Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][CH:4]([NH:19][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:3]1=[O:33].[OH-].[Na+].[NH4+].[Cl-]>C1COCC1.CO.O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][CH:4]([NH:19][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:3]1=[O:33]
Reactant: CCOC(=O)CCCCCCC(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN1C(=O)C(NC(=O)CCCCCCC(=O)O)N=C(c2ccccc2)c2ccccc21
Yield: 99 %

Procedure:
15 (0.58 g, 1.29 mmol) and NaOH (0.08 g, 1.5 eq) were stirred in a mixture of THF/MeOH/H2O (2 mL each) for 2 h at room temperature. The mixture was treated with a saturated solution of NH4Cl and extracted with AcOEt. Drying (Na2SO4) and removal of the solvent gave 8-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylamino)-8-oxooctanoic acid in 99% yield as a white solid (m.p. 140-141° C.).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CC1C=CC(S(O)(=O)=O)=CC=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>N1C=CC=CC=1>[C:32]1([O:31][C:29]([NH:1][C@H:2]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:30])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: CC(C)C[C@H](NC(=O)Oc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of H-Leu-OBzl.TsOH (1.01 g) in pyridine (9 ml) was added phenyl chloroformate (386 μl) at 0°-5° C. under argon atmosphere. The mixture was stirred at the same temperature for 2 h and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 1N-hydrochloric acid, water and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel chromatography (Merck, Kieselgel 60) with ethyl acetate/hexane=1/10 for elution to give the product (828 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:23][C:24](=[O:26])[CH3:25])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:4][CH2:5][CH:6]([NH:23][C:24](=[O:26])[CH3:25])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCc1ccc(OCc2ccccc2)cc1)COC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NC(CCc1ccc(O)cc1)COC(C)=O
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 93.4 %

Procedure:
To a solution of 2-acetamido-4-(4-benzyloxyphenyl)butyl acetate (8.32 g) in ethanol (150 ml), 10% palladium-carbon (1 g) was added and the mixture was stirred, under a hydrogen atmosphere, at room temperature for 8.5 hours. Then, the catalyst was filtered off and the solvent was distilled away under reduced pressure. Ethanol (200 ml) and 10% pallladium-carbon (1 g) were added to the residue and the mixture was further stirred, under a hydrogen atmosphere, at room temperature for 3.5 hours. The catalyst was filtered off from the reaction solution and the solvent was distilled away under reduced pressure. The residue was subjected to silica gel chromatography (eluent; ethyl acetate-hexane=1:4) to give the subject compound (5.80 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.IC.[C:23](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:23])[C:10](=[O:12])[C:9]([CH3:13])([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:6]=2[N:20]=1
Reactant: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 18.43 g (0.187 mole) of 2-chloro-9-cyclopentyl-7,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-38) and 500 mL of dimethylformamide was added 26.6 g (0.187 mole) of iodomethane and 30.6 g (0.0939 mole) of cesium carbonate. The mixture was stirred overnight at ambient temperature. The mixture was then filtered and concentrated under reduced pressure. The residue was partitioned between 500 mL of ethyl acetate and 200 mL of water. The aqueous layer was extracted twice with 200 mL of ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 18.47 g of 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38) as an off-white solid.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[N:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:22]#[N:23]>C(O)(C)C>[NH2:23][C:22]1[C:5]2[C:4](=[N:9][CH:8]=[C:7]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=3)(=[O:12])=[O:11])[CH:6]=2)[NH:2][N:1]=1
Reactant: NN
Reactant: N#Cc1cc(S(=O)(=O)Nc2cc(F)cc(F)c2)cnc1Cl
Solvent: CC(C)O
Product: Nc1n[nH]c2ncc(S(=O)(=O)Nc3cc(F)cc(F)c3)cc12
Temperature: 75 °C
Yield: 100 %

Procedure:
0.377 ml (2.63 mmol) of 35% hydrazine is added to 0.217 g (0.658 mmol) of 6-chloro-5-cyano-N-(3,5-difluorophenyl)pyridine-3-sulfonamide diluted in 6 ml of isopropanol. The solution is heated at 75° C. for 2 hours. The solvent is evaporated to yield 0.214 g of 3-amino-N-(3,5-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-sulfonamide in the form of a yellow solid (yield=100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]([O:25]CC)=O)[N:12]([CH3:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].[NH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([NH:28][C:23]([C:11]2[N:12]([CH3:22])[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2Cl)n1C
Reactant: NN1CCCCC1
Product: Cn1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of ethyl 4,5-di-(2,4-dichlorophenyl)-1-methylimidazole-2-carboxylate (20 mg, 0.045 mmol) from Step D in neat 1-aminopiperidine (1 mL) was heated at 90° C. for 72 hr. Most of the amine was evaporated under a stream of nitrogen and the residue was purified by Prep TLC (1 mm, silica) (25% ethyl acetate in hexanes to afford the title compound. HPLC/MS: 497 (M+1), 499 (100%, M+3), 501 (M+5); Rt=3.95 min.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[OH2:5].[CH3:6][CH2:7][N:8]([C:11]([C@H:13]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:14])=[O:12])[CH2:9][CH3:10]>O.CC(C)=O>[CH3:10][CH2:9][N:8]([C:11]([CH:13]([O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=12)[CH3:14])=[O:12])[CH2:7][CH3:6].[CH3:6][CH2:7][N:8]([C:1]([C@H:2]([O:3][C:21]1[C:20]2[C:25](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:24]=[CH:23][CH:22]=1)[CH3:4])=[O:5])[CH2:9][CH3:10]
Reactant: O
Reactant: CC(C)=O
Agent: CCN(CC)C(=O)[C@@H](C)Oc1cccc2ccccc12
Product: CCN(CC)C(=O)C(C)Oc1cccc2ccccc12

Procedure:
The highest concentration of Napropamide was prepared by measuring a calculated volume by weight and diluting with tap water to the full required volume. Lower concentrations were prepared by serial dilution with water. D-Napropamide was prepared by dissolving the calculated weight in acetone and adding water to give the full required volume in 50:50 acetone+water. Lower concentrations were prepared by serial dilution with 50:50 acetone+water. D-Napropamide dissolved completely.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([OH:22])[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=[O:5])=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][N:2]([CH3:30])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([OH:22])[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[N:8]=[CH:7]1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1cc(C(O)c2ccc3ccccc3c2)nc1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cnc(C(O)c2ccc3ccccc3c2)c1

Procedure:
2-(tert-Butyl-dimethyl-silanyl)-4-(hydroxy-naphthalen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (Intermediate-I1) (2.6 g, 5.4 mmol) in THF (30 mL) was treated with tetrabutylammonium fluoride (TBAF) (5.8 mL of a IM soln) at rt for 1 h. The reaction mixture was subjected to an aqueous work-up and the product was purified by chromatography on silica gel with 66% EtOAc:hexane to give 4-(hydroxy-naphthalen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide as a white solid, 1.54 g (80%). 4-(Hydroxy-naphthalen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (1.0 g, 3.0 mmol) was deoxygenated with TES in TFA according to the applicable procedures outlined in Method A to give 4-naphthalen-2-yl-methyl-imidazole-1-sulfonic acid dimethylamide (Intermediate-I2) as a white solid 0.55 g, (58%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].CO[C:18](OC)([CH3:23])[C:19]([O:21][CH3:22])=[O:20]>FC(F)(F)C(O)=O>[CH3:23][C:18]1([C:19]([O:21][CH3:22])=[O:20])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: COC(=O)C(C)(OC)OC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.044 g, 0.20 mmol) in methyl 2,2-dimethoxypropanoate (0.3 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 1 h. Then, the reaction mixture was concentrated, and the obtained residue was dissolved in methanol (10 mL), and the solution was concentrated with NaHCO3 (0.5 g) and silica gel (2 mL), and the residue was purified by flash chromatography (Combiflash, silica gel, dichloromethane to 90:10 dichloromethane/methanol) to give a crude product. Trituration with hexanes/ethyl acetate gave the title compound (0.026 g, 42%) as a yellow solid:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:15][OH:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14].[OH-].[Na+].C(=O)(O)[O-].[Na+].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35].S([O-])(O)(=O)=O.[K+]>CO.O.O1CCOCC1>[OH:16][CH2:15][C@H:3]([NH:2][S:34]([C:25]1[CH:26]=[CH:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1)(=[O:36])=[O:35])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: N[C@@H](CO)CN1C(=O)Cc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=C1Cc2ccccc2N1C[C@H](CO)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A solution of 2.5 g of the product from b) in 30 ml of methanol is treated with 36 ml of 2N hydrochloric acid and stirred overnight. After evaporation of the solvent the residue is azeotroped with toluene. 1.56 g of the resulting 1-[(R)-2-amino-3-hydroxypropyl]-2-indolinone are dissolved in 2 equivalents of 1N sodium hydroxide solution. Thereto there are added 0.8 g of sodium bicarbonate in 8.1 ml of water and subsequently a solution of 1.46 g of 2-naphthylsulphonyl chloride in 28 ml of dioxan and the mixture is stirred overnight. The reaction mixture is poured into 200 ml of aqueous 5% potassium hydrogen sulphate/10% potassium sulphate and extracted with ethyl acetate. After washing the organic phase with water and drying the solvent is distilled off. The residue is purified over silica gel with methyl-ene chloride/methanol (98/2). There are obtained 1.9 g of N-[(R)-2-hydroxy-1-(2-oxo-1-indolinylmethyl)ethyl]-2-naphthylsulf-onamide.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]45[CH2:25][CH2:24][C:21]([C:26]([O:28]C)=[O:27])([CH2:22][CH2:23]4)[CH2:20][CH2:19]5)=[CH:14][CH:13]=3)[C:8]([CH3:31])([CH3:30])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1.[OH-].[Na+].CCO>CO>[NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]45[CH2:23][CH2:22][C:21]([C:26]([OH:28])=[O:27])([CH2:20][CH2:19]4)[CH2:24][CH2:25]5)=[CH:16][CH:17]=3)[C:8]([CH3:31])([CH3:30])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)C12CCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CC1(C)Oc2ncnc(N)c2N=C1c1ccc(C23CCC(C(=O)O)(CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 724.2 %

Procedure:
To a solution of methyl 4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]bicyclo[2.2.2]octane-1-carboxylate (Intermediate 27; 140 mg, 0.33 mmol) in MeOH (10 mL) was added 2M NaOH (0.82 mL, 1.66 mmol). The reaction mixture was allowed to stir at ambient temperature overnight and then after the addition of EtOH (˜5 mL) and 1M NaOH (2 mL) the reaction mixture was heated to 50° C. for 5.5 hrs. The organic solvent was removed by evaporation under reduced pressure and the residue was acidified to pH 2 with 2M HCl. EtOAc was added and the suspension was filtered and dried to provide the title compound (97 mg, 2.39 mmol, 72%); 1H NMR δ 1.60 (s, 6H), 1.82 (s, 12H), 6.97 (s, 1H), 7.40 (d, 2H), 7.65 (d, 2H), 7.95 (s, 1H), NH2 not seen; MS m/e MH+ 407.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:20])[CH:11]=[C:12]([CH:17]([F:19])[F:18])[N:13]([CH2:15][CH3:16])[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:19][CH:17]([F:18])[C:12]1[N:13]([CH2:15][CH3:16])[CH:14]=[C:9]([OH:8])[C:10](=[O:20])[CH:11]=1
Reactant: [H][H]
Reactant: CCn1cc(OCc2ccccc2)c(=O)cc1C(F)F
Agent: [Pd]
Solvent: CO
Product: CCn1cc(O)c(=O)cc1C(F)F
Yield: 64.2 %

Procedure:
A mixture of 5-benzyloxy-2-difluoromethyl-1-ethyl-1H-pyridin-4-one (2.00 g, 7.16 mmol) and 10% Pd/C (200 mg) in methanol (75 mL) was hydrogenated under 15.0 psi pressure in a hydrogen atmosphere in a Parr apparatus for 23 min. The reaction mixture was worked up as described above. The title compound (0.87 g, 64%) was obtained as an off-white solid. HPLC purity (peak area percent) of the compound is 97.7% at λ=280 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.61 (s, 1H), 7.15 (t, J=52.7 Hz, 1H, CF2H), 6.46 (s, 1H), 4.03 (q, J=7.0 Hz, 2H, N—CH2), 1.31 (t, J=7.1 Hz, 3H, CH3); MS-ESI (m/z): 190.2 [M+1]+, 142.2 (100%); Anal. Calcd. for C8H9F2NO2: C, 50.80; H, 4.80; N, 7.40%. Found: C, 50.64; H, 4.85; N, 7.38%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:37])[NH:13][C:14](=[O:36])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][NH:28][C:29](SC)=[CH:30][N+:31]([O-:33])=[O:32])[CH:17]=2)=[CH:3]1.[NH3:38]>C(O)C>[NH2:38][C:29]([NH:28][CH2:27][CH2:26][CH2:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:15]2[C:14](=[O:36])[NH:13][C:12](=[O:37])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:17]1)=[CH:30][N+:31]([O-:33])=[O:32]
Reactant: CSC(=C[N+](=O)[O-])NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: N
Solvent: CCO
Product: Cn1cc(C2=C(c3cn(CCCNC(N)=C[N+](=O)[O-])c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 80 °C

Procedure:
A solution of 128 mg of the product of Example 51 in 30 ml of ethanol was treated with 10 ml of a saturated solution of ammonia in ethanol and the mixture was heated at 80° C. for 3 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with 10% methanol in dichloromethane to give 39 mg of 3-[1-[3-(1-amino-2-nitrovinylamino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 206°-209° C. (decomposition).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH3:17]O>>[S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH3:17])=[O:11]
Reactant: O=C(O)c1cc2c(s1)CCNC2
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2c(s1)CCNC2

Procedure:
To a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (1 eq) obtained in step IV in methanol was added thionyl chloride (1.5 eq) at 0° C., and the reaction was refluxed for 3.0 h Reaction mixture was concentrated and neutralized to afforded the methyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[C:14]1([C:20]2[C:28]3[C:27]([N:29]4[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]4)=[N:26][CH:25]=[N:24][C:23]=3[S:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:2]([OH:1])[CH2:3][NH:35][CH:32]2[CH2:33][CH2:34][N:29]([C:27]3[C:28]4[C:20]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[CH:21][S:22][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:30][CH2:31]2)=[CH:7][CH:8]=1
Reactant: OCc1ccc(OCC2CO2)cc1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Product: OCc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)cc1
Yield: 19 %

Procedure:
Synthesis followed SP6 (4 h), using 120 μmol (4-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 19% yield upon purification by prep. HPLC (reversed phase).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:16]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[N:17][N:18]([CH2:28][CH3:29])[C:19]=2[NH:20]C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11](OC)=[O:12])=[C:4]([CH3:36])[CH:3]=1.BrC1C=CC(C=O)=CC=1.C(N1C(N)=CC(C2C=CC=CN=2)=N1)C.C(O)(C(F)(F)F)=O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[NH:20][C:19]3[N:18]([CH2:28][CH3:29])[N:17]=[C:16]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[C:15]2=3)=[C:4]([CH3:36])[CH:3]=1
Reactant: CCn1nc(-c2ccccn2)c(C(CCC(=O)OC)c2ccc(Br)cc2C)c1NC(=O)OC(C)(C)C
Agent: CCn1nc(-c2ccccn2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=Cc1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(-c2ccccn2)c2c1NC(=O)CCC2c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
A solution of methyl 4-(4-bromo-2-methylphenyl)-4-(5-((tert-butoxycarbonyl)amino)-1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)butanoate (0.072 g, 0.129 mmol, Prepared using W from 4-bromobenzaldehyde, X from 1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine, Y then Z) in DCM (3 mL) was treated with TFA (3 mL) and the reaction was stirred for about 20 min at rt. Solvents were removed in vacuo and the residue was taken up in toluene (5 mL) containing p-TSA (0.049 g, 0.26 mmol) and the reaction was heated at about 100° C. for about 3 h. The reaction was cooled to rt, diluted with EtOAc (5 mL) to solubilize the product and washed with sat. aq. NaHCO3 (5 mL), then water (5 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Crude product was further purified on silica gel (4 g) using a gradient of 60-90% EtOAc in heptane. Product fractions were combined and concentrated to solids and dried in the vacuum oven overnight to yield 4-(4-bromo-2-methylphenyl)-1-ethyl-3-(pyridin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]azepin-7(1H)-one as an off-white solid (0.037 g, 0.087 mmol, 67%); LC-MS (Table 1, Method g) Rt=2.31 min, m/z 425/427 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.37-8.30 (m, 1H), 7.84 (br. s, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.58-7.48 (m, 1H), 7.14 (s, 1H), 7.06-6.94 (m, 2H), 6.61 (d, J=8.3 Hz, 1H), 5.30-5.20 (m, 1H), 4.20 (q, J=7.3 Hz, 2H), 2.74-2.66 (m, 2H), 2.47 (s, 3H), 2.41-2.30 (m, 1H), 1.94-1.83 (m, 1H), 1.50 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][N:7]=1)#[N:2].[Na].[CH3:15][OH:16]>>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH2:8][N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[C:1](=[NH:2])[O:16][CH3:15]
Reactant: CO
Reactant: N#Cc1nccn1Cc1cccs1
Agent: [Na]
Product: COC(=N)c1nccn1Cc1cccs1

Procedure:
A mixture was prepared from 7.6 g of 2-cyano-1-(2-thienylmethyl)-1H-imidazole, 300 ml of methanol and 100 mg of sodium. This gave a methanol solution of methyl 1-(2-thienylmethyl)-1H-imidazole-2-carboximidate which was mixed with 6.9 g of ammonium chloride. The resulting mixture was flash chromatographed (chloroform:methanol:ammonium hydroxide 56:7:1) to give a pale tan oil which crystallized on drying under vacuum. A portion of this solid was dissolved in hot ethanol and an ethanolic solution of hydrogen chloride was added. Crystals formed in the solution slowly. The solid which thus formed was separated by filtration to give 1-(2-thienylmethyl)-1H-imidazle-2-carboximidamide dihydrochloride melting at above 245°-248° C.
Reaction SMILES: Cl[Si:2]([CH3:9])([CH3:8])[CH2:3][CH:4]([CH3:7])[CH2:5]Cl.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>>[CH3:8][Si:2]1([CH3:9])[CH2:3][CH:4]([CH3:7])[CH2:5][N:13]1[CH2:10][CH:11]=[CH2:12]
Reactant: C=CCN
Reactant: CC(CCl)C[Si](C)(C)Cl
Product: C=CCN1CC(C)C[Si]1(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The 2,2,4-trimethyl-1-allyl-1-aza-2-silacyclopentane was prepared as follows. Chlorodimethyl(3-chloro-2-methylpropyl)silane (100 g, 0.54 mol) was slowly added to 211.73 g (3.71 mol, 6.87 eq) of undistilled allyl amine resulting in an exothermic reaction. This reaction mixture was stirred at room temperature for 15 hours, heated to reflux at atmospheric pressure for 72 hours, and heated to 120° C. under about 50 psig pressure for 16 hours. The following GC-MS ratios shown in the Table exemplified the reactions progression and the spectra observed were as shown.