Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2](=[C:10]([F:12])[F:11])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].[Cl:15][C:16]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:17]=1[CH2:18]Br>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:17]=1[CH2:18][C:5]([CH2:4][CH2:3][C:2]([F:1])=[C:10]([F:11])[F:12])([C:6]#[N:7])[C:8]#[N:9]
Reactant: FC(F)(F)c1ccc(CBr)c(Cl)c1
Reactant: N#CC(C#N)CCC(F)=C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1ccc(C(F)(F)F)cc1Cl
Yield: 44.3 %

Procedure:
Using 0.30 g of (3,4,4-trifluoro-3-butenyl)malononitrile, 5 ml of N,N-dimethylformamide, 75 mg of sodium hydride (60% in oil), and 0.52 g of 2-chloro-4-(trifluoromethyl)benzylbromide, and according to the process described in the Production Example 1, there was obtained 0.28 g of 2-(2-chloro-4-(trifluoromethyl)benzyl)-2-(3,4,4-trifluoro-3-butenyl)malononitrile (the present compound (62)).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:7]=[CH:6][NH:5][N:4]=1.Cl[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:17][C:16]1[C:11]([N:5]2[CH:6]=[N:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ncn(-c2ncccc2Cl)n1
Temperature: 120 °C
Reaction time: 27 h
Yield: 11.3 %

Procedure:
A mixture of 3.5 g of 3-trifluoromethyl-1H-1,2,4-triazole, 3.8 g of 2,3-dichloropyridine, 6.0 g of potassium carbonate and 30 ml of N,N-dimethylformamide was stirred at 120° C. for 27 hours. After the reaction mixture was allowed to cool to room temperature, water was poured and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.72 g of 3-chloro-2-(3-trifluoromethyl-1H-1,2,4-triazol-1-yl)pyridine of the formula:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[O:25]([C:32]1[CH:33]=[CH:34][C:35]([NH:36][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:22])=[CH:37][CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4ccc(Oc5ccccc5)cc4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 4-phenoxyaniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 501 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH3:13].C([O-])=O.[NH4+]>CO.O1CCCC1.[Pd]>[NH2:14][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[C:2]([F:1])[CH:3]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nccn1-c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
3-Fluoro-4-(2-methylimidazol-1-yl)nitrobenzene (40 g, 0.181 M) was dissolved in a mixture of methanol (200 ml) and tetrahydrofuran (800 ml), cooled to 0° under nitrogen, and treated with ammonium formate (57 g, 0.905 M) followed by palladium on charcoal (10%, 2 g). The mixture was stirred at ambient temperature for 18 hours, filtered through celite, celite washed with methanol (100 ml), and filtrate evaporated to dryness. The residue was partitioned between ethyl acetate (800 ml) and 10% aqueous sodium bicarbonate (250 ml). The organic layer was separated, washed with brine (250 ml), dried (magnesium sulfate) and evaporated to give title compound (34.6 g).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2].[CH3:31][O:32][C:33]1[C:34](=O)[C:35](=[O:39])[C:36]=1[O:37]C.CCN(C(C)C)C(C)C>CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:34]2[C:35](=[O:39])[C:36](=[O:37])[C:33]=2[O:32][CH3:31])[CH2:4]1)[CH3:2]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC[C@@H]1C[C@H](Nc2c(OC)c(=O)c2=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 71.5 %

Procedure:
To a solution of (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.40 g, 0.942 mmol, Example #8 Step M) in MeOH (3 mL) was added 3,4-dimethoxycyclobut-3-ene-1,2-dione (0.14 g, 0.98 mmol) and DIEA (0.18 mL, 1.0 mmol). The reaction was stirred at rt for about 16.5 h. Then the solid from the reaction mixture was collected via vacuum filtration, while washing with cold MeOH (about 4° C., 10 mL), and dried in a vacuum oven at about 60° C. to give crude 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione (0.36 g, 73%, 90% purity): LC/MS (Table 1, Method a) Rt=2.13 min; MS m/z: 535 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5](=O)[O:6]C1C=CC([N+]([O-])=O)=CC=1)[C:2]#[CH:3].[Cl:17][C:18]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][NH2:28])[CH2:22]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:17][C:18]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][NH:28][C:5]([NH:4][CH2:1][C:2]#[CH:3])=[O:6])[CH2:22]1
Reactant: C#CCNC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC[C@H]1CN(Cc2cccc(Cl)c2Cl)CCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNC(=O)NC[C@H]1CN(Cc2cccc(Cl)c2Cl)CCO1
Reaction time: 16 h
Yield: 51.5 %

Procedure:
A solution of Intermediate 22 (0.024 g) in dichloromethane (1 ml) was stirred with Intermediate 20 (0.033 g) and N,N-diisopropylethylamine (0.022 ml) for 3 h at 23° C. The solvent was removed in vacuo and the residue was purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol. The basic fraction was concentrated in vacuo, and the residue was dissolved in dichloromethane (5 ml), and the solution shaken with polystyrene methyl isocyanate resin (Argonaut technologies, 0.256 g, 1.43 mmol/g) for 16 h. The solution Was drained from the resin and the resin washed with dichloromethane (8 ml); the combined filtrate and washings were concentrated in vacuo to give the title compound as a pale yellow gum (0.02 g).
Reaction SMILES: O[C:2]1([CH3:25])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:3]1.COCCN(S(F)(F)[F:36])CCOC>C(Cl)Cl.C1COCC1>[F:36][C:2]1([CH3:25])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCN(C(=O)OC(C)(C)C)CC(C)(O)C1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1N1CCN(C(=O)OC(C)(C)C)CC(C)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of tert-butyl 6-hydroxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (100 mg, 0.28 mmol) in DCM (5 mL) was added deoxo-Fluor® (50% in THF, 0.26 mL, 0.7 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (30 mL), cooled in an ice water bath and quenched by dropwise addition of saturated aqueous NaHCO3 (40 mL). The resulting mixture was stirred for 10 min. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. The crude product was purified via silica gel column chromatography (0-50% EtOAc/isohexane) to give tert-butyl 6-fluoro-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (70 mg, 70%) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.80 (s, 3H), 3.73-3.32 (m, 6H), 3.26-3.03 (m, 2H), 1.50 (s, 9H), 1.32 (d, J=20.1 Hz, 3H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:9]1([NH:15]N)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1>O>[CH2:5]1[C:6]2[NH:15][C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:1]=2[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CCCCC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: c1ccc2c3c([nH]c2c1)CCCC3
Temperature: 115 °C
Reaction time: 8 h

Procedure:
Cyclohexanone (2.0 ml., 0.020 mole), phenylhydrazine hydrochloride (2.88 g., (0.020 mole) and 6.0 ml. of freshly distilled pyridine are combined, heated at reflux (115° C) for 3 hours, then allowed to cool to room temperature and allowed to stir overnight. About 25 ml. of water is added and the precipitated solids are collected by decantation. After washing again with water, the solids are dissolved in a mixture of 20 ml. of ethanol and 5 ml. of water and set aside. The resulting crystals are collected by filtration, washed with aqueous ethanol and dried to afford 2.65 g. (77.5% of theory) of the title compound, M.P. 119°-120° C. A mixture of the product and an authentic sample of 1,2,3,4-tetrahydrocarbazole also melted at 119°-120° C.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[OH-].[Na+].[S:8]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:18])[C:15]([OH:17])=[O:16])=[CH:9]1.Cl>CO>[S:8]1[CH:12]=[CH:11][C:10]([CH:13]2[C:14]([C:15]([OH:17])=[O:16])([OH:18])[CH2:5][C:3](=[O:4])[CH2:1][CH2:2]2)=[CH:9]1
Reactant: O=C(O)C(=O)Cc1ccsc1
Reactant: C=CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCC(c2ccsc2)C(O)(C(=O)O)C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 699.5 %

Procedure:
17.1 cm3 (21 mmol) of methyl vinyl ketone and 7.2 g (18 mmol) of sodium hydroxide pellets are successively added to a solution, cooled to 0° C., of 22.4 g (13 mmol) of (3-thienyl)pyruvic acid in 150 cm3 of methanol and then the reaction mixture is stirred at a temperature in the region of 20° C. for two hours. After neutralizing with 60 cm3 of a 3N aqueous hydrochloric acid solution, the precipitate formed is filtered off, washed with water and then dried at 20° C. 21.85 g (70%) of 6-(3-thienyl)-3-oxocyclohexan-1-ol-1-carboxylic acid are thus obtained in the form of a yellow powder, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].Cl[C:15]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C>C1COCC1>[C:10]([O:9][C:7](=[O:8])[CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:15]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)CC1CCCN1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCCC2CC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Tert-butyl 2-(pyrrolidin-2-yl)acetate (1.00 g, 5.40 mmol) was added to a solution of methyl 6-chloro-5-nitronicotinate (1.169 g, 5.40 mmol) in THF (Volume: 10 ml). The reaction mixture was stirred at rt for 1 h and K2CO3 (0.760 g, 5.50 mmol) was added. The reaction mixture was stirred for 2 h and triethylamine (0.379 ml, 2.70 mmol) was added. The mixture was stirred for 1 h, filtered and concentrated in vacuo. Flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 9:1) afforded methyl 6-(2-(2-tert-butoxy-2-oxoethyl)pyrrolidin-1-yl)-5-nitronicotinate (1.79 g, 4.90 mmol, 91% yield) as a yellow oil. [M+H] calc'd for C17H23N3O6, 365; found, 365.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)(=[O:29])=[O:28])[CH2:9][C:10]([NH:12][CH:13]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18]=[C:17]([CH2:23][CH2:24][OH:25])[N:16]=[CH:15][C:14]2=3)=[O:11])=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)(=[O:29])=[O:28])[CH2:9][C:10]([NH:12][CH:13]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18]=[C:17]([CH2:23][CH2:24][O:25][S:41]([CH3:40])(=[O:43])=[O:42])[N:16]=[CH:15][C:14]2=3)=[O:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)NC1CCCc2nc(CCO)ncc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ncc2c(n1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(4-fluorophenyl)-N-[2-(2-hydroxy-ethyl)-5,6,7,8-tetrahydro-quinazolin-5-yl]-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (56.6 mg, 0.1 mmol) in dry CH2Cl2 at 0 C was added MsCl (34 mg, 0.3 mmol), followed by Et3N (50 mg, 0.5 mmol). After stirring at 0° C. for 20 min, the reaction was quenched with Sat. NaHCO3 solution, extracted with EtOAc, dried over Na2SO4, and evaporated in vacuo. Flash chromatography (SiO2, EtOAc/MeOH=100:3 to 100:5 to 100:7) gave the title compound as a white solid. MS: 645.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH2:6])[CH3:2].[NH2:15][C:16]1[NH:25][C:24](=[O:26])[C:23]2[C:22]3[CH:27]=[C:28]([NH:31][S:32]([C:35]4[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[CH:29]=[CH:30][C:21]=3[CH:20]=[CH:19][C:18]=2[N:17]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH2:15][C:16]1[NH:25][C:24](=[O:26])[C:23]2[C:22]3[CH:27]=[C:28]([NH:31][S:32]([C:35]4[CH:43]=[CH:42][C:38]([C:39]([NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:40])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[CH:29]=[CH:30][C:21]=3[CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: Nc1nc2ccc3ccc(NS(=O)(=O)c4ccc(C(=O)O)cc4)cc3c2c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(S(=O)(=O)Nc2ccc3ccc4nc(N)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of L-glutamic acid diethyl ester (0.81 g, 4.0 mmoles) and 4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoic acid (0.43 g, 0.9 mmoles) in dry dimethylformamide (20 ml) was added 1-hydroxybenzotriazole monohydrate (0.43 g, 3.2 mmoles) and dicyclohexylcarbodiimide (0.66 g, 3.2 mmoles). The solution was stirred at room temperature under a nitrogen atmosphere for 20 hrs, after which time the solvent was removed under reduced pressure. The residue was recrystallized successively from methylene chloride:methanol/9:1 and methanol to give diethyl N-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoyl)-L-glutamate as a white solid. (0.215 g, 36%). 1HNMR(DMSO-d6, 300 MHz) δ: 1.12(t, J=7 Hz, 3H, ester-CH3); 1.15(t, J=7 Hz, 3H, ester-CH3); 1.89-2.13(m, 2H, glu-CH2); 2.40(t, J=7.6 Hz, 2H, glu-CH2); 4.00(q, J=7 Hz, 2H, ester-CH2); 4.08(q, J=7 Hz, 2H, ester-CH2); 6.55(br s, 2H, NH2); 7.16(d, J=8.9 Hz, 1H, Ar); 7.23(dd, J=8.7, 2 Hz, 1H, Ar); 7.73(d, J=8.7 Hz, 1H, Ar); 7.89(d, J=8.9 Hz, 1H, Ar); 7.96(m, 4H, Ar); 8.89(d, J=7.4 Hz, 1H, glu-NH); 9.48(d, J=2 Hz, 1H, Ar); 10.67(s, 1H, NH); 11.08(s, 1H, NH). Anal. Calculated for C28H29N5O8S: C, 56.46; H, 4.91; N, 11.7.6; S, 5.38. Found: C, 56.45; H, 4.94; N, 11.75; S, 5.43.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([Cl:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][N:16]1[C:20](=[O:21])[C:19]2[C:22]([CH:28]([CH3:30])[CH3:29])=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=2[S:17]1(=[O:32])=[O:31].[F-].[K+]>CN(C=O)C>[CH:28]([C:22]1[C:19]2[C:20](=[O:21])[N:16]([CH2:15][O:12][C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]([Cl:13])[CH:10]=3)[S:17](=[O:32])(=[O:31])[C:18]=2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=1)([CH3:30])[CH3:29]
Reactant: O=C1CC(Cl)=NN1c1ccccc1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(Cl)nn1-c1ccccc1)C2=O
Temperature: 0 °C
Yield: 31.9 %

Procedure:
A mixture 2,4-dihydro-2-phenyl-5-chloro-3H-pyrazol-3-one (350 mg; 1.8 mmol), 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benziso thiazol-3(2H)-one 1,1-dioxide (686 mg, 1.98 mmol), and KF (209 mg; 3.6 mmol) in DMF (8 ml) was stirred at 20° C. for 3 hours and the mixture was diluted with ice water. The above mixture was extracted with ether (3×) and the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 25-50% ethyl acetate/hexane; methylene chloride/hexane, 20-100%) and recrystallized from ethyl acetate/hexane to afford 265 mg (32%) of 4-isopropyl-6-methoxy-2-(1-phenyl-3-chloropyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1, 1-dioxide (Formula I: R1 =phenyl; R2 =Cl; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 109°-110° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.CI>O1CCCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[CH3:1]
Reactant: Fc1cncc(Br)c1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)cncc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To the solution of diisopropylamine (10.08 mL, 0.0738 mol) in tetrahydrofuran (80 mL), n-butyl lithium (46 mL, 0.0738 mol, 1.6M), was added at −78° C. and then it was warmed to 0° C. and stirred for 30 min, then it was cooled to −78° C. and the solution of 3-bromo-5-fluoro-pyridine (10.0 g, 0.056 mol) in tetrahydrofuran (10 mL) was added and stirred for 30 min. Methyl iodide (4 mL, 0.062 mol) was added to reaction mixture and allowed to room temperature for 2 h. Reaction mass was quenched with saturated ammonium chloride (100 mL) solution. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.31 (s, 1H), 2.38 (s, 3H). LCMS (M+3): 192.2.
Reaction SMILES: [C:1]([C@H:4]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:5]12[CH2:6][C:7]([OH:9])=[O:8])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])[CH2:19][CH2:20]1)[N:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:14]3)(O)=[O:2].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([NH:35][C:1]([C@H:4]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:5]12[CH2:6][C:7]([OH:9])=[O:8])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])[CH2:19][CH2:20]1)[N:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:14]3)=[O:2])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N1C[C@H]2[C@@H]3CC[C@H](C(=O)O)[C@@]3(CC(=O)O)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12CC(=O)O

Procedure:
A sample of 17β-carboxy-6-t-butylcarboxy-6-azaandrost-4-en-3-one (2.03 g, 4.86 mmol), from part F, is coupled with t-butyl amine as described in Example 1, part A, to give crude 17β-N-t-butylcarbamoyl-6-t-butylcarboxy-6-azaandrost-4-en-3-one which is dissolved in methylene chloride (30 mL) and treated with trifluoroacetic acid (4 mL) at room temperature. After 3 hrs the reaction is concentrated, methylene chloride (50 mL) and saturated aqueous bicarbonate (50 mL) added, the layers separated, methylene chloride washed with saturated aqueous NaCl, dried over MgSO4, concentrated and chromatographed on silica gel (0-10% methanol/methylene chloride) to give 17β-N-t-butylcarbamoyl-6-azaandrost-4-en-3-one as a white solid; yield: 1.04 g (57%). Recrystallization from methylene chloride/hexanes gives an analytical sample as a white crystalline solid; m.p. 186°-189° C. Anal. Calcd. for C23H36N2O2 ·3/8H2O; C, 72.83; H, 9.77; N, 7.38. Found C, 72.95; H, 9.85; N, 7.22.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:30][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH2:26][CH3:27])[C:20]([CH2:28][CH3:29])=[N:19]4)(=O)=O)=CC=1.[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][CH:36]=[C:35]2[C:41]1[CH2:42][CH2:43][NH:44][CH2:45][CH:46]=1>CS(C)=O.C(OCC)(=O)C>[CH2:26]([C:21]1[C:20]([CH2:28][CH3:29])=[N:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][CH:13]([CH2:12][N:44]4[CH2:43][CH:42]=[C:41]([C:35]5[C:34]6[C:38](=[CH:39][CH:40]=[C:32]([F:31])[CH:33]=6)[NH:37][CH:36]=5)[CH2:46][CH2:45]4)[O:30][C:17]3=2)[N:22]=1)[CH3:27]
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CCc1nc2ccc3c(c2nc1CC)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO3
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1nc2ccc3c(c2nc1CC)OC(CN1CC=C(c2c[nH]c4ccc(F)cc24)CC1)CO3
Temperature: 80 °C

Procedure:
To a solution of (2R)-8,9-diethyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.300 g, 0.700 mmole) in methyl sulfoxide (20 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.606 g, 2.800 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.161 g (49%) of the (S)-enantiomer of the title compound as a yellow crystalline solid. Rf=0.38 (silica, methanol:ethyl acetate 1:9); mp>120° C. dec.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:9][CH:8]=[CH:7][CH:6]=2.[CH2:21]([O:23][CH2:24][C:25](Cl)=O)[CH3:22].C(N(CC)CC)C>>[CH2:21]([O:23][CH2:24][C:25]1[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:22]
Reactant: CCOCC(=O)Cl
Reactant: CCOC(=O)CCCNc1c(N)cnc2cccnc12
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Yield: 99.8 %

Procedure:
Ethyl 4-(3-amino[1,5]naphthyridin-4-ylamino)butanoate (2.5 g, 9.1 mmol, prepared in Parts A and B of Example 37) was treated with ethoxyacetyl chloride (1.02 mL, 10.0 mmol) and cyclized according to a modification of the method described in Part C of Example 37. The reaction with triethylamine (3.8 mL, 27 mmol) was heated at reflux overnight and was complete. Following the work-up procedure, 3.11 g of ethyl 4-(2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanoate were obtained as a brown oil.