Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14]Cl)[C:8](=[O:16])[C:7](=[O:17])[NH:6]2.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:21]1[NH:20][CH:24]=[CH:23][N:22]=1)[C:8](=[O:16])[C:7](=[O:17])[NH:6]2
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n(CCCl)c1=O
Reactant: c1c[nH]cn1
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n(CCc2ncc[nH]2)c1=O

Procedure:
392 mg (1 mmol) of 2-[(6 trifluoromethylquinoxaline-2,3-dion-1-yl)ethyl chloride is heated with 150 mg (2.2 mmol) of imidazole for 3 hours to 150° C. bath temperature. The organic phase is concentrated by evaporation with dispersion in 10 ml of ethyl acetate and 10 ml of water, and the residue is chromatographed on silica gel with methanol:butanol:water:ammonia=75:25:17:3 as eluant. 54 mg (17% of theory) of 2-((6 trifluoromethylquinoxaline-2,3-dion-1-yl)ethylimidazole of melting point>250° C. is obtained.
Reaction SMILES: F[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[CH3:18][O-:19].[Na+].Cl>O>[F:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2)=[C:3]([N+:15]([O-:17])=[O:16])[C:2]=1[O:19][CH3:18]
Reactant: C[O-]
Reactant: O=c1[nH]c2cc(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1c(F)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Reaction time: 0 h
Yield: 77.5 %

Procedure:
To a solution of 21 mg (0.086 mmol) of 6,7-difluoro-5-nitro-1,4-dihydroquinoxaline-2,3-dione in 0.5 mL of DMSO-d6 was added 16 mg (0.29 mmol) of sodium methoxide. The solution was shaken in a vortex for 10 s and kept at room temperature for 3 h. It was then added to 3 mL of water and acidified with 2N HCl to pH=4. The precipitate was filtered, washed with water, and dried to leave a yellow solid (17 mg, 77%); mp 290-292° C.; 1H NMR (DMSO-d6), 3.899 (s, 3), 7.163 (1, d, J=11.6), 11.97 (mb, 1), 12.137 (s, 1). 19F NMR, -134.48 (mb). MS, 255 (M+, 100), 243 (15), 179 (16), 151 (40). HRMS, Calcd for C9H6FN3O5 255.0287, found 255.0308.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2[CH2:12][OH:13].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:19]([O:18][C:16]([CH2:15][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2[CH2:12][OH:13])=[O:17])[CH3:20]
Reactant: OCC1CCCc2c(O)cccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCCC2CO

Procedure:
A suspension of (5-hydroxy-1,2,3,4-tetrahydro-1-naphthyl)methanol (0.20 g), ethyl bromoacetate (0.15 ml), potassium iodide (catalytic amount) and potassium carbonate (0.20 g) in acetonitrile (10 ml) was stirred under reflux for 2.5 hours. The solvent was removed and the residue was partitioned between ether and 1N hydrochloric acid. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (n-hexane-ethyl acetate) over silica gel to afford (5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-1-naphthyl)methanol (0.29 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[NH:12][C:13](=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:11])[C:3]=1[NH:12][C:13](=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:15]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1OC1CCCC1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cc(N)cc2Cl)cc1OC1CCCC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A solution of N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide (1.5 g) in glacial acetic acid (22 mL) is treated with iron pin dust (1.3 g) and the mixture is heated with stirring at 90° C. for 1 hour. The reaction mixture is cooled, basified to pH 8 by treatment with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate (2×150 mL). The combined organic extract is dried over magnesium sulfate and concentrated in vacuo, to give a white solid. This solid is subjected to flash chromatography, eluting with a mixture of ethyl acetate and pentane (1:1 v/v), to give N-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide (0.8 g), m.p. 170-172° C. [Elemental analysis: C, 54.8; H, 5.04; N, 6.5; Cl, 17.4%. calculated: C, 57.7; H, 5.1; N, 7.1; Cl, 17.9%].
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([NH:27][CH2:28][C:29](O)=[O:30])(OCC1C=CC=CC=1)=O.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)(Cl)[Cl:48]>>[ClH:48].[NH2:27][CH2:28][C:29]([NH:16][C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:30]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(N)(Cc1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(Cc1ccccc1)(NC(=O)CN)c1ccccc1
Product: Cl
Reaction time: 4 h

Procedure:
To a stirred solution of 1,2-diphenyl-2-propylamine (21.0 g, 0.085 mol) in chloroform (500 ml) under nitrogen was added N-CBZ-glycine (23.0 g, 0.11 mol), and then a solution of dicyclohexylcarbodiimide (20.6 g, 0.1 mol) in chloroform (100 ml) and the mixture stirred for 14 hours. The precipitated solid was removed by filtration and the solvent evaporated. The residue was dissolved in methylene chloride (500 ml), filtered and evaporated to a yellow oil. This was treated with ether (700 ml) and 500 ml of ice cold water, basified with 5 ml of 50% NaOH, the layers shaken and separated. The ether layer was washed with water (2×125 ml), dried and evaporated to an oil, 33.5 g. This was dissolved in methanol (500 ml) and 10% HCl (50 ml) and hydrogenated at 40 psi in a Parr apparatus over 3.0 g of 10% Pd/C catalyst for 4 hours. The catalyst was removed by filtration, and the solvent evaporated to a white solid. This was dissolved in 80 ml of hot methanol and treated with 200 ml of ether. Upon cooling a solid crystallised which was recrystallised from 100 ml of isopropanol and 100 ml of methanol to give 8.4 g of 2-amino-N-(1,2-diphenyl-1-methylethyl)acetamide hydrochloride which, after vacuum drying at 80 ° C. for 24 hours, had mp 253°-254° C.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][C:6]1([OH:23])[C:12]2[CH:13]=[C:14]([S:17][CH3:18])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2.OO.S(=O)=[O:28].[OH-:30].[Na+]>C(O)(=O)C>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1([OH:23])[C:12]2[CH:13]=[C:14]([S:17]([CH3:18])(=[O:28])=[O:30])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2
Reactant: CSc1ccc2c(c1)C(O)(CCCN(C)C)c1ccccc1C=C2
Reactant: [OH-]
Reactant: O=S=O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)CCCC1(O)c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21

Procedure:
5-(3-Dimethylaminopropyl)-5-hydroxy-3-methylmercapto-5H-dibenzo[a,d]cycloheptene, 21.53 g. (0.063 mole), is dissolved in glacial acetic acid, 250 ml., and the solution is cooled in an ice-bath while 30% hydrogen peroxide, 25.8 ml., is added dropwise with stirring. After standing at room temperature for twenty-two hours, the solution is saturated with sulfur dioxide for 1 hour with periodic cooling in an ice-bath. The solution is made basic with 10 N. sodium hydroxide solution, 625 ml., and extracted with three 300 ml. portions of benzene. After washing the combined extracts with water, solvent is distilled under reduced pressure leaving a yellow oily residue, weight 23.20 g. The oil solidifies on standing at room temperature. Four recrystallizations from methanol-water gives 13.22 g. (57%) of product melting at 170.5°-171.5°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=C(C=C(F)C=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.[CH3:82][C@H:83]1[CH2:85][O:84]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:82][C@@H:83]([OH:84])[CH3:85])[CH2:30][CH2:31]5)=[N:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)cc(F)c6)c5)c4c3)cn2)CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 82.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 2 compound of example 133) (100 mg, 0.16 mmol) was alkylated using (S)-2-methyloxirane (14 mg, 0.24 mmol), DIPEA (31 mg, 0.24 mmol) and ethanol (2 mL) to get 90 mg (82.5%) of the titled compound after purification by column (Silica gel 60/120) using 5% methanol in dichloromethane as eluent. MS: m/z=684.2 (M+1).
Reaction SMILES: C(NC1C=C(O[C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH:18]([C:22]([NH:24]C4C=C(C(F)(F)F)C=C(OC[C@H]5COC(C)(C)O5)C=4)=[O:23])[CH2:19]3)=[CH:14][CH:13]=2)C=CN=1)(=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>CO.O>[CH2:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:12][CH:21]=2)[CH2:16][CH2:17][CH:18]1[C:22]([NH2:24])=[O:23]
Reactant: CC(=O)Nc1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(OC[C@H]4COC(C)(C)O4)cc(C(F)(F)F)c2)CC3)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: NC(=O)C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 285.3 %

Procedure:
A mixture of 7-{[2-(acetylamino)pyridin-4-yl]oxy}-N-[3-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (100 mg, 0.16 mmol) and pTSA (28 mg, .16 mmol) in MeOH (7 mL) and water (1 mL) was allowed to stir at rt overnight and then at 70° C. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 7-{[2-(acetylamino)pyridin-4-yl]oxy}-N-3-{[(2R)-2,3-dihydroxypropyl]-oxy}-5-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (I-412) (80 mg, 68%) as a white solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 10.52 (s, 1H), 8.24 (d, 1H), 7.66 (br s, 1H), 7.56 (br s, 1H), 7.29-7.17 (m, 2H), 7.06-6.86 (m, 4H), 4.07-3.75 (m, 3H), 3.46-3.40 (m, 2H), 3.00-2.74 (m, 5H), 2.19-2.05 (m, 4H), and 1.89-1.71 (m, 1H). LCMS: (FA) ES+560.1, ES−558.0.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C(O)(=O)C>C(O)C.[OH-].[OH-].[Pd+2]>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([CH2:5][NH:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1ccc2cnccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2CNCCC21
Yield: 74.6 %

Procedure:
A mixture of tert-butyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.45 g, 11.23 mmol) and palladium hydroxide on carbon (20%, 1 g, 1.424 mmol) in ethanol (8 ml)/acetic acid (16 mL) was hydrogenated at 50 psi and 60° C. overnight. The reaction mixture was filtered through celite. Solvent was evaporated in vacuo and the residue was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, The crude was be used without purification. tert-butyl octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (1.896 g) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[CH2:5][N:6]([CH3:26])[C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=1)=[O:8].O1[CH2:36][CH2:35]OCC1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[CH2:5][N:6]([CH3:26])[C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11]([N:10]2[CH2:36][CH2:35][N:6]([CH3:5])[CH2:7][CH2:9]2)[N:10]=1)=[O:8]
Reactant: C1COCCO1
Reactant: Cc1cc(C)cc(CN(C)C(=O)c2nc(S(C)(=O)=O)ncc2-c2ccccc2C)c1
Product: Cc1cc(C)cc(CN(C)C(=O)c2nc(N3CCN(C)CC3)ncc2-c2ccccc2C)c1
Reaction time: 16 h
Yield: 123 %

Procedure:
To a solution of 0.28 g (0.66 mmol) 2-methanesulfonyl-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-dimethyl-benzyl)-methyl-amide in 10 ml dioxane 0.18 ml (1.65 mmol) 1-methylpiperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml H2O. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) to give 0.18 g (61%) 2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-dimethyl-benzyl)-methyl-amide as a colorless foam, MS (ISP): 444.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.[CH3:11][O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(O)CCC>[Cl:10][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([O:12][CH3:11])[CH2:14][CH2:15]2)[C:5]=1[NH2:9]
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: CO[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CO[C@H]1CC[C@H](Nc2nc(N)nc(Cl)c2N)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2,5-diamino-4,6-dichloropyrimidine (6 g, 33.5 mmol), trans-4-methoxy cyclohexyl amine (4.32 g, 33.5 mmol, 1 equiv.), sodium bicarbonate (9.85 g, 117.2 mmol, 3.5 equiv.) and 1-butanol (350 mL) were heated together at 150° C. in a sealed tube. After 3 days, when the reaction appeared to be complete (by HPLC), the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, gradual elution with 96/4 methylene chloride/methanol to 90/10 methylene chloride/methanol) to give the desired product as a brown solid (69% yield). MS (EI) m/z 272 (MH)+.
Reaction SMILES: [Li][C:2](C)(C)C.[I:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[I:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[CH2:2])[CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1
Reactant: CC(C)C(=O)c1ccc(I)cc1
Reactant: [Li]C(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(I)cc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 7.07 g (20 mmol) of methyltriphenylphosphonium bromide in 50 mL of dry THF at 0° C. were added t-BuLi of (14.7 ml, 1.5 M in hexane) and the solution turned brown. After 1 hour of stirring at 0° C., the crude 1-(4-Iodo-phenyl)-2-methyl-propan-1-one from the last step in 20 mL of THF were added dropwise and the solution was stirred for 14 hours at room temperature. After cooling to ca. 20° C., 52 mL of water were added and the solution was extracted with dichloromethane (3×50 mL). The organic layer was dried over MgSO4 and the solvent was removed to give the crude title compound as white solid. The product was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1>O1CCOCC1.CO>[NH3:12].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Cn1cc(N)ccc1=O
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cc(NS(=O)(=O)c2ccccc2F)ccc1=O
Product: N
Temperature: 25 °C
Reaction time: 28 h
Yield: 82.6 %

Procedure:
2-Fluorobenzenesulfonyl chloride (0.46 mL, 3.5 mmol) was added to a solution of 5-amino-1-methyl-1,2-dihydropyridin-2-one (478 mg, 3.85 mmol) in 1,4-dioxane (10 mL) and stirred for 28 h at rt. After concentration in vacuo purification by column chromatography eluting with DCM:MeOH:7M NH3 in MeOH (90:5:5) yielded the title compound (448 mg, 1.59 mmol).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:15]([O:17]C)=[O:16])=[CH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([CH:13]=[O:14])[CH:9]=[CH:8][CH:7]=2)=[O:2].[Li+].[OH-]>C1COCC1.O>[CH:13]([C:10]1[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=1)=[CH:5][C:4]1[C:15](=[O:17])[O:16][CH:1]([OH:2])[C:3]=1[CH:12]=2)=[O:14]
Reactant: COC(=O)c1cc2cccc(C=O)c2cc1C=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccc2cc3c(cc12)C(O)OC3=O
Reaction time: 1.5 h
Yield: 19 %

Procedure:
To a solution of the impure methyl 3,5-diformyl-2-naphthoate in THF (10 mL) at rt was added 1.0 M aqueous LiOH (5 mL, 5 mmol). After 1.5 hours, the reaction mixture was diluted with H2O and washed with Et2O. The aqueous layer was acidified with 1.0 M aqueous HCl and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo to give the title compound (200 mg, 19% from methyl 3,5-diethenyl-2-naphthoate) as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]1([OH:14])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>C1COCC1>[CH2:15]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][C:11]1([O:14][CH3:24])[CH2:12][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OC1(CCN(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(CCN(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
A 0° C. solution of 1-(2-(dibenzylamino)ethyl)cyclopropanol (3 g, 10.6 mmol) in THF (50 mL), under N2, was treated portion-wise with NaH (60%, 0.85 g, 21.3 mmol), stirred at 0° C. for 0.5 h, treated drop-wise with MeI (1.82 g, 12.8 mmol), warmed to RT and stirred for 3 h. The mixture was cooled to 0° C., quenched with satd. NH4Cl and partially concentrated. The residue was extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated and purified via silica gel chromatography to afford N,N-dibenzyl-2-(1-methoxycyclopropyl)ethanamine (1.2 g, 38%). 1H NMR (400 MHz, CDCl3): δ 7.39-7.21 (m, 10 H), 3.60 (s, 4 H), 3.12 (s, 3 H), 2.65 (t, J=8 Hz, 2 H), 1.75 (t, J=8 Hz, 2 H), 0.68-0.65 (m, 2 H), 0.34-0.31 (m, 2 H).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[CH:12]=[C:11]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[C:10]([O:26][CH2:27][CH2:28][CH3:29])=[CH:9][C:8]=2[C:7]([CH3:31])([CH3:30])[CH2:6][CH:5]=1)([CH3:3])[CH3:2].[CH:32](=O)[CH3:33]>>[CH2:32]([N:14]([C:11]1[C:10]([O:26][CH2:27][CH2:28][CH3:29])=[CH:9][C:8]2[C:7]([CH3:31])([CH3:30])[CH2:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]=2[CH:12]=1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1)[CH3:33]
Reactant: CCCOc1cc2c(cc1Nc1ccc(C(=O)OCC)cc1)C(C(C)C)=CCC2(C)C
Reactant: CC=O
Product: CCCOc1cc2c(cc1N(CC)c1ccc(C(=O)OCC)cc1)C(C(C)C)=CCC2(C)C
Yield: 70 %

Procedure:
Following General Procedure D, ethyl 4-(8-isopropyl-5,5-dimethyl-3-n-propoxy-5,6-dihydronaphthalen-2-ylamino)benzoate (Compound 117, 0.18 g, 0.43 mmol) was reacted with acetaldehyde to afford 0.14 g (70%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:17]#[N:18].[Na+].O=O.C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[C:17]([CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:16][N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)#[N:18]
Reactant: [C-]#N
Reactant: c1ccc(N2CCc3ccccc3C2)cc1
Agent: O=C([O-])O
Agent: O=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#CC1c2ccccc2CCN1c1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
N-phenyl-1,2,3,4-tetrahydroisoquinoline (1 mmol), RuCl3-nH2O (0.05 mmol) and sodium cyanide (1.2 mmol) were charged into a 25-ml side-arm flask, the interior of the reacting container was replaced by oxygen, and an oxygen balloon was attached to supply oxygen at 1 atm. Then, 1.7 ml of a mixed solvent of methanol-acetic acid (volume ratio 3/1) was added thereto at room temperature. Reaction was effected by stirring the mixed liquid at 60° C. for 4 hours. After the reaction mixture liquid was made alkaline with the addition of saturated sodium bicarbonate aqueous solution, the mixture was extracted with 10 ml ethyl acetate once and with 5 ml ethyl acetate twice. The extracted liquid thus obtained was washed with saturated saline solution, and dried over sodium sulfate, thereby obtaining an ethyl acetate solution of 1-cyano-N-phenyl-1,2,3,4-tetrahydroisoquinoline. After this solution was concentrated under reduced pressure, the mixture was analyzed by a 1H NMR internal standard method, which revealed the conversion rate of N-phenyl-1,2,3,4-tetrahydroisoquinoline being 91% with a yield of 1-cyano-N-phenyl-1,2,3,4-tetrahydroisoquinoline being 79% (vs. N-phenyl-1,2,3,4-tetrahydroisoquinoline). By using silica gel chromatography, 1-cyano-N-phenyl-1,2,3,4-tetrahydroisoquinoline was isolated at a yield of 76%.
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[S:10])[O:7]CC)[CH:2]([CH3:4])[CH3:3].S(OCC)(O[CH2:19][CH3:20])(=O)=O>>[CH2:11]([N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6](=[O:10])[S:7][CH2:19][CH3:20])[CH:12]([CH3:13])[CH3:14]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCOC(=S)N(CC(C)C)CC(C)C
Product: CCSC(=O)N(CC(C)C)CC(C)C
Temperature: 160 °C
Yield: 92 %

Procedure:
43.4 g. (0.2 mole) of O-ethyl N,N-diisobutyl-thiocarbamate are introduced into a 100 ml. round-bottomed flask, and 2.5 g. of diethyl sulfate are added. The mixture is refluxed for 90 minutes on an oil bath heated to 160°C, and thereafter the product is isolated by vacuum distillation. 39.8 g. (92 %) of S-ethyl N,N-diisobutyl-thiocarbamate are obtained; b.p.: 137°-138°C/20 Hgmm., nD25 = 1.4689.