with 100 ml of water and then dried over anhydrous magnesium sulfate. The salt was filtered out and the filtrate was concentrated under vacuum. The residue was dissolved under heating by adding 120 ml of ethanol and then cooled to 5° C. to deposit crystals. The crystals were collected by filtration, washed with 30 ml of cold ethanol and then dried under vacuum to obtain 38.09 g (yield 83%) of 4-hydroxy-8-methoxy-2-methyl- 6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (2), m.p. 152°-3° C. IR and NMR spectra of the resultant product are listed below. ##STR35##
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:5]([CH2:24][CH3:25])[CH:4]=1)=O.[C:26](#[N:30])[CH2:27][C:28]#[N:29]>>[CH2:24]([C:5]1[CH:4]=[C:3]([CH:1]=[C:27]([C:26]#[N:30])[C:28]#[N:29])[CH:8]=[CH:7][C:6]=1[N:9]=[C:10]1[S:14][CH2:13][C:12]2([CH2:15][CH2:16][CH2:17][CH2:18]2)[N:11]1[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:25]
Reactant: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reactant: N#CCC#N
Product: CCc1cc(C=C(C#N)C#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was reduced according to Method D11a to give 2-(4-formyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with malononitrile according to Method D12c according to afford 2-(2-ethyl-4-(2,2-dicyanovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([CH3:12])[CH:3]=1.[C:13](O)([CH3:16])([CH3:15])[CH3:14].S(=O)(=O)(O)O>O>[C:13]([C:7]1[C:2]([OH:1])=[CH:3][C:4]([CH3:12])=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)O
Reactant: Cc1cc(O)ccc1CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(O)c(C(C)(C)C)cc1CC(=O)O
Temperature: 25 °C

Procedure:
A solution of 8.5 g (51 mmol) of (4-hydroxy-2-methyl-phenyl)-acetic acid (Indian J. Chem. Sect B. 26, 1987:679-682), tert-butanol (60 g), and conc. sulfuric acid (2 mL) was stirred at 70° C. for 5 days. The solution was cooled to room temperature, poured into water, and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4), and concentrated to give (5-tert-butyl-4-hydroxy-2-methyl-phenyl)-acetic acid.