Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][NH:11][N:10]=2)[CH:8]=1)#[N:2].Cl[CH2:29][C:30]1[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:29][C:30]3[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=3)[N:10]=2)[CH:8]=1)#[N:2]
Reactant: Cn1nccc1CCl
Reactant: COc1ccc(C#N)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1-c1nn(Cc2ccnn2C)cc1NC(=O)c1cnn2cccnc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 32.1 %

Procedure:
To a solution of N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (144 mg, 0.40 mmol) in 3 mL of DMF was added 5-(chloromethyl)-1-methyl-1H-pyrazole (78 mg, 0.6 mmol) and cesium carbonate (391 mg, 1.20 mmol). The reaction mixture was stirred at 60° C. for 6 hours, then cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 58.3 mg (32%) of N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=454.1; 1H NMR (400 MHz, CDCl3) δ: 9.58 (s, 1H), 8.74 (dd, 1H), 8.64 (s, 1H), 8.48 (dd, 1H), 8.21 (s, 1H), 7.81 (s, 1H), 7.69 (dd, 1H), 7.39 (s, 1H), 7.07 (d, 1H), 6.96 (dd, 1H), 6.31 (s, 2H), 5.33 (s, 2H), 3.86 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1Cl.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>O.C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: OCc1cnc(-c2ccccc2)c(Cl)c1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A solution of 5,6-dichloro-pyridin-3-yl-methanol (10.0 g, 56.2 mmol), phenylboronic acid (7.5 g, 61.5 mmol), K2CO3 (20.0 g, 145 mmol) in H2O (140 mL) and dimethoxyethane (140 mL, 0.4 M), is degassed and treated with tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmol) and warmed to a gentle reflux under nitrogen for 4 h. After cooling to room temperature, ethyl acetate (100 mL) is added and the solids are filtered and washed with ethyl acetate (20 ml). The filtrate is extracted with ethyl acetate (100 mL) and the organic layer is washed with H2O (200 mL), saturated aq NaCl (200 mL) and dried over Na2SO4. The product is purified by MPLC (30-90% ethyl acetate in n-heptane) to provide 5-chloro-6-phenyl-pyridin-3-yl-methanol as a light yellow solid (12.0 g, 97%): Rf 0.24 (30% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.47 (br s, 1 H), 7.78 (br s, 1 H), 7.70-7.65 (m, 2 H), 7.50-7.40 (m, 3 H), 4.67 (s, 2 H); ESI-LCMS m/z calcd for C12H10ClNO: 219.0; found 220.0 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=[O:10])[CH2:6]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[N:26](OCCCC)=[O:27]>O1CCCC1>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4](=[N:26][OH:27])[C:5](=[O:10])[CH2:6]2
Reactant: CN1C2CCC1CC(=O)C2
Reactant: CCCCON=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C2CCC1C(=NO)C(=O)C2
Temperature: 0 °C
Yield: 26 %

Procedure:
A solution of 8-methyl-8-azabicyclo[3.2.1]octan-3-one (2.79 g, 20 mmol) in anhydrous tetrahydrofuran (40 mL) under nitrogen was cooled (-68° C.) and treated (via syringe) with 1.0N lithium bis(trimethylsilyl)amide/tetrahydrofuran (36 mL, 36 mmol) at a rate to keep the pot temperature below -55° C. The mixture was warmed to 0° C., then recooled (-68° C.), and treated dropwise with a solution of n-butyl nitrite (2.6 mL, 22 mmol) in anhydrous tetrahydrofuran (15 mL) at a rate to keep the pot temperature below -60° C. The mixture was warmed to room temperature over one h, stirred for one h, and quenched with saturated ammonium chloride (15 mL). The organic layer was separated and the aqueous solution was extracted with toluene (50 mL) containing some 2-propanol. The combined organic solution was dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel (eluted with 9:1 ethyl acetate/methanol, then with 3:2 ethyl acetate/methanol) to afford, first, 8-methyl-8-azabicyclo[3.2.1]octane-2,3-dione-2-oxime (0.43 g, 13%, beige solid), then recovered starting material (1.40 g). Product yield was 26% based on recovered starting material.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:39]([O:40][CH3:41])=[CH:38][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)=[O:28])=[C:25]([F:42])[CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO.O>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:39]([O:40][CH3:41])=[CH:38][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]5)=[O:28])=[C:25]([F:42])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCN1CCC(NC(=O)c2cc(OC)c(N)cc2F)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CC(C)CC(C)O
Product: CCN1CCC(NC(=O)c2cc(OC)c(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)cc2F)CC1
Temperature: 160 °C
Yield: 39 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 121 mg, 0.39 mmol) and 4-amino-N-(1-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide (Intermediate 205; 116 mg, 0.39 mmol) were taken up in 4-methyl-2-pentanol (4 mL) and p-toluenesulphonic acid monohydrate (150 mg, 0.79 mmol) added. The reaction mixture was heated at 160° C. by microwave irradiation for 1 hour. The cooled reaction mixture was poured into a mixture of methanol & water (5:2 v/v, 7 mL) and the resultant solution loaded onto an SCX-3 cartridge (5 g), which had been pre-wet with methanol. The cartridge was washed through with methanol (40 mL) and eluted with 2M ammonia in methanol (30 mL). The ammoniacal solution was evaporated to give an amber gum afforded which was purified by base modified reverse phase preparative HPLC which was re-purified by flash chromatography on a silica column eluting with 2.5-10% ammonia/methanol in DCM. Product containing fractions were combined and evaporated and the residue triturated with diethyl ether and resultant solid dried under vacuum, at 60° C., for 3 hours to yield the title compound as a flocculent white solid (86 mg, 39%)
Reaction SMILES: [CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10](Cl)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:26][C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33]>CN1CCCC1=O.C(OCC)(=O)C.O>[CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10]([O:34][C:29]4[CH:30]=[CH:31][C:32]([F:33])=[C:27]([F:26])[CH:28]=4)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCn1c(Cl)nc2nc(C3CCCC3)[nH]c2c1=O
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCn1c(Oc2ccc(F)c(F)c2)nc2nc(C3CCCC3)[nH]c2c1=O
Temperature: 130 °C
Yield: 19 %

Procedure:
To a solution of 8-cyclopentyl-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.06 g, 0.21 mmol) in N-methyl-2-pyrrolidone (0.2 ml) was added K2CO3 (0.044 g, 0.32 mmol) followed by 3,4-difluoro phenol and the reaction mixture was heated at 130° C. overnight. The reaction mixture was diluted with ethyl acetate and water. The layers were separated and ethyl acetate layer was washed with water. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using 3% methanol in DCM to give the product (0.015 g, 19%) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:9][C:8]=2[N+:21]([O-:23])=[O:22])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25].[NH:36]1[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][NH2:44])[N:38]=[CH:37]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:36]1[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][NH:44][C:24]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:12]=[CH:11][C:10]([C:13]4[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=4)=[CH:9][C:8]=3[N+:21]([O-:23])=[O:22])[CH2:2][CH2:3]2)=[O:25])[N:38]=[CH:37]1
Reactant: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c([N+](=O)[O-])c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: NCCCc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(N2CCN(C(=O)NCCCc3c[nH]cn3)CC2)c([N+](=O)[O-])c1
Temperature: 70 °C

Procedure:
3.0 g (9.5 mmol) of 6-[4-(1-Piperazinyl)-3-nitro-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 1.7 g (10.5 mmol) of carbonyl diimidazole are stirred together in 30 ml of DMF at room temperature for 2 hours. 1.88 g (15 mmol) of 3-(1H-imidazol-4-yl)-propylamine are then added and the reaction mixture is heated to 70° C. for 8 hours. After cooling, 10 ml of a saturated aqueous potassium carbonate solution are added and the reaction mixture is extracted with chloroform. The organic phase is concentrated by evaporation under vacuum and the residue is chromatographed on silica gel (Solvent F). Concentration of the main fractions by evaporation and crystallization of the residue yields 2.3 g (52% of theoretical) of orange crystals which have a melting point of 182° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[C:8]1[CH:9](OC)[O:10][C:11](=[O:12])[C:7]=1[CH:6]=[CH:5]2.CO.[CH3:20][NH2:21]>C1COCC1>[Br:1][C:2]1[CH:17]=[CH:16][C:15]2[C:8]3[CH:9]([OH:10])[N:21]([CH3:20])[C:11](=[O:12])[C:7]=3[CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: CN
Reactant: COC1OC(=O)c2ccc3cc(Br)ccc3c21
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)c2ccc3cc(Br)ccc3c2C1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-Bromo-1-methoxynaphtho[1,2-c]furan-3(1H)-one (1.03 g) was dissolved in THF (10 mL), and 40% methylamine methanol solution (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hr., and the solvent was evaporated to give the title compound (1.03 g) as pale-yellow crystals.
Reaction SMILES: [O:1]1[CH2:5][CH2:4]CC1.[CH2:6]([C:8]1[CH:14]=[CH:13][C:11]([OH:12])=[CH:10][C:9]=1[OH:15])[CH3:7].[H-].[Na+].[P:18](Cl)([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19]>O>[CH2:21]([O:20][P:18]([O:12][C:11]1[CH:13]=[CH:14][C:8]([CH2:6][CH3:7])=[C:9]([O:15][P:18]([O:1][CH2:5][CH3:4])([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=1)([O:23][CH2:24][CH3:25])=[O:19])[CH3:22]
Reactant: C1CCOC1
Reactant: CCc1ccc(O)cc1O
Reactant: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOP(=O)(OCC)Oc1ccc(CC)c(OP(=O)(OCC)OCC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a tetrahydrofuran solution (10 ml) of 4-ethylresorcinol (691 mg), sodium hydride (60% dispersion in liquid paraffin) (440 mg) was added and stirred at 0° C. for 30 minutes. Then, diethyl chlorophosphate (1.73 ml) was added dropwise. After stirring at room temperature for 3 hours, water (10 ml) was added to the reaction mixture, and the extraction was carried out with ethyl acetate (30 ml). Then, the extract was washed with saturated brine (10 ml), dried with anhydrous sodium sulfate and then concentrated. The residue (2.43 g) was subjected to silica gel chromatography (silica gel 40 g, chloroform to chloroform:methanol=10:1), to give the title compound (2.05 g, yield: 100%) as a pale yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O-:11].[Na+].C1C2C(=CC=CC=2)C=C[C:14]=1[OH:23].[OH2:24]>>[OH:11][C:2]1[C:3]([C:14]([OH:23])=[O:24])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: [O-]c1ccc2ccccc2c1
Reactant: O
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2cc1O
Reaction time: 5 h

Procedure:
A mixer 1 was fed hourly with 83 kg of sodium β-naptholate, 181 kg of light oil (boiling at 200°-310° C.) and 57.2 kg of β-naphthol, and they were mixed and dispersed. About one-third of the light oil layer (upper layer) formed in the separating tank was removed, and fed into a recovery apparatus (not shown) to recover the dissolved β-naphthol and a tiny amount of sodium β-naphtholate as an aqueous solution of sodium β-naphtholate. The mixture remaining in the separating tank 2 consisted of 81 kg of sodium β-naphtholate, 42.4 kg of β-naphthol and 130 kg of light oil. The liquid mixture was fed into a reactor 3 at a rate of 253.4 kg per hour, and reacted with carbon dioxide at a pressure of 5 kg/cm2.G and a temperature of 250° C. The residence time was 5 hours. The reaction mixture which left the reaction tank 3 was cooled in a heat exchanger (not shown), and mixed with 400 liters/hour of water in a stirring tank 4, and sent to a separating tank 5 where the mixture was separated at 85° C. into a light oil layer and an aqueous layer. From the upper light oil layer, β-naphthol was recovered by using a recovery device (not shown). The lower aqueous layer was sent to a pH adjusting tank 6, and after adjusting its pH to 5.5 with dilute sulfuric acid, was introduced into a separating tank 7. From the lower tarry layer in the separating tank 7, β-naphthol was recovered by using a vacuum distillation device (not shown). The upper layer was sent to an extracting device 8 where it was extracted with 250 liters/hr of xylene at 80° C. The xylene layer was sent to a recovery device (not shown) to recover β-naphthol. The aqueous layer in the extracting tank 8 was sent to an acid precipitation tank 9 where it was subjected to acid precipitation at a pH of 2.0 using dilute sulfuric acid at 85° C. Thus, 41.3 kg/hr of 2-hydroxynaphthalene-3-carboxylic acid (melting range 220°-221° C.) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH3:15])=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8]2)=[N:3]1.[Li+].[OH-]>CO.O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH3:15])=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8]2)=[N:3]1
Reactant: COC(=O)c1cc(C)c2nn(C)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)cc2cn(C)nc12
Temperature: 50 °C
Yield: 106.7 %

Procedure:
To a solution of methyl 2,7-dimethyl-2H-indazole-5-carboxylate (140 mg, 0.69 mmol) in methanol/water (V:V 1:1, 2 mL) was added LiOH (38 mg, 1.6 mmol). The solution was heated at 50° C. for 1 hour, cooled to room temperature, concentrated and acidified to pH 2 with KHSO4. The solid material was isolated by filtration to provide the title compound as a white solid (140 mg, 107%).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[N:37]([CH3:38])[C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[N:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>O.C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[N:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: Cn1c(C(=O)CBr)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3nc4ccccc4n3C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 24 h
Yield: 19.4 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 2-bromo-1-(1-methyl-1H-benzoimidazol-2-yl)ethanone (1.0 g) and N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at 50° C. for 24 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.28 g, 19%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([Si:20]([O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].CN([CH:36]=[O:37])C>C1COCC1>[Si:20]([O:23][CH2:24][CH2:25][C:26]1[C:27]([F:32])=[C:28]([CH:29]=[CH:30][CH:31]=1)[CH:36]=[O:37])([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:21])[CH3:22]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(C=O)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,2,6,6-tetramethylpiperidine (11.0 g) in anhydrous THF (200 mL) was cooled to −78° and treated with butyllithium (37.5 mL), added steadily over 5 minutes via a syringe. The solution was stirred at −78° for 15 minutes and then treated with a solution of tert-butyl(2-fluorophenethoxy)dimethylsilane [Aromatic Intermediate 5, step a] (9.9 g) in THF (25 mL), added dropwise over 15 minutes. The solution that was stirred at −78° for 2 hours, then treated with a solution of DMF (9.0 mL) in THF (25 mL), added dropwise over 10 minutes. The solution was stirred at −78° for 1 hour, then the cooling bath was removed and the solution was allowed to warm to room temperature overnight. The reaction mixture was poured into aqueous HCl (0.5M) and extracted three times with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the titled compound. Yield 10.1 g.
Reaction SMILES: N[C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C=O.[C:18]([BH3-])#[N:19].[Na+].[C:22](O)(=O)C>CO.O.C(Cl)Cl>[CH3:22][N:19]([CH3:18])[C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CN(C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl trans-4-aminocyclohexylcarbamate (750 mg, 3.5 mmol), paraformaldehyde (320 mg, 10 mmol), and sodium cyanoborohydride (660 mg, 13 mmol) in methanol (30 mL) was added acetic acid (catalytic) and the reaction was stirred at room temperature for 18 h. The reaction mixture was diluted with water and methylene chloride the layers were separated. The aqueous layer was adjusted to pH 10 using 1 M sodium hydroxide followed by extraction with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated to afford the desired product (800 mg, 95%) as a white solid: ESI MS m/z 243 [C13H26N2O2+H]+.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Cl:13])[CH:12]=1)[NH:9][C:8](=[O:14])[CH:7]=[N:6]2.I[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(O)C>[CH2:20]([O:19][C:17]([CH2:16][N:9]1[C:10]2[C:5](=[CH:4][C:3]([Cl:2])=[CH:12][C:11]=2[Cl:13])[N:6]=[CH:7][C:8]1=[O:14])=[O:18])[CH3:21]
Reactant: O=c1cnc2cc(Cl)cc(Cl)c2[nH]1
Reactant: CCOC(=O)CI
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cn1c(=O)cnc2cc(Cl)cc(Cl)c21
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere sodium (0.13 g, 5.62 mmol) was dissolved in 25 ml of abs. ethanol and 6,8-dichloroquinoxalin-2(1H)-one (1.10 g, 5.11 mmol) was added. The mixture was refluxed for 20 min., and ethyl iodoacetate (0.729 ml, 6.13 mmol) was added. The reaction mixture was refluxed for 72 h, cooled to room temperature, then poured onto crushed ice and acidified by dilute hydrochloric acid (pH=2). The precipitated compound was extracted with dichloromethane (4×30 ml) and purified by column chromatography on silica gel (eluent 10% THF in heptane) to give 1-ethoxycarbonylmethyl-6,8-dichloroquinoxalin-2(1H)-one. 1H-NMR (DMSO-d6):δ1.23 (t, 3H), 4.22 (q, 2H), 5.29 (s, 2H), 7.97 (dd, 2H), 8.45 (s, 1H).
Reaction SMILES: [S:1](Cl)([OH:4])(=O)=[O:2].[F:6][C:7]([F:15])([F:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][NH:30][CH3:31])[CH2:25][CH2:24]1>O.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][N:30]([CH3:31])[S:1]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([F:15])([F:14])[F:6])=[CH:9][CH:10]=2)(=[O:4])=[O:2])[CH2:27][CH2:28]1
Reactant: CNC[C@H]1CC[C@H](CCCCCBr)CC1
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C[C@H]1CC[C@H](CCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
0.786 ml Diisopropyl-aethylamine, 0.619 g (2.53 mmol) 4-trifluoromethyl-benzene sulfochloride and 0.952 mg potassium carbonate (dissolved in the minimal amount of water) were added to a solution of 0.718 g (2.30 mmol) trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-amine hydrochloride in 15.0 ml of tetrahydrofuran kept at −10° C. The reaction mixture was then intensively stirred for 1 hour at −10° C. and for 1 hour at room temperature. It was subsequently evaporated, poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with dichloromethane as the eluent giving 1.03 g (92.6%) trans-N-[4-(5-bromo-pentyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless amorphous solid, MS: 404 [(M−Br)+].
Reaction SMILES: [CH3:1][I:2].[CH2:3]([S:7][C:8]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][S:10][N:9]=1)[CH2:4][CH2:5][CH3:6]>>[I-:2].[CH2:3]([S:7][C:8]1[C:12]([C:13]2[CH:14]=[N+:15]([CH3:1])[CH:16]=[CH:17][CH:18]=2)=[N:11][S:10][N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCSc1nsnc1-c1cccnc1
Reactant: CI
Product: CCCCSc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl iodide (1 ml, 15 mmol) was added to a solution of 3-(3-butylthio-1,2,5-thiadiazol-4-yl)pyridine (0.6 g, 2.3 mmol) and the reaction mixture was stirred at room temperature for 48 h and evaporated.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])=[CH:5][CH:4]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>>[N:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])=[CH:5][CH:4]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CO[Si](OC)(OC)c1ccc(CCl)cc1
Agent: [Na+]
Product: CO[Si](OC)(OC)c1ccc(CN=[N+]=[N-])cc1
Temperature: 150 °C

Procedure:
1.0 mole of p-chloromethylphenyltrimethoxysilane and 1.1 moles of sodium azide were heated in the presence of 5 mole percent of the catalyst described in Example 1 (a) for three hours under stirring at 150° C. Then the salt formed was separated and the subsequent distillation under reduced pressure gave the p-azidomethylphenyltrimethoxysilane in a yield of 89 weight percent with the following characteristics: