Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:31][C@@H:30]2[C@:25]([CH3:39])([CH2:26][CH2:27][C@H:28]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH2:29]2)[C@@H:24]2[C@@H:10]1[C@H:11]1[C@:21]([CH3:40])([CH2:22][CH2:23]2)[C@@H:14]([C@H:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[O:19])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:41]([Mg]Cl)([CH3:43])[CH3:42].[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][C@@H:9]1[CH2:31][CH:30]2[C@:25]([CH3:39])([CH2:26][CH2:27][C@H:28]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH2:29]2)[C@@H:24]2[C@@H:10]1[C@H:11]1[C@:21]([CH3:40])([CH2:22][CH2:23]2)[C@@H:14]([C@H:15]([CH3:20])[CH2:16][CH2:17][CH:18]([OH:19])[CH:41]([CH3:43])[CH3:42])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Mg]Cl
Reactant: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)CC4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 77.2 %

Procedure:
A solution of compound 2009 (0.374 g, 0.679 mmol) in anhydrous THF (10 ml) under argon was treated with isopropylmagnesium chloride (2 ml, 2M in THF, 5.43 mmol) at room temperature. The reaction was stirred until no starting material remained by TLC. Aqueous NH4Cl solution (10%, 15 ml) was added to quench the reaction and the THEF was removed in vacuo. Distilled H2O (5 ml) was added and the solution extracted 3x with 15 ml CH2Cl2. The combined organic layers were washed with aqueous saturated NaCl solution (15 ml), dried over anhydrous MgSO4, filtered and the solvent removed in vacuo. Flash chromatography (SiO2, 12:1 hexanes:EtOAc) gave compound 2010 (0.3117 g, 77%) as a white foam. 1H NMR (500 MHz, CDCl3) δ: 7.35-7.34 (m, 5H, benzyl Ar-H), 4.71-4.69 (m, 1H, THP ether methine H), 4.585 (d, J=11.9 Hz, 1H, benzyl-CH2), 4.31 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 4.295 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 3.94-3.91 (m, 1H, THP, OCH2), 3.62-3.58 (m, 1H, THP OCH2), 3.50-3.48 (m, 1H, C-3 H), 3.45 (s, 1H, C-7 H), 3.32-3.31 (m, 1H, C-24 H), 0.81 (s, 3H, C-19 H), 0.63 (d J=2.4 Hz, 3H, C-18 H) (Note: product is a mixture of diastereomers); IR (CHCl3) 3605, 2900 cm-1 ; MS (CI/isobutane) m/z 595 (M+1, 10%), 401 (M+1-THP-Bn-H2O, 25%), 385 (M+1-THP-HOBn, H2O, 100%); m.p. 55°-59° C.; Anal. calcd. for C39H62O4 : C=78.74, H=10.50; Found: C=78.65, H=10.54.
Reaction SMILES: CCOCC.[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]#[N:15])[CH2:10][CH2:9]1.[OH:16][NH:17][C:18](=N)[CH3:19].Cl>CCOC(C)=O.CCO.[Cl-].[Cl-].[Zn+2]>[CH3:19][C:18]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][OH:6])[CH2:9][CH2:10]2)[O:16][N:17]=1
Reactant: N#CN1CCC(CO)CC1
Reactant: CC(=N)NO
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1noc(N2CCC(CO)CC2)n1
Yield: 12.9 %

Procedure:
[1-(3-Methyl-1,2,4-oxadiazol-5-yl)-4-piperidinyl]methanol (143 mg, 13%) was prepared from a solution of 1N ZnCl2 in Et2O (6.8 mL, 6.8 mmol), 4-(hydroxymethyl)-1-piperidinecarbonitrile (prepared as in Example 20, Step 1, 0.79 g, 5.6 mmol) and N-hydroxyacetamidine (0.5 g, 6.8 mmol) in EtOAc (10 mL) followed by concentrated HCl (2 mL) in EtOH (2 mL) in a manner similar to Example 20, Step 3. 1H NMR (400 MHz, CDCl3): δ 4.22-4.10 (m, 2H), 3.54 (d, 2H, J=6.4 Hz), 3.11-3.01 (m, 2 H), 2.21 (s, 3H), 1.89-1.79 (m, 2H), 1.78-1.69 (m, 1H), 1.41-1.20 (m, 2H); LRMS (ESI), m/z 198 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:19]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:20]#[CH:21]>CN(C)C=O.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.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:21]#[C:20][CH2:19][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCCC1)c1ccc(C#CCN2CCOCC2)cc1
Temperature: 70 °C
Yield: 81.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with 4-prop-2-ynyl morpholine (626 mg, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and a half-saturated aqueous sodium chloride solution (1×20 mL). The aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were washed with a half-saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-l-ynyl)-phenyl]-propionic acid methyl ester (582 mg, 82%) as an amber oil: EI-HRMS m/e calcd for C22H29NO3 (M+) 355.2147, found 355.2150.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:17][C:18]1[N:23]=[C:22]([N:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]2[CH3:34])[C:21]([CH3:35])=[C:20]([CH3:36])[N:19]=1>CN(C)C=O>[ClH:17].[CH3:35][C:21]1[C:22]([N:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]2[CH3:34])=[N:23][C:18]([NH:9][CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[N:19][C:20]=1[CH3:36]
Reactant: NCCc1ccccc1
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NCCc2ccccc2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 70.3 %

Procedure:
After 2-phenethylamine(0.33 ml, 2.61 mmol) and triethylamine(0.36 ml, 2.59 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.74 mmol) in dimethylformamide, 500 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:13]([CH2:14][CH2:15][CH:16]=2)=[N:12][N:11]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:10]=3)=[CH:4][CH:3]=1.C(O)C.[H][H]>[Pt](=O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[C:9]2=[CH:10][N:11]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[N:12]=3)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCC=C3c2ccc(Cl)cc2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCCC3c2ccc(Cl)cc2)cc1
Yield: 68.8 %

Procedure:
4-(4-Chlorophenyl)-2-(p-tolylsulfonyl)-6,7-dihydroindazole (0.62 g, 1.89 mmol) is added to ethanol (20.0 mL) and ethyl acetate (10 mL). Platinum (IV) oxide (0.22 g) is added and the reaction is stirred under 40 psi of hydrogen at room temperature for 6.0 h. The mixture is filtered through a plug of diatomaceous earth and evaporated under reduced pressure to give the title compound (0.503 g, 80%). LC/MS m/z 389 (M+H), Tr=2.704 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[N:19]3[CH:20]4[CH:15]([CH:16]=[CH:17][C:18]3=[O:21])[N:14]=[CH:13][C:12](=[O:22])[N:11]4[CH2:10]2)[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].[Cl:54]CCl>CO>[ClH:54].[ClH:54].[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[N:14][C:15]=6[CH:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: NC1CCN(CC2CN3C(=O)C=NC4C=CC(=O)N2C43)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1cnc2ccc(=O)n3c2n1CC3CN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Reaction time: 0.25 h
Yield: 60 %

Procedure:
A solution of 1-[(4-amino-1-piperidinyl)methyl]-1,2,5a,8b-tetrahydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (22.8 mg, 0.0757 mmol) in anhydrous dichloromethane (3 ml) and anhydrous methanol (0.6 ml) was treated with 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (12.5 mg, 0.076 mmol) (for a synthesis see WO2004058144 Example 2(c) or WO03/087098 Example 19(d)) and stirred, under argon, for 15 minutes and then treated with sodium triacetoxyborohydride (48 mg, 0.226 mmol) and stirred at room temperature for 17 hours. The reaction was then treated with a further portion of 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (2 mg) and sodium triacetoxyborohydride (10 mg) and the mixture was stirred for 4 hours, treated with saturated aqueous NaHCO3 solution (1 ml) and stirred for 10 minutes. The layers were separated and the aqueous layer was washed with 9:1 dichloromethane:methanol (2×10 ml). The combined organic extracts were passed through a hydrophobic frit and evaporated to a brown gum which was chromatographed eluting with 0 to 30% methanol in dichloromethane to give the free base of the title compound as a yellow gum (20.6 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8]([N+:13]([O-:15])=[O:14])=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8]([N+:13]([O-:15])=[O:14])=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:20])=[O:6]
Reactant: O=C(O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a suspension of 25.6 g (100 mmol) of 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid in 75 ml of dichloromethane was added 14.0 g (110 mmol) of oxalyl chloride. This mixture was treated with four drops of dry N,N-dimethylformamide, and the rapidly bubbling solution was stirred overnight at room temperature. The mixture was concentrated to give 27.0 g of the title compound which was used without purification in the next step.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([N:19]4[CH2:24][CH2:23][N:22](CC5C=CC=CC=5)[CH2:21][CH2:20]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:32]C(OC(Cl)C)=O>ClCCCl>[ClH:32].[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(N3CCN(Cc4ccccc4)CC3)cccc21
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cl
Product: O=S(=O)(c1ccccc1)n1ncc2c(N3CCNCC3)cccc21
Yield: 62.6 %

Procedure:
A solution of 1-phenylsulfonyl-4-(4-benzylpiperazin-1-yl)-1H-indazole (433 mg, 1.0 mmol) in 1,2-dichloroethane is treated with 1-chloroethyl chloroformate (0.27 mL, 2.5 mmol) heated at reflux temperature for 2 hr, and concentrated in vacuo. The resultant residue is heated at reflux temperature in methanol for 1.5 hr, cooled, concentrated in vacuo and reconcentrated from ether. The resulting tan solid is triturated with ether and crystallized from hot ethanol to give the title compound as a tan solid 237 mg (63% yield), mp 203-205° C., identified by HNMR and mass spectral analyses.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[N:11]=[C:12]([N:15]=[C:16]([NH2:18])[NH2:17])[S:13][CH:14]=2)[N:9]=1.[CH:19]1([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[CH:19]1([C:26]([NH:3][CH2:4][C:5]2[S:6][CH:7]=[C:8]([C:10]3[N:11]=[C:12]([N:15]=[C:16]([NH2:18])[NH2:17])[S:13][CH:14]=3)[N:9]=2)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)C1CCCCCC1
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: NC(N)=Nc1nc(-c2csc(CNC(=O)C3CCCCCC3)n2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
A suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (2.0 g), cycloheptanecarboxylic acid (1.02 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.50 g), 1-hydroxybenzotriazole hydrate (1.07 g) and triethylamine (1.24 g) in N,N-dimethylformamide (50 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was suspended in water (200 ml). The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution and then extracted with a mixture of ethyl acetate (250 ml) and tetrahydrofuran (50 ml). The extract was dried over magnesium sulfate and then was evaporated. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol =10:1. Recrystallization from a mixture of methanol, tetrahydrofuran and diisopropyl ether afforded 4-(2-cycloheptanecarbonylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (0.72 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[S:14][C:15]([CH2:18]Cl)=[CH:16][N:17]=1>CN1CCCC1=O.O>[Cl:12][C:13]1[S:14][C:15]([CH2:18][NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:16][N:17]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: Nc1nccc2ccccc12
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ncc(CNc2nccc3ccccc23)s1
Temperature: 220 °C
Yield: 10.9 %

Procedure:
A mixture of 1-aminoisoquinoline (0.56 g, 3.9 mmol) and 2-chloro-5-(chloromethyl)thiazole (0.50 g, 3.0 mmol) in N-methylpyrrolidinone (3 mL) was heated to 220° C. in a microwave reactor for 10 min. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with diethyl ether (5×20 mL). The combined organic extracts were concentrated under reduced pressure, and the resulting residue was purified by chromatography on silica gel eluted with 20-50% ethyl acetate/hexane to give the title compound as a pale yellow solid (0.09 g).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[NH:20][C:19]([C:21]3[N:26]=[CH:25][C:24]([CH:27]([OH:30])[CH2:28][OH:29])=[CH:23][CH:22]=3)=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11](SC)=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCC[CH2:32]1.O.O[O:38][S:39]([O-:41])=O.[K+]>C(OCC)(=O)C.CO>[CH:1]1([CH2:6][CH:7]([C:16]2[NH:20][C:19]([C:21]3[N:26]=[CH:25][C:24]([CH:27]([OH:30])[CH2:28][OH:29])=[CH:23][CH:22]=3)=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:39]([CH3:32])(=[O:41])=[O:38])=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: CSc1ccc(C(CC2CCCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)nc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a mixture of 1-[6-(5-{2-cyclopentyl-1-[5-(methylsulfanyl)pyridin-2-yl]ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]ethane-1,2-diol (124 mg), tetrahydrofuran (2 mL), water (2 mL) and methanol (2 mL) was added Oxone (registered trademark) (216 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (57.1 mg, yield 43%) 15 was obtained as a white amorphous solid from a fraction eluted with ethyl acetate-hexane (99:1, volume ratio). MS: 456 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22]>>[ClH:15].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][C:2]1[C:3]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1ccccc1Cl
Reactant: Cc1csc(Nc2ncccc2Br)n1
Product: Cc1csc(Nc2ncccc2Sc2ccccc2Cl)n1
Product: Cl

Procedure:
Prepared according to the method of Example 13, with 3-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine and 2-chlorobenzenethiol. 1H NMR (d6-DMSO) δ 8.45 (m, 1H), 7.80 (bs, 1H), 7.57 (m, 1H), 7.27 (m, 2H), 7.07 (m, 1H), 6.84 (m, 1H), 6.62 (m, 1H), 2.21 (s, 3H); Mass spectrum (esi) m/z=334.2 (100)(M+H—HCl).
Reaction SMILES: N#N.[OH-].[K+].[CH3:5][O:6][C:7]12[CH2:14][CH2:13][CH:10]([CH:11]=[CH:12]1)[CH2:9][CH:8]2[C:15]([O:17]C)=[O:16]>CO.O>[CH3:5][O:6][C:7]12[CH2:14][CH2:13][CH:10]([CH:11]=[CH:12]1)[CH2:9][CH:8]2[C:15]([OH:17])=[O:16]
Reactant: COC(=O)C1CC2C=CC1(OC)CC2
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC12C=CC(CC1)CC2C(=O)O
Yield: 87.8 %

Procedure:
In a 3 liter flask equipped with a mechanical stirrer, thermometer, reflux condenser, addition funnel and N2 atmosphere, potassium hydroxide (4.59 mole) was dissolved in methanol (1 L). To the resulting hot solution was added, over a five minute period, methyl 1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylate (1.53 mole) and the resulting light brown solution was heated to reflux for 5 hours. The reaction was then diluted with H2O (700 ml) and stripped under reduced pressure to a tan slimy solid. This solid was dissolved in fresh H2O (1 L) and washed with methylene chloride (1×500 ml). The separated aqueous layer was acidified to pH 1.5 with 420 ml conc. HCl at reduced temperature and extraced with methylene chloride (3×500 ml). The combined organic layers were washed with H2O (1 L) and brine. Drying and stripping under reduced pressure yielded 87.8% of title product as brown solids; mp 77°-81°; pnmr/CDCl3 /TMS/delta 1.65-2.0 (m, 6, C3H, C7H, C8H), 2.6-2.8 (m, 2, C4H, C2H), 3.4 (s, 3, OCH3), 6.2 (m, 2, C5H, C6H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14](=[O:24])[CH2:15][CH:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([OH:39])=[O:38])[CH2:33][CH2:32]1>CS(C)=O.O>[CH3:12][O:13][C:14](=[O:24])[CH2:15][CH:16]([NH:23][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([N:31]2[CH2:36][CH2:35][CH:34]([C:37]([OH:39])=[O:38])[CH2:33][CH2:32]2)[CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: O=C(O)C1CCNCC1
Reactant: COC(=O)CC(N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CC(Nc1cccc(N2CCC(C(=O)O)CC2)c1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2,6-difluoronitrobenzene (272 mg, 1.71 mmol) in DMSO (2 mL) was added methyl-3-amino-3-phenylpropanoate (553 mg, 2.57 mmol) and potassium carbonate (709 mg, 5.13 mmol), and the suspension stirred at room temperature for 24 hours. 4-Piperidinecarboxylic acid (335 mg, 2.59 mmol) was added, and the resulting suspension stirred at room temperature for 24 hours, and then heated at 100° C. for 3 hours. The suspension was cooled to room temperature, and diluted with water. The aqueous solution was extracted with ethyl acetate, and the separated aqueous layer acidified with dilute hydrochloric acid (pH<4), and re-extracted with ethyl acetate. The second organic extracts were evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (96:4) to afford the title compound, 1H NMR: (CDCl3) 7.36-7.22 (m, 5H), 7.02 (t, J=8.06, 1H), 6.34 (dd, J=8.06, 1.10, 1H), 6.19 (d, J=8.06, 1H), 4.89-4.85 (m, 1H), 3.66 (s, 3H), 3.25-3.21 (m, 2H), 2.87-2.77 (m, 4H), 2.48-2.41 (m, 1H), 2.02-1.82 (m, 4H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=O)[C:3]1=O.[CH2:17]([O:24][CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC([OH:37])C>[Cl-].[Zn+2].[Cl-]>[CH2:17]([O:24][CH2:25][CH2:26][N:27]1[C:2]2[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]3[CH2:12][CH2:13][CH2:14][CH2:15][N:10]3[CH:11]=[O:37])[C:3]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(COCCNc2ccccc2)cc1
Reactant: CC(C)O
Reactant: O=C1C(Br)CCCC1C(=O)N1CCCCC1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=CN1CCCCC1C1CCCc2c1c1ccccc1n2CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
A mixture of 2-bromo-6-(piperidine-1-carbonyl)-cyclohexanone (20) (1.5 g, 5.2 mmol) and (2-benzyloxy-ethyl)-phenyl-amine (21) (3.2 g, 10.4 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (5 mL) and dry zinc chloride (2.13 g, 15.6 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with 2 N HCl (30 mL), water (2×30 mL) and aqueous potassium carbonate solution (2×30 mL) then dried and concentrated in vacuo. The crude material was purified by SCX cartridge and then silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (30-100% B, 12 g, 41 CV, 30 mL/min) to afford 600 mg (27%) of [9-(2-benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (22) as an oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 21.5, 21.7, 24.5, 25.7, 26.3, 273, 37.7, 42.8, 43.1, 46.7, 60.2, 68.7, 73.1, 108.2, 108.7, 117.8, 118.9, 120.5, 126.4, 127.3, 127.4, 128.1, 136.2, 137.8, 172.9.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21]>CC#N>[CH3:16][C@H:3]([CH2:2][N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][CH:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23]2)[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15]
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Solvent: CC#N
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)CCc2ccccc21
Reaction time: 20 h
Yield: 35 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.185 g, 0.56 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (0.112 g, 0.62 mmol) in MeCN (0.5 mL) and shaken at 40° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; n-heptane/EtOAc 4:1) to give the title compound (107LH55) (0.075 g, 35%). 1H NMR (CD3OD) δ 7.28-7.18 (m, 3H), 7.01 (t, J=7.2 Hz, 1H), 4.03 (d, J=7.0 Hz, 2H), 3.11-3.04 (m, 2H), 2.90-2.85 (m, 2), 2.64-2.56 (m 2H), 2.28-2.11 (m, 4H), 1.97-1.84 (m, 3H), 1.66-1.54 (m, 3H), 1.42-1.21 (m, 10H), 0.90-0.85 (m, 2 CH3); 13C NMR (CD3OD) δ 173.1, 140.3, 129.1, 128.4, 128.3, 124.3, 117.1, 61.4, 60.2, 58.3, 46.4, 39.5, 37.1, 37.0, 33.1, 32.9, 32.2, 29.5, 29.4, 28.5, 27.9, 26.3, 23.7, 17.1, 14.4.