Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[C:9]([C:25]([NH2:27])=[O:26])[CH:10]=[CH:11][C:12]=3[C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[NH:7][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.C(Cl)Cl>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:12]1[CH:11]=[CH:10][C:9]([C:25]([NH2:27])=[O:26])=[C:8]2[C:13]=1[C:14]1[CH2:15][CH2:16][CH:4]([CH:1]([OH:3])[CH3:2])[CH2:5][C:6]=1[NH:7]2
Reactant: CC(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(-c4c(F)cccc4F)c23)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(O)C1CCc2c([nH]c3c(C(N)=O)ccc(-c4c(F)cccc4F)c23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2-acetyl-5-(2,6-difluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (Example 27-1, 30 mg, 0.081 mmol) and sodium borohydride (6.2 mg, 0.163 mmol) in methanol (1 mL) was stirred at rt for 1 h. The mixture was diluted with DCM, washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was purified by preparative HPLC to provide two diastereomers of 5-(2,6-difluorophenyl)-2-(1-hydroxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide. Each one was partitioned between 1 M aqueous sodium hydroxide and DCM, followed by drying and concentration, to provide the separated racemic diastereomers of 5-(2,6-difluorophenyl)-2-(1-hydroxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide. The more polar diastereomer (Example 28-1) was a white solid (10 mg, 33%). 1H NMR (400 MHz, chloroform-d) δ 1.26 (d, J=6.59 Hz, 3H) 1.30-1.43 (m, 1H) 1.78-1.89 (m, 1H) 1.97-2.05 (m, J=12.74 Hz, 1H) 2.14-2.22 (m, 1H) 2.24-2.35 (m, 1H) 2.57 (dd, J=16.04, 10.77 Hz, 1H) 2.81 (dd, J=16.48, 5.05 Hz, 1H) 3.70-3.79 (m, 1H) 6.96-7.04 (m, 3H) 7.32-7.41 (m, 2 H) 10.05 (s, 1H). Mass spectrum m/z 371.1 (M+H)+. The less polar diastereomer (Example 28-2) was a white solid (8 mg, 27%). 1H NMR (400 MHz, chloroform-d) δ 1.26 (d, J=6.15 Hz, 3H) 1.34-1.40 (m, 1H) 1.42-1.53 (m, 1H) 1.75-1.90 (m, 2H) 2.24-2.35 (m, 1H) 2.68 (dd, J=16.26, 10.11 Hz, 1H) 2.94 (dd, J=16.26, 5.27 Hz, 1H) 3.80 (s, 1H) 6.96-7.05 (m, 3H) 7.34-7.40 (m, 2H) 10.05 (s, 1H). Mass spectrum m/z 371.1 (M+H)+.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[N:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH3+:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)=[O:5].[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[C:22]([NH:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14](/[N:13]=[N:12]/[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:11][CH:10]=2)=[CH:19][CH:18]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)c1ccc(N=Nc2ccc(C[NH3+])cc2)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Product: CCCC(=O)NCc1ccc(/N=N/c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Into the solution of the amine 4 (915 mg, 3.0 mmol) in pyridine (15 mL) was added dropwise butyryl chloride (477 mg, 4.5 mmol), and the reaction was stirred overnight at room temperature. The solvent was evaporated, the residue dissolved in chloroform, washed with hydrochloric acid (1.0 M), water and brine, and dried with magnesium sulfate. Silica gel chromatography with chloroform as eluent gave pure 10 (916 mg, 90%) as orange crystals. 1H NMR (360 MHz, CDCl3): δ 8.19 (d, J=8.4 Hz, 2H), 7.96-7.91 (m, 4H), 7.44 (d, J=8.0 Hz, 2H), 5.86 (br s, 1H), 4.55 (d, J=6.0 Hz), 3.97 (s, 3H), 2.56 (t, J=7.6 Hz, 2H), 1.73 (q, J=7.6 Hz, 2H), 0.99 (t, J=7.6 Hz, 3H). 13C NMR (100.61 MHz, CDCl3): δ 172.55, 166.14, 154.70, 151.49, 141.99, 131.44, 130.22, 128.06, 123.11, 122.26, 51.95, 42.77, 38.29, 18.78, 13.42. HRMS (m/z): [M+H]+ calcd. for C19H21N3O3 340.1656. found 340.1669.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C(O)(=O)C.[C:21]1([CH2:27][N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[OH-]>CCO>[C:21]1([CH2:27][N:28]2[CH2:33][CH2:32][C:31]3([C:16]4=[C:15]5[C:10](=[N:9][C:8]4=[C:3]4[C:2](=[CH:7][CH:6]=[CH:5][CH2:4]4)[NH:1]3)[CH:11]=[CH:12][CH:13]=[CH:14]5)[CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: C1=CCC2=C3N=c4ccccc4=C3C3(CCN(Cc4ccccc4)CC3)NC2=C1

Procedure:
To a mixture prepared from 7.6 g of 2-(2-aminophenyl)indole, 2.5 ml of acetic acid and 90 ml of ethanol was added 7.4 ml of 1-phenylmethyl-4-piperidone. The resultant solution was refluxed for 6 hours. Concentration gave a solid/gum mixture which was taken up in EtOH and treated with dilute NH4OH. Filtration gave 12.45 g of yellow solid. This was recrystallized from CH3OH/H2O to give 9.0 g of yellow solid. High vacuum drying (90°) gave 2.6 g of dark yellow solid, m.p. 155°-157° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:14](=[O:16])[CH3:15])[C:3]=1[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[Br:1][C:2]1[C:11]2[C:10]([CH3:12])([CH3:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:14](=[O:16])[CH3:15])[C:3]=1[O:17][CH3:18]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc2c(c(Br)c1O)C(C)(C)CCC2
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C(C)=O)cc2c(c1Br)C(C)(C)CCC2
Temperature: 25 °C

Procedure:
To a solution of 1-(4-bromo-3-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Compound A-91, 11.8 g, 39.7 mmol), potassium carbonate (14.4 g, 119.1 mmol) in acetone (350 mL) was added methyl iodide (19.8 mL, 317.6 mmol). After heating to reflux for 16 h, the mixture was cooled to room temperature, diluted with water and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a yellow oil. The material was used in the next step without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].O>CC(O)=O>[CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)n1c2ccccc2c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: CC(C)n1c2ccccc2c2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A solution of 9-Isopropyl-9H-carbazole (Acros, 1.5 9, 7.2 mmol) in AcOH (50 ml) was treated dropwise with a solution of nitric acid (3.35 ml) in AcOH (10 mL) over 30 minutes. When the reaction was complete the mixture was poured into water and stirred for 15 minutes, then the solid filtered and washed with Et2O to afford the desired product as a solid (1.6 g, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH2:28])[C:19]2=[O:29])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[Cl:30][CH2:31][C:32](Cl)=[O:33]>CCOCC>[Cl:30][CH2:31][C:32]([NH:28][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:26](=[O:27])[N:18]([CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:19]2=[O:29])=[O:33]
Reactant: O=C(Cl)CCl
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Solvent: CCOCC
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Yield: 96 %

Procedure:
A mixture of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-aminoisoindoline-1,3-dione (2.0 g, 4.8 mmol) and chloroacetyl chloride (2 mL, 25 mmol) was heated to reflux for 30 minutes. The solvent was removed in vacuo to give a solid. The solid was stirred in ether (40 mL) for 1 hour to give a suspension. The suspension was filtered and washed with ether to give 2-chloro-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid (2.28 g, 96% yield); mp, 166-168° C.; 1H NMR (CDCl3) δ1.48 (t, J=6.9 Hz, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.13 (q, J=7.0 Hz, 2H, CH2), 4.24 (s, 2H, CH2), 4.57 (dd, J=10.5, 14.3 Hz, 1H, CHH), 5.89 (dd, J=4.5, 10.3 Hz, 1H, NCH), 6.84-6.88 (m, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.57 (d, J=7.2 Hz, 1H, Ar), 7.70 (t, J=7.6 Hz, 1H, Ar), 8.77 (d, J=8.3 Hz, 1H, Ar), 10.53 (s, 1H, NH); 13C NMR (CDCl3) δ14.60, 41.52, 42.67, 48.72, 54.51, 55.88, 64.48, 111.46, 112.44, 116.37, 119.06, 120.38, 124.74, 129.17, 131.22, 136.04, 136.29, 148.58, 149.75, 165.21, 167.25, 169.01; Anal Calcd for C22H23N2O7ClS+0.1 H2O: C, 53.19; H, 4.71; N, 5.50; H2O, 0.36. Found: C, 52.89; H, 4.52; N, 5.50; H2O, 0.17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:23]Cl.[NH:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:23][N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: CC(C)c1ccc(S(=O)(=O)n2cc(CCl)c3cc(Br)ccc32)cc1
Reactant: C1CNCCNC1
Product: CC(C)c1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3cc(Br)ccc32)cc1

Procedure:
Using essentially the same procedure as described in example 127, 5-Bromo-1-(4-isopropylbenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[CH3:12][C:13](=[N:17]O)[C:14](=O)[CH3:15].[ClH:19].C(OCC)(=O)C>>[Cl:19][CH2:12][C:13]1[N:17]=[C:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[O:8][C:14]=1[CH3:15]
Reactant: Cl
Reactant: CC(=O)C(C)=NO
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: Cc1oc(-c2cccc([N+](=O)[O-])c2)nc1CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.6 %

Procedure:
A mixture of 3-nitrobenzaldehyde (18.67 g), 2,3-butanedione-2-oxime (12.50 g) and 4N hydrogenchloride-ethyl acetate (400 mL) was stirred at room temperature for 16 hrs. The reaction mixture was concentrated. A mixture of the residue, tetrahydrofuran (400 mL) and thionyl chloride (13.6 mL) was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and the crude product obtained from a fraction eluted with ethyl acetate-hexane (1:4-1:3, v/v) was washed with diethyl ether-hexane to give 4-chloromethyl-5-methyl-2-(3-nitrophenyl)-1,3-oxazole as colorless crystals (2.67 g, yield 8.6%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 111-113° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][N:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][C:22]=4[N:23]3S(C3C=CC(C)=CC=3)(=O)=O)=[CH:19][CH:18]=2)[C:13](=[O:41])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:42].CCOCC>C(Cl)Cl.CO>[ClH:42].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][N:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][C:22]=4[NH:23]3)=[CH:19][CH:18]=2)[C:13](=[O:41])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(OCc6ccccc6)cc5=O)cc42)CCN(C)C3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CN1CCc2c([nH]c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc23)C1
Reaction time: 2 h
Yield: 34 %

Procedure:
NaOH (644 mg, 16.1 mmol) was added to a solution of the 4-(benzyloxy)-1-(2-methyl-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (174 mg, 0.322 mmol) in CH2Cl2/MeOH (10 mL) that had been degassed with N2. The resulting solution was heated at reflux with stirring for 2 h under N2. The solution was allowed to cool, saturated NH4Cl solution and CH2Cl2 were added, and the phases were separated. The organic phase was washed with saturated NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure to yield a white solid. 1 M HCl in Et2O (0.38 ml, 0.38 mmol) was added to a solution of the white solid in 9:1 CH2Cl2/MeOH (10 mL) under N2, and the resulting solution was stirred at 25° C. for 30 min. The solution was concentrated, and the residue was diluted with a small amount of CH2Cl2/CH3CN. The resulting suspension was filtered, and the solid was dried under reduced pressure to yield the title compound (46 mg, 34%) as a white solid: mp 168-170° C.; 1H NMR (500 MHz, DMSO-d6) δ 11.30 (s, 1H), 10.50-10.41 (m, 1H), 7.58-7.52 (m, 2H), 7.49-7.40 (m, 4H), 7.39-7.35 (m, 2H), 6.96 (br d, J=8.0 Hz, 1H), 6.09 (br d, J=7.5 Hz, 1H), 5.97 (br s, 1H), 5.15 (s, 2H), 4.60 (br d, J=15.0 Hz, 1H), 4.41 (dd, J=15.0, 7.5 Hz, 1H), 3.78-3.71 (m, 1H), 3.45-3.38 (m, 1H), 3.09-2.98 (m, 5H); ESI MS m/z 386 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:38][C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:40](=[O:41])[C:39]([CH3:44])([CH3:43])[CH3:38])[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
Dissolve the product of Example 3 (220 mg, 0.43 mmol) in pyridine (5 mL) and treat sequentially with trimethylacetyl chloride (0.144 mL, 1.17 mmol) and dimethylaminopyridine (DMAP, catalytic amount). Stir at ambient temperature for 18 hours and evaporate pyridine. Re-constitute the residue in ethyl acetate and wash with saturated aqueous NH4Cl, saturated aqueous NaHCO3, and brine. Dry the organic layer (Na2SO4), filter, and evaporate to obtain 277 mg of crude material. Pre-adsorb onto silica gel and chromatograph on a SiO2 column eluting the material with methanol in dichloromethane (0 to 6%) to give 235 mg of 2,2-dimethyl-propionic acid 6-(4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalene-2-yl ester. Dissolve the free base in a mixture of ethyl acetate and diethyl ether (20 mL; 1:1). Cool in an ice bath and treat with 2M HCl in diethyl ether (0.3 mL, 0.6 mmol). Collect the precipitate on filter paper and rinse with diethyl ether to obtain 220 mg of the title compound (80%): mass spectrum (ion spray): m/z=602.4 (M+H−HCl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.CI.[C:18](=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([N:8]([CH3:18])[S:9]([CH3:12])(=[O:10])=[O:11])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CS(C)=O
Product: CN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Reaction time: 24 h

Procedure:
N-(5-fluoro-2-nitrophenyl)methanesulfonamide compound (5 g, 21 mmol), methyl iodide (3 mL) and potassium carbonate (10 g) were stirred together in DMSO (100 mL) at 80° C. overnight. The reaction was not complete and a further 1 mL of methyl iodide was added. After a further 24 hours at 80° C., water (1000 mL) was added. The solution was decanted from a small amount of sticky residue. The product crystallized out from the aqueous solution (48 hours) and was collected by filtration, washed with water and dried. Yield 3.3 g (63%); 1H NMR (400 MHz, CDCl3) δ 3.04 (s, 3 H), 3.30 (s, 3 H), 7.20 (m, 1 H), 7.31 (dd, J=8.54, 2.68 Hz, 1 H), 8.0 (dd, J=9:3, 5.6 Hz, 1 H); MS (ESI+) for C8H9FN2O4S m/z 248 M+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:9]=2)[CH:3]=1.[Cu][C:27]#[N:28].C(O)C[OH:31].O1CCOCC1>[Cl-].[Na+].O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:12][C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=2)[C:27]([NH2:28])=[O:31])=[N:9]1
Reactant: N#C[Cu]
Reactant: OCCO
Reactant: Fc1ccccc1Cn1nc(-c2cc(Br)ccn2)nc1-c1nccs1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1ccnc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)c1
Temperature: 100 °C
Yield: 11 %

Procedure:
To a stirring suspension of 2-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole (I-36, 1 equiv) in ethylene glycol-dioxane (approx. 4:1) in a sealed tube was added copper(I) cyanide (3 equiv). The resultant reaction mixture was heated at 100° C. for 24 hr and then cooled to room temperature, treated with brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified using SiO2 chromatography (ethyl acetate/hexanes) to afford 2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)isonicotinamide as a solid in 11% yield.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]2[CH2:39][NH:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:25])=[CH:19][CH:18]=1>CO>[ClH:1].[ClH:1].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH:27]2[CH2:39][NH:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:25])=[CH:21][CH:22]=1
Reactant: COc1ccc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2CNc2cccnc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)N2CCNCC2CNc2cccnc2)cc1
Reaction time: 1 h
Yield: 82 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(4-methoxyphenylcarbamoyl)-3-((pyridin-3-ylamino)methyl)piperazine-1-carboxylate TFA salt (81.7 mg, 0.147 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and treated with 4 M HCl in 1,4-dioxane (6 mL). The mixture was concentrated under reduced pressure to give 49.9 mg (82%) of the title compound as a white solid. LC-MS: RT=1.95 min, [M+H]+=342.1.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:8][C:9]=1[NH:10]2.[CH3:29][C:30]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32]>>[NH2:32][C:31]1[C:30]([CH3:29])=[C:36]([C:2]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]3[C:3]=2[C:4]2[CH2:5][CH2:6][CH:7]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:8][C:9]=2[NH:10]3)[CH:35]=[CH:34][CH:33]=1
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(NC(=O)OCc1ccccc1)CC3
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3c(c12)CCC(NC(=O)OCc1ccccc1)C3

Procedure:
Using the procedure of Example 3-2, benzyl 5-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazol-2-ylcarbamate (Intermediate 50-4(a), 300 mg, 0.678 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate 50-1, 237 mg, 1.017 mmol) were converted into benzyl 5-(3-amino-2-methylphenyl)-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazol-2-ylcarbamate, TFA salt, isolated as a white solid after preparative HPLC purification (60 mg, 15%). 1H NMR (400 MHz, methanol-d4) δ 7.63 (1 H, dd, J=7.7, 2.9 Hz), 7.18-7.46 (8 H, m), 6.82 (1H, dd, J=7.5, 2.8 Hz), 5.10 (2 H, s), 3.90 (1 H, br. s.), 3.14 (1 H, d, J=4.8 Hz), 2.72 (1H, br. s.), 1.77-2.19 (6 H, m), 1.51-1.68 (1 H, m). Mass spectrum m/z 469.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl

Procedure:
Tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: C(OC([O:6][CH2:7][C:8]#[C:9][C:10](=[O:21])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)C)C.Cl>O1CCCC1.O>[OH:6][CH2:7][C:8]#[C:9][C:10](=[O:21])/[CH:11]=[CH:12]/[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: CCOC(C)OCC#CC(=O)/C=C/c1ccc(OC)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(/C=C/C(=O)C#CCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3 g (10.4 mmol) of (E)-6-(1-ethoxy-ethoxy)-1-(4-methoxyphenyl)-1-hexen-4-yn-3-one in 50 ml of tetrahydrofuran was treated at room temperature with 3 ml of 1N hydrochloric acid and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted twice with ether. The combined organic phases were dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 100 g of silica gel (elution agent methylene chloride/ether 4:1) and was subsequently crystallized from methylene chloride/ether/hexane. There was obtained (E)-6-hydroxy-1-(4-methoxyphenyl)-1-hexen-4-yn-3-one of melting point 68°-69°.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1cccnc1
Product: COc1cc2ncn(-c3nc(-c4cccnc4)c(C(=O)O)s3)c2cc1OC
Yield: 6.8 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and pyridine-3-boronic acid (18.4 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-pyridin-3-yl-thiazole-5-carboxylic acid (2.6 mg, 7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.68 (br.s., 1 H); 9.07 (d, 1H); 8.85 (s, 1 H); 8.66 (dd, 1 H); 8.31 (dt, 1 H); 7.81 (s, 1 H); 7.55 (ddd, 1 H); 7.40 (s, 1 H); 3.86 (s, 3 H); 3.85 (s, 3 H). MS m/z 383 (M+1).