Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[C:14]([CH2:26][CH2:27][CH3:28])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:11][CH:10]=1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[ClH:25].[NH2:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[C:14]([CH2:26][CH2:27][CH3:28])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:11][CH:10]=1
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(NC(=O)OC(C)(C)C)cc2n1Cc1ccccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCc1c(C(=O)C(C)C)c2ccc(N)cc2n1Cc1ccccc1Cl
Reaction time: 4 h
Yield: 105.2 %

Procedure:
To a solution of 6-tert-butoxycarbonylamino-1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole (110 mg) in ethyl acetate (1 ml) was added 4N hydrogen chloride in ethyl acetate at 20° C., and the mixture was stirred at the same temperature for 4 hours. The precipitates were collected by filtration and washed with ethyl acetate to give 6-amino-1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole hydrochloride (50 mg) as powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH:30]1([CH2:33]O)[CH2:32][CH2:31]1>>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:33][CH:30]2[CH2:32][CH2:31]2)=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: OCC1CC1
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC1CC1

Procedure:
Using the procedure of Step A of Example 7, 1.4 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 0.3 ml of cyclopropylcarbinol were reacted and the product was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 1.5 g of (S)α-cyano-3-phenoxybenzyl (1R,cis) 2,2-dimethyl-3-(cyclopropylmethoxycarbonyl-ethynyl)-cyclopropane-carboxylate melting at 72° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:17])[CH2:12][C:13]([CH2:15]Br)=O)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[CH3:21][NH:22][C:23]([NH2:25])=[S:24].C(=O)(O)[O-].[Na+]>O>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:12][C:13]2[N:25]=[C:23]([NH:22][CH3:21])[S:24][CH:15]=2)=[O:17])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nnc(NC(=O)CC(=O)CBr)s1
Reactant: CNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNc1nc(CC(=O)Nc2nnc(C(C)(C)C)s2)cs1
Yield: 87.2 %

Procedure:
A reaction mixture containing 11.4 g (0.035 mole) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-4-bromoacetoacetamide, 150 ml of ethanol and 3.3 g (0.036 mole) of N-methylthiourea was refluxed for 4 hours. The reaction solution was poured into 300 ml of water and treated with excess aqueous sodium bicarbonate. The product was isolated and dried. There was obtained 9.5 g (87.2%) of white solid, m.p. 198°-200° (dec.). N.M.R. (CDCl3) ∂ 1.4 [C(CH3)3 ], 3.0 (CH3), 3.8 (CH2), 6.4 (hetero-aromatic).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:9]1([C:7]([C:4]2[CH:3]=[CH:2][C:1]([CH2:13][Br:14])=[CH:6][CH:5]=2)=[O:8])[CH2:10][CH2:11][CH2:12]1
Reactant: Cc1ccc(C(=O)C2CCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)C1CCC1

Procedure:
Cyclobutyl p-tolyl ketone (30 g) and N-bromosuccinimide (31 g) in carbon tetrachloride (200 ml) were irradiated and heated under reflux with a tungsten lamp for 1.5 hours, and cooled. The mixture was filtered and the filtrate was evaporated. The residue was distilled under reduced pressure and the fraction b.p. 120°-125°/0.015 mm was collected.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([OH:15])[C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)c1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc2c(c1)C(O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Commercially available 2-amino-9-fluorenone 1 (10 mmol) was dissolved in 100 mL of methanol and 0.38 g (10 mmol) of sodium borohydride was added. The mixture was stirred at 25° C. for 1 h and concentrated to dryness under vacuum. The residue was suspended in 100 mL of saturated aqueous NaHCO3− and extracted with ethylacetate (100 mL). The ethylacetate layer was concentrated under vacuum and the residue was crystallized from ethylacetate/hexane (2:1) to afford 1.4 g of pure 2-amino-9-hydroxyfluorene 2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][O:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])=[N:2]1.C([O-])([O-])=O.[K+].[K+].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>CC(C)=O.O>[C:24]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][O:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])=[N:2]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(OCc1n[nH]c2ccccc12)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(OCc1nn(C(=O)c2ccccc2)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.7 %

Procedure:
To a solution of 2-(1H-indazol-3-ylmethoxy)-2-methylpropanoic acid (6 g; 0.026 mol) in acetone (50 ml) stirred at room temperature was added K2CO3 (6.8 g; 0.049 mol) and then, slowly, a solution of benzoyl chloride (5 ml; 0.043 mol) in acetone (30 ml). The mixture was stirred at room temperature for 24 hours and then poured into water (1 L). The solution was then brought to basic pH with 5N NaOH and washed with diethyl ether (3×150 ml). The alkaline phase was then acidified with concentrated HCl and extracted with diethyl ether (3×300 ml). The combined organic phases were concentrated under reduced pressure and the crude residue obtained was purified by crystallization from a 1/1 hexane/ethyl acetate mixture. 2 g of 2-[(1-benzoyl-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid were obtained, m.p.=132-135° C.
Reaction SMILES: [OH-].[Na+].CC(O)C.[N:7]1([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([OH:39])=[C:18]([CH:38]=2)[C:19]([NH:21][C:22]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[CH:28][C:23]=2[C:24]([O:26]C)=[O:25])=[O:20])[CH2:10][CH2:9][CH2:8]1.[ClH:40]>O>[ClH:40].[N:7]1([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([OH:39])=[C:18]([CH:38]=2)[C:19]([NH:21][C:22]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[CH:28][C:23]=2[C:24]([OH:26])=[O:25])=[O:20])[CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(OCCN2CCC2)ccc1O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.11 mL) was added to a 2-propanol (1.0 mL) suspension of the obtained methyl 2-(5-(2-(azetidin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate (0.032 g), followed by stirring at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and water was added thereto. After adjusting the pH to 6.0 with 1.0 mol/L hydrochloric acid, the solid substance was collected by filtration. Ethyl acetate (1.5 mL) and a 4.0 mol/L hydrogen chloride-dioxane solution (0.10 mL) were added to the obtained solid substance, followed by stirring at room temperature for 1 hour and 30 minutes. The solid substance was collected from the reaction mixture by filtration to obtain 0.021 g of 2-(5-(2-(azetidin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoic acid hydrochloride as a light yellow solid.
Reaction SMILES: [CH2:1]([S:3]([C:5]1[S:6][C@@H:7]2[C@@H:24]([O:25][CH3:26])[C:23](=[O:27])[N:8]2[C:9]=1[C:10]([O:12]CC1C=CC([N+]([O-])=O)=CC=1)=[O:11])=[O:4])[CH3:2].C([O-])(O)=O.[Na+:32]>O1CCOCC1.O>[CH2:1]([S:3]([C:5]1[S:6][C@@H:7]2[C@@H:24]([O:25][CH3:26])[C:23](=[O:27])[N:8]2[C:9]=1[C:10]([O-:12])=[O:11])=[O:4])[CH3:2].[Na+:32]
Reactant: CCS(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](OC)[C@H]2S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)C1=C(C(=O)[O-])N2C(=O)[C@H](OC)[C@H]2S1

Procedure:
A mixture of p-nitrobenzyl (5R,6S)-2-ethylsulfinyl-6-methoxy-pen-2-em-3-carboxylate (48 mg, 0.12 mmol) and 10% pd/C (100 mg) in dioxane (8 ml) and H2O (4 ml) is shaken under a H2 pressure of 45 psi for 60 minutes. The reaction mixture is diluted with H2O (20 ml) containing NaHCO3 (10 mg, 0.12 mmol) and filtered to remove the catalyst. The filtrate is washed with Et2O (3×20 ml), concentrated under vacuum to ca. 5 ml volume, and lyophilized to provide the crude product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of 5-nitro-indole-1-carboxylic acid tert-butyl ester (0.50 g) and catalytic amount of Pd(OH)2 in a mixture of MeOH-EtOAc was stirred at room temperature under hydrogen for 1 h. The reaction mixture was filtered through celite and the filtrate was concentrated to provide 5-amino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.44 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14]COC(C)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Yield: 96 %

Procedure:
A mixture of 3-fluoro-4-nitrobenzoic acid(2.07 g, 11.2 mmol) and cH2SO4(0.5 ml) in MeOH(10 ) was refluxed for 8 h. The solvent was evapolated. The residue was dissolved in AcOEt and washed with saturated NaHCO3 aqueous solution, water, brine, dried (Na2SO4) and concentrated to give 2.14 g(96%) of ivory solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:23]=1.[CH2:40]1[O:42][CH2:41]1>O1CCCC1.O>[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:23]=1[CH2:40][CH2:41][OH:42]
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: C1CO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CCO)n(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
To a solution of lithium diisopropylamide prepared from diisopropylamine (1.11 g) and n-butyllithium (1.61 M in hexane; 7.0 ml), in dry tetrahydrofuran under nitrogen atmosphere at -70° C. was added dropwise over 20 minutes a solution of 3-methyl-1-phenylsulfonylindole (2.71 g) in tetrahydrofuran (20 ml). The mixture was stirred for 1 hour below -70° C. and then allowed to warm slowly to 0° C. over 1 hour. The resulting solution was cooled to -70° C. and then treated with ethylene oxide (484 mg) in dry tetrahydrofuran (5 ml). The mixture was stirred for 1 hour below -70° C. and then allowed to warm slowly to room temperature over 3 hours. After stirring overnight, the reaction mixture was treated with cold water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed over silica gel (eluted with 5% ethyl acetate in toluene) to give 2-[3-methyl-1-(phenylsulfonyl)indol-2-yl]ethanol (1.19 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=3[C:15]=2[C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)=[CH:7][CH:6]=1.C(S)C.COC1C=CC(C2SC3C=CC=CC=3C=2CC2C=CC(O)=CC=2)=CC=1>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]3[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=3[C:15]=2[C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Agent: COc1ccc(-c2sc3ccccc3c2Cc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(O)cc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 2.9 g. (0.12 mole) of sodium hydride in oil were added 13 g. (0.035 mole) of 2-(4-methoxyphenyl)-3-(4-methoxybenzoyl)benzothiophene (prepared as in Example 13) dissolved in DMF. The resulting mixture then was added to a cold solution of DMF containing 7.5 g. of ethyl mercaptan. The mixture was stirred at 70° C. for two hours and was monitored by TLC until little or no starting material remained. The total reaction time was about two hours. The mixture then was concentrated to dryness, water was added, and the aqueous mixture was acidified and extracted with ethyl acetate. The ethyl acetate extract was washed, dried over magnesium sulfate, and evaporated to a residue. The residue was recrystallized from benzene to obtain 9.1 g. (73 percent) of 2-(4-methoxyphenyl)-3-(4-hydroxybenzyl)benzothiophene, melting point 188°-189° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][C:34](Cl)=[O:35].IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:35]
Reactant: Cc1ccccc1CCC(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: Cc1ccccc1CCC(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 63.6 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 3-(2-methylphenyl)propionic acid chloride (0.114 mmol), the title compound (28 mg, yield 64%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][S:6][S:7][CH2:8][CH2:9][NH2:10].[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F)([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+]>O>[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[NH:3][CH2:4][CH2:5][S:6][S:7][CH2:8][CH2:9][NH:10][C:15]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[N+:11]([O-:13])=[O:12])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCSSCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(NCCSSCCNc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
A 25 mL round-bottom flask fitted with a magnetic stirrer was charged with 225 mg (1.0 mmol) of cystamine dihydrochloride, 409 mg (2.2 mmol) 2,4-dinitrofluorobenzene, 25 mg of K2CO3, and 10 mL of H2O. The mixture then stirred in a 75° C. oil bath for 18 h. After cooling, the solvent was decanted from a yellow insoluble sludge. The sludge crystallized on trituration with 10 mL of CH2Cl2. The yellow crystals were washed with additional CH2Cl2 and recrystallized from 0.5 mL of 15:85 H2O/DMF. The isolated product was washed with 1:1 H2O/DMF affording 77 mg of N,N'-bis-(2,4-dinitrophenyl) cystamine, mp 175°-176° C. Calcd for C16H16N6O8S2:C, 39.67; H, 3.31; N, 17.36; S, 13.22. Found: C, 39.74; H, 3.38; N, 17.26; S, 13.48. 200 MHz NMR (DMSO-d6): 3.08 (t, J =6.6, 4H), 3.80 (4 lines, 4H), 7.27 (d, J =9.6, 2H), 8.25 (dd, J =2.8, 9.6, 2H), 8.84 (dd, J =2.8, 0.8, 2H), 8.93 (t, J=5.6, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NCCCO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCCO)cc2c1=O
Yield: 68.5 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 3-amino-propan-1-ol according to the GPA affording 24.1 mg (68.5%) of a red powder. Rt=3.09 min.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:15][C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17]1>O1CCOCC1>[CH3:15][C@@H:16]1[CH2:17][N:18]([C:22]2[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:19][CH2:20][N:21]1[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=2[N:6]=1
Reactant: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)ccc2[nH]1

Procedure:
A mixture of 2-chloro-6-trifluoromethyl-1H-benzoimidazole (176 mg, 0.8 mmol, Example 1c) and (3R)-3-methyl-1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (245 mg, 1.0 mmol, Example 79a) in dioxane (2 mL) reacted under the conditions of Example 3c to give the title compound. MS (ESI, pos. ion) m/z: 430 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18]
Reactant: O=S([O-])c1ccccc1
Reactant: COC(=O)C=CC=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C=CC=CCS(=O)(=O)c1ccccc1
Temperature: 20 °C
Yield: 73.2 %

Procedure:
A mixture of 6-bromohexa-2,4-dienoic acid methyl ester (0.41 g, 2.0 mmol), sodium benzene sulfinate (0.33 g, 2.0 mmol) and tetra-n-butylammonium iodide (37 mg, 0.1 mmol) was heated at reflux in dry THF (10 mL) under an atmosphere of nitrogen for 2 hours. The resulting slurry was allowed to cool to 20° C. and filtered. The filtrate was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (20 mL). This solution was washed successively with saturated aqueous sodium hydrogen carbonate (10 mL), distilled water (10 mL), then with brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (7:3 to 1:1 to 1:1 60-80° C. petroleum ether:diethyl ether) to give a solid that was recrystallised to give the title compound (0.39 g, 73%) as white crystals, mp 105° C.
Reaction SMILES: CC([C@@H](N)CO)C.[CH2:8]([O:10][C:11]([C@H:13]([NH:22][C@H:23]1[CH2:29][S:28][CH2:27][C@@H:26]([CH:30]([CH3:32])[CH3:31])[N:25]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]1=[O:41])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[CH3:9].C(OC([C@@H](N[C@H]1CSC[C@@H](C(C)C)N(CC(OC(C)(C)C)=O)C1=O)CCC1C=CC=CC=1)=O)C>>[CH2:8]([O:10][C:11]([CH:13]([NH:22][C@H:23]1[CH2:29][S:28][CH2:27][C@@H:26]([CH:30]([CH3:31])[CH3:32])[N:25]([CH2:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C:24]1=[O:41])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@H]1CSC[C@@H](C(C)C)N(CC(=O)OC(C)(C)C)C1=O
Agent: CC(C)[C@@H](N)CO
Agent: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@@H](C(C)C)N(CC(=O)OC(C)(C)C)C1=O
Product: CCOC(=O)C(CCc1ccccc1)N[C@H]1CSC[C@@H](C(C)C)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
The procedure described in steps (a) to (h) of Example 1 was repeated, except that D-2-amino-3-methyl-1-butanol was used as the starting material. Two isomers (derived from the asymmetric carbon atom to which the phenethyl group is attached), that is t-butyl α-{6(R)-[1(R)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-isopropyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer A) and t-butyl α-{6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-isopropyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer B), were obtained as oils.
Reaction SMILES: COC(=O)COC1C=C(OC)C(SCCCNC2C=CC(C3C=CC=CC=3)=CN=2)=CC=1C.C=O.C[O:36][C:37](=[O:68])[CH2:38][O:39][C:40]1[CH:45]=[C:44]([O:46][CH3:47])[C:43]([S:48][CH2:49][CH2:50][CH2:51][N:52]([CH2:65]C)[C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:55][N:54]=2)=[CH:42][C:41]=1[CH3:67]>>[CH3:47][O:46][C:44]1[C:43]([S:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:65])[C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)=[CH:55][N:54]=2)=[CH:42][C:41]([CH3:67])=[C:40]([CH:45]=1)[O:39][CH2:38][C:37]([OH:68])=[O:36]
Reactant: CCN(CCCSc1cc(C)c(OCC(=O)OC)cc1OC)c1ccc(-c2ccccc2)cn1
Agent: C=O
Agent: COC(=O)COc1cc(OC)c(SCCCNc2ccc(-c3ccccc3)cn2)cc1C
Product: COc1cc(OCC(=O)O)c(C)cc1SCCCN(C)c1ccc(-c2ccccc2)cn1

Procedure:
Compound 64B was reacted with paraformaldehyde in a manner analogous to Compound 64C to give the title product. MS m/z 467 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:16](=[CH:17][CH:18]=1)[O:15][C:9]1([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:8][C:7]2=O)[CH3:2].Cl.O([NH2:23])C.N1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CO.O1CCCC1.CCOCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:16](=[CH:17][CH:18]=1)[O:15][C:9]1([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[NH2:23])[CH3:2]
Reactant: CCOc1ccc2c(c1)C(=O)CC1(CCCCC1)O2
Reactant: CON
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc2c(c1)C(N)CC1(CCCCC1)O2
Temperature: 25 °C

Procedure:
A mixture of Example 10A (1.182 g, 4.55 mmol), methoxylamine hydrochloride (380 mg, 4.55 mmol), and pyridine (1.8 mL, 22.3 mmol) in methanol (15 mL) was stirred overnight at room temperature. After this time, the solvent was evaporated in vacuo, then the residue was dissolved in ether and washed with water and brine. The organic layer was dried (Na2SO4), filtered and was evaporated in vacuo, and the residue was further dried azeotropically (CH3CN). A solution of the residue (942 mg, 3.26 mmol) in tetrahydrofuran (10 mL) was treated slowly with 1M LiAlH4 in tetrahydrofuran (5 mL, 5 mmol). After the addition was complete, the reaction was refluxed for 2.5 h. The mixture was cooled to room temperature and carefully quenched with water and was then filtered. The filter pad was washed with ethyl acetate, and the combined filtrates were evaporated in vacuo to afford a gold oil. This was taken up in ether and extracted with 1N HCl, then the acidic extracts were basified with 2N NaOH and were extracted with ethyl acetate. Drying of the organic extracts (Na2SO4), filtered, followed by evaporation in vacuo, afforded the title compound as a gold oil, 320 mg (38%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.10 (d, J=2.7 Hz, 1H), 6.58-6.66 (m, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.78 (m, 1H), 2.04 (m, 1H), 1.36-1.77 (m, 11H), 1.17 (t, J=7.0 Hz, 3H). MS (DCI+) m/z 262 (M+H).