Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH2:15][C:14]([C:17](O)=[O:18])=[CH:13][C:12]=3[CH:20]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.Cl.[CH3:33][N:34]([CH2:41][C@H:42]1[CH2:47][CH2:46][C@H:45]([NH2:48])[CH2:44][CH2:43]1)[CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH2:15][C:14]([C:17]([NH:48][C@H:45]4[CH2:44][CH2:43][C@H:42]([CH2:41][N:34]([CH3:33])[CH:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)[CH2:47][CH2:46]4)=[O:18])=[CH:13][C:12]=3[CH:20]=2)=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CO3)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N[C@H]2CC[C@H](CN(C)C4CCOCC4)CC2)CO3)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 6-(4-methylphenyl)-2H-1-benzopyran-3-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (114 mg) in acetonitrile (15 ml) was added at room temperature 1-ethyl-3-(340 -dimethylaminopropyl)carbodiimide hydrochloride (162 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (253 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (257 mg) and triethylamine (0.16 ml) in acetonitrile (20 ml), and the resulting mixture was stirred for 5 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:1) and to recrystallization (ethyl acetate/hexane) to obtain trans-6-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]-2H-1-benzopyran-3-carboxamide (compound 67) (144 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34].[Na+].[Cl-]>CN(C=O)C.CCOC(C)=O.O>[CH:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2CC1CCCCC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 9-[(cyclohexyl)methyl]-4-hydroxy-5-carbamoyl carbazole (60 mg, 0.186 mmol) and Cs2CO3 (150 mg; 0.460 mmol) in 2 mL of DMF was treated with methyl bromoacetate (0.023 mL; 0.242 mmol). The reaction was stirred for 2 hours at ambient temperature, then it was diluted with EtOAc and H2O (10 mL each). The aqueous layer was saturated with solid NaCl and extracted with EtOAc (2×10 mL). The combined organic layers were washed with H2O (2×25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (elution with a gradient of 0% to 90% EtOAc/hexanes) followed by trituration with Et2O/EtOAc afforded 45 mg (0.114 mmol; 61%) of title compound as an off-white solid. MS (ES) m/e 395 (M+1), 378 (M+H—NH3), 453 (M+AcO−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=3[O-:20])[C:7]=2[CH:21]=1)#[N:2].C1(C)C=CC=CC=1.O=O>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][C@@H:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=3[O-:20])[C:7]=2[CH:21]=1)#[N:2]
Reactant: CC1(C)C=C(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Agent: O=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1(C)C[C@@H](c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Reaction time: 20 h

Procedure:
100 mg (359 mmol) of 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine 1-oxide, 9 ml of toluene, 1 ml of dichloromethane, 5.8 mg (14.4 mmol) of [Rh(COD)2 ]BF4 and 6.1 mg (14,4 mmol) of (R)-BIPHAS were placed in a 30 ml autoclave in a glove box (O2 content <1 ppm). The autoclave was sealed and the hydrogenation was carried out at 40° while stirring and a pressure of 40 bar. The hydrogenation was interrupted after 20 h. In order to determine the e.e. value and the conversion, a sample of the hydrogenation solution was evaporated and analyzed by HPLC on a chiral phase (Chiralcel OD-H). (R)-2-(6-Cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4yl)-pyridine 1-oxide was obtained in quantitative yield: e.e.=85%; chem. purity >99%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]2[CH2:15][C@@H:11]([CH:12]=[CH:13]2)[C@@H:10]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[N:34]1C=CC=CC=1.O1CCOCC1.C(=O)(O)[O-].[NH4+]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[C@@H:10]([C:16](=[O:18])[NH2:34])[C@H:11]2[CH2:15][C@@H:14]1[CH:13]=[CH:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N[C@H]1[C@@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1[C@@H](C(N)=O)[C@@H]2C=C[C@H]1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
(1S,2S,3R,4R)-3-tert-Butoxycarbonylamino-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (6.66 g, 26.3 mmol), Di-tert-Butyldicarbonate (8.6 g, 39 mmol) and Pyridine (3.8 mL, 47 mmol) were added to 1,4-Dioxane (40 mL, 500 mmol) and the reaction stirred for 30 minutes at room temperature. Ammonium Bicarbonate (5.8 g, 74 mmol) was added, and the reaction mixture was stirred overnight. The reaction was quenched by addition of water. Extraction (2×) with EtOAc, washing 2× with 0.1 N HCl, and once w/ brine, drying (MgSO4), concentration, provided ((1R,2R,3S,4S)-3-Carbamoyl-bicyclo[2.2.1]hept-5-en-2-yl)-carbamic acid tert-butyl ester as a white solid (6.47 grams).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1>O>[CH3:9][O:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1
Reactant: COCC1CCCN1
Reactant: Nc1cccc(F)n1
Solvent: O
Product: COCC1CCCN1c1cccc(N)n1
Temperature: 205 °C
Yield: 73.6 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol) and 2-(methoxymethyl)pyrrolidine (0.617 g, 5.35 mmol) in water (0.2 mL) was heated to 205° C. for 0.5 h in a sealed tube in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:15) to afford 6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-2-amine (0.68 g, 74%) as a yellow oil. LC-MS: [M+1]+=208, tR=1.052 min.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]2=[C:10]([NH:13][CH3:14])[NH:11][N:12]=[C:6]2[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:4]1=[O:23])[CH3:2].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]2=[C:10]([NH:13][CH3:14])[N:11]([CH3:26])[N:12]=[C:6]2[N:5]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:4]1=[O:23])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCn1c(=O)c2c(NC)[nH]nc2n(Cc2ccc(C)cc2)c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(NC)n(C)nc2n(Cc2ccc(C)cc2)c1=O
Temperature: 60 °C
Reaction time: 30 h

Procedure:
A mixture of 5-ethyl-3-methylamino-7-(4-methylbenzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.5 g, 1.6 mM), methyl iodide (0,46 g, 3.2 mM) and potassium carbonate (0,45 g, 3.2 mM) in DMF (8 ml) was stirred at 60° C. for 30 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)([CH2:18][CH3:19])/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15].CN1CCOCC1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)([CH2:18][CH3:19])/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(/C=C/C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(/C=C/C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (E)-methyl 4-(4-amino-1H-indazol-1-yl)-4-(4-chlorophenyl)hex-2-enoate (120 mg) and NMM (98 mg) in DCM (5 mL) was added MsCl (45 mg). Then the mixture was stirred at room temperature for 2 h. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=5/1) to afford the title compound as a pale yellow solid. LC/MS m/z=448.2[M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[N:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:12]1[CH:11]=[C:10]([NH2:9])[CH:15]=[N:14][CH:13]=1
Reactant: Nc1cncc(B(O)O)c1
Reactant: Brc1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cncc(-c2ncccn2)c1
Temperature: 95 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
The mixture of 2-bromopyrimidine (0.76 g, 4.80 mmol), (5-aminopyridin-3-yl)boronic acid hydrochloride (1.00 g, 5.75 mmol), Pd(Ph3P)2Cl2 (0.73 g, 0.96 mmol) and K2CO3 (2.78 g, 20.2 mmol) in dioxane (40 mL) and water (10 mL) was degassed with argon stream. It was stirred at 95° C. in argon atmosphere for overnight. The mixture was concentrated in vacuo to dryness. The solid was triturated with dioxane and EtOAc. The organic solutions were combined, filtered, concentrated and subjected to flash column (0-8% MeOH in DCM) to isolate 5-(pyrimidin-2-yl)pyridin-3-amine (0.24 g).
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:43])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[N:25]=[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:41])[F:40])[O:27][C:28]=3[C:29]([F:32])([F:31])[F:30])=[O:23])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C1COCC1.O>[F:32][C:29]([F:30])([F:31])[C:28]1[O:27][C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])=[N:25][C:24]=1[C:22]([NH:21][CH2:20][CH2:19][C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][C:3]([OH:44])=[O:2])[CH2:6][CH2:7]2)=[CH:16][CH:15]=1)=[O:43])=[O:23]
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4C(F)(F)F)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4C(F)(F)F)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-{[5-trifluoromethyl-2-(2-trifluoromethylphenyl)oxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (455 mg, 0.727 mmol) was put into THF/water (50 mL, 3:1) solvent, and NaOH (145.47 mg, 3.637 mmol) was added thereto. The mixture was stirred at room temperature for 24 hours, THF was removed, and pH of the mixture was adjusted to be 2-3 with 1N hydrochloric acid. The reaction mixture was extracted with EtOAC (3×100 mL), washed with brine and dried with anhydrous sodium sulfate, and the solvent was removed. The obtained crude material was crystallized with acetonitrile to obtain the desired compound (435 mg, 98%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]3[CH:36]=[CH:37][CH:38]=[C:28]3[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:35]1[C:30]2[N:29]3[CH:36]=[CH:37][CH:38]=[C:28]3[CH2:27][CH2:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:40][CH:39]=3)=[O:24])[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)cc1

Procedure:
To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 7 mmol of triethylamine and 5 mmol of 6,7-dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine. The reaction mixture is washed with water, 2M citric acid, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid; mass spectrum (CI):422(M+H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)=[O:4].[C:14]1([CH2:20][O:21][C:22]2[C:23]([CH2:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.CCOCC>C1COCC1>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:38]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][CH2:28][C:23]2[C:22]([O:21][CH2:20][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:6][C:7]=1[CH2:12][OH:13]
Reactant: c1ccc(CNCCCCCCOCCCc2ncccc2OCc2ccccc2)cc1
Reactant: O=C(CBr)c1ccc(O)c(CO)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CN(CCCCCCOCCCc1ncccc1OCc1ccccc1)Cc1ccccc1)c1ccc(O)c(CO)c1
Yield: 56.2 %

Procedure:
A solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (460 mg), N-[6-[3-[3-(phenylmethoxy)-2-pyridinyl]propoxy]hexyl]benzenemethanamine (800 mg) and DEA (485 mg) in THF (15 ml) was left at room temperature overnight. Water (30 ml) and ether (30 ml) were added, the phases were separated and the organic layer was re-extracted with ether (50 ml). The combined extracts were washed with water and brine, dried and concentrated to an oil which was purified by FCC eluting with ethyl acetate/triethylamine (99:1) followed by ethyl acetate/methanol/triethylamine (90:10:1) to give the title compound as an orange oil (620 mg), t.l.c. (ethyl acetate/methanol/triethylamine 80:20:1) Rf 0.66.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:7]([N:14]1[CH2:20][C:19]2[N:21]=[CH:22][C:23](Cl)=[N:24][C:18]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:7]([N:14]1[CH2:20][C:19]2[N:21]=[CH:22][C:23]([O:4][CH:1]([CH3:3])[CH3:2])=[N:24][C:18]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reactant: CC(C)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Oc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 0.25 h
Yield: 42 %

Procedure:
To a solution of isopropanol (83 μL) in toluene (2 mL) was added sodium hydride (87 mg) at room temperature, and the mixture was stirred for 15 min. A solution of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (297 mg) and BINAP (30 mg) in toluene (2 mL) was added to the reaction mixture. After substitution with an argon gas, Pd2(dba)3 (20 mg) was added, and the mixture was stirred under an argon atmosphere at 100° C. for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane) to give the title compound (137 mg, 42%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][O:22][CH2:21][CH2:20][O:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[CH3:29][O-:30].[Na+].C(Cl)(Cl)Cl>CO>[O:19]1[CH2:20][CH2:21][O:22][CH2:23][CH:18]1[C:17]1[C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][N:28]=[C:3]([CH2:2][O:30][CH3:29])[CH:4]=3)=[N:13][C:12]=2[C:14]([O:24][CH3:25])=[CH:15][CH:16]=1
Reactant: C[O-]
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COCc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccn1

Procedure:
From (+)-2-chloromethyl-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with sodium methylate in methanol. [α]D20=+65.1° (c=0.55, CHCl3), ES-MS m/e (%): 416 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH3:14][O:1][C:2]1([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCC1(O)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC1(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
tert-Butyl (1-hydroxycyclopropyl)methylcarbamate (150 mg) was dissolved in dry DMF (2 mL) and Cs2CO3 (313 mg, 0.961 mmol) was added, followed by MeI (0.053 mL, 0.841 mmol). The light yellow suspension was stirred in a sealed vessel at room temperature overnight. More MeI (0.050 mL, 0.801 mmol) was added and stirring was continued for 2 d. The reaction mixture was partitioned between aqueous saturated NaHCO3 (25 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 (2×25 mL). The organic layer was washed with brine (2×25 mL) and dried on Na2SO4 before concentration in vacuo to give a yellow oil. The product was filtered over a plug of silica (eluent heptane/iPr2O 1:1) to give the title compound (90 mg, 16% from 1-(aminomethyl)cyclopropanol) as a colorless oil.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH:36]1[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>>[OH:42][CH:39]1[CH2:40][CH2:41][N:36]([CH2:7][CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]5[CH:32]=[CH:31][S:30][CH:29]=5)[CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:37][CH2:38]1
Reactant: OC1CCNCC1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCC(O)CC4)CC3)c[nH]c12
Yield: 11.9 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (40 mg, 0.13 mmol) and 4-piperidinol (0.068 mL, 0.65 mmol) were allowed to react in the presence of K2CO3 (74 mg, 0.65 mmol). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (8.2 mg, 13%).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[O:34])[C:21](=[O:33])[N:22]2[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O1C2C=CC(O)=CC=2OC1.[CH3:45][C:46]1([CH3:56])[CH2:50][C:49]2[CH:51]=[CH:52][C:53]([OH:55])=[CH:54][C:48]=2[O:47]1>>[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]([OH:34])([C:52]1[C:53]([OH:55])=[CH:54][C:48]3[O:47][C:46]([CH3:56])([CH3:45])[CH2:50][C:49]=3[CH:51]=1)[C:21](=[O:33])[N:22]2[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CN1C(=O)C(=O)c2c(Br)cccc21
Reactant: CC1(C)Cc2ccc(O)cc2O1
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl (4-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate and 1,3-benzodioxol-5-ol with 2,2-dimethyl-2,3-dihydrobenzofuran-6-ol, the title compound was obtained: MS (ES+) m/z 498.5 (M+23), 500.5 (M+23).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)=[O:14])[CH:7]=1)[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cccc(-c3ccccc3)n2)c1
Temperature: 80 °C

Procedure:
{3-[(6-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (77)(198 mg, 0.54 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. for 25 min. The crude product was purified by column chromatography using 20% EtOAc in heptane to give the title compound.