Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:2]2[CH:9]=[N:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:20][CH:19]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: N#Cc1ccncc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccncc1C#Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 3-iodo-isonicotinonitrile (911 mg, 3.96 mmol) in DMF (10 ml) are added bis(triphenylphosphine)-palladium(II)-chloride (139 mg, 0.20 mmol), copper(I) iodide (22.6 mg, 0.12 mmol), triethylamine (1.10 ml, 7.9 mmol) and 1-bromo-4-ethynyl-benzene (716 mg, 3.96 mmol). The mixture is flushed with nitrogen, heated to 80° C. and stirred in a closed reaction vial at this temperature for 18 hours. The reaction mixture is allowed to cool to room temperature and partitioned between dichloromethane and 1 N HCl. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(4-bromo-phenylethynyl)-isonicotinonitrile as beige solid; HPLC/MS 2.13 min (A), [M+H] 283/285.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC.[C:47]([OH:51])(=[O:50])[CH:48]=[CH2:49]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:49]=[CH:48][C:47]([OH:51])=[O:50])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)O
Reactant: O=S(=O)(Nc1ccc(I)cc1)c1ccccc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)C=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
To a solution of 28 (500 mg, 1.39 mmol), in DMF (10 mL) at room temperature were added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3; 38 mg, 1.67 mmol), tri-o-tolylphosphine (P(o-tol)3, 25 mg, 0.83 mmol), Et3N (483 μL, 3.48 mmol) and finally acrylic acid (84 μL, 1.67 mmol). The resulting solution was degassed and purged several times with N2 then heated overnight at 100° C. The solution was filtrated through a Celite pad with a fritted glass funnel then the filtrate was evaporated. The residue was purified by flash chromatography using CH2Cl2/MeOH (95:5) as solvent mixture yielding the title compound 35 (415 mg, 99%) as yellowish solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Cc1cccc(C)c1O
Product: Cc1cccc(C)c1Oc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2

Procedure:
The title compound was prepared from 2,6-dimethylphenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 252.7–258.6° C. 1H NMR (acetone-d6/300 MHz) 7.88 (s, 1H), 7.71 (s, 1H), 7.22 (m, 3H), 6.04 (s, 1H), 5.77 (q, 1H, J=7.0 Hz), 2.13 (s, 6H). 19F NMR (acetone-d6/282 MHz) −79.6 (d, J=7.2 Hz). FABLRMS m/z 397 (M−H). ESHRMS m/z 397.0450 (M−H, Calc'd 397.0454). Anal. Calc'd for C19H14ClF3O4: C, 57.23; H, 3.54; Cl, 8.89. Found: C, 57.21; H, 3.56; Cl, 8.98.
Reaction SMILES: [C:1]12([C:11]3[CH:25]=[CH:24][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[Li+].Cl>O.C1COCC1>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:24][CH:25]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of ethyl 4-(4-(adamantan-1-yl)phenoxy)butanoate (1.1 g, 3.50 mmol) in H2O/THF (1 mL/1.20 mL) was added lithium hydroxide monohydrate (0.14 g, 7.00 mmol), and stirred at room temperature overnight. The reaction mixture was adjusted to acidic solution with 1 N aqueous HCl and extracted with dichloromethane. The organic layer was washed with H2O and brine, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 4-(4-(adamantan-1-yl)phenoxy)butanoic acid as a white solid (0.98 g, 97.12% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[S:17][CH3:18])[N:10]3[CH2:19][CH2:20][CH2:21][CH:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:9]=23)=[CH:4][CH:3]=1.C1C=C(C([O-])=[O:36])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[S:17]([CH3:18])=[O:36])[N:10]3[CH2:19][CH2:20][CH2:21][CH:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:9]=23)=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CCOC(=O)CC1CCCn2c1c(-c1ccc(Cl)cc1)c1c(SC)cccc12
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CC1CCCn2c1c(-c1ccc(Cl)cc1)c1c(S(C)=O)cccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the sulfide of Step 12 (110 mg, 0.1 mmol) in 8 ml of CH2Cl2/MeOH (10:1) at 0° C. was added MMPP (79 mg, 0.1 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then quenched with a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 70% EtOAc in Hexanes to provide 40 mg of the less polar diastereomer and 38 mg of the more polar diastereomer as a white solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH:27](O)=[O:28]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][CH:27]=[O:28])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=CO
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=CN[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (18 mg, 20%), MS (ISP) m/z=357.3 [(M+H)+], mp 142° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and formic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[O:12]1[CH2:15][CH:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:13]1>CCO>[N+:8]([C:7]1[CH:6]=[CH:5][N+:4]([O-:11])=[CH:3][C:2]=1[N:19]1[CH2:20][CH2:21][N:16]([CH:14]2[CH2:15][O:12][CH2:13]2)[CH2:17][CH2:18]1)([O-:10])=[O:9]
Reactant: C1CN(C2COC2)CCN1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Solvent: CCO
Product: O=[N+]([O-])c1cc[n+]([O-])cc1N1CCN(C2COC2)CC1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A mixture of 3-bromo-4-nitro-1-oxido-pyridin-1-ium (500 mg, 2.283 mmol) and 1-(oxetan-3-yl)piperazine (649.3 mg, 4.566 mmol) in EtOH (10 mL) were heated at reflux for 17 hours. The reaction was cooled to ambient temperature and the solvent removed in vacuo. The residue was passed through a 25 g SCX-2 cartridge (pre-wetted with MeOH), eluting with 2M NH3 in MeOH/DCM. The solvents were removed in vacuo and the residue purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give 1-(4-nitro-1-oxido-pyridin-1-ium-3-yl)-4-(oxetan-3-yl)piperazine as an orange solid (553 mg, 86% Yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:33]=[N:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH3:41])[CH3:22])=[CH:29][CH:28]=1)[C:32]1[CH:33]=[N:34][C:35]([CH:38]([CH3:39])[CH3:40])=[CH:36][CH:37]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cn1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 41.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl)methyl](6-isopropylpyridin-3-yl)amine (0.48 g) as starting materials, 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.39 g) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([C:19](OC)=[O:20])=[CH:18][C:13]=3[O:12][CH:11]=2)[CH2:5]1.Cl.O>O1CCCC1>[OH:20][CH2:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([N:6]3[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[CH:11][O:12][C:13]=2[CH:18]=1
Reactant: COC[C@H]1CN(c2coc3cc(C(=O)OC)ccc23)C(=O)O1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H]1CN(c2coc3cc(CO)ccc23)C(=O)O1
Temperature: 55 °C

Procedure:
22 ml of a 2M solution (0.044 mol) of a borane-dimethyl sulphide complex in tetrahydrofuran are added, in two steps, to a solution of 3.3 g (0.011 mol) of methyl (R)-3-[5-(methoxymethyl)-2-oxooxazolidin-3-yl]benzofuran-6-carboxylate in 40 ml of tetrahydrofuran and the mixture is heated for five hours at 55° C. The mixture is hydrolysed with 1N hydrochloric acid. The mixture is poured into water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. The product is purified by chromatography on silica gel with a 99/1 mixture of dichloromethane and methanol. After crystallization from ethyl ether, 2.0 g of product are recovered.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22](Br)[S:21]4)[O:17][C:13]=2[CH:12]=[C:11]([Cl:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:31][OH:32].C[O-].[Na+]>CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:32][CH3:31])[S:21]4)[O:17][C:13]=2[CH:12]=[C:11]([Cl:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: Clc1cc(OCc2ccccc2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1nn2cc(-c3cc4c(OCc5ccccc5)cc(Cl)cc4o3)nc2s1
Yield: 81.5 %

Procedure:
To a stirred solution of 6-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole (Example 37G, 1.18 g, 2.56 mmol) in DCM (40 mL, 622 mmol) and methanol (10 mL, 247 mmol) was added sodium methoxide (1.164 mL, 5.12 mmol). The reaction mixture was stirred at r.t. for 1 h 15 min while monitoring by TLC (7:3 hexanes:EtOAc). The reaction mixture was quenched with 1N HCl and extracted with DCM. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness. The residue was triturated with MeOH (sonication) and the solid material was filtered off, rinsed with MeOH and sucked dry to give the desired compound as a brown solid (859 mg, 2.086 mmol, 81% yield). LC (Method A): 2.478 min. LCMS (APCI) calcd for C20H15ClN3O3S [M+H]+ m/z 412.05. found 412.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.50 (s, 1H), 7.52 (m, 2H), 7.43 (m, 2H), 7.36 (m, 2H), 7.09 (d, J=0.8 Hz, 1H), 7.00 (d, J=1.6 Hz, 1H), 5.31 (s, 2H), 4.21 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Br:17][C:16]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2cc3ncccn3n2)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Fc1ccc(-c2nn3cccnc3c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine (5.8 g, 0.027 mol) in chloroform (60 mL) is added, at 0° C., N-bromosuccinimide (4.8 g, 0.027 mol). The mixture is stirred at room temperature for 1 h 30. The reaction mixture is then poured into water and extracted with dichloromethane (3×100 mL). The organic layer is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is filtered through a short pad of silica. 6 g (75%) of 3-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine are obtained as a brown solid which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=2[C:18]([OH:20])=O)=[CH:4][CH:3]=1.[O:21]=[C:22]1[CH:27]([N:28]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:26][CH2:25][C:24](=[O:44])[NH:23]1>>[O:21]=[C:22]1[CH:27]([N:28]2[C:18](=[O:20])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][CH2:7][C:5]3[O:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:12]2=[O:14])[CH2:26][CH2:25][C:24](=[O:44])[NH:23]1
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(CNc2cccc(C(=O)O)c2C(=O)O)o1
Product: Cc1ccc(CNc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)o1
Yield: 20 %

Procedure:
3-[(5-Methyl-furan-2-ylmethyl)-amino]-phthalic acid (5 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The residue was purified by preparative HPLC (Symmetry C18, isocratic, 35/65 acetonitrile/water) to give 0.31 g (20%) of product as a yellow solid: mp 305-307° C.; 1H NMR (DMSO-d6) δ 11.10 (s, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.06 (d, J=7.1 Hz, 1H), 6.93 (t, J=6.0 Hz, 1H), 6.22 (d, J=2.9 Hz, 1H), 5.98 (d, J=1.9 Hz, 1H), 5.07 (dd, J=5.3 and 12.5 Hz, 1H), 4.49 (d, J=6.0 Hz, 2H), 2.97-2.82 (m, 1H), 2.62-2.44 (m, 2H), 2.22 (s, 3H), 2.06-1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.77, 170.02, 168.77, 167.21, 151,04, 150.02, 145.80, 136.04, 132.08, 117.57, 110.96, 109.63, 108.27, 106.34, 48.55, 38.94, 30.95, 22.10, 13.24; Anal. Calcd. For C19H17N3O5: C, 62.12; H, 4.66; N, 11.44. Found: C, 61.75; H, 4.71; N, 11.15.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([CH3:16])[CH2:12]2)C1C=CC=CC=1.C(O)C>[Pd].O>[CH3:16][N:11]1[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH2:10]1
Reactant: CN1CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CN1CC2CCC(C1)N2
Reaction time: 20 h

Procedure:
A solution of 8.2 g (0.038 mole) 8-benzyl-3-methyl-3,8-diazabicyclo [3.2.1]octane in 80 ml absolute ethanol containing 0.11 mole dry hydrogen chloride was hydrogenated in the presence of 1.5 g 10% palladium on charcoal at ambient temperature and pressure for 20 hours. The precipitated hydrochloride salt of the desired product was dissolved by addition of a little water, and, after filtration, the solvent was removed carefully in vacuo. The crystalline residue (6.9 g) was triturated with ethanol-diethyl ether containing dry hydrogen chloride to insure complete formation of the somewhat unstable dihydrochloride salt. Filtration gave 6.0 g (79%) of pure product, melting point 272°-280°C (dec.) with sublimation above 200°C.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[CH:4]=1.[CH3:25][O:26][CH2:27]C(Cl)=O>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[O:24][N:23]=[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[C:5]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:16])[CH2:11][CH2:10]3)[CH:4]=2)[N:1]=1
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)no1

Procedure:
2,2-Dimethylpropyl 4-{4-[amino(hydroxyimino)methyl]pyridin-2-yl}piperazine-1-carboxylate (84 mg) obtained in Example 26-1) was dissolved in pyridine (2 mL), and methoxyacetyl chloride (0.035 mL) was added thereto and heated under reflux for 90 minutes. The reaction liquid was diluted with ethyl acetate, washed with 1 N hydrochloric acid, aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through silica gel column chromatography (hexane/ethyl acetate=7/3) to obtain 54 mg of the entitled compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=N[CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:25]1C=CC=CC=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:25][CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Reactant: Brc1ccccc1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2ccccc2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using Bromobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=325.0 (M+H+).
Reaction SMILES: I[C:2]1[CH:20]=[N:19][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:10](=[O:18])[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[N:21]1([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([C:34]3[CH:39]=[CH:38][C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][CH:35]=3)=[O:33])[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:12]1([CH2:11][C:10]([N:9]2[CH2:8][CH2:7][NH:6][C:5]3[N:19]=[CH:20][C:2]([C:37]4[CH:38]=[CH:39][C:34]([C:32]([N:29]5[CH2:28][CH2:27][CH:26]([N:21]6[CH2:22][CH2:23][CH2:24][CH2:25]6)[CH2:31][CH2:30]5)=[O:33])=[CH:35][CH:36]=4)=[CH:3][C:4]2=3)=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Reactant: O=C(Cc1ccccc1)N1CCNc2ncc(I)cc21
Product: O=C(c1ccc(-c2cnc3c(c2)N(C(=O)Cc2ccccc2)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 52 %

Procedure:
1-(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)-2-phenylethanone (30 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a white foam (52% yield). M.p. (foam), LCMS: m/z=510.13 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.47-1.62 (m, 2H), 1.75-2.05 (m, 3H), 2.22-2.29 (m, 1H), 2.53-2.62 (m, 5H), 2.82-3.10 (m, 3H), 3.33-3.52 (m, 2H), 3.71-3.88 (m, 3H), 3.95 (s, 2H), 4.51-4.63 (m, 1H), 5.25 (bs, 1H), 7.12-7.34 (m, 5H), 7.35-7.48 (m, 4H), 8.16 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[ClH:15]>S(Cl)(Cl)=O.O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: Cl
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Br
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Br

Procedure:
10 g of 4-bromo-3-sulfamoylbenzoic acid were heated under reflux in a mixture of 80 ml of thionyl chloride and 50 ml of dioxane until HCl had completely developped. Then, the reaction mixture was concentrated under reduced pressure to 40 ml, 200 ml of petroleum ether were added and the crystals were filtered off. Melting point: 138° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13]S(C)(=O)=O)[CH2:10][C@H:9]1[C:18]([O:20][CH3:21])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O-])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>CS(C)=O.C(OCC)(=O)C>[C:22]([O:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@H](OC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A mixture of (2S,4R)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (32.3 g) and sodium benzoate (28.8 g) in dimethyl sulfoxide (320 ml) was stirred at 90° C. overnight and cooled to room temperature. The mixture was diluted with ethyl acetate (600 ml) and washed successively with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The oil was crystallized from n-hexane to give (2S,4S)-4-benzoyloxy-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (31.0 g) as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH2:26]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH3:18])[C:6]1[CH2:11][C@H:12]3[NH:17][C@@H:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Reactant: C=Cc1ccccc1C
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2C)C[C@@H]2CCC[C@H]1N2

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.486 mmol; Example 118A) and 1-methyl-2-vinylbenzene (115 mg, 0.972 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound as a racemic mixture. Individual enantiomers were obtained by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minutes) to afford the title compound as the second-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.10-1.34 (m, 3H), 1.59-1.96 (m, 4H), 2.00 (s, 3H), 2.40 (s, 3H), 2.79 (dd, J=17, 7 Hz, 1H), 2.97-3.09 (m, 1H), 3.11-3.22 (m, 1H), 3.37-3.43 (m, 1H), 4.20 (ddd, J=14, 9, 5 Hz, 1H), 4.31-4.42 (m, 2H), 6.90-6.97 (m, 2H), 6.99-7.11 (m, 3H), 7.14 (s, 1H), 7.27 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 345 (M+H)+.