Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:12]1([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=3)=[CH:20][C:19]=2[N+:32]([O-:34])=[O:33])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O1CCOCC1>[C:1]([NH:9][C:10]([N:15]1[CH2:16][CH2:17][N:12]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=3)=[CH:20][C:19]=2[N+:32]([O-:34])=[O:33])[CH2:13][CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Product: CC1CC(=O)NN=C1c1ccc(N2CCN(C(=S)NC(=O)c3ccccc3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.0 g (0.165 mol) of benzoyl isothiocyanate are added at room temperature to 52.4 g (0.165 mol) of 6-[4-(1-piperazinyl)-3-nitro-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 1200 ml of 1,4-dioxane. The reaction mixture is stirred at room temperature for 2 hours and then concentrated to 700 ml under vacuum and left to crystallize. 76 05 g (96% of theoretical) of orange-yellow crystals melting at 174.5°-177° C. are obtained after suction filtration.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:21][C:22](=[O:25])[O:23][CH3:24])([CH3:20])[CH3:19])=[CH:14][CH:13]=1>CN(C=O)C>[CH3:20][C:18]([NH:21][C:22](=[O:25])[O:23][CH3:24])([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:13][CH:14]=1)[CH3:19]
Reactant: Cc1ccc(S)cc1C
Reactant: COC(=O)NC(C)(C)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: COC(=O)NC(C)(C)c1ccc(CSc2ccc(C)c(C)c2)cc1

Procedure:
A solution of 3,4-dimethylbenzenethiol (9.24 g) in DMF (30 ml) reacted with a solution of methyl N-[1-(4-bromomethylphenyl)-1-methylethyl]carbamate (19.15 g) in DMF (100 ml) by Method 6a) to give methyl N-{1-methyl-1-[4-(3,4-xylylthiomethyl)phenyl]ethyl}carbamate as a sticky solid.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:15][C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[O:8]1)(=O)=O.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][NH:22][C:21]1=[O:28]>>[O:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:15][CH:7]1[CH2:6][NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][C:24]([CH3:26])([CH3:27])[CH2:23][NH:22][C:21]1=[O:28]
Reactant: CC1(C)CNC(=O)N(CCCN)C1
Reactant: CS(=O)(=O)OCC1Oc2cccnc2O1
Product: CC1(C)CNC(=O)N(CCCNCC2Oc3cccnc3O2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
A mixture of intermediate (6) (0.0092 mol) and intermediate (13) (0.0183 mol) was stirred for 2 hours at 100° C. The crude reaction mixture was purified by open column chromatography over silica gel (eluent: CH2Cl2/CH3OH 90/10). The desired fractions were collected and the solvent was evaporated. The residue was washed with DIPE, then dried, yielding 1.48 g of (±)-1-[3-[(1,3-dioxolo[4,5-b]pyridin-2-ylmethyl)amino]-propyl]tetrahydro-5,5-dimethyl-2(1H)-pyrimidinone (compound 10).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH:10]([F:12])[F:11])=[CH:4][C:3]=1[OH:13].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH:10]([F:11])[F:12])=[CH:4][C:3]=1[O:13][CH2:15][CH:16]1[CH2:18][CH2:17]1
Reactant: Oc1cc(OC(F)F)c(F)cc1Br
Reactant: BrCC1CC1
Product: Fc1cc(Br)c(OCC2CC2)cc1OC(F)F

Procedure:
Starting from 2-bromo-5-(1,1-difluoro-methoxy)-4-fluoro-phenol (example A5) and bromomethyl-cyclopropane the title compound is obtained as colorless oil.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([NH:11]N)[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>S(=O)(=O)(O)O.O1CCOCC1>[CH:2]([C:5]1[CH:10]=[CH:9][C:8]2[C:16]3[CH2:15][N:14]([CH3:13])[CH2:19][CH2:18][C:17]=3[NH:11][C:7]=2[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc(NN)c1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)c1ccc2c3c([nH]c2c1)CCN(C)C3
Temperature: 25 °C
Yield: 18 %

Procedure:
A solution of (3-isopropylphenyl)hydrazine hydrochloride (5 g, 0.0267 mol) and 1-methyl-4-piperidone (3.3 mL, 0.0267 mol) in 7% sulfuric acid in dioxane (100 mL) was heated at 80° C. for 1 h. After completion, the reaction mixture was cooled to RT and the organic layer decanted. The residue was basified with 10% sodium hydroxide solution and extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure affording crude material, which was purified by silica gel column chromatography (6% MeOH:DCM) to yield 7-isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.1 g, 18% yield).
Reaction SMILES: CO.[C:3]1([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:10][C:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][OH:19])[N:13]([CH:20]([CH3:22])[CH3:21])[CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4].C1C=CC=CC=1.C(OCC)(=O)C>[C:23]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][C:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH:18]=[O:19])[N:13]([CH:20]([CH3:22])[CH3:21])[CH:12]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)n1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)n1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1C=O
Reaction time: 5 h
Yield: 54.2 %

Procedure:
To a methanol solution (120 ml) of 1.600 g of 3-diphenylmethoxy-6-hydroxymethyl-1-isopropyl-4-pyridone is added 10.00 g of active manganese dioxide at room temperature, and the mixture is stirred for 5 hours, then at 50° C. for 1 hour. After insolubles are removed by filtration, the filtrate is condensed under reduced pressure and the residue is subjected to flash column chromatography on 100 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of benzene-ethyl acetate (1:2) to perform separation and purification. The title compound (0.862 g) is obtained as colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.[C:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br)([OH:29])=[O:28]>O1CCCC1.CCCCCC>[C:12]([C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([S:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH2:33][C:32]1[CH:31]=[C:30]([CH:37]=[CH:36][CH:35]=1)[C:27]([OH:29])=[O:28])#[N:13]
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Reactant: O=C(O)c1cccc(CBr)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(C#N)(Cc2cccc(C(=O)O)c2)Sc2ccc(C)cc2)cc1OC
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 85.1 %

Procedure:
To a cold (-78° C.) solution of 1.86 g of 3,4-dimethoxy-α-[(4-methylphenyl)thio]benzene acetonitrile in 15 mL of tetrahydrofuran is added drop-wise a solution of 2.9 mL of n-butyl lithium (2.2M) in hexane. This solution is stirred at -78° C. for 35 minutes. A solution of 0.67 g of m-carboxybenzyl bromide in 5 mL of anhydrous tetrahydrofuran is added drop-wise, stirred at -78° C. for 40 minutes and then at room temperature for 15 minutes. The mixture is quenched with water and extracted with ethyl acetate. The ethyl acetate extract is washed with brine, dried and filtered. The filtrate is evaporated in vacuo to yield a yellow oil. This oil is purified by flash chromatography using methylene chloride/methyl alcohol (95:5) to yield 1.15 g of the desired product as a yellow foam.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:12]1([CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: C1CNC1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1nc([N+](=O)[O-])cc1CN1CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
To a solution of 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (436 mg, 1.98 mmol) in tetrahydrofuran (10 mL) was added azetidine (141 mg, 0.17 mL, 2.48 mmol) and diisopropylethyl amine (307 mg, 0.42 mL, 2.38 mmol) drop wise and the resulting mixture was stirred at room temperature for 24 h. The solution was concentrated and the residue dissolved in dichloromethane (50 mL), washed with water (50 mL). The aqueous layer was extracted with methylene chloride (2×50 mL) and the organic phases combined and dried over magnesium sulfate. The resulting mixture was filtered and evaporated and the residue purified by flash chromatography (40 g, 1% to 5% methanol in dichloromethane) to give 5-(azetidin-1-ylmethyl)-1-methyl-3-nitro-1H-pyrazole (349 mg, 90%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:12](=[O:21])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C)C=O>[C].[Pd].C(O)=O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([N:13]2[CH:8]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=3)[CH2:9][CH2:10][CH2:11][C:12]2=[O:21])=[CH:19][CH:18]=1
Reactant: O=C1CCCC(c2ccc(Cl)cc2)N1c1ccc(F)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CN(C)C=O
Product: O=C1CCCC(c2ccccc2)N1c1ccc(F)cc1
Yield: 60.8 %

Procedure:
A mixture of 2.32 g of 6-(4-chlorophenyl)-1-(4-fluorophenyl)-2-piperidone, 25 ml of dimethylformamide, 5 ml of formic acid, and 1.0 g of palladium-carbon was refluxed for 6 hours. The catalyst was filtered off, and the filtrate was extracted with ethyl acetate. The ethyl acetate solution was washed with water and an aqueous sodium hydrogen carbonate solution and dried. After removal of the solvent, the residue was recrystallized from a mixture of isopropyl ether and n-hexane to give 1.25 g of 1-(4-fluorophenyl)-6-phenyl-2-piperidone as colorless prisms.
Reaction SMILES: [ClH:1].Br.[C:3]([C:6]1[S:7][CH:8]=[C:9]2[CH2:13][NH:12][CH2:11][C:10]=12)([OH:5])=[O:4].[CH2:14](O)[CH3:15]>>[ClH:1].[CH2:14]([O:4][C:3]([C:6]1[S:7][CH:8]=[C:9]2[CH2:13][NH:12][CH2:11][C:10]=12)=[O:5])[CH3:15]
Reactant: CCO
Reactant: O=C(O)c1scc2c1CNC2
Agent: Br
Agent: Cl
Product: CCOC(=O)c1scc2c1CNC2
Yield: 80 %

Procedure:
A stream of hydrochloric acid is passed into a suspension of 3.3 g (13.2 mmol) of 1-carboxy-5,6-dihydro-4H-thieno[3,4-c]pyrrole hydrobromide in 75 ml of ethanol, heated at reflux for 4 h. The solvent is then evaporated and the residue triturated with twice 20 ml of diethyl ether. 2.46 g of a beige solid are obtained. Yield 80%. Melting point: 163° C. (with decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C@@H:17]3[CH:22]4[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]4)[CH2:18]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[N:19]12[CH2:20][CH2:21][CH:22]([CH2:23][CH2:24]1)[C@@H:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[CH:15][CH:14]=1)[CH2:18]2
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)cc2)cc1
Yield: 98.7 %

Procedure:
The product of Example 16A (580 mg, 1.79 mmol) was treated with Pd/C (Aldrich, wt. 10%, 100 mg) in ethanol (50 mL) under H2 at ambient temperature for 30 min. After the reaction was complete, the catalyst was removed through a short column of diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the title compound (520 mg, yield, 99%). 1H NMR (300 MHz, CD3OD) δ 1.44-1.58 (m, 1H), 1.63-1.89 (m, 2H), 1.99-2.13 (m, 1H), 2.15-2.23 (m, 1H), 2.72-3.04 (m, 5H), 3.29-3.39 (m, 1H), 4.50-4.58 (m, 1H), 6.77 (dt, J=8.8, 2.5 Hz, 2H), 6.91 (dt, J=8.8, 2.4 Hz, 2H), 7.32 (dt, J=8.5, 2.5 Hz, 2H), 7.43 (dt, J=9.2, 2.8 Hz, 2H) ppm. MS (DCI/NH3) m/z 295 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].B1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:17]=2)OC(C)(C)C(C)(C)O1.Br[C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[C:33]([NH:44][C:45]([C:47]2[CH:48]=[N:49][CH:50]=[C:51]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH:52]=2)=[O:46])[CH:32]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.COCCOC.O>[C:26]([O:25][C:23]([O:22][C:18]1[CH:17]=[C:16]([C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[C:33]([NH:44][C:45]([C:47]3[CH:48]=[N:49][CH:50]=[C:51]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH:52]=3)=[O:46])[CH:32]=2)[CH:21]=[CH:20][CH:19]=1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)Oc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3cncc(-c4ccccc4)c3)c2)c1
Temperature: 25 °C

Procedure:
Water (0.6 mL), sodium carbonate (58 mg), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbonate (85 mg), and bis(triphenylphosphine)palladium(II) dichloride (3.0 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) suspension of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, and then ethyl acetate and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-80% hexane/ethyl acetate] to obtain tert-butyl 4-(3-(tert-butoxycarbonyl)oxyphenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.Br[CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:34][CH2:33][CH2:32][CH2:31][N:19]1[CH:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[CH:9]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20]1(=[O:27])=[O:28])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCCCOCc1ccccc1
Reactant: Cc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Product: Cc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1CCCOCc1ccccc1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 2, step c) and (3-bromo-propoxymethyl)-benzene. MS: ESI (negative): 503 (M−H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[SH:17][CH2:18][CH2:19][CH2:20][OH:21]>C(#N)C>[Br:1][C:2]1[C:3]([S:17][CH2:18][CH2:19][CH2:20][OH:21])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: OCCCS
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCCSc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.47 g (10.8 mmol) of 5-Bromo-2,4-dichloropyrimidine in 30 ml of acetonitrile at −20° C. is mixed with 1.5 ml (10.8 mmol) of triethylamine and 1.00 g (10.8 mmol) of 3-Mercapto-propan-1-ol. The batch is slowly warmed to room temperature and stirred for 16 hours. The batch is filtrated to remove the solid precipitate. The filtrate is concentrated by evaporation. 2-Methoxy-2-methyl-propane is added to the remaining residue and the batch is stirred for 15 minutes. The batch is filtrated and the solid precipitate is dried. 3.03 g (10.6 mmol, corresponding to 98% of theory) of the product is obtained.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]([CH3:19])[NH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+].[C-:27]#[N:28].[K+]>O>[C:27]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]([CH3:19])[NH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1)#[N:28]
Reactant: [C-]#N
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(C#N)cc1
Reaction time: 1 h
Yield: 45.8 %

Procedure:
A solution of sodium nitrite (1.14 g) in water (3 ml) was added dropwise to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (3.06 g) in a mixture of water (12 ml) and conc. hydrochloric acid (4.5 ml) over a period of 30 minutes under ice cooling. The resultant diazonium solution was cautiously neutralized with a saturated solution of sodium carbonate in water and then a cold mixture of potassium cyanide (1.88 g) and cuprous cyanide (1.17 g) in water (12 ml) was added to the solution. After stirring for 1 hour, the resultant precipitates were collected by filtration, washed successively with water, 1N-sodium hydroxide solution, 1N-hydrochloric acid, water, and then dissolved in aqueous ethanol. The solution was treated with activated charcoal and then evaporated in vacuo. The residue was chromatographed on silica gel (190 g) with a mixture of chloroform and methanol (20:1) as an eluent. The eluents containing object compound were evaporated in vacuo and the residue was recrystallized from aqueous ethanol to give 6-(4-cyanophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.469 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:14][N:13]=2)=[O:10])=[CH:4][CH:3]=1.[N:25]1([C:31](=[O:33])[CH3:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CCOC(C)=O>[C:31]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:14][N:13]=3)=[O:10])=[CH:4][CH:3]=2)[CH2:27][CH2:26]1)(=[O:33])[CH3:32]
Reactant: O=C(Cc1ccc(Cl)nc1)Nc1ccc(-c2cccc(F)c2)cn1
Reactant: CC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(CC(=O)Nc3ccc(-c4cccc(F)c4)cn3)cn2)CC1

Procedure:
2-(6-Chloropyridin-3-yl)-N-(5-(3-fluorophenyl)pyridin-2-yl)acetamide 140-1 (100 mg, 0.29 mmol) was heated with 1-(piperazin-1-yl)ethanone (0.8 ml) at 108° C. for 4 hours. The mixture was dissolved in EtOAc (30 ml), washed with water (40 mL), and dried over Na2SO4. After concentration by evaporation, the residue was subjected to reverse phase HPLC to afford 2-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(5-(3-fluorophenyl)pyridin-2-yl)acetamide 140 as solid.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:6][CH2:5][C:4]2([CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]2)[CH2:3]1>CO.[C].[Pd]>[ClH:1].[NH:2]1[CH2:6][CH2:5][C:4]2([CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]2)[CH2:3]1
Reactant: C1=CC2(CCNC2)Oc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ccc2c(c1)CCC1(CCNC1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
Spiro[chromene-2,3′-pyrrolidine] hydrochloride (150 mg) synthesized in Example 33(1) and 5% palladium-carbon (30 mg) were suspended in methanol (10 mL), and the suspension was stirred overnight under a hydrogen atmosphere at room temperature. The catalyst was removed by filtration through celite, and the solvent was evaporated under reduced pressure to give the object product (130 mg, 86%).
Reaction SMILES: CN(C)CCCNC(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[CH:55]=[CH:54][C:53]([C:56](O)=[O:57])=[CH:52][CH:51]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH2:65]>C1COCC1>[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:56]([C:53]1[CH:52]=[CH:51][C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:55][CH:54]=1)=[O:57]
Reactant: O=C(O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1
Reactant: CN(C)CCCCN
Agent: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Solvent: C1CCOC1
Product: CN(C)CCCCNC(=O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1
Yield: 62.2 %

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (4-dimethylamino-butyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.80 g, 2.19 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.36g, 2.23 mmol, 1.02 eq.) followed by 4-dimethylaminobutylamine (0.31 g, 2.63 mmol, 1.2 eq.) as described. When complete, the reaction was worked up leaving a yellow oil that later crystallized. The solid was purified via silica gel flash chromatography using 5% 2M NH3 in methanol in chloroform as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (4-dimethylamino-butyl)-amide (0.63 g, 62% yield) as a white solid.
Reaction SMILES: O1CCCOC1[CH2:7][CH2:8][C:9]1[C:10]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:11]=2[N:12]=[C:13]([NH2:15])[N:14]=1.Cl[C:28]1N=C(C(C)C)C2N=C(C3C=CC(F)=CC=3)C=CC=2N=1>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:9]([CH:8]([CH3:7])[CH3:28])[C:10]=3[N:19]=2)=[CH:25][CH:24]=1
Reactant: Nc1nc(CCC2OCCCO2)c2nc(-c3ccc(F)cc3)ccc2n1
Reactant: CC(C)c1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Product: CC(C)c1nc(N)nc2ccc(-c3ccc(F)cc3)nc12

Procedure:
The procedure for the synthesis of 4-(2-[1,3]dioxan-2-yl-ethyl)-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-ylamine was repeated, except for the use of 2-chloro-6-(4-fluoro-phenyl)-4-isopropyl-pyrido[3,2-d]pyrimidine instead of 2-chloro-4-(2-[1,3]dioxan-2-yl-ethyl)-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine. The resulting title compound was characterized as follows: MS (m/z) 283.0 [M+H]+; HPLC Rt=3.42 minutes (Method A).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.FC(F)(F)C(O)=O.C(#N)C>O>[NH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1
Reactant: CC(C)(C)OC(=O)NCCn1cnc2c(N)nc3ccccc3c21
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCCn1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C
Yield: 29.2 %

Procedure:
Tert-butyl N-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (14.8 g, 45.2 mmol), trifluoroacetic acid (100 mL) and acetonitrile (100 mL) were combined and maintained at ambient temperature overnight. The acetonitrile was removed and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was concentrated under vacuum to provide a tan solid. This material was dissolved in a minimal amount of hot water. The solution was adjusted to pH 14 and allowed to cool. The solution was concentrated under vacuum. The resulting residue was extracted with refluxing ethanol. The ethanol extract was concentrated under vacuum to provide 3.0 g of 1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid, m.p. 265° C. 1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.08 (dd, J=8.0, 1.5 Hz, 1H), 7.62 (dd, J=8.0, 1.5 Hz, 1H), 7.44 (dt, J=8.0, 1.5 Hz, 1H), 7.25 (dt, J=8.0, 1.5 Hz, 1H), 6.58 (broad s, 2H), 4.54 (t, J=7.0 Hz, 2H), 3.01 (t, J=7.0 Hz, 2H), 1.60 (broad s, 2H); MS (EI) m/e 227.1171(227.1171 calcd for C12H13N5).