Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:14]=[CH:13][C:11](N)=[CH:10][C:9]=2[F:15])=[C:5]([O:18][CH3:19])[CH:4]=1)[CH3:2].N([O-])=[O:21].[Na+].C([O-])(O)=O.[Na+].[NH4+].[OH-]>OS(O)(=O)=O.O.S([O-])([O-])(=O)=O.[Cu+2].[Cu-]=O>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:14]=[CH:13][C:11]([OH:21])=[CH:10][C:9]=2[F:15])=[C:5]([O:18][CH3:19])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc(N)cc2F)c(OC)c1
Reactant: O=N[O-]
Agent: O=[Cu-]
Agent: [Cu+2]
Agent: O=C([O-])O
Solvent: O
Product: CCc1ccc(Oc2ccc(O)cc2F)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
To a solution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (215 mg; 0.82 mmol) in H2SO4 35%, at 0° C., was added a solution of NaNO2 (69 mg; 1 mmol) in water (1 mL). The mixture was stirred 30 min. at 0° C. A solution of copper(II) sulphate (1.85 g; 11.6 mmol) in 6 mL of water was added, followed by copper(I) oxide (99 mg; 0.69 mmol). The reaction was stirred 45 min. at room temperature, then hydrolysed with NaHCO3 sat (6 mL) and NH4OH. The mixture was extracted with ethyl acetate (3*5 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo. The title compound (85 mg; 0.032 mmol; 39%) was obtained as an oil, after purification by preparative TLC (cyclohexane/ethyl acetate: 7/3).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:23]C(=O)OC(C)(C)C)[CH:9]([N:12]([CH3:22])[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])[CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCOCC.CCO>[NH2:23][C@H:8]([CH:9]([N:12]([CH3:22])[C:13](=[O:14])[O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[CH2:10][CH3:11])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC([C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)N(C)C(=O)OCC[Si](C)(C)C
Solvent: CCO
Solvent: CCOCC
Product: CCC([C@@H](N)CC1CCCCC1)N(C)C(=O)OCC[Si](C)(C)C

Procedure:
The (2S)-tert-butyl 1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)pentan-2-ylcarbamate (137 mg, 0.14 mmol) was dissolved in Et2O (5 mL), anhydrous TSA (24 mg, 0.14 mmol) dissolved in EtOH was added. The solvent was removed in vacuo using a hot bath at 60° C. for 30 min to give (S)-2-(trimethylsilyl)ethyl 2-amino-1-cyclohexylpentan-3-yl(methyl)carbamate. MS ESI +ve m/z 343 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[N:13]=O.[CH3:15][CH:16]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH3:17].O>C1(C)C=CC=CC=1.[Pd]>[CH3:1][N:2]1[C:3]2[CH:12]=[CH:11][C:10]3[C:5]([C:4]=2[N:13]=[C:23]1[C:22]1[CH:25]=[CH:26][C:19]([O:18][CH:16]([CH3:17])[CH3:15])=[CH:20][CH:21]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: CNc1ccc2ccccc2c1N=O
Agent: [Pd]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(-c2nc3c4ccccc4ccc3n2C)cc1
Reaction time: 1 h

Procedure:
A solution of 11.16 g (0.06 mole) of 2-methylamino-1-nitrosonaphthalene in 800 cc of toluene is hydrogenated at room temperature and at the atmospheric pressure in the presence of 3 g of Palladium-on-carbon. After one hour, when the theoretical amount of hydrogen has been consumed, 0.06 mole of 4-(1-methylethoxy)-benzaldehyde are added and the obtained reaction mixture is heated to the reflux temperature under an inert atmosphere for about 3 hours. The water which forms during the reaction distillates as binary azeotrope with toluene and is separated through a Dean-Stark apparatus. Then further 1.5 g of 5% Palladium-on-carbon are added and reflux is prolonged for two additional hours. Filtration of the hot solution followed by concentration of the filtrate to dryness under vacuum affords a residue which has been purified by cristallization from ethyl ether. M.p. 144°-5° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2cnn(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2cnn(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)c2c1
Reaction time: 15 h
Yield: 48.1 %

Procedure:
To a stirred solution of N-tert-butyl-2-(6-methyl-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 209 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane, 15 min gradient) gave 2-(6-methyl-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (35 mg, 48%). MS (M+H)+=349; 1H NMR (DMSO-d6) δ: 8.95 (s, 1H), 8.45 (d, J=0.8 Hz, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.71 (s, 1H), 7.21 (dd, J=8.3, 0.8 Hz, 1H), 2.53 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[CH:3]=1.C([O-])([O-])=O.[Ca+2].O.[C:18](Cl)(Cl)=[S:19]>C(Cl)Cl>[CH3:8][C:6]1[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[CH:3]=[C:2]([N:1]=[C:18]=[S:19])[N:7]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(N)nc(C)c1C#N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(N=C=S)nc(C)c1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A suspension of 6-amino-3-cyano-2,4-dimethylpyridine (0.1 g, 0.68 mmol) in CH2Cl2 (1 mL) was added to a vigorously stirred mixture of CaCO3 (0.41 g, 4.11 mmol) in a 1:2 water:CH2Cl2 mixture (9 mL total) at room temp. The reaction mixture was cooled to 0° C. and thiophosgene (0.09 g, 0.78 mmol) was added dropwise. The resulting mixture was allowed to warm to room temp and was stirred overnight. The resulting aqueous layer was back-extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with water (10 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 10% EtOAc/hex) to give 2,4-dimethyl-3-cyano-6-pyridyl isothiocyanate (0.12 g, 91%): CI-MS m/z 190 ((M+H)+).
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)([O-:3])=[O:2].C([N:14](CC)CC)C.ClC(OCC)=O.N.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH2:14])=[O:11])([O-:3])=[O:2]
Reactant: O=C(O)CCCCO[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: NC(=O)CCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 85 %

Procedure:
To a solution of compound 2 (1.30 g, 1.0 eq) in dry dichloromethane (20.0 mL) cooled to 0° C. was added triethylamine (1.30 mL, 1.2 eq) followed by ethyl chloroformate (0.83 mL, 1.1 eq). The reaction mixture was stirred at 0° C. for 45 minutes and 30% aqueous ammonia solution (15.0 mL) was added. The solution was stirred from 0° C. to RT for 18 hours and sodium sulphate was added to dry the mixture. The resulting mixture was filtered off and the filtrate was concentrated under vacuum. The residue was adsorbed on silica gel and purified by flash chromatography [Biotage®, dichloromethane/methanol 100/0→98/2 (12CV*), 98/2 (6CV)] affording compound 3 as a white solid (1.10 g, yield=85%).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10](=[O:13])([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:5]([C:4]1[CH:7]=[C:8]([CH:9]=[CH:2][CH:3]=1)[O:13][CH2:10][C:2]1[CH:9]=[C:8]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:7]=[CH:4][CH:3]=1)#[N:6]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(O)c1
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1cccc(OCc2cccc(-c3cccc(C#N)c3)c2)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A solution of 500 mg of “B” and 238 mg of 3-hydroxybenzonitrile in 10 ml of acetonitrile is treated with 652 mg of caesium carbonate and stirred at room temperature for 40 hours. After customary working up, the residue is chromatographed on a reversed-phase column using acetonitrile/water 65:35. 3′-(3-Cyanophenoxymethyl)biphenyl-3-carbonitrile (“C”), FAB 311, is obtained as a colourless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[NH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>C1COCC1.C(Cl)Cl>[OH:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2([NH:28][C:2]3[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]4[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=4)[N:3]=3)[CH2:30][CH2:31]2)=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reactant: NC1(c2ccc(O)cc2)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NC3(c4ccc(O)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
To a solution of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (2 g, 4.94 mmol) in THF (30 mL) was added 4-(1-aminocyclopropyl)phenol (0.811 g, 5.44 mmol) and Hunig's Base (3.45 mL, 19.76 mmol). The resulting mixture was stirred for 16 h. The reaction was then warmed to 65° C. for 2 h at which point the reaction became a homogeneous solution. The reaction was cooled and diluted with DCM and washed with water and brine. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum to give an oily residue. The residue was purified by silica gel chromatography using 20-40% EtOAc/Hexanes to give tert-butyl 4-(4-(1-(4-hydroxyphenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (2 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30-1.37 (m, 4H), 1.60 (s, 9H), 4.67-4.77 (m, 2H), 4.85 (br. s., 1H), 6.04 (br. s., 1H), 6.70-6.81 (m, 2H), 7.11-7.22 (m, 2H), 7.47-7.66 (m, 2H), 7.79-8.01 (m, 2H); LC-MS (Condition A), MS m/z (M++H) 518.0.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:3]=1.O.[CH3:21][N:22](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:21]([C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:3]=1)#[N:22]
Reactant: CN(C)C=O
Reactant: Cc1cc2c(I)nn(CC(=O)OC(C)(C)C)c2cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Solvent: O
Product: Cc1cc2c(C#N)nn(CC(=O)OC(C)(C)C)c2cn1

Procedure:
A mixture of tert-butyl 2-(3-iodo-5-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (1.00 g, 2.55 mmol), Zn(CN)2 (329 mg, 2.55 mmol), Pd(dppf)C2 (208 mg, 0.25 mmol), Pd2(dba)3 (233 mg, 0.25 mmol), water (2.7 mL) and DMF (20 mL) was subjected to microwave irradiation at 120° C. for 30 min under argon. The reaction mixture was filtered through a pad of Celite and the filtrate was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Phase separator) and concentrated under vacuum. The residual oil was purified by flash chromatography on silica gel (EtOAc/c-hexane 1:2 then 1:1) to give the title compound. MS (LC/MS): 273.0 [M+H]+; tR (HPLC conditions d): 3.04 min.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][O:11][C:12]1[CH:31]=[CH:30][C:15]([CH2:16][NH:17][C:18]2[N:23]=[C:22]3[NH:24][CH:25]=[C:26]([C:27](=[O:29])[CH3:28])[C:21]3=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C1COCC1>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:24]1[C:22]2=[N:23][C:18]([NH:17][CH2:16][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:31][CH:30]=3)=[CH:19][CH:20]=[C:21]2[C:26]([C:27](=[O:29])[CH3:28])=[CH:25]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(CNc2ccc3c(C(C)=O)c[nH]c3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(CNc2ccc3c(C(C)=O)cn(CC(=O)OC(C)(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Tert-butyl bromoacetate (27 μL, 0.18 mmol) was added to a suspension of 1-[6-(4-methoxy-benzylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl]-ethanone (0.17 mmol) and potassium carbonate (27.5 mg, 0.20 mmol) in CH3CN (0.33 mL) and THF (0.33 mL). The reaction mixture was stirred at RT for 7 h. Potassium carbonate (27.5 mg, 0.20 mmol) and tert-butyl bromoacetate (27 μL, 0.18 mmol) were added again and stirring was continued overnight, this operation was repeated the next day. The suspension was filtered, the filtrate concentrated under reduced pressure and the crude residue was purified by flash column chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH 98:2). TLC, Rf (CH2Cl2/MeOH 9:1)=0.9; MS (UPLC/MS): 410.2 [M+H]+, 819.4 [2M+H]+, 841.3 [2M+Na]+, 454.1 [M+HCOO]−; tR (HPLC conditions f): 2.30 min.
Reaction SMILES: [C:1]([CH:4]([NH:13][C:14]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:27])[CH:20]=2)[N:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([OH:3])=[O:2].[H-].[Na+].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.Cl>CN(C=O)C.O>[C:1]([CH:4]([NH:13][C:14]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:27])[CH:20]=2)[N:15]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Oc2ccc3ccccc3n2)cc1)C(=O)O
Temperature: 110 °C
Reaction time: 40 h

Procedure:
A mixture of 2-[1-carboxy-2-(4-hydroxy-phenyl)-ethylamino]-6-chloro-quinoline-3-carboxylic acid (114 mg, 0.294 mmol) (prepared according to the procedure described in Example 34), sodium hydride (60% oil dispersion; 65 mg, 1.44 mmol) and 2-chloroquinoline (118 mg, 0.72 mmol) in dry DMF (1 mL) is stirred for 40 h at 110° C. in closed reaction vial. After cooling, the reaction mixture is poured in water and acidified by aqueous HCl. Precipitate is filtered, washed with water, then with hexane. The residue is treated with methanol and filtered. Filtrate is concentrated under reduced pressure, water is added and the precipitate is recrystallized from a mixture of acetone-water, 4:1, to provide the title compound in low yield.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[C:3]=1[C:4]#[N:5].[S:22](Cl)(=[O:25])(=[O:24])[NH2:23]>C(#N)C>[NH2:5][C:4]1[C:3]2[C:6]([O:10][CH2:11][C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:7][CH:8]=[CH:9][C:2]=2[NH:1][S:22](=[O:25])(=[O:24])[N:23]=1
Reactant: CCCC(=O)N1CCC[C@@H]1COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Product: CCCC(=O)N1CCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.8 %

Procedure:
To a solution of (R)-2-amino-6-((1-butyrylpyrrolidin-2-yl)methoxy)benzonitrile (84 mg, 0.29 mmol) (Example 176a) in acetonitrile (9 mL), was added sulfamoyl chloride (70 mg, 0.60 mmol). The reaction was stirred at rt for 20 h, and upon completion was concentrated in vacuo. The resulting residue was dissolved in EtOH (1 mL), and 2N aqueous NaOH (4 mL) was added. The mixture was refluxed for 2 h, and upon completion was cooled to rt, neutralized with 1N HCl and stirred at 0° C. The resulting precipitate was collected by vacuum filtration to provide the desired product (38 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.89 (t, J=7.3 Hz, 3H), 1.54 (sext, J=7.3 Hz, 2H), 1.94 (m, 4H), 2.26 (t, J=7.3 Hz, 2H), 3.49 (m, 2H), 4.10 (m, 1H), 4.25 (m, 1H), 4.43 (m, 1H), 6.62 (d, J=8.2 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 7.45 (t, J=8.2 Hz, 1H), 8.08 (br s, 1H), 8.34 (br s, 1H), 10.93 (br s, 1H). MS 367 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][CH:26]=O)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[NH2:28][CH2:29][CH2:30][OH:31].[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:31][CH2:30][CH2:29][NH:28][CH2:26][CH2:25][CH:22]1[S:21][C:20]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:2]([CH3:1])[S:3]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)(=[O:5])=[O:4])=[N:24][CH2:23]1
Reactant: CN(c1cccc2cc(C3=NCC(CC=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: NCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(c1cccc2cc(C3=NCC(CCNCCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of N-methyl-N-{2-[5-(2-oxoethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (300 mg) in methanol (5 mL) was added 2-aminoethanol (70 μL), and the mixture was stirred with heating under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature, sodium borohydride (55 mg) was added, and the mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (220 mg, yield 67%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (10:1, volume ratio). MS: 465 (MH+).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[S:16](=[O:18])(=[O:17])[N:15]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:14](=[O:26])[CH:13]2[CH3:27])=[C:8]([Br:28])[CH:7]=1)(=O)C.C(Cl)(=O)C>C(#N)C.CO>[Br:28][C:8]1[CH:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][C:9]=1[CH:12]1[S:16](=[O:18])(=[O:17])[N:15]([O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[C:14](=[O:26])[CH:13]1[CH3:27]
Reactant: CC(=O)OCc1ccc(C2C(C)C(=O)N(OCC[Si](C)(C)C)S2(=O)=O)c(Br)c1
Solvent: CC#N
Solvent: CC(=O)Cl
Solvent: CO
Product: CC1C(=O)N(OCC[Si](C)(C)C)S(=O)(=O)C1c1ccc(CO)cc1Br
Reaction time: 24 h
Yield: 88.8 %

Procedure:
To a solution of 3-bromo-4-(1,1-dioxido-3-oxo-2-[2-(trimethylsilyl)ethoxy]-methylisothiazolidin-5-yl)benzyl acetate (10 mg, 0.02 mmol) in acetonitrile (0.5 mL) and methanol (0.5 mL) was added acetyl chloride (2.9 μL, 0.041 mmol) at room temperature. The resulting solution was stirred for 24 h and then the reaction was concentrated. The residue was purified by silica gel chromatography (5%–40% ethyl acetate/hexanes) to afford product as oil (8.0 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 7.74 (m, 1H), 7.36 (m, 2H), 5.54 (dd, J=8.0, 6.3 Hz, 1H), 5.07 (dd, J=16.4, 11.3 Hz, 2H), 4.73 (d, J=5.6 Hz, 2H), 3.66 (dd, J=9.4, 7.4 Hz, 2H), 3.50 (dd, J=17.6, 8.0 Hz, 1H), 3.24 (dd, J=17.6, 6.3 Hz, 1H), 1.82 (t, J=5.6 Hz, 1H), 0.96 (dd, J=9.4, 7.4 Hz, 2H), 0.01 (s, 9H). LCMS found for C16H24BrNO5SSiNa (M+Na)+: m/z=472, 474.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2
Reactant: O=[N+]([O-])c1cccc(CCBr)c1
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2cccc([N+](=O)[O-])c2)c1

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-(2-bromo-ethyl)-3-nitro-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 1H NMR (DMSO-d6) δ 8.28 (s, 1H), 7.96 (dd, J=8.0, 1.3 Hz, 1H), 7.53-7.42 (m, 2H), 7.07-7.03 (m, 1H), 7.00 (d, J=9.0 Hz, 1H), 6.87 (dd, J=3.1, 9.0 Hz, 1H), 6.53 (d, J=2.8 Hz, 1H), 4.60 (t, J=6.9 Hz, 2H), 3.71 (s, 3H), 3.62 (s, 3H), 3.33 (t, J=6.9 Hz, 2H); LC-MS [M+H]+ 453.13.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][N:13]=[CH:12][C:11]=3[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:25]O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][N:13]=[CH:12][C:11]=3[CH2:15][CH2:16][C:17]([O:19][CH3:25])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CCc1cnoc1-c1ccc2c(c1)OCO2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc2c(c1)OCO2
Yield: 97 %

Procedure:
A mixture of 3-[5-(1,3-benzodioxol-5-yl)-4-isoxazolyl]propionic acid (4.19 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(1,3-benzodioxol-5-yl)-4-isoxazolyl]propionate (4.26 g, yield 97%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 84–85° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C(OCC)(=O)C.[I-].[K+]>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([NH:12][CH:9]2[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]2)[CH:19]=1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 140 °C
Reaction time: 15 h
Yield: 62.9 %

Procedure:
Ethyl-4-amino-1-piperidine-carboxylate (29.6 g, 0.17 mol) was added to a stirred suspension of 2,4-dichloronitrobenzene (30.0 g, 0.16 mol), sodium carbonate (16.5 g, 0.16 mol) and potassium iodide (0.26 g, 0.0016 mol) in dimethylformamide (300 mL). The mixture was heated to 140° C., stirred for 15 hours and then allowed to cool. The reaction mixture was diluted with water (400 mL) and ethyl acetate (600 mL). The aqueous phase was separated and the organic phase was extracted with water (2×300 mL). The organic phase was dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica, eluting with ethyl acetate/hexane (1:3) to give the title compound (33.0 g, 65% yield) as an orange solid. (Rf: 0.4 (ethyl acetate/hexane 1:3))