Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:5]1[CH:9]=[C:8]([NH2:10])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)n1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)n1cc(N)cn1
Yield: 91.3 %

Procedure:
A mixture of 1-tert-butyl-4-nitro-1H-pyrazole (20 g, 118 mmol) and Pd/C (10%, 2 g, 1.9 mmol) in MeOH (100 mL) was hydrogenated under 1 atmosphere of hydrogen at RT for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 1-tert-butyl-1H-pyrazol-4-ylamine (15 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ 7.08 (s, 1 H), 6.90 (s, 1H), 3.70 (s, 2 H), 1.41 (s, 9 H); MS (ESI) m/z: 140.1 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]>C(O)C.O.O>[C:4]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][C:1]#[N:2])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
Sodium cyanide (1.07 g, 22 mmol) was added to a stirred solution of 4-t-butylbenzylbromide (5 g, 22 mmol) in a mixture of EtOH-H2O (6:1) (70 mL). The reaction mixture was allowed to stir under reflux conditions for 4 hours. After cooling the mixture to room temperature, the solvent was evaporated under reduced pressure to afford a yellow oil. The oil was suspended in water (20 mL) and extracted with ether (3×25 mL). The solvent was removed under reduced pressure to give a yellow oil which was purified by distillation (Kugelrohr, bp 120-125° C., 0.2 mm Hg) to afford 3.37 g (89%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].ClCCl.S([O-])(O)(=O)=O.[K+]>C1COCC1.[Zn]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:18])[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 27.1 %

Procedure:
To a solution of the target compound in step (2) (7.16 g, 28.5 mmol) in dichloromethane (85 mL) were added successively triethylamine (15.8 mL, 113.9 mmol) and a solution of sulfur trioxidepyridine complex (18.1 g, 113.9 mmol) in dimethylsulfoxide (85 mL). The resulting mixture was stirred at room temperature for 15 min, poured into a mixture of ice and saturated brine (300 mL), and then extracted with cold ether. The organic layer was washed successively with cold 10% aqueous citric acid solution and cold saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and hexane was added to the obtained residue to suspend same. Insolubles were collected by filtration to give 6.41 g (90%) of N-tert-butoxycarbonylphenylalaninal. To a suspension of zinc powder (5.59 g, 85.5 mmol) in THF (1 mL) was added dropwise a solution of the above-mentioned N-tert-butoxycarbonylphenylalaninal (6.41 g, 25.7 mmol) and ethyl bromodifluoroacetate (11.1 mL, 85.5 mmol) in THF (16 mL) with ultrasonication. After 3 hr of ultrasonication, dichloromethane (200 mL) and 1N aqueous potassium hydrogensulfate solution (100 mL) were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was separated and purified by silica gel column chromatography (hexane-ethyl acetate, 75:25) to give 2.60 g (27%) of ethyl 4(S)-[(tert-butoxycarbonyl)amino]-2,2-difluoro-3(R)-hydroxy-5-phenylpentanoate as colorless crystals.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][C:9]1[O:13][C:12]([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]=1[CH2:21][O:22][C@H:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH2:30][C:31](=[CH2:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:24]1>CS(C)=O>[CH3:8][C:9]1[O:13][C:12]([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]=1[CH2:21][O:22][C@H:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH2:30][C:31]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:4][CH2:37]2)[CH2:24]1
Reactant: C[S+](C)C
Reactant: C=C(CO[C@@H]1CCC[C@H](OCc2nc(-c3cccc(C)c3)oc2C)C1)C(=O)OCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(CO[C@@H]2CCC[C@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
At room temperature, 12 mg of a 60 percent strength sodium hydride suspension are added to a suspension of 55 mg of trimethylsulfonium iodide in 2 ml of DMSO, and the mixture is stirred at room temperature for 20 min. At 10° C. 100 mg of ethyl (1R,3S)-2-[3-(5-methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxymethyl]acrylate, dissolved in 2 ml of DMSO, are then added, and the mixture is stirred at room temperature for 90 min. The mixture is poured into ice-water and extracted with methyl tert-butyl ether. The organic phase is dried over sodium sulfate, the solvent is removed under reduced pressure and the residue is purified by flash chromatography on silica gel (n-heptane/ethyl acetate=2:1). This gives ethyl (1R,3S)-1-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]cyclo-propanecarboxylate as a colorless oil. C25H33NO5 (427.55), MS (ESI): 428 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].C(N(CC)CC)C.[CH:65]1([C:68](Cl)=[O:69])[CH2:67][CH2:66]1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:68]([CH:65]3[CH2:67][CH2:66]3)=[O:69])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1NC(=O)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added triethylamine (10 μl) followed by a solution of cyclopropane carbonyl chloride (5 mg) in methylene chloride (0.1 ml). The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: Br[CH:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:15])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl.[C:35]([NH2:38])(=[NH:37])[CH3:36]>C(#N)C.C(Cl)(Cl)Cl>[CH3:36][C:35]1[NH:37][C:8]2[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=3[N:5]([C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=3)=[O:15])[CH2:4][CH2:3][C:2]=2[N:38]=1
Reactant: CC(=N)N
Reactant: COC(=O)c1ccc(C(=O)N2CCC(Br)C(=O)c3ccccc32)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C(=O)N2CCc3nc(C)[nH]c3-c3ccccc32)cc1OC
Temperature: 90 °C
Yield: 43.7 %

Procedure:
To a suspension of methyl 4-(4-bromo-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl-2-methoxybenzoate (240 mg) and potassium carbonate (767 mg) in acetonitrile (8 ml) was added acetamidine hydrochloride (472 mg) and the mixture was heated at 90° C. for 3 hours. After cooling, the reaction mixture was diluted with chloroform and washed with water. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography (SiO2; 30 g, ethyl acetate) to give methyl 4-(2-methyl-1,4,5,6-tetrahydro-imidazo[4,5-d][1]benzazepin-6-yl)carbonyl-2-methoxybenzoate (95 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOCC.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.9 %

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (750 mg, 1.77 mmol) was added to a solution of 1-(t-butoxycarbonyl)-4-(hydroxymethyl)piperidine (339 mg, 1.57 mmol, from Procedure 17, Step A) in methylene chloride (10 mL) and the mixture was stirred at rt. After 45 min., and additional portion of 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (150 mg, 0.35 mmol) was added. After an additional 30 min., ether (30 mL) and 1.3 N NaOH (10 mL) were added and stirring was continued for 20 min. The mixture was transferred to a separatory funnel with additional ether (30 mL) and 1.3 N NaOH (15 mL). The organic layer was separated, washed with water (20 mL), dried (sodium sulfate) decanted, and evaporated to give 291 mg of 1-(t-butoxycarbonyl)-4-piperidinecarboxaldehyde as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)N)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1>Cl>[CH3:22][N:23]1[CH2:28][CH2:27][C:26]2[N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:12]3[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=3[C:25]=2[CH2:24]1
Reactant: CN1CCC(=O)CC1
Reactant: COC(=O)c1ccc(N(N)CCc2ccc(C)nc2)cc1
Agent: Cl
Product: Cc1ccc(CCn2c3c(c4cc(C(=O)O)ccc42)CN(C)CC3)cn1
Temperature: 100 °C
Yield: 4.1 %

Procedure:
Methyl 4-(1-(2-(6-methylpyridin-3-yl)ethyl)hydrazinyl)benzoate (0.1 g, 0.350 mmoles) and 1-methylpiperidin-4-one (0.052 g, 0.350 mmoles) was taken up in 1M HCl (4 mL) and heated at 100° C. for 18 hr. LCMS of the reaction mixture shows the formation of the product. The reaction mixture was concentrated and purified by reverse phase HPLC to give 5 mg of 2-Methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid, as a white solid, 4% yield.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Br)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]=[C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[NH:20]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15][N:27]3[CH2:26][CH2:25][CH:24]([N:23]4[C:22]5[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=5[NH:20][C:19]4=[O:18])[CH2:29][CH2:28]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(CBr)Nc1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)Nc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A mixture of N-(4-cyclohexyl-phenyl)-2-bromoacetamide (50 mg, 0.17 mmol), 4-(2-keto-1-benzimidazolinyl)-piperidine (41 mg, 0.18 mmol), and potassium carbonate (34 mg, 0.25 mmol) in dimethylsulfoxide (2 mL) was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated to give a yellow oil. The crude oil was purified on reverse phase silica gel column using 100% acetonitrile to give N-(4-cyclohexyl-phenyl)-2-[4-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)-piperidin-1-yl]-acetamide as a yellow solid (21 mg, 30%): mp 130-132° C. 1H NMR (300 MHz, CDCl3) d 9.28 (s, 1 H), 9.05 (s, 1 H), 7.53 (d, 2 H), 7.22 (d, 2 H), 7.11 (m, 4 H), 4.33 (m, 1 H), 3.22 (s, 2 H), 3.12 (d, 2 H), 2.40-2.60 (m, 5 H), 1.70-1.90 (m, 7 H), 1.20-1.60 (m, 5 H). MS m/z 433 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:15][C:16]2[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](I)[CH3:30].O>CN(C=O)C>[CH2:29]([N:15]([C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=1)[C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1)[CH3:30]
Reactant: CCOC(=O)c1cnc(Nc2cc(C(C)(C)C)cc(C(C)(C)C)c2)nc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N(CC)c2cc(C(C)(C)C)cc(C(C)(C)C)c2)nc1
Yield: 99 %

Procedure:
Ethyl 2-[N-(3,5-di-tert-butylphenyl)amino]pyrimidine-5-carboxylate (50 mg) was dissolved in dry DMF (2 ml), and the solution was added with a suspension of NaH (45 mg) in DMF (1 ml). The mixture was then added with ethyl iodide (0.3 ml) and stirred. After the disappearance of the materials was observed with TLC, the reaction mixture was poured into water, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was evaporated. The residue was purified by silica gel flash column chromatography (n-hexane: AcOEt=10:1) to obtain white crystals of ethyl 2-[N-ethyl-N-(3,5-di-tert-butylphenyl)amino]pyrimidine-5-carboxylate (53 mg, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:6][CH:7]([CH:10]=[O:11])[CH:8]=[O:9].C(O)(=O)C.[CH:21]([NH2:23])=[NH:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:6][C:7]1[C:8]([OH:9])=[N:22][CH:21]=[N:23][C:10]=1[OH:11]
Reactant: N=CN
Reactant: COc1ccc(OC(C=O)C=O)cc1OC
Solvent: CC(=O)O
Product: COc1ccc(Oc2c(O)ncnc2O)cc1OC

Procedure:
By condensing 2-(3,4-dimethoxy-phenoxy)-propane-1,3-dione acid with formamidine acetate there was obtained 5-(3,4-dimethoxyphenoxy)-pyrimidine-4,6-diol, therefrom with POCl3 there was obtained 4,6-dichloro-5-(3,4-dimethoxy-phenoxy)-pyrimidine, therefrom with p-tert-butylbenzenesulfonamide K there was obtained 4-tert-butyl-N-[6-chloro-5-(3,4-dimethoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide and therefrom with Na ethylene glycolate there was obtained p-tert-butyl-N-[5-(3,4-dimethoxy-phenoxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-benzenesulfonamide.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:7][C:8]1[N:13]=[C:12](Cl)[C:11]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[F:26])=[C:10]([CH3:27])[N:9]=1>O1CCOCC1>[NH2:7][C:8]1[N:9]=[C:10]([CH3:27])[C:11]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[F:26])=[C:12]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[N:13]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(F)c1
Reactant: CCCCCN
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(C(=O)OC)cc1F
Temperature: 100 °C
Reaction time: 50 h

Procedure:
Pentylamine (5.82 mL) was added to a solution of the product from step (iii) (3.1 g) in dioxane (50 mL). The resulting mixture was stirred at 100° C. for 50 h. The mixture was allowed to cool and then the solvent was evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with 2 to 5% MeOH in DCM. to give the subtitle compound as a yellow solid 1.52 g.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][N:29]4C(OC(C)(C)C)=O)=[CH:24][CH:23]=3)[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]2[C:8](=[O:41])[N:7]([CH3:42])[C:6]1=[O:43])[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]4)=[CH:26][CH:27]=3)[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]2[C:8](=[O:41])[N:7]([CH3:42])[C:6]1=[O:43])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(C4CCCCN4C(=O)OC(C)(C)C)cc3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(C4CCCCN4)cc3)nc21
Temperature: 25 °C
Yield: 50.8 %

Procedure:
tert-butyl 2-(4-((7-isobutyl-5-methyl-4,6-dioxo-3-(phenylamino)-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidin-2-yl)methyl)phenyl)piperidine-1-carboxylate (76 mg) is dissolved in 2 mL of dichloromethane, and then TFA (2 mL) is added. The mixture is stirred at room temperature for an hour. After evaporation, the residue is purified by a semi-preparative HPLC to give 32 mg of pure product as white solids. MS (ESI) m/z 487.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[S:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:13]2[S:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccc(C2CC(=O)c3c(C)ccnc3C2)s1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C2CC(=NNC(=N)N)c3c(C)ccnc3C2)s1
Yield: 78.1 %

Procedure:
A mixture of 4-methyl-7-(5-methyl-2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (257 mg), aminoguanidine hydrochloride (117 mg) and concentrated hydrochloric acid (0.2 ml) in ethanol (5 ml) was refluxed for 30 minutes. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 5-guanidinoimino-4-methyl-7-(5-methyl-2-thienyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 71) (273 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]3[NH:35][N:34]=[N:33][N:32]=3)[CH:26]=2)(=[O:24])=[O:23])[CH:12]=1)C(=O)OC(C)(C)C.C(OCC)(=O)C.[ClH:42]>CO>[ClH:42].[CH3:1][NH:2][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:13]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]3[NH:32][N:33]=[N:34][N:35]=3)[CH:26]=2)(=[O:24])=[O:23])[CH:12]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(-c3nnn[nH]3)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(-c3nnn[nH]3)c2)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a solution (10 mL) of tert-butyl methyl[(5-phenyl-1-{[3-(1H-tetrazol-5-yl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]carbamate (52 mg) in methanol was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 ml), and the mixture was stirred at 65° C. for 1.5 hr and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as crystals (yield 42 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11](I)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:40]([N:43]1[CH:47]=[CH:46][N:45]=[CH:44]1)[CH:41]=[CH2:42]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([CH:42]=[CH:41][CH2:40][N:43]2[CH:47]=[CH:46][N:45]=[CH:44]2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C=CCn1ccnc1
Reactant: CCOC(=O)c1ccc(I)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C=CCn2ccnc2)cc1Cl

Procedure:
A mixture of ethyl 2-chloro-4-iodobenzoate (0.92 g, 2.96 mmol), triphenylphosphine (0.014 g, 0.0534 mmol), triethylamine (0.58 g, 5.73 mmol), 1-allylimidazole (1.2 g, 11.1 mmol), and palladium acetate (0.007 g) in acetonitrile (0.6 ml) was stirred and heated at 120° for 6 h in a steel bomb. The reaction mixture was cooled and concentrated to give an oily solid. The solid was purified by `flash` chromatography to give 1-[3-(3-chloro-4-ethoxycarbonylphenyl)prop-2-enyl]imidazole as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH3:26][NH2:27].O1CCCC1.Cl>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([OH:24])[CH2:25][NH:27][CH3:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: CN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@H]2CO2)ccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC[C@@H](O)Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
2-Chloro-5-[(2S)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 13b) (110 mg), methylamine (40% aqueous solution, 2 mL) and tetrahydrofuran (10 mL) were heated together at 50° C. under nitrogen for 20 hours, cooled and concentrated to give an oil. This was purified by Waters' MCX resin and then by column chromatography eluting with 9:1:0.1 dichloromethane/methanol/ammonia. The oil obtained was dissolved in dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) was added. The resulting white solid was filtered off to give the titled compound (121 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Cl:12]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([Cl:12])[S:8][C:7]=2[CH:11]=1
Reactant: ClCl
Reactant: COc1ccc2ccsc2c1
Product: COc1ccc2cc(Cl)sc2c1

Procedure:
The same operations as in Preparation example 1 were carried out using 495 mg of 6-methoxybenzo[b]thiophene, and chlorine gas in place of cyclohexanone, and then purification was carried out by TLC (developing solvent, chloroform:n-hexane=4:1) to obtain 172 mg of 6-methoxy-2-chlorobenzo[b]thiophene.
Reaction SMILES: [CH:1]([CH:4]([C:10]([CH3:12])=O)[C:5](OCC)=[O:6])([CH3:3])[CH3:2].[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][SH:15].[Na]>>[OH:6][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[C:10]([CH3:12])[S:15][C:14]=1[C:13]([O:17][CH3:18])=[O:16]
Reactant: CCOC(=O)C(C(C)=O)C(C)C
Reactant: COC(=O)CS
Agent: [Na]
Product: COC(=O)c1sc(C)c(C(C)C)c1O

Procedure:
Prepared by the method described in Example 1 from ethyl α-isopropylacetoacetate (prepared by the procedure of Manuel and Hagen, Org. Syn., 7, 248 (1951)) (12 g, 70 mmoles), methyl thioglycolate (15.7 g, 140 mmoles) and sodium (3.2 g, 139 mmoles). The product is extracted with CH2Cl2 twice. The combined extracts are washed with aqueous NaCl twice, dried over MgSO4 and stripped of solvent under reduced pressure. Distillation of the residue gave the product (3.3 g); bp 68°-71° C. (0.3 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:21])[C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[O:12].[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[F-].C[N+](C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:21])[C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)([OH:12])[C:23]([F:25])([F:24])[F:22]
Reactant: COc1ccc(Cl)c(C(C)C(=O)c2ccc(=O)n(C)c2)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Product: COc1ccc(Cl)c(C(C)C(O)(c2ccc(=O)n(C)c2)C(F)(F)F)c1

Procedure:
In analogy to Example 165, step 3, 5-[2-(2-chloro-5-methoxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a light grey foam. MS (m/e)=376.2 [M+H+].