Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]3[CH:21]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]3[CH:21]=2)=[CH:6][CH:5]=1
Reactant: NC(=O)c1cccn2cc(-c3ccc([N+](=O)[O-])cc3)nc12
Reactant: [H][H]
Agent: [Pd]
Product: NC(=O)c1cccn2cc(-c3ccc(N)cc3)nc12

Procedure:
The product from Example 2 was dissolved in alcohol and, after addition of palladium/carbon, hydrogenated with hydrogen. This was followed by filtration and concentration of the filtrate in vacuo. The product was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.Cl[CH2:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][CH2:11][N:3]1[C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc([N+](=O)[O-])[nH]1
Reactant: OCCCCl
Product: Cc1ncc([N+](=O)[O-])n1CCCO

Procedure:
The reaction mixture of 2-methyl-5-nitroimidazole (127 g, 1.0 mol) and 1-chloro-3-hydroxypropane (500 g, 5.3 mol) will be refluxed for 24 h. Then, the excessive amount of 1-chloro-3-hydroxypropane will be removed via evaporation under a condition of 2660 Pa. To the residue, 200 ml of water will be added. The mixture will be filtered. The filtrate will be collected. The filter residue will be then rinsed with water. The water phases will be combined and alkalified with saturated sodium bicarbonate aqueous solution up to pH 9. The solution will be placed in the cold room overnight for crystallization. The crystals will be filtered, washed with water, and then dried. The crude product will be recrystallized from ethyl acetate to give 1-(3-hydroxypropyl)-2-methyl-5-nitro-1H-imidazole.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[N:22]([CH2:23][C:24](=[O:31])[N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:21]=[CH:20][N:8]2[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1>[CH2:12]([O:11][C:10]1[C:9](=[O:19])[N:8]2[CH:20]=[CH:21][N:22]([CH2:23][C:24](=[O:31])[N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[C:7]2=[N:6][C:5]=1[C:3]([OH:4])=[O:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1nc2n(CC(=O)N3CCCCC3)ccn2c(=O)c1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1nc2n(CC(=O)N3CCCCC3)ccn2c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A mixture of the product of example 3 (1.0 g, 2.358 mmol) and LiOH (aq., 1N, 14 ml) in THF (10 ml) was stirred at room temperature for about 3 hours. Then diluted HCl (1N) was added dropwise to adjust the pH ˜2. The resulting solids were collected by filtration, washed with ethyl acetate and dried to give the titled compound (740 mg, yield 76.3%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])(O)=O.[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH2:16]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 60 °C
Yield: 77.9 %

Procedure:
A solution of 2,4-dihydroxy-benzaldehyde (101 g, 0.731 mol) in acetonitrile (700 mL) is treated with KI (12.1 g, 73.1 mmol) and NaHCO3 (70.0 g, 0.834 mol). The mixture is stirred while heating to 60° C. Benzyl chloride (120 g, 0.950 mol) is added and the mixture is refluxed at 82° C. for 16 hours and cooled to room temperature. The solvent is evaporated and the reaction is quenched with water (250 mL) and HCl (5.0 N, 30 mL). The mixture is extracted with EtOAc (300 mL×2), and the organic layers is dried over Na2SO4, filtered, and concentrated to an approximate volume of 200 mL. To 400 mL hexanes is added and the resulting solution is heated to 60° C. to dissolve. The solution is cooled to room temperature and crystallized for 16 hours The solid is filtered and dried to obtain the title compound (130 g, 78%). LC-ES/MS m/e 227.0 (M−1).
Reaction SMILES: [C:1]([O-:13])(=O)[CH2:2][C:3]([CH2:8][C:9]([O-:11])=O)([C:5]([O-])=O)O.[OH2:14]>>[CH3:5][C:3]1[C:2]2[CH:1]=[CH:2][C:3]([OH:14])=[CH:5][C:1]=2[O:13][C:9](=[O:11])[CH:8]=1
Reactant: O
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: Cc1cc(=O)oc2cc(O)ccc12
Reaction time: 0.5 h

Procedure:
An enzymatic reaction was started by adding 25 μl of the lipase/buffer solution after 50 μl of the 4-MUO/buffer solution and 25 μl of distilled water (or an aqueous solution of each sample) were added and mixed in a 96-well microplate at 25° C. After the reaction was performed for 30 minutes, the reaction was stopped by adding 100 μl of a 0.1 M citrate buffer (pH 4.2) and the fluorescence of 4-methylumbelliferone produced by the reaction (excitation 355 nm, emission 460 nm) was measured using a fluorescence plate reader (Fluoroskan Asent CF from Labsystems).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.[CH2:14]([O:16][C:17](=[O:25])[C:18]([O:20][Si](C)(C)C)=[CH2:19])[CH3:15]>C(Cl)Cl>[CH2:14]([O:16][C:17](=[O:25])[C:18](=[O:19])[CH2:20][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13])([CH3:10])[CH3:9])[CH3:15]
Reactant: C=C(O[Si](C)(C)C)C(=O)OCC
Reactant: COc1ccc(F)cc1C(C)(C)O
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1cc(F)ccc1OC
Temperature: -78 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
Stannic chloride (5 mL of 1 M solution in methylene chloride, 5 mmol) was added to a stirred solution of 2-(5-fluoro-2-methoxyphenyl)propan-2-ol (2.85 g, 15.5 mmol) and 2-trimethylsilanyloxy-acrylic acid ethyl ester (23.3 mmol, 4.37 g) in anhydrous methylene chloride (45 mL) cooled to −78° C. After 7 hours with the temperature maintained in the range of −78° C. to −50° C., TLC in hexanes-EtOAc (9:1) indicated that a significant amount of starting material remained. More stannic chloride (5 mL of 1 M solution in methylene chloride, 5 mmol) was added with the temperature around −50° C. After 2 hours, all the starting material had been consumed. The reaction mixture was treated with water (100 mL), stirred for 15 minutes and diluted with methylene chloride. The methylene chloride layer was separated, washed with two 50 mL portions of the water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a light brown oil. The crude product was purified by flash column chromatography over silica gel eluting with 10% EtOAc in hexanes and a fraction corresponding to Rf=0.28 was collected to give the title compound (35%) as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: NC1CCCCC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CNC2CCCCC2)cc1
Yield: 68.8 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-((cyclohexylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), cyclohexanamine (0.105 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 2 to 10% methanol in dichloromethane) furnished 0.057 g (69%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[N:22][C:5]2[NH:6][CH2:7][CH2:8][C:9](=O)[N:10]([CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[Cl:20])[C:4]=2[N:3]=1.S(C)C>>[Br:1][C:2]1[CH:23]=[N:22][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[Cl:20])[C:4]=2[N:3]=1
Reactant: O=C1CCNc2ncc(Br)nc2N1Cc1c(F)ccc(F)c1Cl
Solvent: CSC
Product: Fc1ccc(F)c(CN2CCCNc3ncc(Br)nc32)c1Cl

Procedure:
2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine was prepared from 3-bromo-5-(2-chloro-3,6-difluorobenzyl)-5,7,8,9-tetrahydro-6H-pyrazino[2,3-b][1,4]diazepin-6-one by reducing the amide functionality using BH3.Me2S as described in Example 1.
Reaction SMILES: Cl.[CH3:2][NH2:3].[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][N:11]2[C:15]([CH:16]=O)=[CH:14][N:13]=[CH:12]2)=[CH:8][CH:7]=1)#[N:5].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCOC(C)=O>ClC(Cl)C>[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][N:11]2[C:15]([CH2:16][NH:3][CH3:2])=[CH:14][N:13]=[CH:12]2)=[CH:8][CH:7]=1)#[N:5]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CNCc1cncn1Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of methylamine hydrochloride in 5 mL dichloroethane at 0° C. are added 4 Å sieves (0.5 g), followed by 1 mmol of the aldehyde from Step E and 1.5 mmol Na(OAc)3BH. The reaction is stirred for 10 minutes at 0° C., warmed to room temperature and stirred for 2 hours. The reaction is poured into EtOAc/ sat. NaHCO3 solution. The organic layer is washed with brine, dried (Na2 SO4), filtered, and concentrated in vacuo. The crude product is taken up in 10 mL dichloromethane and 2 mL n-propylamine, stirred at room temperature for 1 hour, concentrated in vacuo , and purified by flash chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]([N:16]2[CH:20]=[CH:19]N=C2)=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N)C.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH2:20]([NH:16][C:14]([O:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]1)=[O:15])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)n2ccnc2)C1
Agent: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C

Procedure:
To a solution of [(35)-1-tert-butoxycarbonylpyrrolidin-3-yl]imidazole-1-carboxylate (173 mg, 0.61 mmol) in THF (2.5 mL) at room temperature under an atmosphere of nitrogen was added a solution of ethanamine (369 mg, 461 μL of 2 M, 0.9 mmol) in THF followed by the addition of DIEA (119 mg, 161 μL, 0.9 mmol). The reaction mixture was heated at 60° C. for 1.5 h, cooled to room temperature and diluted with EtOAc. The organic layer was washed with 5 mL of 1M HCl solution, dried over MgSO4, filtered and concentrated under reduced pressure to obtain tert-butyl (35)-3-(ethylcarbamoyloxy)pyrrolidine-1-carboxylate. LC/MS m/z 259.2 [M+H]+.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.C[O:18][C:19]1[C:24]([O:25]C)=[CH:23][C:22]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[CH:21][N:20]=1>>[OH:25][C:24]1[C:19](=[O:18])[NH:20][CH:21]=[C:22]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[CH:30]=2)[CH:23]=1
Reactant: COc1cc(SCc2cccc(C(F)(F)F)c2)cnc1OC
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: O=c1[nH]cc(SCc2cccc(C(F)(F)F)c2)cc1O

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 1) from 2,3-dimethoxy-5-{[3-(trifluoromethyl)benzyl]sulfanyl}pyridine (Intermediate 11).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[C:13]2[C:21]([O:23]CC)=O)=[CH:8][C:7]=1[F:26]>C(O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[C:13]2[C:21]([NH:4][CH2:1][CH2:2][CH3:3])=[O:23])=[CH:8][C:7]=1[F:26]
Reactant: CCOC(=O)c1nc2cccnc2n1-c1ccc(Cl)c(F)c1
Reactant: CCCN
Solvent: CCO
Product: CCCNC(=O)c1nc2cccnc2n1-c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
n-Propylamine (148 mg, 2.5 mol) was added to a solution of ethyl 3-(4-chloro-3-fluorophenyl)-3H-imidazo[4,5-b]pyridine-2-carboxylate (C13) (80 mg, 0.25 mmol) in ethanol (5 mL) and the reaction mixture was stirred at room temperature for 18 hours. After concentration under reduced pressure, the residue was purified by preparative thin layer chromatography on silica gel (Eluent: 1:1 petroleum ether/ethyl acetate) to provide the product as a pale yellow solid. Yield: 28 mg, 84 μmol, 34%. LCMS m/z 332.9 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.43 (dd, J=4.8, 1.4 Hz, 1H), 8.26 (dd, J=8.2, 1.5 Hz, 1H), 7.67 (dd, J=8.4, 8.2 Hz, 1H), 7.45-7.50 (m, 2H), 7.30 (ddd, J=8.5, 2.3, 1.2 Hz, 1H), 3.28-3.34 (m, 2H, assumed; partially obscured by solvent peak), 1.58-1.68 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:8]=1)#[N:2].Cl.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O.C(O)(C)C>[N:21]1[CH:22]=[CH:23][C:18]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH2:11][CH2:12]2)=[CH:19][CH:20]=1
Reactant: N#Cc1ccc(OC2CCNCC2)nc1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(OC2CCN(c3ccncc3)CC2)nc1
Yield: 10.8 %

Procedure:
4-(5-Cyano,2-pyridinoxy)piperidine (337 mg) and 4-chloropyridine hydrochloride (284 mg) were dissolved in water (10 mL) and treated with triethylamine (0.47 mL) in isopropanol (1 mL) and refluxed for 24 hours. The reaction was quenched by evaporation of the solvent. The residue was dissolved in dichloromethane and washed with aqueous sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated. The residue was triturated with diethyl ether to give 1-(4-pyridyl),4-(5-cyano,2-pyridinyloxy)piperidine (50 mg) as a pale cream crystalline solid; microanalysis, found: C, 66.4; H, 5.6; N, 19.0%; C16H16N3O0.5.H2O requires: C, 66.4; H, 5.9; N, 19.4%; NMR: (CDCl3) 1.90 (m,2H), 2.10 (m,2H), 3.32 (m,2H), 3.67 (m,2H), 5.37 (m,1H), 6.68 (d,2H), 6.80 (d,1H), 7.78 (dd,1H), 8.28 (d,2H), 8.47 (d,1H): MS: m/z 281 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.CN([CH:31]=[O:32])C>CCOCC>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH:31]=[O:32])[CH:3]=[C:4]2[CH2:10][CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)[Si](C)(C)N1CCc2cc(C=O)cnc21
Temperature: 25 °C
Yield: 103.1 %

Procedure:
To a stirred and cooled (−78° C.) solution of the bromide 4 (5.00 g, 15.96 mmol) in Et2O (92 mL) was added dropwise 1.5 M solution of tert-butyllithium in pentane (22.3 mL, 33.5 mmol). After 45 min additional stirring at −78° C., DMF (5.6 mL, 72.3 mmol) was added dropwise, and the mixture was allowed to slowly warm to r.t. After 20 h the mixture was partitioned between saturated aqueous NaHCO3 solution and CH2Cl2. The organic layer was separated, dried (MgSO4), and concentrated to afford the crude aldehyde 13 (4.32 g). 1H NMR (400 MHz; CDCl3) δ 0.32 (s, 6H), 0.92 (s, 9H), 3.02 (m, 2H), 3.70 (m, 2H), 7.55 (d, J=2.0 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 9.61 (s, 1H).
Reaction SMILES: Br[C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH2:4][CH2:5][C:6](=[O:22])[CH:7]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[CH3:17][C@:16]12[CH2:18][C:19](=[O:20])[C@H:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:23])[CH2:4][CH2:5][C:6](=[O:22])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:21]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12Br
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Yield: 80.6 %

Procedure:
Under argon gas, 1 g of 9α-bromo-11β-hydroxy-4-androstene-3,17-dione is agitated in 5 ml of "Dowtherm" A for 3 minutes at 250° C. To work up the reaction mixture, the solvent is removed by steam distillation, the residue is dried and recrystallized from methylene chloride-isopropyl ether, thus obtaining 635 mg of 4-androstene-3,11,17-trione, mp 214°-216° C.
Reaction SMILES: [CH2:1]([NH2:9])[C:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3].[CH3:10][C:11]([O:14][C:15](ON=C(C1C=CC=CC=1)C#N)=[O:16])([CH3:13])[CH3:12].CCN(CC)CC>O1CCOCC1>[NH:9]([C:15]([O:14][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:16])[CH2:1][C:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCC(=O)NCC(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Yield: 56.4 %

Procedure:
An oven-dried 20 mL vial equipped with septum and stir bar was charged with 6 mL dioxane, Gly—Gly (1.325 g, 10.0 mmol), BOC—ON (2.714 g, 11.0 mmol), and Et3N (2.10 mL, 15 mmol). The mixture was stirred for 2 hours during which time a clear yellow solution formed. The mixture was extracted with EtOAc (20 mL) and H2O (15 mL). The aqueous layer was collected, washed with EtOAc and added to 50 mL 5% citric acid. The t-BOC-GlyGlyOH was extracted with EtOAc (200 ml) and dried over anhydrous Na2SO4. The EtOAc was removed in vacuo and triturated with hot Et2O. White crystals were collected, washed with Et2O and dried to give 1.309 g of the title compound: 1H NMR (300 MHz, DMSO-d6): δ 12.3 (bs 1H, CO2H), 8.04 (t, 1, NH), 6.98 (t, 1H, NH), 3.75 (d, 2H, CH2), 3.56 (d, 2H, CH2), and 1.38 (s, 9H, C(CH3)3).
Reaction SMILES: [C:1]1(=[O:15])[N:5]([CH2:6][C:7](=[O:9])[CH3:8])[C:4](=[O:10])[C:3]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]12.[Br:16]Br>C(O)COCCO>[Br:16][CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:4](=[O:10])[C:3]2[C:2](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]1=[O:15]
Reactant: BrBr
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: OCCOCCO
Product: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Commercially available phthalimidoacetone (2.0 g, 9.8522 mmol), under a nitrogen atmosphere, was taken up in diethylene glycol (13 mL) and cooled to 0° C. in an ice bath. Bromine (0.51 mL, 9.9242 mmol) was added dropwise. The reaction was shielded from light, allowed to reach ambient temperature, and stirred overnight. LCMS: (M+H)+=282.0.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH2:9]2)[CH2:16][CH2:15]1
Reactant: CN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane, N-methyl-4-piperidone (5 g) was added to the mixture, followed by 12 g NaBH(OAc)3 and 1 mL of glacial ACOH. The mixture was stirred at RT overnight. Saturated NaHCO3 solution (200 mL) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 EtOAc:MeOH to afford an orange oil. MS: 262 (M+1). Calc'd. for C14H19N3O2—261.32.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH3:16])[C:12](OC)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>>[NH:1]([C:12](=[O:13])[C@@H:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:6])([CH3:5])[CH3:4])[CH3:16])[NH2:2]
Reactant: NN
Reactant: COC(=O)[C@H](C)NC(=O)OC(C)(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NN
Temperature: 72 °C
Yield: 88.7 %

Procedure:
A solution of hydrazine (234 mg, 7.31 mmol, 1.5 equv. in 8 ml of THF) was added to (S)-methyl 2-(tert-butoxycarbonylamino)propanoate (1000 mg, 4.88 mmol, 1.0 equv.), it was stirred in a sealed tube and refluxed (72° C.) overnight (18 hours), the solvent was removed to yield the desired product (880 mg, white solid) in 84% yield.
Reaction SMILES: [O:1]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O.[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].[ClH:33].Cl.Cl.[NH2:36][NH:37][C:38]([NH2:40])=[NH:39]>CO>[ClH:33].[ClH:33].[C:28]([NH:31][N:32]=[CH:21][C:20]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:11]=[N:36][NH:37][C:38](=[NH:39])[NH2:40])[CH:19]=1)(=[NH:30])[NH2:29]
Reactant: COc1ccc(C=O)cc1OCCCCCOc1cc(C=O)ccc1OC
Reactant: N=C(N)NN
Agent: Cl
Solvent: CO
Product: COc1ccc(C=NNC(=N)N)cc1OCCCCCOc1cc(C=NNC(=N)N)ccc1OC
Yield: 211 %

Procedure:
Compound 25, FIG. 7E.25: 3,3'-(pentamethylenedioxy)di-p-anisaldehyde (0.748 g), aminoguanidine hydrochloride (0.553 g), and aminoguanidine dihydrochloride (0.01 g) were heated in methanol (5 mL) for 18 hr. Cooling and filtration gave 0.080 g of 3,3'-(pentamethylenedioxy)di-p-anisaldehyde bis(amidinohydrazone) dihydrochloride, mp 195°-8° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:13]=[C:12]2[CH:26]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].N1CCCCC1>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:13]=[C:12]2[CH:26]=[C:32]1[S:28][C:29](=[O:34])[NH:30][C:31]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cn(-c2ccc(Cl)c(Cl)c2)c2ccc(OCc3ccccc3)cc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cn(-c3ccc(Cl)c(Cl)c3)c3ccc(OCc4ccccc4)cc23)S1

Procedure:
A solution of 5-benzyloxy-N-(3,4-dichlorophenyl)-indole-3-carbaldehyde (1 eq.), 2,4-thiazolidinedione (1.5 eq.) and piperidine (1.5 eq.) in EtOH was heated to 70° C. for 18 hrs. Volatiles were removed under reduced pressure and the residue was taken up in EtOAc. Addition of ether precipitated the product, which showed the appropriate mass ion and was greater than 60% pure by HPLC (uv readout at 254 nm): isocratic 35:65 H2O/CH3CN. Pure material was obtained by column chromatography on silica gel; (5:3) EtOAc/hexanes. Purity by HPLC was 85%; m\e 510 (M+1); 44% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Br:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22](Cl)(=[O:24])=[O:23])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[S:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9]([NH2:12])(=[O:10])=[O:11])(=[O:24])=[O:23])=[CH:18][CH:19]=1
Reactant: Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Br)cc1
Product: Cc1ccc(NS(=O)(=O)/C=C/c2ccc(Br)cc2)c(S(N)(=O)=O)c1
Yield: 96 %

Procedure:
The title compound was synthesized as described for Example 178 in 96% yield, starting from 2-amino-5-methylbenzenesulfonamide and (E)-2-(4-bromophenyl)ethenesulfonyl chloride (US20040186134 A1). Purification by column chromatography using a gradient of 10-50% ethyl acetate in heptane as the eluent.