Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:14][CH2:15][O:16][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C1(CCO)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(CCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-ethoxycarbonyl-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (1.92 g) in a mixture of triethylamine (1.15 ml) and methylene chloride (40 ml) was added methanesulfonyl chloride (0.592 ml) at −78° C., and the mixture was stirred for 1 hour. After completion of the reaction, aqueous sodium hydrogencarbonate was added and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and dried under reduced pressure to give the title compound (2.38 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)C.C(=O)=O.[Br:32]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([Br:32])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(N)ncnn23)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(Br)c3c(N)ncnn23)CC1
Temperature: -20 °C
Reaction time: 4 h
Yield: 134.1 %

Procedure:
To a solution of 4-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (252 mg, 0.758 mmol) in THF (8 mL) at −20° C. (IPA and dry ice) was added 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (108 mg, 0.379 mmol). The reaction was stirred at −20° C. for 4 h. After removal of solvent, the residue was purified by silica gel column using 4% methanol in dichloromethane to obtain 209 mg (67%) of desired product. 1H-NMR (CD2Cl2) δ 7.81 (s, 1H), 7.23 (s, 1H), 6.61 (s, 1H), 3.86 (s, 1H), 3.41 (t, J=2.4, 4H), 2.48 (s, 4H), 1.43 (s, 9H) MS [M+H]+=410.9; LCMS RT=1.87 min
Reaction SMILES: [ClH:1].C([NH:9][C@H:10]([C:20]([OH:22])=[O:21])[CH2:11][S:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(OC(C)(C)C)=O.[CH2:23](O)[CH3:24]>>[ClH:1].[CH2:23]([O:22][C:20](=[O:21])[C@H:10]([CH2:11][S:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:9])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCc1ccccc1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H](N)CSCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl(g) is bubbled into a solution of BOC-S-benzyl-L-cysteine (9.33 g, 30 mmol) in ethanol (200 mL) for 15 minutes. The container is stoppered and stirred at room temperature overnight. The solvent is evaporated in vacuo and the residue stirred in diethyl ether (150 mL) for 1.5 hours to yield S-benzyl-L-cysteine ethyl ester hydrochloride as a solid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[N:4]=1)[NH2:2].Cl.[O-:11][C:12]#[N:13].[K+]>O>[F:9][C:5]1[N:4]=[C:3]([NH:1][NH:2][C:12]([NH2:13])=[O:11])[CH:8]=[CH:7][CH:6]=1
Reactant: NNc1cccc(F)n1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NNc1cccc(F)n1
Temperature: 35 °C

Procedure:
A solution was prepared by admixing 55 g (0.43 m) of 2-hydrazino-6-fluoropyridine in 240 ml of water with 40 g of concentrated hydrochloric acid in 60 ml of water. The mixture was stirred at 35° C. until a clear solution formed. To this reaction mixture was added 37 g (0.46 m) of potassium cyanate in 100 ml of water. After the addition was completed, the reaction mixture was stirred for 21/2 hours at room temperature and then cooled to 10° C. on an ice bath. The 2-(6-fluoro-2-pyridinyl)hydrazinecarboxamide product was isolated by filtration and washed with methylene chloride in quantitative yield. The product melted at 210°-212° C. and upon analysis, was found to have carbon, hydrogen and nitrogen contents of 42.42, 4.23 and 32.83 percent, respectively, as compared with the theoretical contents of 42.35, 4.14 and 32.93 percent, respectively, as calculated for the above named compound.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:15][C:16]([F:34])([F:33])[O:17][C:18]1[CH:32]=[CH:31][C:21]([O:22]/[C:23](=[CH:27]\[C:28]([OH:30])=O)/[C:24]([OH:26])=[O:25])=[CH:20][CH:19]=1>CS(O)(=O)=O>[F:33][C:16]([F:15])([F:34])[O:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:31][CH:32]=1)[O:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][C:28]2=[O:30]
Reactant: O=C(O)/C=C(\Oc1ccc(OC(F)(F)F)cc1)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=C(O)c1cc(=O)c2cc(OC(F)(F)F)ccc2o1
Temperature: 70 °C
Reaction time: 7 h
Yield: 93 %

Procedure:
A solution of phosphorous pentoxide (1.17 g, 8.21 mmole) in methanesulfonic acid (14.38 g) is treated with 2-[4-(trifluoromethoxy)phenoxy]fumaric acid (2.00 g, 6.85 mmole), stirred for 16-18 hours at ambient temperatures and for 7 hours at 70° C., cooled to room temperature and poured onto ice. The resultant mixture is filtered and the filtercake is dried to afford the title product, 1.75 g, (93% yield), mp 192°-194° C., identified by 1H and 13CNMR, IR, mass spectral and elemental analyses.
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=O)[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].BrC[C:23](OCC)=[O:24].[OH-].[Na+]>C(O)C.O>[O:24]=[C:23]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1][CH:8]([C:9]([OH:11])=[O:10])[CH2:14]1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CC(C(=O)O)Cc2ccccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
100 mL (0.425 mol) of diethyl benzylmalonate were added dropwise to a stirred suspension of 28 g (0.7 mol) of NaH (60% dispersion in mineral oil) in 550 mL of absolute ethanol at room temperature. The reaction mixture was refluxed 2 h, then cooled to 50° C. and 47.1 mL (0.425 mol) of ethyl bromoacetate were added dropwise. The reaction mixture was refluxed 2 h, then quenched with 150 mL of water; a solution of 140 g (3.5 mol) of NaOH in 400 mL of water was added and the mixture was heated to reflux for 1 h. EtOH was removed in vacuo, the aqueous solution was washed with Et2O and then carefully brought to acidic pH with 350 mL of 37% HCl and extracted with AcOEt. The solvent was removed in vacuo and the resulting residue was heated to 180° C. for 30 min. After cooling to room temperature, 100 mL of 95% H2SO4 were added and the reaction mixture stirred for 2 h, then it was poured onto 500 g of crushed ice and extracted with Et2O. The organic phase was dried and the solvent removed in vacuo. The resulting residue was taken up in Et2O, washed with 40% NaOH solution then brought to acidic pH with 37% HCl and extracted with Et2O. The organic phase was dried and the solvent removed in vacuo. The resulting solid residue was triturated with Et2O, filtered and dried yielding 15 g of the title compound, used without further purification. m.p.=146-147° C. IR (cm−1): 2924, 1692, 1600; NMR (300 MHz, DMSO, δ ppm): 12.6-12.5 (bs, 1H); 7.9 (d, 1H); 7.6-7.5 (m, 1H); 7.4-7.3 (m, 2H); 3.3-3.1 (m, 3H); 2.7 (m, 2H). MS (m/z): 191.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=S(Cl)[Cl:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[C:13]([Cl:18])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C2CC2C(=O)O)cc1F
Product: COc1ccc(C2CC2C(=O)Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
After 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid (0.848 g, 4.03 mmol) obtained in Step A was dissolved in anhydrous MC (10 mL), SOCl2 (3 mL, 40.34 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]([C:17]([N:30]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)=[O:19])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:7])=[CH:20][CH:21]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccc(Cl)cc1
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Product: COC(=O)CCCN(C(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)phenylalanine and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(p-chlorobenzoyl)phenylalanyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)phenylalanyl]-4-(p-anisidino)butyric acid (M.P. 163° to 165°).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[N:1]1([C:6]2[N:11]=[C:10]([C:12]([NH:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)=[O:14])[CH:9]=[N:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cncc(N2CCCC2)n1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCCC2)n1

Procedure:
To a suspension of 2.90 g of 6-(1-pyrrolidinyl) pyrazine-2-carboxylic acid in 45 ml of tetrahydrofuran, 2.30 ml of triethylamine and 2.00 ml of pivaloyl chloride were added dropwise successively at 0 ° C. under stirring. After stirring for 1 hour at 0 ° C., 1.40 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 1 hour at room temperature, and then refluxed for 12 hours, The reaction mixture was evaporated, and water was added to the residue. The precipitate was collected by filtration, and recrystalized from dimethylsulfoxide affording 1.63 g of the desired compound as yellow needles. The obtained crystal was consistent with that of (a)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:9]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:9])[CH:7]=1
Reactant: Oc1cnc(Cl)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Cl)ncc1=O
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 5-chloro-pyrazin-2-ol (100 mg, 0.76 mmol) in DMF (3 mL) was added K2CO3 (211 mg, 1.53 mmol) and CH3I (0.25 ml, 4 mmol) at room temperature. The mixture was stirred overnight, quenched by H2O, and extracted with EtOAc. The organic phase was concentrated to give the crude product, which was purified by TLC to give 5-chloro-1-methyl-1H-pyrazin-2-one (70 mg, 64%). 1H NMR (CD3OD): δ3.52 (s, 3H), 7.78 (s, 1H), 7.87 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[NH:11][CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][NH2:20]>C(O)C>[NH2:19][N:20]1[C:1]([OH:8])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[C:10](=[CH:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)[N:11]=[CH:12]1
Reactant: O=CNc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Product: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reaction time: 20 h

Procedure:
A mixture of 0.1 mole of 2'-benzoyl-4'-chloroformanilide and 0.15 mole of hydrazine are stirred at room temperature in ethanol. Stirring is continued for 20 hours. The reaction mixture is chilled, and the precipitate filtered. The solid is washed and recrystallized from dimethylformamide to give 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:15][C:16]([OH:18])=[O:17])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A mixture of 3-trifluoromethoxy-benzaldehyde (3 g, 15.78 mmol), malonic acid (2.13 g, 20.51 mmol), piperidine (0.134 g, 1.58 mmol) and pyridine (10 ml) was kept at reflux temperature until carbon dioxide formation ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 60 g ice and 30 ml 6N HCl. The precipitate was isolated, washed with water and dried yielding 2.21 g (60%) 3-(3-trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][OH:24])[CH2:28][CH2:29]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: OCCN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Solvent: CCCCO
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCN(CCO)CC2)nc1

Procedure:
Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 90 μL of 1-(2-hydroxyethyl)piperazine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)nicotinamide. MS (Q1) 438.0 (M)+.
Reaction SMILES: Br[C:2]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4][CH2:3]1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[NH:30]([CH2:3][C:2]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:13])[Cl:14])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1(Br)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: Nc1ccccc1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Yield: 48 %

Procedure:
2,2,2-Trichloroethyl 3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (1.10 g) was dissolved in methylene chloride (15 ml) and to this solution was added aniline (0.28 g). And to the solution was added silver fluoroborate (0.5 g) under stirring under ice-cooling and the mixture was stirred for 4 hours at the same temperature. After the reaction was completed, the reaction mixture was filtered. The filtrate was washed with a dilute aqueour solution of phosphoric acid and then with water, dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (25 g) and eluted with chloroform. The eluate was separated into fractions of each about 20 ml and the second to eighth fractions were collected and then the solvent was distilled off to give 2,2,2-trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g), mp 148° to 149° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:19])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:7]=1.[CH3:20][O:21][C:22]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:23]=1[NH2:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:19][C:5]1[N:4]=[N:3][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)=[CH:28][C:22]=2[O:21][CH3:20])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)nnc2Cl)cc1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1nnc(Cl)c(Nc2ccc(P(C)(C)=O)cc2)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,2,4-triazin-5-amine (0.7 mmol), 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([C:8]3[CH:9]=[C:10]([C:15]4[CH:16]=[N:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=4)[CH:11]=[C:12]([CH3:14])[N:13]=3)[CH:5]=2)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
The title compound was prepared from 6′-(3-bromo-phenyl)-2′-methyl-6-trifluoromethyl-[3,4′]bipyridinyl (example B.12) (0.197 g, 0.5 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.142 g, 0.55 mmol) according to the general procedure III. Obtained as a white foam (0.245 g, 93%). MS (ISP) 526.7 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>ClCCl.CC(=O)OCC>[Br:16][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(C)c(C(=O)OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)c(C(=O)OC)c1
Yield: 72.6 %

Procedure:
To a solution of dimethyl 4-methylisophthlate (Chemical Formula 4) (4 g, 19.2 mmol) in distilled dichloromethane were added N-bromosuccinimide (NBS, 4.8 g, 26.9 mmol) and benzoic peroxyanhydride (0.47 g, 19.2 mmol), followed by reaction at 80° C. for 24 hours in a pressure vessel with constant stirring. The reaction progress was monitored by TLC [Hex:EA=3:1]. When the reaction was detected to have reached completion, saturated NaHCO3 was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer thus formed was dried over anhydrous MgSO4, filtered and concentrated in a vacuum. The purification of the concentrate through column chromatography [Hexane: EtOAc=20:1] produced 4 g of dimethyl 4-(bromomethyl)isophthalate (Chemical Formula 5) (70%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:21])C>S(=O)(=O)(O)O>[OH:21][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCC(F)(F)C(F)(F)F)cc[n+]([O-])c1C
Agent: O=S(=O)(O)O
Product: Cc1c(OCC(F)(F)C(F)(F)F)ccnc1CO
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (2 drops) was added to a solution 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine-1-oxide (2.5 g) in acetic anhydride (8 ml) and the mixture was stirred at 110° C. for 2 hours and then concentrated. The residue was dissolved in methanol (30 ml), 2 N aqueous sodium hydroxide (20 ml) was added, and the mixture was stirred at room temperature for 2 hours. After concentration, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was then distilled off, and te residue was applied to a silica gel (50 g) column. Elution with chloroform-methanol (10:1) and recrystallization from isopropyl ether gave 1.6 g of 2-hydroxymethyl-3-methyl-4-(2,2,3,3, 3-pentafluoropropoxy)pyridine as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[C:11](OCC)=[CH:10][S:9][CH:8]=1)=[O:5]>O>[CH:8]1[S:9][CH:10]=[C:11]2[C:7]=1[NH:6][C:4](=[O:5])[C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[NH:1]2
Reactant: CCOc1cscc1NC(=O)c1ccccc1N
Solvent: O
Product: O=C1Nc2cscc2Nc2ccccc21

Procedure:
A 7.2 g. portion of the above benzamide in 100 g. of polyphosphoric acid is heated at 115°-125° C. for 2 hours, cooled, poured into ice and water and extracted with chloroform. The extract is washed with water, dried over magnesium sulfate, filtered and evaporated, giving 4H-thieno[3,4-b][1,4]benzodiazepin-9(10H)-one as a yellow solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH2:24][C@H:25]([N:30]2[CH2:35][CH2:34][N:33]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[C:26]([O:28][CH3:29])=[O:27])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[C:40]1([C:46]2[CH:51]=[C:50]([CH2:52]O)[CH:49]=[CH:48][N:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:39][S:36]([N:33]1[CH2:32][CH2:31][N:30]([C@@H:25]([CH2:24][NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:52][C:50]3[CH:49]=[CH:48][N:47]=[C:46]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:51]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[C:26]([O:28][CH3:29])=[O:27])[CH2:35][CH2:34]1)(=[O:38])=[O:37]
Reactant: OCc1ccnc(-c2ccccc2)c1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccnc(-c3ccccc3)c2)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
0.23 ml (1.4 mmol) of diethyl azodicarboxylate is added slowly to a solution of 400 mg (0.9 mmol) of methyl (S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate (prepared as described in example 5.1), 193 mg (1.0 mmol) of (2-phenylpyridin-4-yl)methanol and 373 mg (1.4 mmol) of triphenylphosphine in 4 ml of tetrahydrofuran. The reaction mixture is stirred for one hour at ambient temperature and then evaporated to dryness. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 60/40 heptane/ethyl acetate mixture. 318 mg (57%) of methyl (S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy)-benzenesulfonylamino]propanoate are obtained in the form of a white powder.