Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]=[N:3][S:4]([Cl:7])(=[O:6])=[O:5].[CH3:8][C:9]([OH:12])([CH3:11])[CH3:10].CCCCCC>C1C=CC=CC=1>[Cl:7][S:4]([NH:3][C:2](=[O:1])[O:12][C:9]([CH3:11])([CH3:10])[CH3:8])(=[O:6])=[O:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(oxomethylene)sulfamoyl chloride (13.4 mmol) was dissolved in dry benzene (5 mL) and dropwise added t-BuOH (13.4 mmol) while the temperature was kept below 25° C. The reaction mixture was stirred at 25° C. for 2 h, added hexane (5 mL) and cooled to 0° C. Precipitate was collected by filtration, washed with hexane affording tert-butyl N-chlorosulfonylcarbamate as white crystals. 4-(4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (4.6 mmol) (intermediate 21) was suspended in dry DCM (25 mL) and added triethylamine (6.9 mmol). To this suspension was slowly added tert-butyl N-chlorosulfonylcarbamate (4.6 mmol) at rt. After 15 min all starting material has been consumed. The obtained reaction mixture was concentrated in vacuo on celite. The product was purified by flash chromatography on silica using EtOAc:MeOH in heptane as eluent.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:20][CH2:19]1)[CH2:11]2.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1>O.C1(C)C=CC=CC=1.C(O)C.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>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:20][CH2:19]2)[CH2:11]3)=[CH:30][N:31]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: O=C1c2ccc(Br)cc2CN1C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ncc(-c2ccc3c(c2)CN(C2CC2)C3=O)cn1
Temperature: 120 °C
Yield: 45.5 %

Procedure:
A solution of potassium carbonate (0.10 g, 0.75 mmol) in water (0.7 mL) was added to a mixture of 5-bromo-2-cyclopropylisoindolin-1-one (0.095 g, 0.38 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.12 g, 0.56 mmol), and tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol) in toluene (1.4 mL) and ethanol (0.7 mL). The resulting mixture was heated at 120° C. for 15 min. The reaction mixture was then quenched with saturated sodium bicarbonate (5 mL) and extracted with EtOAc. The organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with 10% methanol in dichloromethane to afford the desired product (0.046 g, 46%). LCMS: (M+H)=267.1.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[Cl:9][CH2:10][CH2:11][CH2:12]Cl>CN(C=O)C>[Cl:9][CH2:10][CH2:11][CH2:12][N:5]1[CH2:6][CH2:7][O:3][C:4]1=[O:8]
Reactant: O=C1NCCO1
Reactant: ClCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCN1CCCCl
Temperature: 25 °C
Yield: 95 %

Procedure:
To a mechanically stirred, room temperature suspension of NaH (0.305 mole, hexane washed) in 50 mL of DMF under N2, was added 2-oxazolidinone (0.287 mole) portion wise. After stirring the resulting gelatinous mixture overnight, 1,3-dichloropropane (0.643 mole) was added and the mixture stirred 4 days at room temperature. The volatiles were then removed in vacuo and the resulting white residue taken up in CH2Cl2 and washed with H2O and brine, and dried over MgSO4. After filtration, the material was passed through a short column (SiO2 : EtOAc/Hex) to give (XVI) as a clear oil in 95% yield: 1H NMR (CDCl3) δ4.22 (t, 2H, J=6.6 Hz), 3.47 (m, 4H), 3.24 (t, 2H, J=7.0 Hz), and 1.98 (p, 2H, J=6.5 Hz); 13C NMR (CDCl3) δ158.5, 61.8, 45.0, 42.0, 41.8, and 30.2. Anal. Calcd for C6H10ClNO2 : C, 44.05; H, 6.16; N, 8.56. Found: 41.17; H, 5.77; N, 8.26.
Reaction SMILES: [N:1]([C:4]1[C:5]([CH3:11])=[N:6][CH:7]=[C:8]([CH3:10])[N:9]=1)=[N+]=[N-].Cl.O.O.[Sn](Cl)(Cl)(Cl)Cl>CO.C(OCC)(=O)C>[NH2:1][C:4]1[C:5]([CH3:11])=[N:6][CH:7]=[C:8]([CH3:10])[N:9]=1
Reactant: Cc1cnc(C)c(N=[N+]=[N-])n1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cnc(C)c(N)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 38 %

Procedure:
To a stirred solution of 3-azido-2,5-dimethyl pyrazine (100 mg; 0.66 mmol) in methanol (800 μL) was added 12N HCl (100 μL) and tin chloride dihydrate (149 mg; 0.66 mmol). The reaction was heated to 60° C. and stirred for 12 hours. The reaction was cooled to room temperature, diluted with 50 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×50 mL), brine (50 mL), then dried (MgSO4), and filtered. The material was purified using a biotage 12i cartridge eluting with ethyl acetate to yield an off white solid (38% yield).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].Br[C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1>COCCOC.O.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>[Cl:7][C:8]1[CH:9]=[C:10]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: Nc1ncccc1Br
Reactant: CC(C)Oc1ccc(B(O)O)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)Oc1ccc(-c2cccnc2N)cc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A mixture of sodium carbonate (760 mg), tetrakis(triphenylphosphine)palladium(0) (207 mg), 3-chloro-4-isopropoxyphenylboronic acid (1.00 g) and 3-bromopyridin-2-amine (621 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (770 mg) as a pale yellow solid.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15][CH3:16])[C@@H:13]([CH3:17])[CH2:12][O:11][C@H:10]1[C:18]([O:20]C)=O)C1C=CC=CC=1.[CH2:22]([NH2:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>>[CH2:22]([NH:29][C:18]([C@H:10]1[C@H:9]([OH:8])[C@@H:14]([O:15][CH3:16])[C@@H:13]([CH3:17])[CH2:12][O:11]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1OCc1ccccc1
Reactant: CCCCCCCN
Agent: Cl
Product: CCCCCCCNC(=O)[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1O
Temperature: 90 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
A mixture of methyl (2R,3R,4S,5S)-3-benzyloxy-4-methoxy-5-methyltetrahydro-2H-pyran-2-carboxylate (7 mg, 0.024 mmole) and heptylamine (0.1 ml, 0.68 mmole) was heated at 90° C. for 3 hr. The reaction mixture was adjusted to pH 3 with 0.1N aqueous HCl, and partitioned between ether (10 ml) and water (10 ml). The ether layer was dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. A solution of the resulting crude amide in MeOH (5 ml) was stirred under hydrogen atmosphere in the presence of Pd-black (5 mg) at room temperature for 12 hr. The catalyst was removed by filtration and washed with methanol (2 ml×2). The combined filtrate and washings were evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using AcOEt/n-hexane (4:6) as an eluent to give (2R,3R,4S,5S)-N-heptyl-3-hydroxy-4-methoxy-5-methyltetrahydro-2H-pyran- 2-carboxamide (3.4 mg, 50% yield) as an oil; FAB-MS: m/z 288 (MH+). 1H-NMR (CDCl3)d: 0.91 (3H,t,J=6.5 Hz), 1.05 (3H,d,J=7 Hz), 1.25 (10H,br.s), 2.2 (1H,m), 3.10~3.6 (7H,br.m), 3.3 (3H,s), 3.81 (1H,dd,J=2.5 & 12 Hz), 8.0 (1H,br.s).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:15][CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH2:4]1.C(O[C:20](=[O:22])[CH3:21])(=O)C>>[CH2:4]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH2:14][CH2:15][CH:3]1[N:2]([CH3:1])[C:20](=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CNC1CCc2c([nH]c3ccccc23)C1
Product: CC(=O)N(C)C1CCc2c([nH]c3ccccc23)C1
Reaction time: 8 h

Procedure:
A mixture of 10.0 g (0.05 mol) of 2,3,4,9-tetrahydro-N-methyl-1H-carbazol-2-amine and 70 ml of acetic anhydride was heated at reflux until complete solution occurred (2-3 min). After standing overnight at room temperature and further cooling at 0°, the precipitated solid was filtered, washed first with small portions of cold acetic anhydride and then thoroughly with anhydrous ether. The crude product was recrystallized from ethanol to give the title compound, mp 215°-216°.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)(OC)OC.Cl.Cl[S:17]([OH:20])(=[O:19])=[O:18]>C1CCCCC1>[OH:2][C:1]1([S:17]([OH:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH2:3]1
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ccc(O)cc1
Agent: Cl
Solvent: COC(=O)OC
Solvent: C1CCCCC1
Product: O=S(=O)(O)C1(O)C=CC(O)=CC1
Temperature: 60 °C

Procedure:
15.0 g (0.136 moles) of hydroquinone, 102 g dimethyl carbonate and 68 g cyclohexane were charged under nitrogen to a 4-necked one litre reactor fitted with stirrer, thermometer and condenser attached to an HCl scrubber system. The reaction mixture was heated to 60° C. and 15.1 g (0.13 moles) of chlorosulphonic acid added over a period of 4 h with removal of hydrogen chloride gas. On completion of the addition, the reaction mixture is heated to 70-72° C. for 1 h, and then cooled to 20° C. The reaction mixture separated into two layers with the lower layer containing 1,4-dihydroxybenzene sulphonic acid (60% by hplc) and hydroquinone (38% by hplc).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][N:22]=2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[O:29]1CC[CH2:31][CH2:30]1.C(O)CO>C(N(CC)CC)C>[CH2:30]1[O:29][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:10]2[CH:20]=[CH:21][N:22]=[C:8]([C:6](=[O:7])[C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)[O:12][CH2:31]1
Reactant: C1CCOC1
Reactant: O=C(Nc1ccccc1)c1ccnc(C(=O)c2ccc(Cl)cc2)c1
Solvent: CCN(CC)CC
Solvent: OCCO
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(Cl)cc1)c1cc(C2(Nc3ccccc3)OCCO2)ccn1
Reaction time: 0.33 h
Yield: 80 %

Procedure:
2-(4-Chlorobenzoyl)-isonicotinanilide (11 g) was reacted with thionyl chloride as in Synthesis 1. To the resulting product, tetrahydrofuran (150 ml) and ethylene glycol (30 ml) were added and the mixture was stirred for about 20 minutes under cooling with ice. To the resulting solution, triethylamine (25 ml) was added dropwise. After completion of the addition, the solution was stirred for 1 hour, followed by stirring at room temperature for another 4 hours. The resulting solution was treated as in Synthesis 1 to produce the titled compound in an amount of 10.2 g (yield: 80%). m.p. 102°-103° C.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Bi](Br)(Br)Br.O[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)[CH3:14]>C(Cl)(Cl)(Cl)Cl>[CH:1]1([O:7][CH:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: Br[Bi](Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(C)OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
To the solution of cyclohexanol (167 mg, 1.67 mmol) in carbon tetrachloride (50 mL) was added bismuth (III) bromide (744.4 mg, 1.67 mmol), the mixture was stirred for 30 minutes at room temperature, the methyl 4-(1-hydroxyethyl)benzoate (300 mg, 1.67 mmol) was added, the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl 4-(1-(cyclohexyloxy)ethyl)benzoate (60 mg, 14%) as oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:29])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][N:32]=1>CC(O)C.C(OCC)(=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:31]5[C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=[CH:33][N:32]=5)[C:3]=4[CH3:29])=[CH:9][N:10]=[C:11]([C:26]([NH2:28])=[O:27])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3C)c12
Reactant: Clc1ncnc2ccccc12
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(Nc4ncnc5ccccc45)c3C)c12
Temperature: 115 °C
Yield: 25.2 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (51 mg, 0.131 mmol), and 4-chloroquinazoline (47.3 mg, 0.287 mmol) in 2-Propanol (5 mL) was heated at 115° C. under microwave for 30 min. The mixture was diluted with ethyl acetate (80 mL), washed with saturated NaHCO3 solution (20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The solvent was removed under vacuum, and the residue was purified by reverse phase HPLC. The correct fractions were concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (18.0 mg, 0.033 mmol, 25.5% yield) as a yellow solid. LCMS (M+H)+=519.30. 1H NMR (500 MHz, DMSO-d6) δ: 11.65 (s, 1H), 10.17 (s, 1H), 8.61 (s, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 7.89 (m, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.75 (s, 1H), 7.66 (m, 1H), 7.55-7.49 (m, 2H), 7.38-7.36 (m, 2H), 7.33 (d, J=8.9 Hz, 1H), 6.80 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 4.17 (m, 2H), 3.73 (m, 2H), 3.34 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: [H-].[K+].[C:3]1([CH:13]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][N:17]3[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[S:14]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C1COCC1>[CH3:28][N:29]([CH3:33])[C:30]([O:20][C:19]1[C:18]2=[CH:21][CH:22]=[CH:23][N:17]2[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[S:14][C:13]=1[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)=[O:31]
Reactant: CN(C)C(=O)Cl
Reactant: O=C1c2cccn2-c2ccccc2SC1c1cccc2ccccc12
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C(=O)OC1=C(c2cccc3ccccc23)Sc2ccccc2-n2cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a suspension of potassium hydride (0.167 g, 1.46 mmol, 35% in oil) in anhydrous THF (4.0 mL) was added the the (±)-6-(1-naphthyl)pyrrolo[2,1-d][1,5]benzothiazepin-7(6H)-one (500 mg, 1.46 mmol) dissolved in anhydrous THF (5 mL). The reaction mixture was stirred at rt for 2 h, and then dimethylcarbamoyl chloride (0.181 g, 1.68 mmol) was slowly added. After stirring for 8 h at 30° C., the solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was chromatographed (dichloromethane) to give the PBOX-8 in 82% yield. IR (neat) 1725 cm−1; 1HNMR (CDCl3) δ 2.43 (s, 3 H), 2.58 (s, 3 H), 6.45 (m, 1 H), 6.64 (m, 1 H), 7.18-7.57 (m, 10 H), 7.77-7.86 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]4[CH2:15][CH2:16][CH:11]([CH2:12][CH2:13]4)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]4[CH2:15][CH2:16][CH:11]([CH2:12][CH2:13]4)[C:7]=3[N:8]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=3)[C:9]=2[CH:10]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2c3c([nH]c2c1)C1CCN3CC1
Product: Cc1ccc2c3c(n(CCc4ccc(C)nc4)c2c1)C1CCN3CC1

Procedure:
The coupling of 7-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (110 mg, 0.52 mmol; Example 217) and 2-methyl-5-vinylpyridine (93 mg, 0.78 mmol; prepared as described in International Publication No. WO 2001017968) was performed according to the procedure described in Example 106A to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 0.88-1.03 (m, 2H), 1.71-1.82 (m, 2H), 2.38 (s, 3H), 2.41-2.48 (m, 2H), 2.44 (s, 3H), 3.07-3.17 (m, 5H), 4.42 (t, J=6.3 Hz, 2H), 6.89 (d, J=8.2 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 7.16 (s, 1H), 7.25 (dd, J=7.9, 2.1 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H); MS (DCI) m/z 332 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:18])=[O:17])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:4]1.[N+:25]([O-])([OH:27])=[O:26]>C(Cl)Cl>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:18])=[O:17])[C:9]=3[C:8]([N+:25]([O-:27])=[O:26])=[CH:7][C:6]=2[N:5]([C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH2:4]1
Reactant: O=[N+]([O-])O
Reactant: NC(=O)c1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Solvent: ClCCl
Product: NC(=O)c1cccc2c3c(cc([N+](=O)[O-])c12)N(C(=O)C(F)(F)F)CC3CCl
Yield: 45 %

Procedure:
A stirred solution of 128 (300 mg, 0.84 mmol) in CH2Cl2 (20 mL) was treated with filming HNO3 (2 mL) for 30 min at room temperature, then quenched with ice and extracted with CH2Cl2 (3×50 ml). The extracts were dried and concentrated under reduced pressure, and the residue was chromatographed on silica gel. Elution with EtOAc/petroleum ether/methanol (from 5:1:0 to 9:0:1) gave 1-(chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-6-carboxamide (129) (150 mg, 45%) as yellow solid: mp 272-277° C. (EtOAc/petroleum ether); 1H NMR [(CD3)2SO] δ 8.78 (s, 1H), 8.30 (dd, J=8.4, 1.1 Hz, 1H), 8.24 (s, 1H), 7.91 (dd, J=7.1, 1.0 Hz, 1H), 7.80 (dd, J=8.4, 7.1 Hz, 11), 7.57 (s, 1H), 4.69-4.61 (m, 2H), 4.52-4.47 (m, 1H), 4.21-4.15 (m, 1H), 4.13-4.07 (m, 1H); 13C NMR δ 169.3, 153.6 (q, JC-F 37.8 Hz), 148.1, 138.6, 133.4, 132.4, 130.1, 128.7, 127.9, 126.1, 119.3, 115.6 (q, JC-F 288 Hz), 114.4, 52.7, 47.5, 41.2. Anal. (C16H11ClF3N3O4) C, H, N, Cl.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]1([CH2:18][CH:19]2[NH:24][CH2:23][CH2:22][NH:21][C:20]2=[O:25])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([N:24]1[CH2:23][CH2:22][NH:21][C:20](=[O:25])[CH:19]1[CH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1NCCNC1Cc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1NCCN(C(=O)OCc2ccccc2)C1Cc1ccccc1

Procedure:
Benzyl chloroformate (8.5 g.) is added to a stirred mixture of 3-(phenylmethyl)piperazinone (XXIX, Example 62, 6.8 g.), chloroform (75 ml.), and saturated sodium bicarbonate solution (20 ml.). After 30 minutes the chloroform phase is separated, washed twice with water, and concentrated. The residual oil is crystallized from ethyl acetate-SSB and then ethyl acetate again to give the title compound, m.p. 125°-127.5°.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([N+:14]([O-])=O)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1O)(=[O:3])[CH3:2].O.NN.[ClH:21]>C(O)C.[Pd]>[ClH:21].[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][C:13]=1[NH2:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(O)cc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)O)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred mixture of 107 (1.00 g, 4.46 mmol) and 10% Pd-C (1.0 g) in ethanol (10 mL) and 5% HCl (1.2 mL) was added dropwise hydrazine hydrate (55% hydrazine, 1.0 mL, 17 mmol). The mixture was stirred at room temperature for 1 hour, the catalyst was filtered, and the filtrate was concentrated under reduced pressure. Compound 108 (0.875 g, 100%) was obtained as a white solid residue: mp 220°-223° C. (methanol/hexane). A literature reference (Ellis and Jones, 1974) did not report the mp.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([CH2:2][OH:1])[CH2:8][CH2:7]1)=[O:11])[CH3:18]
Reactant: CCO
Reactant: O=C(O)[C@H]1CC[C@H](CO)CC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H]1CC[C@H](CO)CC1

Procedure:
To a solution of cis/trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (10.0 g, 63.2 mmol) in ethanol (316 ml) was added a catalytic amount of sulfuric acid. The reaction mixture was heated at reflux for 20 h. The solvent was evaporated. The residue was partitioned between ethyl acetate (150 ml) and 2 M aqueous sodium carbonate solution (100 ml). The aqueous layer was separated. The organic layer was washed with one 100-ml portion of water and one 50-ml portion of brine. The combined aqueous layers were extracted with one 100-ml portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the tile compound as colorless oil (11.5 g, 98.1%). MS m/e: 187 ([M+H]+)
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)=O.CC(C[AlH]CC(C)C)C>C1COCC1>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:7]=[N:6][C:5]([CH2:3][OH:2])=[CH:10][CH:9]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)nn1

Procedure:
0.582 g (2.062 mmol) of the above prepared 6-(4-trifluoromethyl-phenyl)-pyridazine-3-carboxylic acid methyl ester in 20 ml of abs. THF was cooled down to −15° C. and reacted with 5.16 ml of DIBAL-H-solution (1.0 M in toluene, 2.5 eq.) for ½ h. Careful quenching with ice/HCl dil., twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, AcOEt) to yield 0.155 g of the title compound as light brown solid.