Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: OCCCCCCCCO
Reactant: C1=COCCC1
Product: OCCCCCCCCC1CCCCO1

Procedure:
1,8-Octanediol is treated with one equivalent of dihydropyrane in the presence of acid to give the 8-(tetrahydropyran-2-yl)octanol. 8-(Tetrahydropyran-2-yl)octanol, N-hydroxyphthalimide and triphenylphosphine in DMF are treated at 0° C. with diisopropylazodicarboxylate utilizing Mitsunobu reaction conditions to give O-[8-(tetrahydropyran-2-yl)octanol)phthalimide. Acid treatment of O-[8-(tetrahydropyran-2-yl)octanol]phthalimide will yield O-(octanol)phthalimide which in turn when treated with phosphorous tribromide and pyridine utilizing the reaction conditions of Hall, et al., Synthetic Procedures in Nucleic Acid Chemistry, Zorbach and Tipson, Editors, Volume 1, John Wiley & Sons, 1968 will yield O-(8-bromooctanol)phthalimide.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][CH:19]([C:34]2[N:39]=[CH:38][C:37]([NH2:40])=[CH:36][N:35]=2)[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[C:43](Cl)(=[O:45])[CH3:44].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][CH:19]([C:34]2[N:35]=[CH:36][C:37]([NH:40][C:43](=[O:45])[CH3:44])=[CH:38][N:39]=2)[C:20]2[CH:21]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N)cn2)C[C@H]1CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(NC(C)=O)cn2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2R*,4S*)-4-{(5-Aminopyrimidin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (4 ml), then thereto are added acetyl chloride (0.03 ml) and triethylamine (0.1 ml), and the mixture is stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→1:1) to give (2R*,4S*)-4-{(5-acetylaminopyrimidin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (132 mg). MS (m/z): 641 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][CH3:33])[CH:26]=2)[CH:6]=[CH:5][C:4]=1[OH:34].C(OC([N:42]1[CH2:47][CH2:46][C:45]2[N:48]([CH2:57][CH2:58][CH2:59][NH:60]C(OCC3C=CC=CC=3)=O)[C:49]([C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)=[CH:50][C:44]=2[C:43]1=[O:71])=O)(C)(C)C.CCO>C1CCCCC=1.[Pd]>[CH3:33][O:32][C:27]1[CH:26]=[C:25]([CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][C:7]2[CH:6]=[CH:5][C:4]([OH:34])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:30]=[CH:29][C:28]=1[OH:31].[NH2:60][CH2:59][CH2:58][CH2:57][N:48]1[C:45]2[CH2:46][CH2:47][NH:42][C:43](=[O:71])[C:44]=2[CH:50]=[C:49]1[C:51]1[CH:52]=[CH:53][N:54]=[CH:55][CH:56]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(-c3ccncc3)n2CCCNC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: COc1cc(CNCCCNCCCCNCCCNCc2ccc(O)c(OC)c2)ccc1O
Solvent: CCO
Solvent: C1=CCCCC1
Product: NCCCn1c(-c2ccncc2)cc2c1CCNC2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DL-6-(3-benzyloxycarbonylamino-propyl)-4-oxo-2-pyridin-4-yl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.4 g) was dissolved in cyclohexene (10 mL) and absolute EtOH (20 mL), 10% Pd on carbon (0.2 g) was added and the mixture was refluxed for 1.5 hours. After filtration through celite and solvent evaporation under reduced pressure, the compound was treated with 4N HCl in dioxane (20 mL) for 2.5 hours at room temperature. The solution was concentrated and the residue treated with ethyl acetate. The precipitate was filtered, washed with little ethyl acetate and dried. The residue was dissolved in 4M HCl in dioxane and stirred for 4 hours at room temperature. The solution was concentrated and the title compound, as the dihydrochloride, was recovered as a yellowish solid (0.29 g, quantitative).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O.NN.C(OCC)C>C(O)C>[N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: NN
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: NCCCCNC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (15.0 g, 42.98 mmol) dissolved in ethanol (215 ml) was added hydrazine hydrate (13.4 ml). The solution was stirred for 16 hours at room temperature under a N2 atmosphere. A white precipitate formed. Diethyl ether (215 ml) was added and the mixture was stirred for 10 min then filtered and concentrated. Purification via column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 96:3:1, v/v/v) afforded the product as a brown oil (6.77 g, 74%). 1H NMR (CDCl3) δ 1.57 (m, 9H), 2.05 (m, 2H), 2.75 (m, 6H), 3.78 (t, 1H), 7.06 (dd, 1H, J=7.89, 4.82 Hz), 7.37 (d, 1H, J=7.89 Hz), 8.39 (d, 1H, J=4.82 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([C@@H:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C@H:9]([CH2:14][CH3:15])[C:10](OC)=[O:11])[C:5]([N+:23]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:23][C:10](=[O:11])[C@@H:9]([CH2:14][CH3:15])[N:8]([C@@H:16]3[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]3)[C:6]=2[N:7]=1
Reactant: CC[C@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])[C@@H]1CCC(F)(F)C1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC[C@@H]1C(=O)Nc2cnc(Cl)nc2N1[C@@H]1CCC(F)(F)C1
Temperature: 70 °C
Yield: 61.5 %

Procedure:
A mixture of (R)-methyl 2-((2-chloro-5-nitropyrimidin-4-yl)((R)-3,3-difluorocyclopentyl)amino)butanoate (677 mg, 1.787 mmol) and iron powder (179.7 mg, 3.217 mmol) in glacial acetic acid (8 mL) was heated to 70° C. for 1 hours. The reaction mixture was filtered hot and the cake was further washed with acetic acid. The mother liquors were concentrated in vacuo. The residue was taken up in a 15% solution of methanol in dichloromethane and filtered through a path of silica gel rinsing with more methanol-dichloromethane solution. The mother liquors were concentrated in vacuo. The residue was triturated with ethanol and the solid was filtered to afford the desired compound as white solid (348 mg, 61% yield).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:24][N:23]=[C:22]([NH2:25])[N:21]=4)[CH:18]=3)[N:13]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+].O1[CH2:43][CH2:42][O:41][CH2:40]C1>>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:24][N:23]=[C:22]([NH:25][CH2:19][C:11]5[CH:12]=[CH:43][C:42]([O:41][CH3:40])=[CH:8][CH:9]=5)[N:21]=4)[CH:18]=3)[N:13]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:27])=[O:28])[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C)C)n3)c3cc(-c4nc(N)ns4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CNc2nsc(-c3ccc4c(c3)c(-c3cncc(NC(C)C)n3)cn4S(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 100 °C
Yield: 20 %

Procedure:
To a solution of 5-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-3-amine (0.5 g, 0.99 mmol) in 1,4-dioxane (5 mL) was added 10% aq NaOH (2.5 mL) and the reaction was heated at 100° C. for 2 hr. The mixture was cooled to RT and was treated with ice cold water to give off white precipitate. The precipitate was filtered and washed with ice cold water and further purified by preparative HPLC (eluent: 10-70% MeCN:MeOH (1:1) in water with 0.01% TFA) to give 5-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (70 mg, 20%). MS (ESI, pos. ion) m/z: 352.1 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 9.05 (d, J=1.2 Hz, 1H), 8.27 (m, 2H), 7.78 (d, J=8.4 Hz, 1H), 7.67 (m, 2H), 7.59 (d, J=8.4 Hz, 1H), 7.20 (m, 1H), 4.61 (m, 1H), 1.32 (d, J=6.4 Hz, 6H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCOC(C)=O>C(O)C>[N:17]1[CH:18]=[CH:19][C:14]([NH:13][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])=[CH:15][CH:16]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1ccncc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1c(Nc2ccncc2)c(=O)c1=O
Yield: 9.9 %

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absolute ethanol (100 mL) was added a suspension of 4-aminopyridine (2.77 g, 29.4 mmol) in ethanol (50 mL). The reaction mixture was refluxed for 4 hours then concentrated to give crude product. Chromatography (EtOAc) afforded 0.632 g (10%) of a white solid: mp 120°-125° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6](=[O:13])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=2)[CH2:3][CH2:2]1.[ClH:14].Cl[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl[O-]>O>[Cl:14][C:7]1[C:6](=[O:13])[NH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[C:10]([OH:12])=[O:11]
Reactant: Cl
Reactant: O=C(O)c1cc(=O)[nH]c(C2CC2)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Temperature: 7.5 °C
Yield: 87.5 %

Procedure:
A 2-L Morton flask with overhead stirrer, thermocouple and addition funnel was charged with 2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (161 g, 0.90 mol), hydrochloric acid (37 wt. % in water, 300 g, 250 mL, 3 mol) and water (400 mL). The reaction mixture was stirred at 5-10° C., and sodium hypochlorite (14 wt % aqueous solution, 522 g, 0.99 mol) was added over 2 h. The reaction mixture was maintained at 10-12° C. for 1 h until a KI-starch paper test using sodium sulfite showed no remaining hypochlorite. The resulting mixture was cooled and filtered. The collected solid was washed with cold water (160 mL), and dried to constant weight in a vacuum-oven at 50° C. to give 169 g (88% yield) of the title compound as a solid melting at 189-190° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Cl:13]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[Cl:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: CC#N
Product: COC(=O)c1cc(C)c(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 300 mL three-necked, round-bottomed flask fitted with a magnetic stirrer, condenser equipped with nitrogen inlet, and thermometer were placed 5.68 (25 mmole) of methyl 4-amino-3-methylbenzoate and 35 mL of acetonitrile. The flask was immersed in a preheated oil bath (oil bath temperature 70° C.) and 5.15 g (37.8 mmole) of N-chlorosuccinimide was added all at once. The resulting mixture was refluxed for 2 hours then cooled to room temperature to stand overnight. The reaction mixture was concentrated by removing solvent using a rotary evaporator and the resulting residue was partitioned between a mixture of 100 ml of ethyl ether and 100 ml of water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed using a rotary evaporator, yielding 6.05 g methyl 4-amino-3-chloro-5-methylbenzoate.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][C:15]=2[S:17][CH3:18])[C:10]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]1[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)=O)(C)(C)C>CS(C)=O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[C:11]3=[N:12][CH:13]=[CH:14][C:15]([S:17][CH3:18])=[C:16]3[NH:8][C:9]=2[C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[CH:20][CH:21]=1
Reactant: CSc1ccnc2c(-c3ccc(F)cc3)c(-c3ccncc3)n(C(=O)OC(C)(C)C)c12
Solvent: CS(C)=O
Product: CSc1ccnc2c(-c3ccc(F)cc3)c(-c3ccncc3)[nH]c12
Temperature: 73 °C
Reaction time: 20 h

Procedure:
1-Tert-butoxycarbonyl-3-(4-fluorophenyl)-7-methylthio-2-(pyridin-4-yl)-pyrrolo[3,2-b]pyridine (29 mg, 0.064 mmol was dissolved in dimethylsulfoxide (1 ml) and the solution was heated to 73° C. After 20 h, the solution was cooled and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 3-(4-fluorophenyl)-7-methylthio-2-(pyridin-4-yl)-pyrrolo[3,2-b]pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)[CH:12]=[C:11]([C:25]([NH2:27])=[O:26])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[C:28]([N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([N:32]1[CH2:37][CH2:36][CH:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]=[C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=5)[CH:12]=[C:11]([C:25]([NH2:27])=[O:26])[C:7]=4[NH:8][C:9]=3[CH:10]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)N1CCC(=O)CC1
Reactant: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N)ccc12
Product: CC(C)(C)N1CCC(Nc2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4cccc(C(F)(F)F)c4)nc23)CC1

Procedure:
This was similarly prepared from 7-amino-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide and 1-(t-butyl)piperidin-4-one. MS (ESI) m/z 510.35 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.10 (1H, s), 8.55-8.63 (2H, m), 8.51 (1H, br. s.), 8.30 (1H, s), 7.90 (1H, d, J=8.55 Hz), 7.80 (1H, br. s.), 7.70-7.78 (2H, m), 6.85 (1H, d, J=1.83 Hz), 6.63 (1H, dd, J=8.70, 1.98 Hz), 6.04 (1H, d, J=7.63 Hz), 3.23 (1H, dd, J=10.22, 3.81 Hz), 2.95-3.08 (2H, m), 2.21 (2H, t, J=10.99 Hz), 2.02 (2H, d, J=12.82 Hz), 1.34-1.52 (2H, m), 1.06 (9H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].Br[C:8]1[N:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Br:31])[C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][CH:18]=2)=[N:11][N:12]=1>C(Cl)(Cl)Cl>[Br:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:9]1[C:10]([C:13]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[N:11][N:12]=[C:8]1[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6]
Reactant: CNCCOC
Reactant: Brc1ccccc1-n1c(Br)nnc1-c1ccc(-c2ccccc2)nc1
Solvent: ClC(Cl)Cl
Product: COCCN(C)c1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1ccccc1Br
Temperature: 200 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
In a sealed tube, N-(2-methoxyethyl)methylamine (3 ml) was added to 5-[5-bromo-4-(2-bromophenyl)-4H-1,2,4-triazol-3-yl]-2-phenylpyridine (1.0 g) prepared in the Production Example 3, and stirred at 180° C. for 13 hours and at 200° C. for 24 hours. After the reaction solution was cooled to ambient temperature, chloroform was added to the solution, which was then washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was washed with ethyl acetate, to afford the entitled compound as white solid (711 mg, 70%). The physico-chemical values are as follows.
Reaction SMILES: ClCl.CSC.[OH:6][CH2:7][C@H:8]1[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@@H:10]([CH2:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:9]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.O>[CH:20]([O:19][C:17](=[O:18])[CH2:16][C@H:10]1[CH2:9][C@@H:8]([CH:7]=[O:6])[O:13][C:12]([CH3:14])([CH3:15])[O:11]1)([CH3:22])[CH3:21]
Reactant: CC(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: ClCl
Solvent: CSC
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)OC(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
Chlorine gas (2469.6 mL, 118 mmol) was charged to toluene (373.3 mL, 16 rel vol) at −60° C. Dimethyl sulphide (11.67 mL, 121 mmol) was then added dropwise to the cooled solution over 30 minutes, keeping the contents at −60° C. After 30 minutes at this temperature, isopropyl 2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxan4-yl}acetate (24.56 g, 95 mmol) in toluene (46.7 mL) was added dropwise to the vessel over 30 minutes, maintaining the internal temperature at −60° C. The reaction mixture was agitated at −60° C. for 30 minutes followed by the dropwise addition of triethylamine (26.36 g, 261 mmol) over 30 minutes, allowing the internal temperature to rise to −50° C. The reaction mixture was then allowed to warm to 25° C. evenly over 75 minutes. The resulting slurry was stirred at 25° C. for 30 minutes, then water (77 mL) was added and the mixture agitated for 30 minutes. The aqueous layer was separated and the pH checked (pH should be between 7.5 and 8.5). The resulting organic portion was washed with water (23.3 mL) and the organic portion separated for vacuum distillation at 150 mbar. Distillation was continued until ˜350 mL of toluene had been removed. Toluene (350 mL) was added to the flask and the vacuum distillation repeated at 150 mbar to remove ˜350 mL of toluene. The resulting solution was transferred to a flask containing activated 4 angstrom molecular sieves and left at ambient temperature overnight. This solution was used directly for the coupling stage.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([OH:18])=O)[C:9]=3[N:8]=2)=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:22])=O>ClCCl.CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([Cl:22])=[O:18])[C:9]=3[N:8]=2)=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2[nH]c(-c3ccncc3)nc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2[nH]c(-c3ccncc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-pyridyl)-1H-benzimidazole-4-carboxylic acid (155 mg) in dichloromethane (2 ml) was added oxalyl chloride (0.056 ml) and N,N-dimethylformamide (2 drops) and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo to give 2-(4-pyridyl)-1H-benzimidazole-4-carbonyl chloride. To a solution of 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (76.8 mg) and triethylamine (65 mg) in dichloromethane (5 mL) was added 2-(4-pyridyl)-1H-benzimidazole-4-carbonyl chloride in dichloromethane (2 ml) under ice bath cooling and stirred at ambient temperature for 6 hours. After the reaction mixture was concentrated in vacuo, the residue was diluted with chloroform and saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (Chromatorex, Fuji Silysia Chemical Ltd.) column chromatography (methanol:chloroform=1:49). To the purified product was added water and 1N hydrochloric acid (0.51 ml). The solution was lyophilized to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(4-pyridyl)-1H-benzimidazol-4-yl]carbonylaminobenzamide trichloride (120 mg).
Reaction SMILES: [H-].[Na+].[S:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:13])[CH2:4]1.I[CH3:15]>O1CCCC1>[CH3:15][S:13][C:5]1[CH2:4][S:3][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: S=C1CSc2ccccc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1=Nc2ccccc2SC1
Reaction time: 0.25 h

Procedure:
To 17 parts of sodium hydride in 1500 parts of tetrahydrofuran at room temperature under nitrogen is added, portionwise with stirring during approximately 15 minutes, 90 parts of 2H-1,4-benzothiazine-3(4H)-thione [J. Med. Chem. 12, 290 (1969)]. After the addition is complete, stirring under nitrogen is continued for 10 minutes, whereupon a solution of 85 parts of iodomethane in 70 parts of tetrahydrofuran is rapidly stirred in and stirring continued thereafter for a still further 15 minutes. Removal of solvent by vacuum distillation under nitrogen affords 3-methylthio-2H-1,4-benzothiazine as the residue. Since the product is subject to spontaneous hydrolytic decomposition, it is not usually isolated for the purposes of this invention but instead is employed as the solution in tetrahydrofuran preparable via the foregoing procedure.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[O:9][C:8]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26]O>>[C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]([O:22][CH3:26])=[O:21])=[CH:23][CH:24]=3)[O:9][C:8]2=[O:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C=Cc1ccc(OCC2CN(c3ccccc3)C(=O)O2)cc1
Reactant: CO
Product: COC(=O)C=Cc1ccc(OCC2CN(c3ccccc3)C(=O)O2)cc1
Yield: 94 %

Procedure:
In 20 ml of methanol was dissolved 200 mg of 4-(3-phenyl-2-oxooxazolidin-5-yl)methoxycinnamic acid (compound 181) obtained in Example 27. Concentrated sulfic acid (0.05 ml) was added to the solution, and the mixture was refluxed with heating for 16 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was washed with water and methanol to give 195 mg of the title compound (compound 185) in a yield of 94%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][C:15]=1[Cl:21])=[O:13].C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:10][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[CH:16][C:15]=1[Cl:21])(=[O:13])[CH3:11]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: CC(=O)c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(Oc2ccc(C#N)c(Cl)c2)cc1Cl
Temperature: 130 °C

Procedure:
To a solution 2-chloro-4-hydroxybenzonitrile (CAS Reg. No. 3336-16-1, 1 g), 2-chloro-4-fluoroacetophenone (CAS Reg. No. 700-35-6, 1.12 g) in DMA (10 ml) was added K2CO3 (1.08 g). The mixture is heated to 110° C. for 2 h and at 130° C. for 1 h. Water was added and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 30% EtOAc/heptane) to give the title compound (780 mg) as light yellow oil. MS (m/e)=306.0 [M+H+].