Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[C:9]([O:10][C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:8][C:7]([CH3:19])=[N:6][CH:5]=1.O.O.[OH-].[Li+:24]>O1CCOCC1>[Cl:18][C:12]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=1[O:10][C:9]1[C:4]([C:3]([O-:20])=[O:2])=[CH:5][N:6]=[C:7]([CH3:19])[CH:8]=1.[Li+:24]
Reactant: COC(=O)c1cnc(C)cc1Oc1cc(Cl)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 420 mg (1.345 mmol) 4-(2,5-dichloro-phenoxy)-6-methyl-nicotinic acid methyl ester in 5 mL dioxane was added 5 mL water and 85 mg (2.018 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred for 2 hours at room temperature and then concentrated under vacuum. The so-obtained light yellow solid was pure enough for the next step without further purification. MS (ESI): m/z=298.004 [M+H]+.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]1[C:17]([OH:18])=[CH:16][N:15]=[C:14]2[N:19]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:21][C:13]=12>CN(C=O)C>[F:11][C:12]1[C:17]([O:18][CH:2]([CH3:4])[CH3:3])=[CH:16][N:15]=[C:14]2[N:19]([Si:22]([CH:26]([CH3:28])[CH3:27])([CH:29]([CH3:31])[CH3:30])[CH:23]([CH3:24])[CH3:25])[CH:20]=[CH:21][C:13]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(O)cnc21
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1F
Temperature: 80 °C
Yield: 28.6 %

Procedure:
2-Bromopropane (120 mg, 0.973 mmol) and potassium carbonate (448 mg, 3.24 mmol) were added to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (200 mg, 0.648 mmol) in DMF (3 mL). The reaction was heated to 80° C. in a sealed tube for 18 hours and then cooled down. The reaction mixture was concentrated to dryness. The mixture was then suspended in DCM and filtered. The filtrate was concentrated and purified by chromatography (SP4, 12+M, water/ACN 80/20→10/90, 20CV) to yield 4-fluoro-5-isopropoxy-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (65 mg, 42%) as a solid.
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13]CCCC(C1C=CC(F)=CC=1)=O>C1(C)C=CC=CC=1.[I-].[K+]>[ClH:13].[C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: [I-]
Agent: [K+]
Agent: c1ccc(C23CNCC2C3)cc1
Solvent: Cc1ccccc1
Product: Cl

Procedure:
A mixture of 15.9 g of 1-phenyl-3-azabicyclo[3.1.0]hexane (Example 9), 20.1 g of γ-chloro-p-fluorobutyrophenone and 10 mg of potassium iodide in 100 ml of toluene is refluxed for 24 hours. Filtration gives 11.6 g of 1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride, m.p. 166°-167° C. Evaporation of the filtrate gives a brown oil which is combined with 2 N hydrochloric acid and chloroform. The crystals which form in the chloroform layer are collected by filtration and recrystallized from ethanol to give 3.10 g of 3-[3-(p-flurorbenzoyl)propyl]-1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride as pale tan crystals, m.p. 151°-153° C.
Reaction SMILES: [CH3:1][NH:2][NH2:3].CO[C:6]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:18])[N:7]=1>C(O)C>[CH3:1][NH:2][NH:3][C:6]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:18])[N:7]=1
Reactant: CNN
Reactant: COc1ncn(-c2ccccc2)c(=O)n1
Solvent: CCO
Product: CNNc1ncn(-c2ccccc2)c(=O)n1
Reaction time: 1 h
Yield: 63.1 %

Procedure:
2.4 ml of methylhydrazine dissolved in 10 ml of absolute ethanol are added to a suspension of 4-methoxy-1-phenyl-1,2-dihydro-1,3,5-triazin-2-one (4.60 g) in 100 ml of absolute ethanol and stirred for one hour. The solid product is filtered, washed with ether and dried to give 3.10 g (63.1%) of 4-methylhydrazino-1-phenyl-s-triazin-2-one, m.p. 219° C.
Reaction SMILES: [I-].[K+].Cl[CH2:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:29]([O:31][C:32](=[O:40])[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1)[CH3:30]>C(C(C)=O)C>[CH2:29]([O:31][C:32](=[O:40])[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([CH2:4][CH2:5][CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:35]1)[CH3:30]
Reactant: ClCCCN1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)CC1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: CCOC(=O)CC1CCCN(CCCN2c3ccccc3CCc3ccccc32)C1
Reaction time: 3 h

Procedure:
A mixture of potassium iodide (19.2 g, 0.12 mol) and methyl ethyl ketone (180 ml) was heated at reflux temperature for 1 h. A solution of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine (5.2 g, 0.019 mol, prepared similarly as described in example 1) in methyl ethyl ketone (25 ml) was added and heating at reflux temperature was continued for 3 h. Potassium carbonate (9.3 g, 0.067 mol) and 3-piperidineacetic acid ethyl ester hydrochloride (5.6 g, 0.027 mol) were added and the reaction mixture was heated at reflux temperature for 2 h. The temperature was lowered to just below reflux and the mixture was left with stirring overnight. After cooling, the reaction mixture was filtered (Hyflo) and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (225 g) using a mixture of heptane and ethyl acetate (1:1) as eluent, to give 5.0 g of 1-(3-(10,11-dihydro-5H-dibenz[b,f]-azepin-5-yl)-1-propyl)-3-piperidine-acetic acid ethyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>O1CCCC1>[N+:8]([C:7]1[C:2](=[O:1])[N:3]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1cccc([N+](=O)[O-])c1=O
Temperature: 25 °C
Yield: 75.1 %

Procedure:
2-Hydroxy-3-nitro-pyridine (75 g, 0.535 mole) and 1400 mL of anhydrous tetrahydrofuran were stirred at 0° C. using a mechanical stirrer. Lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 683.5 mL) was slowly added over 30 minutes. The deep brown reaction mixture was stirred for 30 additional minutes and then t-butyl bromoacetate (109.6 g, 0.561 mole) was slowly added over 30 minutes. The reaction mixture was warmed to 25° C. overnight. The organic solvents were removed under vacuum and the residue was dissolved in 2 liters of ethyl acetate and 500 mL of water. The organic phase was dried with magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed on silica gel using a methylene chloride:ethanol gradient, 100:0 to 98:2, to yield 102.1 g (75 %) of the title compound as a yellow-orange solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C.[Mg].C([O:28][C:29]1[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31](=O)[C:30]=1[CH3:38])C.Cl.C(=O)([O-])O.[Na+]>C(OCC)C.O1CCCC1>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:31]1[C:32]([CH3:36])([CH3:35])[CH2:33][CH2:34][C:29](=[O:28])[C:30]=1[CH3:38]
Reactant: CCOC1=C(C)C(=O)C(C)(C)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=C(CCCCCCCCCCCCCCCO)C(C)(C)CCC1=O
Reaction time: 4 h
Yield: 38.9 %

Procedure:
15-Bromo-1-(t-butyldimethylsiloxy)pentadecane (1 g, 2.36 mmol) dissolved in absolute ethyl ether (3 mL) and magnesium (0.115 g) were mixed, and the mixture was refluxed for 40 minutes. Subsequently, 3-ethoxy-2,6,6-trimethyl-2-cyclohexen-1-one (287.5 mg, 1.57 mmol) dissolved in tetrahydrofuran (2 mL) was added thereto. After stirring the mixture for four hours, 10% hydrochloric acid (3 mL) was added, and the reaction was allowed to continue for a further 17 hours under stirring. The reaction mixture was neutralized with sodium hydrogencarbonate, followed by extraction with ethyl ether three times. The organic layers were combined, washed with aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by means of silica gel column chromatography (hexane/ethyl acetate=9/1-6/4; concentration gradient=5%), to thereby afford 222.7 mg (0.61 mmol) of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)O1.[NH2:27][C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([CH:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)[N:35]=[C:36](I)[C:29]=12.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:27][C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([CH:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)[N:35]=[C:36]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:25])=[CH:13][CH:14]=3)[C:29]=12
Reactant: CC1(C)OB(c2ccc(NC(=O)OCc3ccccc3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(NC(=O)OCc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A mixture of benzyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (9.54 g, 0.027 mol), tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (10.0 g, 0.0225 mol), tetrakis(triphenylphosphine)palladium (1.56 g, 0.00135 mol) and sodium carbonate (5.97 g, 0.0563 mol) was heated in a mixture of ethylene glycol dimethyl ether (120 mL) and water (60 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between water (150 mL) and dichloromethane (150 mL); the organic phase was washed with brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was triturated in diethyl ether and the precipitate was collected by filtration and dried to yield tert-butyl 4-[4-amino-3-(4-[(benzyloxy)carbonyl]aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (10.1 g, 0.0186 mol) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17])([O-])=[O:7]>>[N:6]1[O:7][C:15]([C:16]([OH:18])=[O:17])=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=12
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: O=C(O)c1onc2ccccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
To 1 l of concentrated sulfuric acid, 40 g (0.22 mol) of orthonitrophenylacetic acid were added, followed by stirring at 105°-110° C. for 90 minutes. After cooling, 2.5 l of ice water in limited amounts was added to the reaction mixture. The resultant mixture was extracted with if of ethyl ether. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off, so that 18.1 g (yield: 50.2%) of 2,1-benzisoxazole-3-carboxylic acid was obtained as crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)=[CH:14][CH:15]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]1[CH:23]([CH3:24])[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(O)cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(OC3CCCCO3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cold (0° C.) solution of 1-benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic acid, ethyl ester (Compound 1, 2.3 gm, 6.82 mmol) in CH2Cl2 (31 mL) was added dihydropyran (DHP, 3.1 g, 36.9 mmol) and p-TsOH (50 mg). The cooling bath was removed, and the solution was stirred at ambient temperature for 16 h. The reaction was quenched by adding aqueous NaHCO3 (20 mL) and CH2Cl2 (50 mL). The layers were separated, and the organic layer was washed with brine (20 mL), and dried (MgSO4), and solvent removed under vacuum. The crude mixture was purified by silica gel flash chromatography by eluting with 10% EtOAc in hexanes to isolate 1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indole-3-carboxylic acid, ethyl ester (Compound 11) as a thick pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].C(N(CC)CC)C>ClCCl>[C:12]([C:10]1[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:23]([N:22]([CH3:26])[CH3:21])=[O:24])[CH2:19][CH2:20]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)N(C)C)CC1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with N,N-dimethylcarbamoyl chloride (0.014 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL, 16 mmol) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (27 mg, 72%). LCMS calculated for C18H22ClN4O2 (M+H)+: m/z=361.1; Found: 361.0.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([Cl:25])[C:6]=1[NH:26][CH:27]1[CH2:29][CH2:28]1)C.[OH-].[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[C:21]([O:20][C:18]([NH:17][C@H:14]1[CH2:15][CH2:16][N:12]([C:8]2[C:9]([F:11])=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[C:6]([NH:26][CH:27]3[CH2:28][CH2:29]3)[C:7]=2[Cl:25])[CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)cc(C(=O)O)c(NC3CC3)c2Cl)C1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorobenzoic acid ethyl ester (Example 3c, 2.90 g, 6.56 mmol) in methanol (30 mL) and tetrahydrofuran (30 mL) is added a 1N solution of sodium hydroxide (50 mL). The reaction mixture is stirred at 80° C. for 20 hours, cooled to room temperature, and diluted with ethyl acetate. The organic layer is washed with 1N hydrochloric acid, water, and brine. The organic layer is dried over MgSO4, filtered, and filtrate concentrated to the title compound as a solid (2.74 g). MS CI: m/z 414 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:25]([C:27]1[CH:40]=[CH:39][C:30]([CH2:31][N:32]2[C:36]([CH:37]=O)=[CH:35][N:34]=[CH:33]2)=[CH:29][CH:28]=1)#[N:26].CCOC(C)=O>ClCCCl>[C:25]([C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:32]2[C:36]([CH2:37][NH:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:35][N:34]=[CH:33]2)=[CH:39][CH:40]=1)#[N:26]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: NCCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: N#Cc1ccc(Cn2cncc2CNCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-phenylpropylamine (0.202 mL, 1.42 mmol) in 5 mL of 1,2-dichloroethane at 0° C. was added 4Å powdered molecular sieves (0.38 g), followed by sodium triacetoxyborohydride (301 mg, 1.42 mmol g). The aldehyde 6 from Step 5 of Example 1 (200 mg, 0.947 mmol) was added, and the reaction was allowed to warm to room temperature. After 2 days, the reaction was poured into EtOAc, washed with sat. aq. NaHCO3, and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was taken up in 12 mL of 20% CH2Cl2 /propylamine, stirred for 12 hours, concentrated in vacuo, and purified by preparative HPLC. Thus, the product was taken up in water/MeOH solution and was injected directly onto a Delta-Pak (C-18, 100A, 15 mm, 40 mm×100 mm) prep HPLC column using a gradient with 0.1% trifluoroacetic acid/water and 0.1% trifluoroacetic acid/acetonitrile as solvents. A portion of the pure fractions was then partitioned between methylene chloride and water, and the organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product 10 as a white solid.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br:7][C:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16]([Cl:17])[C:11]=2[NH:10][C:9]=1[CH3:19].[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>CN(C=O)C.ClCCl>[Br:7][C:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16]([Cl:17])[C:11]=2[N:10]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[C:9]=1[CH3:19]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1nc(Cl)c2[nH]c(C)c(Br)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c2c(n1)c(Br)c(C)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.82 g; 45.60 mmol; 60% in oil, washed with hexane), is suspended in dry DMF (125 mL) and dry DMSO (25 mL). To the stirring suspension 7-Bromo-4-chloro-2,6-dimethyl-5H-pyrrolo[3,2-d]pyrimidine from example A8 (10.00 g; 38.00 mmol) dissolved in dry DMF (125 mL) is added dropwise within 30 minutes at ambient temperature. After complete addition the reaction mixture is stirred for one hour at ambient temperature. To the resulting solution 2-(trimethylsilyl)ethoxymethylchloride (8.74 mL; 49.40 mmol) is added dropwise and the reaction mixture is stirred for one hour at ambient temperature. After diluting with water/ice and dichloromethane, the organic layer is separated and the aqueous layer is extracted with dichloromethane (2×400 mL). The combined organic layers are dried over MgSO4 and filtered through a plug of neutral alumina (act. 2-3). The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel (cyclohexane:ethylacetate/9:1) affording the title compound as a white solid.
Reaction SMILES: [N+](C1C=CC(O[C:9]([CH2:11][CH:12]([CH3:26])[CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)=[O:10])=CC=1)([O-])=O.[CH3:29][NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH3:37]>CN(C)C=O>[CH3:29][N:30]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH3:37])[C:9]([CH2:11][CH:12]([CH3:26])[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]2)=[O:10]
Reactant: CNC1CCCCC1C
Reactant: CC(COc1ccc2[nH]c(=O)ccc2c1)CC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(COc1ccc2[nH]c(=O)ccc2c1)CC(=O)N(C)C1CCCCC1C

Procedure:
3.8 Grams of 6-[3-(p-nitrophenoxycarbonyl)-2-methylpropoxy]carbostyril is dissolved in 40 ml of dimethylformamide, followed by addition of 1.6 ml of N-methyl-2-methylcyclohexylamine and 12-hour agitation at 60°-70° C. After the reaction, the solvent is distilled off and the obtained residue is refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: 20/1 (V/V) chloroform/methanol) and the crude crystals are recrystallized from benzene-ligroin to obtain 1.6 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyril in the form of colorless needlelike crystals with melting point of 146°-149° C.
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]1=[O:17].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[N:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH:3]([CH3:18])[CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]3=[O:17])[CH2:31][CH2:32]2)=[CH:38][CH:37]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: C=C(C)n1c(=O)n(CC(C)CCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C=C(C)n1c(=O)n(CC(C)CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2ccccc21

Procedure:
A mixture of 12 parts of 1-(3-chloro-2-methylpropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 5.76 parts of 1-[bis(4-fluorophenyl)methyl]piperazine, 5.3 parts of sodium carbonate, 0.2 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 20 hours with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated, yielding 1-[3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}-2-methylpropyl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: Br[CH:2]1[C:8](=O)[C:7]2[CH:10]=[C:11](F)[CH:12]=[CH:13][C:6]=2[S:5][CH2:4][CH2:3]1.[CH3:15][N:16]([CH3:33])[S:17]([NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30]([NH2:32])=[S:31])[CH2:24][CH2:23]1)(=[O:19])=[O:18]>>[N:32]1[C:8]2[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=3[S:5][CH2:4][CH2:3][C:2]=2[S:31][C:30]=1[NH:29][CH2:28][CH:25]1[CH2:26][CH2:27][CH:22]([CH2:21][NH:20][S:17]([N:16]([CH3:33])[CH3:15])(=[O:19])=[O:18])[CH2:23][CH2:24]1
Reactant: CN(C)S(=O)(=O)NCC1CCC(CNC(N)=S)CC1
Reactant: O=C1c2cc(F)ccc2SCCC1Br
Product: CN(C)S(=O)(=O)NCC1CCC(CNc2nc3c(s2)CCSc2ccccc2-3)CC1

Procedure:
4-Bromo-7-fluoro-2,3,4,5-tetrahydro-1-benzothiepin-5-one (0.200 g, 0.720 mmole) and N-[4-([(dimethylamino)sulfonyl]aminomethyl)-cyclohexyl]methylthiourea (0.250 g, 0.810 mmole) were heated at reflux for 18 hours, the solvent removed under reduced pressure and the crude product chromatographed (silica) to afford N′-(4-[(4,5-dihydrobenzo[2,3]thiepino[4,5-d][1,3]thiazol-2-ylamino)methyl]cyclohexylmethyl)-N,N-dimethylsulfamide.