Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[N:3]1[NH:12][C:13](=[O:32])[C@@H:14]([C@@H:19]([C:29]([OH:31])=O)[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][CH:16]([CH3:18])[CH3:17].[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[N:3]1[NH:12][C:13](=[O:32])[C@@H:14]([C@@H:19]([C:29](=[O:31])[NH:41][O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: NOCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)C2CNCCN2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C2CNCCN2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
A solution of 0.415 g of (E)-N-(1,2,3,5,6,7,8,8a(RS)-octahydro-1,3-dioxoimidazo[1,5-a]pyrazin-2-yl)-2(R)-[1(S)-(carboxy)-4-phenyl-3-butenyl]-4-methylvaleramide in 0.25 ml of dimethylformamide was treated with 0.461 g of O-benzylhydroxylamine and 0.173 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and stirred at room temperature for 4 hours. Evaporation gave a residue which was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate and evaporation gave a residue which was triturated with diethyl ether to give 0.160 g of (E)-N-(1,2,3,5,6,7,8,8a(RS)-octahydro-1,3-dioxoimidazo[1,5-a]pyrazin-2-yl)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH2:9][CH:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:35]([N:37]([CH2:42][CH3:43])[C:38](=[O:41])[CH2:39]Cl)[CH3:36]>C(COC)OC.CCOCC>[CH2:35]([N:37]([CH2:42][CH3:43])[C:38](=[O:41])[CH2:39][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH:10]([OH:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:27][CH:26]=1)[CH3:36]
Reactant: Oc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Reactant: CCN(CC)C(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Product: CCN(CC)C(=O)COc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
4-[2-(N-Benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenol (5.1 g) was added to a stirred solution of potassium t-butoxide (1.57 g) in dimethoxyethane (100 ml). To the resulting solution was added N,N-diethylchloroacetamide (2.1 g) and the mixture was stirred for two hours. The mixture was diluted with ether (300 ml) and washed with brine (2×20 ml). The solution was dried (MgSO4) and evaporated under reduced pressure to yield the crude intermediate (12.5 g). The crude intermediate was purified by chromatography on K60 silica (225 g) using a gradient mixture of methanol and dichloromethane (1% to 3% of methanol) to give N,N-diethyl-4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]-phenoxyacetamide (6.6 g) as a gum. The gum was dissolved in methanol (400 ml) and treated with 10% palladium on carbon (380 mg). The mixture was stirred under an atmosphere of hydrogen for 4 hours. The catalyst was removed by filtration through Kieselguhr, and the filtrate evaporated to give the product (5.0 g) as a colourless oil, which was dissolved in dichloromethane (300 ml) and acidified to pH3with ethereal hydrogen chloride. The solvent was removed by evaporation and replaced with fresh dichloromethane which also was evaporated. The residual gum was dissolved in methyl acetate from which it crystallised as N,N-diethyl-4-[2-(2-hydroxy-3-phenoxypropylamino)ethyl]phenoxyacetamide hydrochloride (4.49 g) m.p. 113°-5° C.; NMR: 1.05[t,3H, CH3 ]; 1.15[t,3H, CH3 ]; 2.90-3.08[m,2H, CH2C6H4 ]; 3.08-3.45(m,8H, CH2NCH2 +CH2NHCH2 ]; 4.0[m,2H,PhOCH2 ]; 4.25[m,CHOH]; 4.75[s,2H,OCH2CO]; 6.85-7.05[m,5H, aromatic H]; 7.25-7.4[m,4H, aromatic H]: microanalysis: found: C, 62.9; H,7.6; N, 6.1; Cl 8.3%; C23H32N2O4.HCl requires: C, 63.2; H,7.6; N, 6.4; Cl 8.1%.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1)Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:29][C@H:30]1[CH2:35][NH:34][C@H:33]([CH3:36])[CH2:32][NH:31]1>CN(C)C=O>[CH3:29][C@H:30]1[CH2:35][NH:34][C@H:33]([CH3:36])[CH2:32][N:31]1[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:11]1[CH:26]=[CH:27][CH:28]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: CN(C)S(=O)(=O)c1ccc(C(Cl)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(c2ccc(S(=O)(=O)N(C)C)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)CN1
Temperature: 140 °C
Yield: 26.6 %

Procedure:
The alcohol (88.8 g, 0.21 mol) was treated with thionyl chloride in dichloromethane as described in Example 1 to give 93.7 g of 4-(3-(tert-butyldimethylsilyloxy)-α-chlorobenzyl)-N,N-dimethylbenzenesulfonamide as a brown oil. The crude benzhydryl chloride (93.7 g, 0.21 mol) was combined with trans-2,5-dimethylpiperazine (71.8 g, 0.63 mol) in 400 mL of dimethylformamide and heated to 140° C. for 1 hour. The mixture was cooled to room temperature, poured into ice water and extracted with diethyl ether. The ether extracts were washed with 1M sodium hydroxide, water, and saturated aqueous sodium chloride, and dried over sodium sulfate. The solvent was removed and the residue was purified by chromatography on silica gel with dichloromethane:methanol to give 28.9 g (27%) of trans-4-(α-(2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-dimethylbenzenesulfonamide as a brown oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23]([OH:25])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.C(OC(=O)[NH:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([C:39](=[O:44])[NH:40][CH:41]2[CH2:43][CH2:42]2)[CH2:35][CH2:34]1)(C)(C)C>>[CH:41]1([NH:40][C:39]([C@H:36]2[CH2:37][CH2:38][C@H:33]([NH:32][C:23]([C:20]3[C:16]4[N:17]=[CH:18][N:19]=[C:14]([C:7]5[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=5[O:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:15]=4[NH:22][CH:21]=3)=[O:25])[CH2:34][CH2:35]2)=[O:44])[CH2:43][CH2:42]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)NC2CC2)CC1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](C(=O)NC5CC5)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A73) and trans-(4-cyclopropylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (A195) the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13]([NH2:16])(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](=[S:19])=[S:18].[OH-].[K+:21].C(OCC)(=O)C>CN(C)C=O>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]([S-:19])[S-:18])(=[O:14])=[O:15].[K+:21].[K+:21]
Reactant: S=C=S
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(N=C([S-])[S-])c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 166.3 %

Procedure:
115.5 g of 2-phenylbenzenesulfonamide were dissolved in 500 ml of dimethylformamide, and 38 g of carbon disulfide and 28 g of potassium hydroxide were added to the resulting solution. The mixture was stirred at room temperature for 7 hours. Potassium hydroxide (28 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Then, 400 ml of ethyl acetate were added dropwise to precipitate pale yellow crystals. The crystals were filtered, and washed with ethyl acetate to give 160 g of potassium N-(2-biphenylylsulfonyl)carbonimidodithioate represented by the following formula: ##STR25##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12](Cl)(=[O:14])[CH3:13].C(N(CC)CC)C.O>C(Cl)Cl>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:14])[CH3:13]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
To a solution of 5-amino-2-chloro-benzoic acid (0.50 g, 2.9 mmol) in DCM (15 mL) was added acetyl chloride (0.30 mL, 4.2 mmol) followed by triethylamine (1.2 mL, 8.6 mmol). The mixture was stirred at RT for 2 h and poured into water. The mixture was extracted with ethyl acetate and the combined organic layers washed with water, brine, dried over Na2SO4 and filtered. The filtrate was concentrated and afforded the title compound (0.17 g, 27%) as a brown solid.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.O.[Cl:10][C:11]1[CH:12]=[C:13]([C@@H:21]([CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:22]([NH:24][C:25]2[CH:30]=[N:29]C(C=C)=[CH:27][N:26]=2)=[O:23])[CH:14]=[CH:15][C:16]=1[S:17]([CH3:20])(=[O:19])=[O:18].[CH3:39][C:40]([CH3:42])=[O:41]>O1CCCC1.[Os](=O)(=O)(=O)=O.C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([C@@H:21]([CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:22]([NH:24][C:25]2[CH:30]=[N:29][C:39]([CH:40]([OH:41])[CH2:42][OH:5])=[CH:27][N:26]=2)=[O:23])[CH:14]=[CH:15][C:16]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Agent: O=[Os](=O)(=O)=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(O)CO)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-methyl morpholine oxide (27 mg, 0.23 mmol) and a 0.2M solution of osmium tetroxide in toluene (5 μL, 0.001 mmol) in acetone (0.5 mL) and water (0.5 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-vinyl-pyrazin-2-yl)-propionamide (prepared as in Example 54, 50 mg, 0.115 mmol). Two drops of tetrahydrofuran were added to fully dissolve the substrate, and the resulting mixture was stirred at 25° C. overnight. The reaction mixture was concentrated in vacuo, and the residue was treated with water (10 mL) and methylene chloride (25 mL). The organic phase was washed with a 1 N aqueous hydrochloric acid solution (10 mL), and each aqueous phase was extracted with a small portion of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(1,2-dihydroxy-ethyl)-pyrazin-2-yl]-propionamide (48 mg) as a colorless foam: (ES)+-HRMS m/e calcd for C21H26N3O5S (M+H)+ 468.1355, found 468.1357.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([C:29]1[CH:34]=[C:33]([C:7]2[CH2:11][CH2:10][CH2:9][C:8]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:32]=[CH:31][CH:30]=1)#[N:28]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2cccc(C#N)c2)CCC1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of ethyl 2-{[(trifluoromethyl)sulfonyl]oxy}-1-cyclopentene-1-carboxylate (1.2 g, 4.16 mmol) in 10 ml anhydrous dioxane was added potassium phosphate (1.32 g, 6.2 mmol), 3-cyanophenyl boronic acid (0.612 g, 4.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50 ml ethyl acetate, washed with 2×50 ml water, 2×50 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Residue was chromatographed on silica gel using 5% EtOAc in hexane as the eluent to give ethyl 2-(3-cyanophenyl)-1-cyclopentene-1-carboxylate (0.7 g, 71%) as a light yellow oil after drying. ES-MS (M+H+): 242.15. H1NMR (CDCl3) δ: 1.09-1.13 (t, 3H); 1.96-2.01 (m, 2H); 2.80-2.84 (m, 4H); 7.39-7.59 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O-:22])(=[S:21])[CH3:20].[K+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:21][C:19](=[O:22])[CH3:20])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 68.7 %

Procedure:
Amine preparation: A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.82 g) and potassium thioacetate (2.31 g) was heated to 60° C. in DMF (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (1.80 g). To a solution of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (607 mg) in dry MeOH (5 mL) was added a solution of sodium methoxide in MeOH (25% wt, 0.59 mL). After stirring for 15 min, toluene-4-sulfonic acid 3-methoxy-propyl ester (described elsewhere, 571 mg) was added in MeOH. After 24 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to yield 4-(3-methoxy-propylsulfanyl)-piperidine-1-carboxylic acid tent-butyl ester. Treatment with mCPBA (as described above) yielded 4-(3-methoxy-propane-1-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.C(N(CC)CC)C.[O:42]1CCCC1>>[O:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([NH2:18])=[O:42])=[CH:13][CH:12]=2)[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:26]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:33])[CH:3]=2)=[N:9]1
Reactant: C1CCOC1
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc2c(c1)c(-c1cccc(NC(=O)c3cccnc3)c1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.150 g, 0.47 mmol) in tetrahydrofuran (5 mL), was added nicotinoyl chloride hydrochloride (0.167 mg, 0.94 mmol) and triethyl amine (0.327 mL, 2.35 mmol). After stirring at room temperature overnight, the crude mixture was partitioned between ethyl acetate and water. The crude compound was isolated as a gummy solid. The yield was not calculated: ES-MS (m/z) 424 [M+H]+.
Reaction SMILES: [F-].[K+].IC1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[F:23][C:24]([Si](C)(C)C)([F:26])[F:25].C[N:32](C=O)C>CCOC(C)=O.[Cu]I>[F:23][C:24]([F:26])([F:25])[C:8]1[CH:7]=[C:6]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH:5]=[N:32][CH:9]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(I)c2)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(C(F)(F)F)c2)CC1
Temperature: 50 °C

Procedure:
Copper(I) iodide (0.49 g, 2.6 mmol) and potassium fluoride (0.15 g, 2.6 mmol) in a flask were flame-heated under gentle shaking and at high vacuum until a greenish color appeared. A solution of tert-butyl 4-(3-iodophenyl)piperazine-1-carboxylate (0.5 g, 1.0 mmol) and (trifluoromethyl)trimethylsilane (0.37 g, 2.6 mmol) in DMF (5 mL) was added. The brown solution was stirred at room temperature overnight. More (trifluoromethyl)trimethylsilane (0.37g) was added. The mixture was heated at 50° C. overnight, diluted with EtOAc and washed with saturated ammonium chloride. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and purified by flash chromatography on silica gel (20% to 40% EtOAc/hexanes) to give 120 mg of desired product. MS calculated for C15H20F3N3O2: (M+H) 332; found 332.1.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH2:26].[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>CC(O)C>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH:26][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]=12.[C:31]([O-:36])(=[O:35])[C:32]([O-:34])=[O:33]
Reactant: COc1ccccc1OCCN
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Reactant: O=C(O)C(=O)O
Solvent: CC(C)O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Product: O=C([O-])C(=O)[O-]
Yield: 81.2 %

Procedure:
A mixture of 4-(oxiran-2-ylmethoxy)-9H-carbazole (II) (25.0 g, 104.60 mmole) and 62.5 ml 2-propanol is heated to 70° C. to 80° C. To this 2-(2-methoxyphenoxy)ethylamine (III) (25.33 g, 151.67 mmole) is added in one lot. The temperature of reaction mass is raised to reflux (80° C. to 85° C.) and maintain at this reaction temperature for one hour. After that, this reaction mass is added to the pre-heated (80° C. to 85° C.) solution of oxalic acid (14.6 g) (162.13 mmole) in 2-propanol (287.5 ml) and continued the reflux for next one-hour, cooled to 50° C. to 55° C. and maintain for 1 hour. The product is filtered at the same temperature followed by three 33.5 ml wash with hot (50° C. to 55° C.) 2-propanol. The wet product dried at 60° C. to 65° C. for 6-8 hours or till constant weight gives 42.0 g of Carvedilol Oxalate (Yield 80.95%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:21][NH2:22])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH3:11])=[N:14][CH:15]=1
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccc(Cl)cn3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(Nc3ccc(Cl)cn3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)-(5-chloro-pyridin-2-yl)-amine and hydrazine monohydrate.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1.C([O-])(=O)C.[K+]>C(#N)C.O>[O:25]1[CH2:26][CH:27]=[C:28]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[NH:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:30]1
Reactant: Brc1cccnc1Oc1ccc(Nc2nc3ccccc3[nH]2)cc1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C1=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4[nH]3)cc2)CCOC1
Temperature: 25 °C

Procedure:
To a round bottomed flask was added N-(4-(3-bromopyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.5674 g, 1.488 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.938 g, 4.47 mmol), PdCl2(PPhtBu2)2 (0.093 g, 0.149 mmol), and potassium acetate (0.698 mL, 11.16 mmol) in ACN (3.72 mL) and water (1.240 mL) at 100° C. to stir. Upon completion, reaction allowed to cool to room temperature. Solvent was evaporated. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 MM, 0.1% TFA in ACN/H2O, gradient 25% to 90% over 20 min to provide N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 385.0 (M+1).
Reaction SMILES: Cl[C:2](=[N:14][OH:15])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl.[C:17](=[NH:22])(OCC)[CH3:18].C(N(CC)CC)C>ClCCl>[CH2:12]([O:11][C:9]([C@H:6]1[CH2:7][CH2:8][C@H:3]([C:2]2[N:22]=[C:17]([CH3:18])[O:15][N:14]=2)[CH2:4][CH2:5]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](c2noc(C)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of cis/trans-ethyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (1.85 g, 7.92 mmol) and ethyl acetimidate hydrochloride (1.96 g, 15.8 mmol) in dichloromethane (40 ml) was added triethylamine (2.2 ml, 16 mmol) at 0-5° C. The cooling bath was removed 15 minutes after completed addition, and stirring for 18 h at room temperature was followed by heating at reflux for 4 h. The reaction mixture was washed with one 50-ml portion of 1 M aqueous hydrochloric acid solution. The aqueous layer was extracted with two 50-ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/tert-butyl methyl ether as eluent gave the title compound (1.05 g, 56%) as colorless oil. MS m/e: 239 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:8].[C:31](OC(=O)C)(=[O:33])[CH3:32]>O1CCCC1.O>[C:31]([NH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20])=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:8])(=[O:33])[CH3:32]
Reactant: Nc1cccc(CNC(=O)c2[nH]c3ccc(Cl)cc3c2S(=O)(=O)c2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(CNC(=O)c2[nH]c3ccc(Cl)cc3c2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-(3-aminobenzyl) 3-phenylsulfonyl-5-chloroindole-2-carboxamide (Examplle 41) (176 mg, 0.4 mmol) in dry tetrahydrofuran (7 mL) containing acetic anhydride (0.05 mL, 0.5 mmol) was stirred at room temperature for 16 hours. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered through charcoal, and the solvents evaporated. The residue was triturated with methylene chloride and the solid collected by filtration to give the product, mp 249°-250° C.