Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:18](=[O:29])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[CH2:30]([N:32](CC)CC)[CH3:31].C(=N)(OCC)C>CO>[ClH:2].[C:30]([N:26]1[CH2:25][CH2:24][CH:23]([NH:22][N:19]2[CH2:20][CH2:21][N:16]([S:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=4)[CH:9]=3)(=[O:14])=[O:15])[CH2:17][C:18]2=[O:29])[CH2:28][CH2:27]1)(=[NH:32])[CH3:31]
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCNCC1
Reactant: CCN(CC)CC
Agent: CCOC(C)=N
Agent: Cl
Solvent: CO
Product: CC(=N)N1CCC(NN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-[1-(tert-Butoxycarbonyl)-4-piperidinylamino]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (300 mg) was combined with a 4N solution of hydrochloric acid in ethyl acetate (10 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to obtain a crude crystal of 4-(6-chloronaphthalene-2-sulfonyl)-1-(4-piperidinylamino)-2-piperazinone hydrochloride. A solution of the resultant 4-(6-chloronaphthalene-2-sulfonyl)-1-(4-piperidinylamino)-2-piperazinone hydrochloride and triethylamine (1.16 g) in methanol (15 ml) was combined with ethyl acetoimidate (712 mg) and stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue was dissolved in dichloromethane, washed with a 1N aqueous solution of sodium hydroxide, dried and concentrated. The resultant residue was dissolved in ethyl acetate, combined with a solution of hydrochloric acid in ethyl acetate to precipitate a hydrochloride, which was collected by filtration and dried to obtain the title compound (243 mg) as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]3=[O:24])[CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[N:14]=[C:13]2[N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]3=[O:24])[CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1n1cnc2ccc(OCc3ccccc3)nc21
Agent: [Pd]
Solvent: CCO
Product: O=C1CCCCC1n1cnc2ccc(O)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-(5-(Benzyloxy)-3H-imidazo[4,5-b]pyridin-3-yl)cyclohexanone (0.400 g, 1.25 mmol), was taken up in ethanol (5 mL). Catalytic palladium on carbon was added, and the solution was placed under an atmosphere of hydrogen and stirred at room temperature for 2 days. The solution was then filtered through Celite®. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound. LCMS m/z=232.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.80-1.95 (m, 1H), 1.95-2.10 (m, 1H), 2.15-2.35 (m, 4H), 2.70-2.50 (m, 2H), 4.50 (dd, J1=13.2 Hz, J2=5.7 Hz, 1H), 6.89 (d, J=8.9 Hz, 1H), 8.16 (d, J=8.9 Hz, 1H), 8.74 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:38][C:39](=[O:51])[C:40]2[CH:45]=[CH:44][C:43]([F:46])=[C:42]([C:47]([F:50])([F:49])[F:48])[CH:41]=2)([C:24]2[CH:29]=[C:28]([O:30][C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])[CH:27]=[C:26]([F:37])[CH:25]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[Li+].[OH-]>C1COCC1.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:38][C:39](=[O:51])[C:40]2[CH:45]=[CH:44][C:43]([F:46])=[C:42]([C:47]([F:50])([F:48])[F:49])[CH:41]=2)([C:24]2[CH:29]=[C:28]([O:30][C:31]([F:36])([F:35])[CH:32]([F:33])[F:34])[CH:27]=[C:26]([F:37])[CH:25]=2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CCCc1ccc(C[C@](NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(Cl)cn2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCc1ccc(C[C@](NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.8 %

Procedure:
(S)-ethyl 4-(4-(2-(5-chloropyridin-2-yl)-2-(4-fluoro-3-(trifluoromethyl)benzamido)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)phenyl)butanoate (11.2 mg, 0.015 mmol) was dissolved in THF (0.2 mL) and a 1N LiOH solution was added. The reaction mixture was stirred at room temperature for 3 days, then diluted with 1N HCl (0.5 mL). The aqueous layer was extracted with CH2Cl2 (3×0.5 mL). The combined organic portions were dried over Na2SO4, filtered and the solvent removed in vacuo to yield (S)-4-(4-(2-(5-chloropyridin-2-yl)-2-(4-fluoro-3-(trifluoromethyl)benzamido)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)phenyl)butanoic acid (9.9 mg, 92% yield) as a clear film. LCMS: RT=1.55 min [M+H] 719.0 (LCMS Method 2) NMR: 400 MHz 1H (CDCl3) 9.02 ppm, 1H, s; 8.29 ppm, 1H, d, J=2.20 Hz; 7.94 ppm, 1H, m; 7.80 ppm, 1H, m; 7.67 ppm, 1H, dd, J=2.42 and 8.57 ppm, 7.13 ppm, 1H, d, J=8.79 Hz; 7.05 ppm, 2H, m; 6.84 ppm, 1H, d, J=8.79 Hz; 6.77 ppm, 2H, d, J=7.91 Hz; 6.38 ppm, 2H, J=7.91 Hz; 5.81 ppm, 1H, tt, J=2.63 and 52.73 Hz; 4.44 ppm, 1H, d, J=12.74 Hz; 3.51 ppm, 1H, d, J=12.74 Hz; 2.47 ppm, 2H, t, J=7.69 Hz; 2.22 ppm, 2H, t, J=7.25 Hz; 1.80 ppm, 2H, m.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[O:30]=[C:31]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)[C@@H:32]([CH3:35])[CH2:33][CH3:34].O>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OCC)(=O)C.C(OCC)C>[CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:42][C:39]3[CH:38]=[CH:37][C:36]([C:31](=[O:30])[C@@H:32]([CH3:35])[CH2:33][CH3:34])=[CH:41][CH:40]=3)=[O:20])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC[C@H](C)C(=O)c1ccc(O)cc1
Reactant: CCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2)nc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCCCCCCCc1cnc(-c2ccc(C(=O)Oc3ccc(C(=O)[C@@H](C)CC)cc3)cc2)nc1

Procedure:
10 ml of CCl4, 5 ml of thionyl chloride and one drop of dimethylformamide were added to 2.0 g of 4-(5-octyl-2-pyrimidinyl)benzoic acid. The mixture was refluxed for 3 hours under stirring. The solvent was distilled off initially under normal pressure and then under reduced pressure. As a result, 2.2 g of 4-(5-octyl-2-pyrimidinyl)benzoic acid chloride was obtained in the form of a colorless plate-form crystal. 1.2 g of the thus obtained 4-(5-octyl-2-pyrimidinyl)benzoic acid chloride was dissolved in a mixed solvent composed of 20 ml of CCl4 and 5 ml of anhydrous pyridine under stirring. The thus obtained solution was added with a solution prepared by dissolving 0.7 g of (S)-4-(1-oxo-2-methylbutyl)phenol in 10 ml of CCl4, and the admixture was stirred at the room temperature for one night. The admixture was heated to reflux for 3 hours. 200 ml of water and 100 ml of ethyl ether were added to the reaction admixture, followed by stirring. The organic phase was separated, and rinsed initially with a dilute hydrochloric acid solution, then with an aqueous solution of NaHCO3 and finally with a saturated aqueous solution of NaCl. The rinsed organic phase was added with anhydrous Na2SO4 and allowed to stand for one night to dry the same. After removing the drying agent by filtration, the solvent was distilled off to obtain 1.86 g of a crude product. The crude product was refined through silica gel column chromatography while using a mixed solvent of hexane/ethyl acetate (ratio by volume: 8/2). The refined product was recrystallized from ethanol to obtain 200 mg of (S)-4-(1-oxo-2-methylbutyl)phenyl 4-(5-octyl-2-pyrimidinyl)benzoate in the form of a colorless crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:20][CH:21]=O)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:15]([O:14][C:13]([N:12]([CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:20][CH2:21][NH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CNCCN(CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-Butyl [2-(4-nitrophenyl)ethyl](2-oxoethyl)carbamate (0.52 g, 1.7 mmol) in MeOH (10 mL) was added ethyl aminoacetate hydrochloride (0.31 g, 2.2 mmol), sodium cyanoborohydride (1.1 g, 5.1 mmol), and a few drops of acetic acid. The mixture was allowed to stir at 25° C. for 16 hours. LC showed clean reaction. The product was purified by silica gel chromatography (Hexane:EtOAc) to deliver Ethyl [(2-{(tert-butoxycarbonyl) [2-(4-nitrophenyl)ethyl]amino}ethyl)amino]acetate. LC-MS (IE, m/z): 396 [M+1]+.
Reaction SMILES: C(O[C:4](=[O:27])[C:5](=[CH:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:17][CH:18]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:20]([NH:19][C:16]1[N:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]2=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(=CNc1ccc(NCc2ccccc2)nc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(NCc3ccccc3)nc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Diethyl(2-benzylamino-5-pyridylaminomethylene)malonate (2.23 g) was added to diphenyl ether (10 mL) preheated to 230° C. Heating was continued for 0.5 h, the reaction flask removed from the oil bath, and the mixture allowed to cool to ambient temperature. The product was triturated with 1:1 ether:hexanes, collected, rinsed with ether, and dried to give 1.47 g of ethyl 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate as a brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[C:15]=2[C:16](=[O:27])[C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]([CH3:26])[CH:18]=2)=[CH:7][CH:6]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>>[CH2:32]([N:34]([CH2:35][CH3:36])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[C:15]=2[C:16](=[O:27])[C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]([CH3:26])[CH:18]=2)=[CH:7][CH:6]=1)[CH3:33]
Reactant: COc1c(C)cc(C(=O)c2c(-c3ccc(OCCBr)cc3)oc3ccccc23)cc1C
Reactant: CCNCC
Product: CCN(CC)CCOc1ccc(-c2oc3ccccc3c2C(=O)c2cc(C)c(OC)c(C)c2)cc1

Procedure:
Reaction of 2-[4'-(2-bromoethoxy)phenyl]-3-(3',5'-dimethyl-4-methoxybenzoyl)benzofuran with diethylamine as described in Example 11 gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[N:10]([N:14]=[N:15][N:16]=3)[CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.[Br:17]N1C(=O)CCC1=O.O.C(N(CC)CC)C>C(O)(=O)C>[Br:17][C:11]1[N:10]2[N:14]=[N:15][N:16]=[C:9]2[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[N:13][CH:12]=1
Reactant: CN1CCN(c2nccn3nnnc23)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CN1CCN(c2ncc(Br)n3nnnc23)CC1
Temperature: 35 °C
Yield: 100 %

Procedure:
8-(4-Methylpiperazin-1-yl)tetrazolo[1,5-a]pyrazine (100 g, 0.456 mol, 1.0 eq.) was suspended in acetic acid (110 ml) under nitrogen and stirred at 35° C. until a solution was obtained. The solution was cooled to 16° C. and N-Bromosuccinimide (82.14 g, 0.461 mol, 1.01 eq.) is added at such a rate that the temperature of the reaction was maintained at 14-18° C. The reaction was monitored and additional aliquots of N-bromosuccinimide added as necessary to ensure conversion was ≧99.5% after 2-3 hours stirring at 20° C. stirring. Water was added, and the solution is cooled to 13° C. The pH of the suspension is adjusted to 8.3-8.5 by addition of triethylamine. The resulting suspension was filtered, washed with water, and dried to afford the desired product (136.02 g, 100% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[N:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]=1[OH:27])([O-])=O.C1(C)C=CC=CC=1.CC(O)CC.C(N(CCCC)CCCC)CCC>[C].[Pd].O>[OH:27][C:14]1[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:18][C:13]=1[N:12]1[N:11]=[C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]2=[N:1]1
Reactant: CC(C)(C)c1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: [Pd]
Solvent: O
Solvent: CCC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 78.5 %

Procedure:
39.0 g (0.1 mol) of 2-nitro-4-chloro-2'-hydroxy-3',5'-di-t-butylazobenzene, 0.125 g of 5% palladium carbon, 100 ml of toluene, 60 ml of 2-butanol, 120 ml of water and 7 g of tributylamine were charged into a 500-ml stainless autoclave with an agitator. Reaction was effected in the same manner as that employed in Example 1. After the reaction had been completed, after treatment was performed in the same way as that employed in Example 1 to obtain 28.1 g of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorbenzotriazole(yield, 78.6%; melting point, 152° to 153° C.).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](OS(C)(=O)=O)([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:24]>C(Cl)Cl.CO>[CH:1]([N:14]1[CH2:17][C:16]([NH2:24])([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: CC1(N)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (12 g, 36.3 mmol) in DCM (100 mL) was added a saturated solution of ammonia in MeOH (200 mL) and the mixture was stirred for 3 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give 1-benzhydryl-3-methyl-azetidin-3-ylamine (5.31 g, 58%), which was used directly in step F. Alternatively, 1-benzhydryl-3-methyl-azetidin-3-ylamine can be prepared via steps D and E. TLC (eluting with 20% EtOAc/heptane) Rf=0.2.
Reaction SMILES: [C:1]([C:11]1[N:15]([CH3:16])[C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=1)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[C:1]([C:11]1[N:15]([CH3:16])[C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(OC)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1

Procedure:
A solution of 3.00 g. (0.0105 mole) of methyl 5-(p-anisoyl)-1-methylpyrrole-2-acetate in 12 ml. (0.012 mole) of 1N sodium hydroxide solution and 5 ml. of 95% ethanol is refluxed for 30 minutes. The solution is diluted with water, and the ethanol is evaporated in vacuo. The solution is filtered, and the filtrate acidified with dilute hydrochloric acid. The precipitated solid is collected by filtration, dried and recrystallized from methanol-water to give white 5-(p-anisoyl)-1-methylpyrrole-2-acetic acid, m.p. 170-171° C. Analysis: Calcd. for C15H15NO4: C, 65.92;H, 5.53; N, 5.13%. Found: C, 66.01; H, 5.62; N, 5.12%
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[SH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:20][C:7]1[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][S:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Reactant: Sc1ccncc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(SCCCSc2ccncc2)ccnc1CSc1ccncc1
Yield: 69 %

Procedure:
According to the procedure indicated in Example 5, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 4-mercaptopyridine and sodium hydroxide solution yields the title compound; m.p. 116-118° C.; Yield 69% of theory.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[CH:13][CH:12]=[C:11]2[O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]2[C:31](=[O:43])[N:32]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=[CH:34][C:35]=2I)=[O:29])=[N:25][CH:26]=1>C(O)(C)C.ClCCl>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[CH:13][CH:12]=[C:11]2[O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]2[C:31](=[O:43])[N:32]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=[CH:34][C:35]=2[NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:29])=[N:25][CH:26]=1
Reactant: COCCN
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4c(I)ccn(-c5ccccc5)c4=O)nc3)c2cc1OC
Solvent: ClCCl
Solvent: CC(C)O
Product: COCCNc1ccn(-c2ccccc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cn1
Temperature: 100 °C
Yield: 75.1 %

Procedure:
2-methoxyethylamine (137 μl, 1573 μmol) was added to a suspension of N-(5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl)-4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (122 mg, 197 μmol) in iso-propanol (1 mL). The reaction mixture was heated at 100° C. for 80 min. An aliquot was taken and analyzed by LCMS: The reaction was done. The reaction mixture was diluted with dichloromethane. The crude was adsorbed on silica and purified by MPLC (CH2Cl2/MeOH: 100/0 to 95/5) to afford the title compound N-(5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl)-4-(2-methoxyethylamino)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (84 mg, 148 μmol, 75% yield). MS (ESI pos. ion) m/z: 568 (MH+). Calc'd exact mass for C31H29N5O6: 567. 1H NMR (400 MHz, DMSO-d6) 13.28 (s, 1H), 10.80-10.71 (m, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.34 (d, J=9.1 Hz, 1H), 8.30 (d, J=2.8 Hz, 1H), 7.79 (dd, J=9.2, 3.1 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.58-7.37 (m, 7H), 6.53 (d, J=5.2 Hz, 1H), 6.32 (d, J=8.1 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.64-3.54 (m, 4H), 3.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[N:9]=1>>[Br:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:2]([CH3:5])([CH3:3])[CH3:1])[N:9]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)(C)c1cccc(Br)n1
Yield: 69 %

Procedure:
To potassium tert-butoxide (1.0M in tert butanol, 100 ml, 100 mmol) was added 2,6-dibromopyridine (15.87 g, 67 mmol), and the resulting mixture heated at reflux for 3.5 hours. The mixture was evaporated and the residue quenched by the addition of water (150 ml). The mixture was extracted with ethyl acetate (3×80 ml) and the combined organic layers washed with brine (100 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica eluting with 2% Et2O in iso-hexanes to give the title compound (9.9 g, 69%) as a clear oil.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]2[N:57]=[CH:56]C(N)=C[CH:53]=2)[CH2:48][CH2:47]1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:56]=[N:57][C:52]([N:49]5[CH2:48][CH2:47][N:46]([CH3:45])[CH2:51][CH2:50]5)=[CH:53][CH:30]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(N5CCN(C)CC5)nc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 6-(4-methylpiperazino)-3-pyridinamine as the aniline component. (37%, MS=569.3 (M+H))
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([S:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:11][CH:12]=1.[C:19](OC)(=[O:24])[C:20]([O:22][CH3:23])=[O:21].[NH4+].[Cl-]>C(OCC)C>[CH:14]1([S:13][C:10]2[N:11]=[CH:12][C:7]([C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:8][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C(=O)OC
Reactant: Brc1ccc(SC2CCCC2)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C(=O)c1ccc(SC2CCCC2)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23.2 %

Procedure:
Under anhydrous condition n-BuLi (1.6 M solution in hexane, 5.08 mL, 8.13 mmol) was added to stirred solution of 5-bromo-2-cyclopentylsulfanyl-pyridine (2.0 g, 8.13 mmol) in 15 mL dry diethyl ether at −78° C. and stirred for 20 minutes. A solution of dimethyl oxalate (1.09 g, 9.30 mmol) in 15 mL of dry diethyl ether was added dropwise with the help of syringe and resulted reaction mixture was allowed to warm slowly to 0° C. within 1 hr. Reaction mixture was poured on aq. saturated solution of NH4Cl (25 mL), mixture was then extracted with (3×50 mL) diethyl ether; organic layer was washed with brine, dried over anhydrous sodium sulfate, sodium sulfate was filtered and washed with diethyl ether and solvent was removed under reduced pressure. The crude material was purified by silica-gel column chromatography (3 to 5% ethyl acetate in hexane) to afford pure compound (0.5 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH:7]([F:9])[F:8])[N:6]=1.[CH:10]1[C:23]2[CH:22]([C:24](Cl)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[F:8][CH:7]([F:9])[N:5]1[N:4]=[N:3][C:2]([NH:1][C:24]([CH:22]2[C:23]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:25])=[N:6]1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: Nc1nnn(C(F)F)n1
Product: O=C(Nc1nnn(C(F)F)n1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 168-169° and MS: (neg. ions): m/e=342.0 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-difluoromethyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH2:9][CH:10]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:9][CH:10]([P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]
Reactant: O=Cc1ccccn1
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(NCc1ccccn1)P(=O)(OCC)OCC
Reaction time: 12 h

Procedure:
A mixture of 2-pyridinecarboxaldehyde (1.23 g, 11.5 mmol), tetraethyl aminomethylenediphosphonate (3.0 g, 9.9 mmol) and a catalytic amount of p-toluenesulfonic acid dissolved in 10 ml toluene was heated to reflux for 7 h. Toluene was evaporated and the residue dissolved in ethanol was submitted for 12 h to catalytic hydrogenation with 10% palladium on charcoal. Ethanol was evaporated and the title compound was obtained as an oil (1.30 g, 33%) by column chromatography (silica gel, CH2Cl2/MeOH 9/1).