Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH2:24]([O:26][C:27]([CH:29]1[C:33](=[O:34])[CH2:32][N:31]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:30]1)=[O:28])[CH3:25]>O>[CH2:24]([O:26][C:27]([CH:29]1[CH:33]([OH:34])[CH2:32][N:31]([C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH2:30]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1O
Temperature: 32 °C
Reaction time: 24 h
Yield: 41.4 %

Procedure:
To a solution of sucrose (3 g) in distilled water (40 mL) was added Baker's yeast (2 g). The suspension was heated at 32° C. for 1 h. The content of the flask was then poured into a flask containing ketoester 71 (2.9 g, 9.88 mmol, dissolved in 4 mL of methanol). Stirring was continued at 32° C. for 24 h after which additional sucrose (3 g) in warm (40° C.) distilled water was added. After 48 h, the suspension was filtered through a pad of Celite. The pad was washed with water and the aqueous layer was extracted with ethyl acetate (3×250 mL) The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography (30% EtOAc/Hexane) to afford alcohol 73 (1.2 g, 41%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:21]([Cl:22])=[C:15]2[C:16](=[O:20])[NH:17][CH2:18][CH2:19][N:14]2[N:13]=1)=O)C>C1COCC1.CCOC(C)=O>[Cl:22][C:21]1[C:12]([CH2:10][OH:9])=[N:13][N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[C:15]=12
Reactant: CCOC(=O)c1nn2c(c1Cl)C(=O)NCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NCCn2nc(CO)c(Cl)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
A 1M solution of lithium aluminum hydride was added to a stirred solution of 3-chloro-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.37 g, 1.51 mmol) in THF (15 mL) at 0° C. The mixture was stirred at room temperature for 2 hours and then diluted with AcOEt. Na2SO4.10H2O was added at 0° C. and the mixture stirred for 15 minutes at 0° C., filtered through a pad of diatomaceous earth and then washed with additional THF. The solvents were evaporated in vacuo to yield 3-chloro-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.24 g, 79% yield) that was used in the next step without further purification.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C.O>[CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)CCl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Temperature: 15 °C

Procedure:
Sodium metal (23 gram, 1 mole) was dissolved in dry ethanol (500 ml) with stirring. To this 160 gram (1 mole) of diethyl malonate (compound [2]) was added in 30 minutes. The reaction mixture was cooled to 15° C. and ethyl chloroacetate (compound [1], 117 gm, 0.095 mole) was then added drop wise in 30 minutes. On completion of addition the reaction mass was refluxed for 6 hours and then poured in 2 liters of water. The organic materials were extracted with dichloromethane (three times with 500 ml). Next, the organic extracts were dried over sodium sulfate, filtered and evaporated to give an oily substance which was then vacuum distilled to give 220 gm (89% of the theoretical maximum yield) of triethyl ethane-1,1,2-tricarboxylate, compound [3].
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](OC2C=CC([N+]([O-])=O)=CC=2)=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]([N:12]2[CH2:11][CH2:10][N:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([CH3:2])[N:8]=3)[CH2:14][CH2:13]2)=[O:29])[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1nccc(N2CCNCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nccc(N2CCN(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Temperature: 110 °C
Reaction time: 5 h
Yield: 71.7 %

Procedure:
2-Methyl-4-(1-piperazinyl)pyrimidine hydrochloride (18.80 g) and 1-(tert-butoxycarbonyl)-4-(4-nitrophenyloxycarbonyl) piperazine (25 g) were stirred in dry DMF (250 ml) and triethylamine (40 ml) under argon. The reaction mixture was stirred at 110° C. for 5 hours and then allowed to cool overnight. The solid was collected by filtration, washed with DMF and isohexane. The solid was purified by chromatography on silica gel using a gradient of dichloromethane to 5% methanol in dichloromethane as eluent to give 1-(tert-butoxycarbonyl)-4-(1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl)piperazine as a pale solid (19.92g); NMR (CDCl3): 8.15 (m, 1H), 6.35 (m, 1H), 3.7 (m, 4H), 3.45 (m, 4H), 3.35 (m, 4H), 3.3 (m, 4H), 2.5 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[CH:6]=[C:5]([CH3:17])[CH:4]=1.C(O)(=O)C.P(=O)(O)(O)O.[ClH:27].[CH2:28]=O>C1C=CC=CC=1>[Cl:27][CH2:28][C:4]1[C:5]([CH3:17])=[CH:6][C:7]2[C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][C:11]([CH3:13])([CH3:14])[C:12]=2[C:3]=1[O:2][CH3:1]
Reactant: Cl
Reactant: COc1cc(C)cc2c1C(C)(C)CCC2(C)C
Reactant: C=O
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1c(CCl)c(C)cc2c1C(C)(C)CCC2(C)C
Temperature: 95 °C

Procedure:
1-Methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (23.2 g, 0.1 mol),prepared according to Example 2, was added to a stirred solution of acetic acid (18.2 g, 0.3 mol), 85% phosphoric acid (17.6 g, 0.15 mol), hydrochloric acid (28.7 g, 0.3 mol) and paraformaldehyde (7.3 g, 0.24 mol). The mixture was stirred and heated at 95° C. for 16 h. The reaction mixture was then cooled to 25° C., benzene (50 mL) added, and stirred vigorously. The organic layer was separated, washed with water (2×25 mL), neutralized with 5% sodium bicarbonate solution, and dried (Na2SO4). The solvent was removed by distillation to provide 2-chloromethyl-1-methoxy-3,5,5,8,8,-pentamethyl-5,6,7,8-tetrahydronaphthalene, GLC purity 84%.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[P:13](=[O:17])([OH:16])([OH:15])[OH:14]>>[P:13]([O-:17])([O-:16])([O-:15])=[O:14].[NH3+:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9].[NH3+:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9].[NH3+:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: O=P(O)(O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: N=C(N)NCCC[C@H]([NH3+])C(=O)O
Product: O=P([O-])([O-])[O-]

Procedure:
t-PA was precipitated by dialysis versus 0.001M sodium succinate buffer at pH 6. The resulting precipitate was isolated by centrifugation, then a measured amount of this material was equilibrated in 1 ml of the desired buffer system for 20 hours at 5° C. with agitation. The buffer systems studied were prepared by titration of arginine with phosphoric acid to produce an argininium phosphate system at pH 6.0. Stock solutions were diluted with water to obtain final buffer solutions containing 0.10 to 0.20M arginine (as argininium ion). Following equilibration with the desired buffer system, the resulting t-PA preparation was centrifuged to remove any nonsoluble material, then the supernatants were assayed for soluble t-PA via the S2288 assay.
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:28]=[CH:27][C:22]3[N:23]([CH3:26])[N:24]=[N:25][C:21]=3[CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:28]=[CH:27][C:22]3[N:23]([CH3:26])[N:24]=[N:25][C:21]=3[CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)nnn4C)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2c(c1)nnn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)quinoxaline-6-carboxylate (110 mg, 0.28 mmol) in methanol (10 ml) was added sodium hydroxide (45 mg, 1.12 mmol) and water (2 ml). The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum, diluted with water (10 ml), and the pH adjusted to 4 with HCl (3N). The solid was collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (56.2 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10](Cl)(=[O:12])=[O:11])=[CH:5][CH:4]=1.C[Si](C)(C)[O:16][C:17]([CH3:19])=[CH2:18].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH2:18][C:17](=[O:16])[CH3:19])(=[O:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NS(=O)(=O)Cl)cc1
Reactant: C=C(C)O[Si](C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(NS(=O)(=O)CC(C)=O)cc1
Temperature: 25 °C

Procedure:
4-Methoxyphenylsulfamoyl chloride (11.0 g, crude from Step B) in acetonitrile (5.0 mL) was added to a mixture of trimethyl(prop-1-en-2-yloxy)silane (0.85 g, 85% purity, 5.56 mmol) and triethylamine (2.0 mL) in acetonitrile (10 mL) at rt. Upon addition, the reaction was warmed up and refluxed for 2 hrs. After cooling to rt., solvent was removed under reduced pressure and product was purified by flash chromatography (silica gel, ethyl acetate/hexanes gradient) to give N-(4-methoxyphenyl)-2-oxopropane-1-sulfonamide as a solid. LC-MS found: (M+1)+=244.2.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>>[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: C[C@H]1CCCN1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: C[C@H]1CCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B53 was prepared following the general procedure reported for B10 using A1 and (S)-2-methylpyrrolidine; yield: 195.5 mg (56%), colorless amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.17 and 1.24 (2 d, J=6.3 Hz, 3H), 1.60-1.70 (m, 1H), 1.82-2.08 (m, 3H), 3.38-3.64 (m, 2H), 4.12-4.29 (m, 1H), 4.18 (s, 2H), 6.82 (2 s, 2H), 6.94-7.00 (m, 1H), 7.25 (t, J=7.9 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.83-7.90 (m, 1H), 8.18 (s, 1H), 9.58 (s, 1H). MS (ES) C15H20N6O2S requires: 348. found: 349 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[N:15]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17][CH:16]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:15]1[CH:20]=[C:19]([CH2:21][O:22][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=2)[CH:18]=[N:17][CH:16]=1
Reactant: Clc1nc(SCc2ccccc2)ns1
Reactant: OCc1cncnc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CSc2nsc(OCc3cncnc3)n2)cc1
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
Into 2 g of N,N-dimethylformamide were dissolved 219 mg of 5-chloro-3-benzylthio-1,2,4-thiadiazole and 200 mg of 5-pyrimidylmethyl alcohol, 44 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes. After stirring for 5 hours at room temperature, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 130 mg of 5-(5-pyrimidylmethyloxy)-3-benzylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (38)).
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][Li].C>C1COCC1.CCOCC>[OH:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1O
Reactant: [Li]C
Agent: C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cccc(C(F)(F)F)c1O
Temperature: 10 °C
Yield: 99 %

Procedure:
A solution of Example 42B (14.1 g, 68.4 mmol) in THF (70 mL) was cooled to 5° C. and methyllithium (133 mL of a 1.6M solution in Et2O, 212 mmol) was added, keeping the temperature ≦20° C. (slow addition, methane generation). The cooling bath was removed and after 10 min, the reaction mixture was complete by LCMS. The reaction was cooled to 10° C. and EtOAc (140 mL) and 2N HCl (140 mL) were added. The layers were partitioned and the organic portion was washed with water (70 mL) and brine (28 mL). The organic portion was dried (Na2SO4), filtered, and concentrated, to give the title compound (14.0 g, 68.6 mmol, 99%) as an orange oil that was used without further purification. MS (DCI/NH3) m/z 222 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].C(O)C[OH:23].B(F)(F)F.CCOCC.[OH-].[Na+]>C1COCC1.O>[O:3]1[CH2:1][CH2:2][O:20][CH:4]1[C:5]1[CH:6]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:15]=[C:16]([CH:17]=1)[C:18]([OH:23])=[O:19]
Reactant: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Reactant: OCCO
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C2OCCO2)c1
Reaction time: 1.5 h

Procedure:
Mix 5-formyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (580 mg, 2.1 mmol), ethane-1,2-diol (0.35 mL, 6.3 mmol), and boron trifluoride diethyl etherate (0.2 mL, 1.6 mmol) in THF (5 mL) and stir for 1.5 h. Add additional ethane-1,2-diol (0.35 mL, 6.3 mmol) and stir for 20 min. Add 1 N NaOH (10 mL) and stir for 1 h. Add additional 5 N NaOH (1 mL) and stir for 30 min. Dilute the reaction mixture with water (10 mL) and wash with diethyl ether (2×10 mL). Acidify the aqueous layer with 0.5 N HCl to about pH=5. Extract with dichloromethane (3×20 mL), dry (sodium sulfate) and concentrate to give the title compound as a crude residue that is used in the next step without further purification.
Reaction SMILES: CN(C(N[C@H](C(O)=O)C(C)C)=[O:13])CC1N=C(C(C)C)SC=1.[NH2:22][C@@H:23]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:24][C@H:25](O)[C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C1COCC1>[NH2:22][C@H:23]([C@@H:24]([OH:13])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 126.3 %

Procedure:
A solution of 70 mg (0.223 mmol) of N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine, 79 mg (0.186 mmol) of (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6diphenyl-3-hydroxyhexane, 30 mg (0.223 mmol) of 1-hydroxybenzotriazole hydrate, and 51 mg (0.266 mmol) of N-ethyl-N'-dimethylaminopropyl carbodiimide in 2 ml of THF was stirred at ambient temperature for 16 h. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 97:3 CH2Cl2 :CH3OH to provide 100 mg (74%) of the desired compound (Rf 0.4, 95:5 CH2Cl2 :CH3OH) as a solid. 1H NMR (d6 -DMSO) δ0.73 (d, J=7 Hz, 6 H), 1.30 (d, J=7 Hz, 6 H), 1.45 (m, 2 H), 1.87 (m, 1 H), 2.5-2.7 (m, 4 H), 2.87 (s, 3 H), 3.23 (heptet, J=7 Hz, 1 H), 3.57 (m, I H), 3.81 (m, 1 H), 3.93 (m, 1 H), 4.15 (m, 1 H), 4.44 (AA', 2 H), 4.62 (d, J=6 Hz, 1 H), 5.13 (AA', 2 H), 6.01 (d, J=9 Hz, 1 H), 6.89 (d, J=9 Hz, 1 H), 7.1-7.2 (m, 11 H), 7.68 (d, J=9 Hz, 1 H), 7.85 (s, 1 H), 9.05 (s, 1 H). Mass spectrum: (M+H)+ -721. Anal. Calcd for C37H48N6O5S2.0.5H2O: C, 60.88; H, 6.77; N, 11.51. Found: C, 60.68; H, 6.53; N, 11.36.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[N:27][C:28]#[N:29])SC)=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].O.[NH2:36][NH2:37]>C(O)C>[NH2:29][C:28]1[N:27]=[C:24]([NH:23][CH2:22][CH2:21][O:20][CH2:19][C:10]2[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:37][N:36]=1
Reactant: NN
Reactant: CCOC(=O)C1=C(COCCNC(=NC#N)SC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=C(COCCNc2nc(N)n[nH]2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl

Procedure:
N-{2-[(4-{2-Chlorophenyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl)methoxy]ethyl}-N'-cyano-S-methyl-isothiourea (0.4 g) and hydrazine hydrate (0.15 ml) were dissolved in ethanol (20 ml) and heated under reflux for 3 hours. The solvent was then evaporated and toluene (10 ml) was added to the residue, and again the solution was evaporated to dryness. The residue was chromatographed on Merck "Kieselgel 60H" (Trade Mark), eluting with 2% methanol in methylene chloride, to give a beige solid. The solid was recrystallised from ethyl acetate plus a trace of ether to give the title compound, yield 0.1 g, m.p. 137°-138°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[CH3:31][O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>C(Cl)Cl>[CH3:31][O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.4 %

Procedure:
METHOD 1 N-tert-butoxycarbonyl L-proline (99.69 g, 0.4631 mol) was dissolved in CH2Cl2 (800 mL). The solution was cooled to 0° C. (icebath) and triethylamine (51.50 g, 0.5089 mol) added. Pivaloyl chloride (61.45 g, 0.5096 mol) was added dropwise, resulting in the precipitation of a white solid. The reaction mixture was stirred for 1 hour at 0° C. before triethylamine (102.99 g, 1.018 mol) was added. Next, L-proline methyl ester hydrochloride (76.87 g, 0.4641 mol) was added in small portions. The icebath was removed and the reaction mixture stirred at room temperature for 17 hours. The volume was increased by addition of CH2Cl2 (2 L) and the solution washed with 30% (w/w) aqueous citric acid (3×1400 mL), saturated NaHCO3 solution (3×1400 mL) and saturated brine (2×1400 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a clear oil (129.14 g, 85%) with spectral characteristics in accordance with literature data.1
Reaction SMILES: [Na].[H-].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.Br[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:34])=[C:23]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1>CN(C=O)C.O.C(OCC)(=O)C>[C:13]([C:12]1[CH:11]=[CH:10][C:9]([N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:34])=[C:23]([O:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=2)[N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)=[CH:16][CH:15]=1)#[N:14]
Reactant: O=C(Oc1cc(CBr)ccc1F)c1ccccc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc(F)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium, hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 h at this temperature and benzoic acid 5-bromomethyl-2-fluoro-phenyl ester (CAB02146, 1.55 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) and water (50 mL) were added. The mixture was transferred into a separation funnel and washed with water (2×50 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc, Rf: 0.32) to give a white solid. Yield: 1.16 g (56%). 1H-NMR (400 MHz, CDCl3) δ=4.91 (s, 2H), 6.67 (d, J=9.0 Hz, 2H), 7.07 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 7.18 (dd, J=9.4, 8.6 Hz, 1H), 7.24 (dd, J=7.0, 2.3 Hz, 1H), 7.49-7.56 (m, 2H), 7.58 (d, J=9.0 Hz, 2H), 7.62-7.70 (m, 1H), 8.15-8.20 (m, 2H), 8.21 (s, 2H). LRMS (FAB+): 414.2 (100, [M+H]+).
Reaction SMILES: [C:1]([C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([Cl:16])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C([Cl:27])(=O)CC.O>O1CCOCC1>[Cl:27][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:1]([C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([Cl:16])[N:10]=1)=[O:8]
Reactant: Nc1ccc(Cl)nc1C(=O)c1ccccc1
Reactant: CCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Nc1ccc(Cl)nc1C(=O)c1ccccc1Cl
Reaction time: 2 h

Procedure:
43 grams of 2-benzoyl-3-amino-6-chloropyridine were dissolved in 100 ml of dioxane, then 16 ml of pyridine and finally with stirring 18 ml of propionyl chloride were added. The mixture was stirred for 2 hours, then water was added until crystallization began. The material which precipitated was recrystallized from methanol/water. Yield 48 grams; M.P. 40° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[C:22]2[C:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[S:32](=[O:40])(=[O:39])[NH:31][N:30]=1.Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CC#N.O.C(Cl)Cl>[C:46]([O:45][C:43](=[O:44])[CH2:42][N:24]1[C:25]2[C:21](=[CH:20][C:19]([F:18])=[CH:27][CH:26]=2)[C:22]([C:29]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[S:32](=[O:39])(=[O:40])[N:31]([CH2:2][CH2:3][O:4][C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=3)[N:30]=2)=[C:23]1[CH3:28])([CH3:49])([CH3:48])[CH3:47]
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Clc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1c(C2=NN(CCOc3ccc(Cl)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Chlorophenyl 2-bromoethyl ether (16 mg, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.