Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17](=[N:19]O)[CH3:18])[CH:9]=1.[H][H]>[Pd].CCO.CC(O)=O>[NH2:19][CH:17]([C:10]1[CH:9]=[C:8]([N:7]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:29])([CH3:1])[CH3:30])[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=1)[CH3:18]
Reactant: [H][H]
Reactant: CC(=NO)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(N)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Yield: 104.7 %

Procedure:
A solution of 1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)pyrazolo[1,5-a]pyrimidin-5-yl]ethanone oxime (4.50 g, 8.77 mmol) in 4:1 EtOH/AcOH (90 mL) under nitrogen in a Parr bottle was treated with 10% Pd on carbon (933 mg, 0.877 mmol), and the mixture was shaken on the Parr apparatus under 45 psi hydrogen for 23 h. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure, azeotroping with toluene at 40-45° C. to remove most AcOH. The oily residue was taken up in EtOAc (˜100 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to give the title compound, 5-(1-aminoethyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (4.02 g, 91% purity, 95% yield) as an oil: MS (ESI+) for C20H39N5O2Si2 m/z 438 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[O:15])=[CH:9][CH:8]=1.Cl.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:14](=[O:15])[CH2:13][C:10]2[CH:11]=[CH:12][C:7]([S:6][CH3:5])=[CH:8][CH:9]=2)=[CH:21][CH:20]=1
Reactant: CSc1ccc(CC(=O)Cl)cc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CSc1ccc(CC(=O)c2ccc(F)cc2)cc1
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 40 %

Procedure:
Thereafter 174 g (1.3 moles) of anhydrous aluminum chloride was suspended in 600 ml of fluorobenzene. To the suspension was added dropwise a solution of 175 g of 4-methylthiophenylacetyl chloride obtained in the same manner as above in 120 ml of fluorobenzene at a temperature of 0° to 3° C. The resulting mixture was stirred at 20° C. for 3.5 hours. Then the reaction mixture was gradually poured into a mixture of ice water and hydrochloric acid, followed by extraction with dichloromethane. The dichloromethane layer was washed sequentially with a 5% aqueous solution of sodium bicarbonate and a saturated saline solution and dried over magnesium sulfate. The dichloromethane was distilled off and the resulting crystals were dissolved in 300 ml of a 2:1 mixture of ethyl acetate and isopropyl ether with heating. Ten grams of activated carbon was added and the solution was filtered. The separated crystals were collected by filtration, giving 92 g (40%) of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone as pale yellow solids.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.I[CH2:26][CH2:27][CH2:28][OH:29]>>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:26][CH2:27][CH2:28][OH:29])[CH:18]=2)=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Reactant: OCCCI
Product: Nc1nc(-c2ccco2)c(-c2ccc(=O)n(CCCO)c2)c(-c2ccco2)n1

Procedure:
The title compound was synthesized in a similar manner to Example 66 using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and 3-iodopropanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1.FC(F)(F)S(OC1C2C=CC([C:49]#[C:50][C:51]3[CH:61]=[CH:60][C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=3)=CC=2C(C)(C)CC=1)(=O)=O>C1COCC1>[CH3:30][C:2]1([CH3:1])[C:11]2[CH:10]=[C:9]([C:49]#[C:50][C:51]3[CH:61]=[CH:60][C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3c2nccs2)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 400 mg (0.84 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) in 2 ml of THF was converted into the title compound (white solid) using a solution of 82 mg (1.26 mmol) of thiazole in 2 ml of THF, 81 mg (0.84 ml, 1.26 mmol) of n-butyllithium (1.5M solution in hexanes), 228 mg (3.36 ml, 1.68 mmol) of zinc chloride (0.5M solution in THF) and 10 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium (0).
Reaction SMILES: NC1(C[O:8]C2C=CC(C#N)=CC=2)CCCC1.[CH3:17][N:18]([CH3:34])[C:19]1([CH2:24][O:25][C:26]2[CH:33]=[CH:32][C:29]([C:30]#N)=[CH:28][CH:27]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:17][N:18]([CH3:34])[C:19]1([CH2:24][O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:8])=[CH:28][CH:27]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CN(C)C1(COc2ccc(C#N)cc2)CCCC1
Reactant: N#Cc1ccc(OCC2(N)CCCC2)cc1
Product: CN(C)C1(COc2ccc(C=O)cc2)CCCC1

Procedure:
Synthesized from 4-(1-aminocyclopentylmethoxy)benzonitrile according to an analogous synthetic method to Preparation Example 18, 4-(1-dimethylaminocyclopentylmethoxy)benzonitrile (1.2 g) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (1.2 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[NH:10][CH2:9][CH:8]=2)[CH:2]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[C:11]4[N:10]([C:19](=[O:20])[NH:18][C:16](=[O:17])[C:15]=4[CH:14]=[N:13]3)[CH2:9][CH:8]=2)[CH:2]=1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n2c3c1cnn3C(c1cccnc1)=CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
A mixture of 4.0 g of 4,5-dihydro-7-(3-pyridinyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 10), 80 ml of dry p-dioxane and 10.0g of 1,1'- carbonyldiimidazole is heated at reflux for 5 hours. Then an additional 5.0 g of 1,1'-carbonyldiimidazole is added and heating is continued for 16 hours. After cooling to room temperature the precipitated solid is collected by filtration, washed with water and dried in vacuo to give 2.0 g of the desired product as a white solid, mp 292-295° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[S-:6].[Na+].[CH3:11][O:12][N:13]=[C:14]([C:20](=[O:23])[CH2:21]Br)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C.C(OCC)(=O)C>[CH3:11][O:12][N:13]=[C:14]([C:20](=[O:23])[CH2:21][S:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Reactant: COc1cccc([S-])c1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NOC)C(=O)CSc1cccc(OC)c1
Temperature: 25 °C

Procedure:
To a stirred solution of sodium 3-methoxythiophenoxide in 150 ml of ethanol (prepared by reacting 14 g of 3-methoxythiophenol with 5.94 g of sodium methoxide) were added dropwise over ten minutes 27.7 g of ethyl 2-methoxyimino-3-oxo-4-bromobutyrate. The reaction mixture was stirred at 25° C. for sixteen hours, and then the solvent was removed by evaporation under reduced pressure to give an oil. The oil was dissolved in ethyl acetate and washed several times with water. The organic layer was dried and the solvent was removed by evaporation to afford 16.28 g of ethyl 2-methoxyimino-3-oxo-4-(3-methoxyphenylthio)butyrate. NMR (CDCl3): δ1.32 (t, 3H); δ3.79 (s, 3H); δ4.05 (s, 3H), δ4.34 (q, 2H); δ6.7-7.3 (m, 4H).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:38][C:39](Cl)=[O:40])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:38][C:39]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH2:8][CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:40])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: c1ccc(C(CC2CCCCN2)c2ccccc2)cc1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N2CCCCC2CC(c2ccccc2)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.65 g (0.01M) of 2-(2,2-diphenylethyl)piperidine in 25 ml of methylene chloride containing 1.5 ml of triethylamine was cooled in ice and a solution of 2.35 g (0.011M) of 3,4-di-methoxyphenylacetyl chloride in 25 ml of methylene chloride was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature overnight. The mixture was then washed with dilute hydrochloric acid, water, dilute sodium hydroxide and saturated sodium chloride solution. Removal of the solvent left an oil which was purified by chromatography on silica gel. The solid thus obtained melted at 113°-114° C. after recrystallization from cyclohexane-ethyl acetate.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]1[CH2:17][C:18]([O:20]C)=[O:19].[Li+].[OH-].O.Cl>C1COCC1.O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:15])([F:14])[F:16])[CH:8]=2)[N:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cn1c(=O)ccc2cc(OC(F)(F)F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)ccc2cc(OC(F)(F)F)ccc21
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetate (1.2 mmol) in THF/water (2:1) was added LiOH. H2O (8.1 mmol). The resulting mixture was stirred overnight. The crude product mixture was slowly acidified with 1N HCl solution and then extracted with EtOAc. The organic phase was separated, dried (MgSO4), filtered and concentrated under vacuum to give 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid. Retention time (min)=1.783, method [1], MS (ESI) 288.1 (M+H).
Reaction SMILES: [C:1]([NH:6][C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[C:8]([CH3:13])[CH:9]=1
Reactant: BrBr
Reactant: CCCC(=O)Nc1ccccc1C
Solvent: O
Solvent: CC(=O)O
Product: CCCC(=O)Nc1ccc(Br)cc1C
Reaction time: 1 h
Yield: 98 %

Procedure:
30 g of N-butyryl-o-toluidine and 150 g of glacial acetic acid were initially charged at 30° C. A solution of 33 g of bromine in 66 g of glacial acetic acid was added with stirring and then stirring was continued at from 25 to 30° C. for 1 hour. 300 ml of water were then added to the reaction mixture which, after continued stirring for a short time, was filtered, the crystals were washed with water and dried under reduced pressure. 42.5 g (98% yield) of N-(4-bromo-2-methylphenyl)butanamide were obtained in 99.4% purity.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23](=O)[CH3:24])=[C:6]([CH3:22])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][C:11]=2[O:19][CH2:20][CH3:21])[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:26][NH2:27]>>[CH2:20]([O:19][C:11]1[CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=[CH:15][C:10]=1[N:7]1[C:8]([CH3:9])=[C:4]2[C:5]([C:23]([CH3:24])=[N:26][N:27]=[C:1]2[CH3:2])=[C:6]1[CH3:22])[CH3:21]
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(OCC)c1
Reactant: NN
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)c(OCC)c1

Procedure:
Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(2,4dihydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone prepared as in Example 70 (12 mg, 0.4 mmol) reacted with bromoethane (30 μL, excess), in the presence of K2CO3 (10 mg), to afford 1-[4-acetyl-1-(2,4-diethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 344 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(2,4-diethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (4 mg) and hydrazine (5 μL) reacted to give 6-(2,4-diethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as off-white solid: 1H NMR (CDCl3, 500 MHz) δ 7.03 (d, 1H), 6.67 (s, 1H), 6.64 (d, 1H), 4.15 (q, 1H), 4.04 (q, 1H), 2.89 (br s, 6H), 2.43 (s, 6H), 1.49 (t, 3H, 1.26 (t, 3H); MS (ESI) 340 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23]Cl)[CH:14]=1)[CH2:3]/[CH:4]=[CH:5]/[C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>CN(C)C=O>[CH3:1][N:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH:14]=1)[CH2:3]/[CH:4]=[CH:5]/[C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(OC/C=C/CCl)c1
Solvent: CN(C)C=O
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(OC/C=C/Cn2ccnc2)c1
Temperature: 80 °C
Yield: 49.5 %

Procedure:
50 mg of (E,E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-(4-chloro-2-butenyloxy)benzylamine was dissolved in 0.5 ml of dimethylformamide, and 30 mg of imidazole was added. The mixture was heated at 80° C. for 1 hour. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue to extract it. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [ethyl acetate→ethyl acetate/methanol=10/1] to give 27 mg (yield 53 %) of the captioned compound as a pale yellow oil.
Reaction SMILES: Br.CS(O[C@H:7]1[C:26]2[C@:21]([CH3:28])([CH2:22][CH2:23][C:24](=[O:27])[CH:25]=2)[C@@H:20]2[C@H:9]([C@H:10]3[C@:17]([CH3:29])([CH2:18][CH2:19]2)[C@@:13]([OH:30])([C:14](=[O:16])[CH3:15])[C:12](=[CH2:31])[CH2:11]3)[C@H:8]1OS(C)(=O)=O)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>C(O)(=O)C.CN(C)C=O>[N:37]([C:7]1[C:26]2[C@:21]([CH3:28])([CH2:22][CH2:23][C:24](=[O:27])[CH:25]=2)[C@@H:20]2[C@H:9]([C@H:10]3[C@:17]([CH3:29])([CH2:18][CH2:19]2)[C@@:13]([OH:30])([C:14](=[O:16])[CH3:15])[C:12](=[CH2:31])[CH2:11]3)[CH:8]=1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: C=C1C[C@H]2[C@@H]3[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(C)=O
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C1C[C@H]2[C@@H]3C=C(N=[N+]=[N-])C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(C)=O

Procedure:
In a manner similar to that described in Example 26, treat 6β,7β-dimethanesulfonyloxy-16β-methyl-16α,17α-oxido-4-pregnene-3,20-dione with hydrogen bromide in acetic acid; treat the resulting 6β,7β-dimethanesulfonyloxy-16-methylene-17α-hydroxy-4-pregnene-3,20-dione with sodium azide in dimethylformamide to obtain 6-azido-16-methylene-17α-hydroxy-4,6-pregnadiene-3,20-dione.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl.N1CCCNCC1.[I-].[Na+].CS(O[CH2:24][CH2:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)=O>C(O)C>[C:27]1([CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:25][CH2:24][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: C1CNCCNC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A mixture of 126 mg of homopiperazine. 218 mg of homopiperazine dihydrochloride, 3 mL of ethanol was heated to 70° C. into a solution. 378 mg of sodium iodide and 289 mg of 3,3-diphenylpropyl methanesulfonate were added sequentially to the solution and the solution was stirred at 70° C. for 15 hours. After the solution was cooled to room temperature, the ethanol was removed under reduced pressure followed by adding 20 mL of aqueous 2N sodium hydroxide and extracting with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1-(3,3-diphenylpropyl)homopiperazine.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]([C:10]1[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[NH:12][CH:11]=1)=[CH:6]2.I.CS[C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[NH:26]>C(O)C.[Pd]>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]([C:10]1[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[NH:26])[CH:17]=3)[NH:12][CH:11]=1)=[CH:6]2
Reactant: CN1C2C=C(c3c[nH]c4ccc([N+](=O)[O-])cc34)CC1CC2
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CN1C2C=C(c3c[nH]c4ccc(NC(=N)c5cccs5)cc34)CC1CC2
Reaction time: 14 h
Yield: 43.8 %

Procedure:
A solution of compound 89 (0.25 g, 0.882 mmol) in dry ethanol (10 mL) was treated with Pd—C (0.025 g) and purged with hydrogen gas. The reaction was stirred under hydrogen atm. (balloon pressure) for overnight (14 h). The solid was filtered off using celite bed and washed with ethanol (2×5 mL). The combined ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.5 g, 1.764 mmol) at room temperature and stirred for 24 h. Ethanol was evaporated and crude material was basified with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography on silica gel (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 90 (0.14 g, 44%) as a solid. mp 93-95° C.; 1H NMR (DMSO-d6) δ 1.60-1.65 (m, 1H), 1.84-1.90 (m, 1H), 2.02-2.26 (m, 4H), 2.41 (s, 3H), 2.83-2.89 (m, 1H), 3.46-3.55 (m, 1H), 6.20 (brs, 2H), 6.67 (d, 1H, J=7.8 Hz), 7.10 (s, 1H), 7.23-7.31 (m, 3H), 7.60-7.72 (m, 2H), 10.99 (s, 1H); ESI-MS m/z (%): 363 (MH+, 65), 182 (100), 119 (48); ESI-HRMS calculated for C21H23N4S (MH+), Calculated: 363.1633; Observed: 363.1637.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH:12]([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[O:11][CH:12]([C:13]([F:14])([F:15])[F:16])[C:17]([F:20])([F:19])[F:18]
Reactant: O=[N+]([O-])c1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
3-Chloro-2-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)-5-nitropyridine (Preparation 255, 2.55 g, 7.9 mmol), ammonium chloride (2.50 g, 46.7 mmol) and iron powder (1.70 g, 30.4 mmol) were suspended in a mixture of ethanol (10 mL) and water (3 mL). The suspension was heated for 3 hours under reflux then allowed to cool to room temperature. The reaction mixture was filtered on a Celite™ pad and the pad was washed with ethanol. The filtrate was concentrated in vacuo and the crude residue was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted by ethyl acetate (2×25 mL). Organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 50% diethyl ether in heptane to afford the title compound as a light yellow oil (2.0 g, 87%).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]1([CH2:14][CH2:15][SH:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][C:18]1[N:26]=[C:25](Cl)[N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[Cl-].[Na+].O>[NH2:17][C:18]1[N:26]=[C:25]([S:16][CH2:15][CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: SCCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(SCCc2ccccc2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 36.2 %

Procedure:
Sodium hydride (300 mg, 7.5 mmol 60% in mineral oil) were added DMF (10 ml), 2-phenylethanethiol (1 ml, 7 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred at 100° C. for 10 hours. After addition of saturated brine the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (51 mg, yield 37%).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:23])=[N-]>CCOCC>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([O:20][CH3:23])=[O:19])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cccc2c1CCC2C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C1CCc2c(C(=O)c3ccccc3)cccc21
Reaction time: 0.5 h

Procedure:
In 50 ml. of ether is dissolved 2.7 g. of 4-benzoylindan-1-carboxylic acid and, then, an ethereal solution of diazomethane is added until the yellow color of the solution has not disappeared. The solution is then allowed to stand for 30 minutes, after which the excess diazomethane and the ether are distilled off. The methyl 4-benzoylindan-1-carboxylate thus obtained as the distillation residue is dissolved in 50 ml. of dimethylsulfoxide and under stirring, the solution is added dropwise to 100 ml. of dimethylsulfoxide containing 1.5 g. of sodium hydride over a period of 15 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:25])[CH2:14][N:15]3[C:19]([CH3:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[N:16]3)[CH2:9][CH2:8]2)[S:5][CH:6]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CO>C1COCC1>[CH3:20][C:19]1[N:15]([CH2:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:4]3[S:5][CH:6]=[C:2]([NH:1][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])[N:3]=3)[CH2:8][CH2:9]2)=[O:25])[N:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(N)cs2)CC1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(NC(=O)Nc3ccccc3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (100 mg, 0.27 mmol) in THF (5 mL) is added dropwise a solution of phenylisocyanate (30 μL, 0.28 mmol) in THF (1 mL) at 0° C. After stirring overnight at RT, methanol (1 mL) is added to the reaction mixture. After stirring 15 min. at RT, the solvents are evaporated and the residue was triturated with diethylether (5 mL) to induce precipitation. The resulting solid is filtered and dried under vacuum to give 1-(2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-3-phenyl-urea as beige solid (Compound No. I.g.024, 105 mg, 79%). M.p.=192.6° C. 1H-NMR (400 MHz, CDCl3): δ=1H-NMR (MeOD): d=1.65 (m, 1H), 1.80 (m, 1H), 2.40 (m, 2H), 2.30 (s, 3H), 2.98 (m, 1H), 3.30 (m, 1H), 3.39 (m, 1H), 4.10 (m, 1H), 4.52 (m, 1H), 5.22 (2d, 2H, diastereotopic), 6.42 (s, 1H), 7.05 (t, 1H), 7.09 (s, 1H), 7.26-7.45 (m, 6H). MS: m/z=494 (M+1).