Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]12[N:8]([C:9]([C:11]3[C:16]([N:17]4[N:21]=[CH:20][CH:19]=[N:18]4)=[CH:15][CH:14]=[CH:13][C:12]=3[F:22])=[O:10])[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.Cl[C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=1.CCN(C(C)C)C(C)C>C(#N)C.O>[CH3:31][C:26]1[CH:27]=[C:28]([CH3:30])[N:29]=[C:24]([N:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:1]([N:8]([C:9]([C:11]4[C:16]([N:17]5[N:18]=[CH:19][CH:20]=[N:21]5)=[CH:15][CH:14]=[CH:13][C:12]=4[F:22])=[O:10])[CH2:7]3)[CH2:2]2)[N:25]=1
Reactant: O=C(c1c(F)cccc1-n1nccn1)N1C[C@@H]2CCNC[C@@H]21
Reactant: Cc1cc(C)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)nc(N2CC[C@H]3CN(C(=O)c4c(F)cccc4-n4nccn4)[C@H]3C2)n1
Yield: 51.7 %

Procedure:
(1R,6S)-3,8-Diazabicyclo[4.2.0]octan-8-yl(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Intermediate 29, 56 mg, 0.19 mmol), 2-chloro-4,6-dimethylpyrimidine (32 mg, 0.22 mmol) and DIPEA (96 μL, 0.56 mmol) in ACN (2 mL) were heated in a microwave reactor for 1 h at 150° C. Then the reaction mixture was diluted with water and extracted with DCM (2×). The combined organics were dried (Na2SO4) and concentrated. Purification via prep HPLC (Agilent, basic) gave 40 mg (53%) of the title compound as a clear oil. MS (ESI) mass calcd. For C21H22FN7O, 407.45; m/z found 408.0 [M+H]+. 1H NMR (CDCl3): 8.00-6.88 (m, 5H), 6.38-5.88 (m, 1H), 4.95-3.57 (m, 6H), 3.29-2.61 (m, 2H), 2.47-1.80 (m, 8H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O.ClCCl>C(#N)C>[N:22]1([C:2]2[S:3][C:4]3[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc2nc(Br)sc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1ccc2nc(N3CCNCC3)sc2c1
Temperature: 25 °C

Procedure:
Methyl 2-bromobenzo[d]thiazole-6-carboxylate (0.52 g, 1.90 mmol), Boc-piperazine (0.44 g. 2.38 mmol) and potassium carbonate (0.53 g, 3.80 mmol) were suspended in acetonitrile (21 ml) and refluxed overnight. The resulting mixture was then cooled to room temperature, concentrated in vacuo to approximately 2 ml, diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated in vacuo to yield a residue which was treated with trifluoroacetic acid/dichloromethane (6 ml, 1:1) for 1.5 hrs. The resulting mixture was concentrated in vacuo, the resulting residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate to yield methyl 2-(piperazin-1-yl)benzo[d]thiazole-6-carboxylate.
Reaction SMILES: [OH:1][C:2]1[C:3]([I:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O-:9])=[O:8].[S:12]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]O)=[CH:13]1.[C:20]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[I:11][C:3]1[C:2]([O:1][CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)=[CH:10][C:6]([C:7]([O:9][CH3:20])=[O:8])=[CH:5][N:4]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C([O-])c1cnc(I)c(O)c1
Reactant: OCCc1ccsc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cnc(I)c(OCCc2ccsc2)c1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a solution containing 5-hydroxy-6-iodonicotinate (3.70 g, 13.3 mmol;), 2-(3-thienyl)ethanol (1.90 mL, 17.2 mmol), and triphenylphosphine (4.52 g, 17.2 mmol;) in tetrahydrofuran (73.3 mL, 903 mmol;) was added Diisopropyl azodicarboxylate (3.39 mL, 17.2 mmol;) dropwise. The reaction mixture was stirred at RT o/n. The reaction mixture was concentrated and purified by flash chromatography EtOAc/Hex (0-100%) (eluted at 30%) to give methyl 6-iodo-5-(2-(thiophen-3-yl)ethoxy)nicotinate (93.2% yield). MS: (ESI+) 390.1
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[O:15]=[C:16]1[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=2[NH:17]1>C(C#N)(C)=O>[C:24]([O:23][C:21]([N:20]1[C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=2[N:17]([C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[C:16]1=[O:15])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: Clc1ncnc(Cl)n1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2ccccc21
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)n1c(=O)n(-c2ncnc(Cl)n2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-(4-Chloro-[1,3,5]triazin-2-yl)-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ester was prepared by a process similar to that described by N. A. Meanwell, et al., J. Org Chem., 60,1565-82 (1995). A mixture of 2,4-dichloro-1,3,5-triazine (0.64, 4.26 mmol) and solid K2CO3 (0.6 g, 4.34 mmol) was suspended in AcCN (10 mL) under nitrogen at RT followed by addition of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (1.0 g, 4.26 mmol). The mixture was stirred at RT for 1.5 h. The mixture was poured onto ice/water and the white solid formed, was collected by suction filtration and dried under vacuum to give 3-(4-chloro-[1,3,5]triazin-2-yl)-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]2)=[CH:2]1.N1C=CC=CC=1.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1C=CC=CC=1>[CH:28]1([C:34]([NH:21][C:19]([NH:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:17][CH2:16]2)=[O:20])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(NC(=O)C1CCCCC1)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
To a suspension of 1-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea (0.35 g) in dry benzene (2 ml) was added anhydrous pyridine (0.12 g) and then cyclohexanoyl chloride (0.18 g). After refluxing the mixture for 2 hours, the title compound was filtered off, washed, dried and converted in ethanolic hydrogen chloride to the hydrochloride (0.52 g) m.p. 236.3° C.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]3[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=3[S:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2csc3c2OC(C)CN(C(=O)OC(C)(C)C)C3)c1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (348 mg), (3-methoxyphenyl)boronic acid (198 mg), dichlorobis(triphenylphosphine)palladium (35 mg) and potassium carbonate (415 mg) in DME-water (1:1, 10 mL) was stirred at 85° C. for 1.5 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (294 mg, 78%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].O1CCCC1.C([Li])CCC.[CH3:22][S:23]SC>CCCCCC.O>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[C:10]([S:23][CH3:22])=[CH:9][CH:8]=[N:7]1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1cccn1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccnn1S(=O)(=O)N(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 4.0 g of N,N-dimethyl-1H-pyrazole-1-sulfonamide and 45 ml of tetrahydrofuran was added dropwise 15.7 ml of a 1.6M n-butyl lithium solution in hexane at −78° C., and the mixture was stirred at −78° C. for 10 minutes. After 2.3 ml of dimethyl disulfide was added to the mixture, the mixture was stirred for 4 hours while the reaction temperature was gradually returned to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with methyl t-butyl ether three times. The combined organic layer was washed successively with a 1N aqueous sodium hydroxide solution and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 4.87 g of N,N-dimethyl-5-methylthio-1H-pyrazole-1-sulfonamide of the formula:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[F:21].[F:22][CH:23]([F:39])[O:24][C:25]1[CH:26]=[C:27]([N:31]2[CH:35]=[C:34]([C:36](O)=[O:37])[CH:33]=[N:32]2)[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>O.CN(C=O)C>[F:39][CH:23]([F:22])[O:24][C:25]1[CH:26]=[C:27]([N:31]2[CH:35]=[C:34]([C:36]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]4)=[CH:4][C:3]=3[F:21])=[O:37])[CH:33]=[N:32]2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1cnn(-c2cccc(OC(F)F)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(F)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cnn(-c4cccc(OC(F)F)c4)c3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 59 %

Procedure:
(S)-tert-Butyl 2-(4-amino-3-fluorophenyl)morpholine-4-carboxylate (104 mg, 0.35 mmol), 1-(3-(difluoromethoxy)phenyl)-1H-pyrazole-4-carboxylic acid (107 mg, 0.42 mmol), HBTU (200 mg, 0.525 mmol) and N-methylmorpholine (106 mg, 115 μl, 1.05 mmol) were combined with DMF (4 ml) to give a light yellow solution. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into 50 ml of water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (20 g Silica gel, 70 to 50% ethyl acetate in heptane) to yield a white solid (110 mg, 59%). MS (ISP): 477.1 (100%, [M-tBu+H]+), 533.2 (30%, [M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[N:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([Sn](CCCC)(CCCC)[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)CCC>O1CCCC1.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>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[N:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: Cc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1-c1cccnc1
Temperature: 80 °C
Yield: 43.3 %

Procedure:
7-(3-Bromo-4-methylphenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (28 mg, 78 μmol) was dissolved in tetrahydrofuran (3 ml) under nitrogen and degassed for 10 min before 3-(tributylstannyl)pyridine (37 mg, 100 μmol) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 9 μmol) were added. The stirred mixture was heated at 80° C. for 48 h. Solvent was removed in vacuo and the residue purified by chromatography (silica gel, 50% EtOAc/isohexane) to give 12 mg of the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 2.37 (3H, s), 7.40–7.44 (1H, m), 7.50 (1H, d, J 8.2), 7.71–7.75 (1H, m), 7.98 (1H, d, J 1.9), 8.03 (1H, dd, J 1.9, 8.0), 8.62 (1H, s), 8.65–8.68 (2H, m), 8.79 (1H, s); MS (ES+) m/z 356 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[C:21]1[CH:22]=[C:23]([CH:38]=[CH:39][N:40]=1)[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:25])=[O:7].[NH:44]1[CH2:49][CH2:48][CH:47]([CH2:50][CH2:51][OH:52])[CH2:46][CH2:45]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:52][CH2:51][CH2:50][CH:47]1[CH2:48][CH2:49][N:44]([CH2:2][C:3]2[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=2)[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[C:21]2[CH:22]=[C:23]([CH:38]=[CH:39][N:40]=2)[C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:25])=[O:7])[CH2:45][CH2:46]1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CN3CCC(CCO)CC3)c2)c1
Reaction time: 12 h

Procedure:
A mixture of 20 mg of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 8.1a, 5.2 mg of 2-(piperidin-4-yl)ethanol, and 9.1 mg of K2CO3 in 2 mL of DMF was stirred for 12 h. The product was isolated by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. MS (ES, m/z) 700.27 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[N:44]([CH3:45])[N:43]=[N:42][N:41]=1)=[C:22]2[C:26]([O:28]CC1C=CC([N+]([O-])=O)=CC=1)=[O:27])([O:4]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].C(O)C.P([O-])([O-])(O)=O.[K+:54].[K+].O>O1CCOCC1.O.[Pt](=O)=O>[OH:4][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[N:44]([CH3:45])[N:43]=[N:42][N:41]=1)=[C:22]2[C:26]([O-:28])=[O:27])([CH3:3])[CH3:1].[K+:54]
Reactant: Cn1nnnc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2C1
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: Cn1nnnc1SC1=C(C(=O)[O-])N2C(=O)[C@@H](C(C)(C)O)[C@H]2C1
Temperature: 25 °C

Procedure:
A mixture of 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(1-methyl-1H-tetrazol-5-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50 mg) and platinum (IV) oxide monohydrate (25 mg) in a mixture of dioxane (10 ml), ethanol (0.5 ml), 0.1M aqueous dipotassium hydrogen phosphate (2.35 ml) and water (3.5 ml) was shaken for an hour under a hydrogen atmosphere (40 psi) at ambient temperature. The catalyst was filtered off and the filtrate was concentrated to half of the original volume. The aqueous concentrate was washed three times with diethyl ether and evaporated in vacuo. The residue was dissolved in water (25 ml) and potassium chloride (1.25 g) was added thereto. The aqueous solution was chromatographed on non-ionic adsorption resin "Diaion HP-20 AG" (1.35×17.5 cm), eluting with water (100 ml) and 10% aqueous isopropyl alcohol (100 ml). The fractions, whose UV spectra showed λmax 289 nm, were combined and lyophilized to give potassium (5R,6R)-6-(1-hydroxy-1-methylethyl)-3-(1-methyl-1H-tetrazol-5-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (17 mg).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH:25]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([F:10])=[CH:19][CH:18]=2)[C:14]([C:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH:25]=2)=[CH:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CC=C(c2cn(C(=O)c3ccccc3)c3ccc(F)cc23)CC1
Temperature: 25 °C
Yield: 38.7 %

Procedure:
Benzoyl chloride (33.3 mg, 0.24 mmol) was added to a solution of 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)indole (Example 4b, 49.6 mg, 0.215 mmol), triethylamine (0.15 mL, 1.1 mmol) and DMAP (5 mg) in dichloromethane (2 mL). The mixture was stirred at room temperature prior to quenching with water and extraction into dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. Purification by flash chromatography (silica gel, 2M methanolic ammonia in chloroform) yielded 1-benzoyl-5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)indole (27.8 mg, 39%, HRMS-FAB+ for C21H20N2OF calculated MH+ : 335.15598; found: 335.15457).
Reaction SMILES: OC[CH2:3][S:4]([CH:7]1[NH:10][C:9](=[O:11])[CH:8]1[CH:12]([O:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])[CH3:13])(=O)=O>C(#N)C.O.C(Cl)Cl>[CH3:3][S:4][CH:7]1[NH:10][C:9](=[O:11])[CH:8]1[CH:12]([O:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:16])[CH3:13]
Reactant: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)NC1S(=O)(=O)CCO
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CSC1NC(=O)C1C(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.17 g (16.7 mmol) of methyl mercaptan Na salt are added at 0° C. to a solution of 4.48 g (11.1 mmol) of 4-(2-hydroxyethylsulphonyl)-3-[1-(p-nitrobenzyloxycarbonyloxy)-ethyl]-azetidin-2-one in 11 ml of acetonitrile and 11 ml of H2O and the mixture is stirred at 0° C. during the course of 20 minutes. The reaction mixture is diluted with 100 ml of methylene chloride and 25 ml of H2O and the aqueous phase is extracted three times with 25 ml each of methylene chloride after separating off the organic phase. The purified organic phases are dried over MgSo4 and filtered, and the solvent is removed in vacuo, 3.80 g of title compound being obtained as a slightly yellowish non-crystalline compound. NMR spectrum in CDCl3 : δ=1.45 (d, J=7 Hz, 3 H), 2.12 (s, 3 H), 3.3 (dd, J=Hz, J=2 Hz), 4.70 (d, J=2 Hz, 1 H), 5.12 (m, 1 H), 5.20 (s, 2 H), 6.45 (wide s, 1 H), 7.50 (d, J=8.5 Hz, 2 H), 820 (d, J=8.5 Hz, 2 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CCCCCC.[CH2:19]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C[O:36]CC1>>[CH2:19]([N:26]1[CH2:31][CH2:30][C:29]([OH:36])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: C1CCOC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: OC1(c2ccccn2)CCN(Cc2ccccc2)CC1
Reaction time: 0.42 h
Yield: 66.41 %

Procedure:
To a stirred solution of 2-bromopyridine (10 mmol) in THF (120 mL) at −78° C. under argon, 2.5 M n-butyl lithium solution in hexane (4.5 mL, 11.25 mmol) was injected over 5 min. After 25 min, 1-benzylpiperidone (10 mmol) was added neat. After 30 min, the mixture was quenched by addition of aqueous NH4Cl solution (50 mL). The mixture diluted with ethyl acetate (200 mL), washed with brine (150 mL), dried (Na2SO4). Solvent was evaporated and the residue was purified by column chromatography (silica gel, EtOAc/Hexane from 20% to 60%) to give the desired product(1.78 g, 66.41% ). 1H-NMR was consistent with the structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH2:12][CH2:13][CH3:14])=[O:5])[CH3:2].[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:27]([C:24]2([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)[CH2:26][CH2:25]2)=[O:28])=[N:8][C:7]=1[CH2:12][CH2:13][CH3:14])=[O:5])[CH3:2]
Reactant: CCCc1nc(N)sc1C(=O)OCC
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(=O)OCC
Temperature: 65 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
2-Amino-4-propyl-thiazole-5-carboxylic acid ethyl ester (0.50 g, 2.3 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (0.48 g, 2.3 mmol) were dissolved in acetonitrile (15 mL) containing triethylamine (0.66 mL, 4.7 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 0.89 g, 2.3 mmol) was added and the solution was allowed to stir at 65° C. for four hours. The crude product was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 10-99% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.58 g, 1.4 mmol, 61%). ESI-MS m/z calc. 402.1. found 403.3 (M+1)+. Retention time of 3.78 minutes. 1H NMR (400 MHz, CD3CN) δ 0.84 (t, J=7.4 Hz, 3H), 1.25-1.35 (m, 5H), 1.50-1.68 (m, 4H), 2.91 (t, J=7.5 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), 6.00 (s, 2H), 6.81 (d, J=7.7 Hz, 1H), 6.95-6.98 (m, 2H), 9.22 (s, 1H).
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[OH:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:40]5[CH2:41][CH2:42][CH:37]([OH:36])[CH2:38][CH2:39]5)[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:25][CH2:26]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: OC1CCNCC1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CCC(O)CC1

Procedure:
1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((4-hydroxypiperidin-1-yl)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and 4-hydroxypiperidine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.