Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:29])[CH:11]([OH:28])[CH:12]([CH3:27])[C:13](=[O:26])[C:14]([CH3:25])([CH3:24])[CH:15]([O:20][CH:21]([CH3:23])[CH3:22])[O:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:37]([O:39][CH2:40][C:41]([Cl:44])([Cl:43])[Cl:42])=[O:38]>C(Cl)Cl>[Cl:42][C:41]([Cl:44])([Cl:43])[CH2:40][O:39][C:37](=[O:38])[O:28][CH:11]([CH:10]([CH3:29])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:12]([CH3:27])[C:13](=[O:26])[C:14]([CH3:24])([CH3:25])[CH:15]([O:20][CH:21]([CH3:22])[CH3:23])[O:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)OC(OC(C)C)C(C)(C)C(=O)C(C)C(O)C(C)COCc1ccccc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(OC(C)C)C(C)(C)C(=O)C(C)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 7-Benzyloxy-5-hydroxy-1,1-diisopropoxy-2,2,4,6-tetramethyl-heptan-3-one 32 (1.0 g, 2.4 mmol) and pyridine (0.8 mL, 7.3 mmol) in CH2Cl2 (10.0 mL) at 0° C. was added 2,2,2-trichloroethyl chloroformate (668.0 μL, 4.9 mmol) and the mixture was then allowed to warm to rt. After 1 h, the reaction mixture was quenched with brine and then extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient hexane to hexane/EtOAc 93:7) to give 32a (1.285 g, 92%) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 1.03-1.09 (m, 12H), 1.15 (d, J=1.8 Hz, 3H), 1.17 (d, J=1.9 Hz, 3H), 1.19-1.21 (m, 6H), 1.97-2.11 (m, 1H), 3.2 (dd, J=6.2 and 9.0 Hz, 1H), 3.54 (dd, J=4.8 and 9.1 Hz, 1H), 3.57-3.60 (m, 1H), 3.82 (qd, J=3.6 and 5.9 Hz, 2H), 4.47 (s, 2H), 4.57 (s, 1H), 4.72 (d, J=11.9 Hz, 1H), 4.81 (d, J=11.9 Hz, 1H), 5.08 (t, J=6.0 Hz, 1H), 7.29-7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 11.9, 15.0, 18.8, 21.4, 21.7, 22.3, 23.2, 23.4, 35.7, 42.5, 53.4, 53.9, 69.4, 70.9, 71.4, 73.3, 81.3, 94.7, 103.4, 127.5, 127.6, 128.2, 138.2, 154.0, 215.6; IR (film, NaCl, cm−1) 2966, 1760, 1698, 1247; LRMS (ESI) calcd for C27H41O7Cl3Na [M+Na+] 605.2, found 605.2; [α]23D=−20.4 (c=1.0, CHCl3.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:40])=[N-]>CO.CCOCC>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[O:37][CH3:40])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Solvent: CCOCC
Solvent: CO
Product: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 0.17 h

Procedure:
The resulting crude 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is dissolved in methanol and a solution of diazomethane in ether is added at 0° C. After 10 minutes, the solution is carefully concentrated and the residue is dried under a high vacuum. The residue is purified by thick layer chromatography (toluene/ethyl acetate, 3:1, silica gel). After eluting the silica gel of the zone at Rf=0.17 with ethyl acetate, and concentrating the solution on a rotary evaporator, 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained; melting point 120° C. (from ether).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:18]1[N:23]=[C:22]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (1.00 g, 4.97 mmol) was added to a suspension of sodium hydride (60 wt %, 0.238 g, 5.96 mmol) in DMF (16.56 mL) and stirred for 30 minutes at room temperature. 2,4-Dichloropyrimidine (1.11 g, 7.45 mmol) was added to the reaction mixture and stirred for 2 hours at room temperature. The mixture was then diluted with ethyl acetate (100 mL) and washed with 1:1 water:brine (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C@@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:6].[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)C[C@@H](N)C(=O)OC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)OC
Reaction time: 18 h
Yield: 86 %

Procedure:
To a suspension of D-aspartic acid dimethyl ester hydrochloride (36.0 g, 182 mmol) in THF (360 mL) was added 4-fluorobenzenesulfonyl chloride (39.0 g, 200 mmol, 1.1 equiv.). To the previous mixture at 0° C. was added dropwise triethylamine (60.8 g, 601 mmol, 3.3 equiv.). After a period of 18 h at room temperature, the reaction mixture was filtered and the solid washed with methyl tert-butyl ether (30 mL). The filtrate was evaporated followed by the addition of methyl tert-butyl ether (300 mL). To the resulting mixture was added 100 mL of HCl 1 M. The organic phase was separated and sequentially washed with water, half-saturated sodium bicarbonate, HCl 0.5 M and half-saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 50 g of the title compound as an oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[CH:11]=O)=[CH:6][CH:5]=1.Cl.[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17]>O1CCCC1>[CH2:20]([O:19][C:16](=[O:18])/[CH:17]=[CH:11]/[C:10]([C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)([CH3:14])[CH3:13])[CH3:21]
Reactant: CC(C)(C=O)c1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of triethyl phosphonoacetate (4.58 ml) in tetrahydrofuran (30 ml) was added portionwise sodium hydride (1.00 g, 60% dispersion in oil). The mixture was stirred for 1 hour at room temperature and then a solution of 2-(4-fluoro-phenyl)-2-methyl-propionaldehyde (3.46 g) in tetrahydrofuran (10 ml) was added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 day. The mixture was then acidified by addition of 1 M aq. hydrochloric acid and taken up in ethyl acetate. The mixture was washed sequentially with water and with saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc gradient) to yield a colourless oil, (4.14 g, 84%); MS (ISP): 237.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])[CH3:22].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])([C:24]([O:23][CH2:21][CH3:22])=[O:25])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate 19 (50 mg) and triethylmethanetricarboxylate (0.073 ml) in toluene (1.5 ml) and tetrahydrofuran (1.5 ml), stirred at RT under an inert atmosphere of nitrogen, was added trimethylphosphine, 1M in toluene (0.344 ml). The resulting solution was cooled to −78° C. and diisopropyl azodicarboxylate (0.068 ml) was added dropwise via syringe and the reaction was stirred at −78° C. for 45 mins. The reaction mixture was removed from the cold bath and allowed to warm to RT and stirred under N2 atmosphere overnight. Reaction mixture concentrated in vacuo. The residue was taken up in DCM (20 ml) and washed with water (20 mL). The 2 phases were separated, the organic extract was dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (48 mg). LC/MS MH+ 505, Rt 3.41 min (5 minute run).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].[C:21](=[O:23])=[O:22].Cl>O1CCCC1>[CH3:6][O:7][C:8]1[C:9]([NH:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[C:10]([CH:11]=[CH:12][CH:13]=1)[C:21]([OH:23])=[O:22]
Reactant: COc1ccccc1NC(=O)C(C)(C)C
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)O)c1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
n-Butyllithium (1.6M solution in hexane; 200 ml, 0.32 mol) was added dropwise under nitrogen at −10° C. to a stirred solution of N-(2-methoxyphenyl)pivalamide (27.6 g, 0.133 mol) in tetrahydrofuran (600 ml), the mixture was allowed to warm to ambient temperature, stirred for a further 2 hours, then it was added to a large excess of crushed solid carbon dioxide. The mixture was allowed to warm to ambient temperature, 3M hydrochloric acid (200 ml) was added and the tetrahydrofuran was removed in vacuo. The resulting solid was collected by filtration and crystallised from acetonitrile to give 3-methoxy-2-pivalamidobenzoic acid (21 g; 63%) as a solid, m.pt. 117-120° C. Concentration of the liquor yielded a second crop (2.6 g; 8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)([OH:14])[C:6]=2[CH:21]=1.[H-].[Na+].[CH3:24]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]([O:14][CH3:24])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1
Reactant: CI
Reactant: CC1(C)COc2ccc(Br)cc2C(O)(c2ccccn2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccccn2)CC(C)(C)COc2ccc(Br)cc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 7-bromo-3,3-dimethyl-5-(2-pyridyl)-benzoxepin-5-ol (5 g, 0.014 mol) in anhydrous DMF (50 ml) is added dropwise to a suspension of sodium hydride (50% dispersed in oil, 0.8 g, 0.0168 mol) in anhydrous DMF (25 ml), the temperature rises to 88° C., stirring is continued for 1 hour and the reaction mixture is maintained at 80° C. A solution of methyl iodide (1.9 g, 0.014 mol) in anhydrous DMF (10 ml) is then added dropwise at 25° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:40]O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[NH:25][C:24]2[C:26]([CH3:33])=[C:27]([C:29]([O:31][CH3:32])=[O:30])[S:28][C:23]=2[C:22]=1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C(Br)(Br)(Br)[Br:68]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:40][Br:68])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[NH:25][C:24]2[C:26]([CH3:33])=[C:27]([C:29]([O:31][CH3:32])=[O:30])[S:28][C:23]=2[C:22]=1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccccc3OC[C@@H](CO)NC(=O)OCc3ccccc3)[nH]c2c1C
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccccc3OC[C@@H](CBr)NC(=O)OCc3ccccc3)[nH]c2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Methyl 5-{2-[((2R)-2-{[(benzyloxy)carbonyl]amino}-3-hydroxypropyl)oxy]phenyl}-6-cyclohexyl-3-methyl-4H-thieno[3,2-b]pyrrole-2-carboxylate and triphenylphosphine (2.27 eq.) were dissolved in DCM (0.02M) and K2CO3 (4.31 eq.) was added. To the stirred mixture CBr4 (2.22 eq.) was added and the yellowish reaction mixture was left stirring at RT for 3 h. All volatiles were evaporated i. vac. and the residual material was subjected to chromatography (PE:EtOAc, 8.5:1.5). The product was obtained as a yellowish sticky solid (86%). MS (ES+) m/z 639, 641 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Li+].[CH3:33]C([N-]C(C)C)C.CI>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)([CH3:33])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a mixture of tert-butyl 4-(5-(1-(4-fluorophenyl)-2-methoxy-2-oxoethyl)pyrimidin-2-yl)piperazine-1-carboxylate (1.0 g, 2.33 mmol) in THF (20 mL) at −78° C. was added LDA (2 M, 2.33 mL, 4.65 mmol) dropwise, After stirred at −78° C. for 30 min, CH3I (0.66 g, 4.65 mmol) was added. After stirred at RT for another 1 h, the reaction was quenched by water and extracted with EA. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was passed a column (silica gel, PE:EA=6:1) to afford the title compound (0.8 g, 77%) as a yellow solid. MS (ES+) C23H29FN4O4 requires: 444. found: 445 [M+H]+.
Reaction SMILES: NC1C=C(CNC(C2NC(=O)C3C(=CC=C(C#N)C=3)N=2)=O)C=CC=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH2:32][NH:33][C:34]([C:36]2[NH:37][C:38](=[O:46])[C:39]3[C:44]([CH3:45])=[CH:43][S:42][C:40]=3[N:41]=2)=[O:35])[CH:29]=[CH:30][CH:31]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCC(O)=O)=N2)C=CC=CC=1.[C:76]1([C:82]([C:97]2[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=2)([C:91]2[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=2)[N:83]2[CH:87]=[N:86][C:85]([C:88](O)=[O:89])=[N:84]2)[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1>>[CH3:45][C:44]1[C:39]2[C:38](=[O:46])[NH:37][C:36]([C:34]([NH:33][CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:88]([C:85]4[N:86]=[CH:87][N:83]([C:82]([C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=5)([C:91]5[CH:92]=[CH:93][CH:94]=[CH:95][CH:96]=5)[C:97]5[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=5)[N:84]=4)=[O:89])[CH:27]=3)=[O:35])=[N:41][C:40]=2[S:42][CH:43]=1
Reactant: Cc1csc2nc(C(=O)NCc3cccc(N)c3)[nH]c(=O)c12
Reactant: O=C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: N#Cc1ccc2nc(C(=O)NCc3cccc(N)c3)[nH]c(=O)c2c1
Agent: O=C(O)CCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: Cc1csc2nc(C(=O)NCc3cccc(NC(=O)c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Step 1 of Example 32, and using, instead of N-[(3-aminophenyl)methyl]-6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxamide, N-[(3-aminophenyl)methyl]-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxamide obtained in Reference Example 48 and using, instead of 3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoic acid, 1-(triphenylmethyl)-1H-1,2,4-triazole-3-carboxylic acid obtained in Reference Example 35, 5-methyl-4-oxo-N-{[3-({[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]carbonyl}amino)phenyl]methyl}-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxamide was obtained as a white powder (575 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[NH:10]1[CH2:18][CH2:17][CH:13]([C:14]([NH2:16])=O)[CH2:12][CH2:11]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:10]1[CH2:18][CH2:17][CH:13]([C:14]#[N:16])[CH2:12][CH2:11]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: NC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: N#CC1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 33 %

Procedure:
General procedure C was followed using 3,4,5-trichloropyridine (0.50 g, 2.7 mmol), isonipecotamide (0.30 mg, 2.7 mmol), NMP (15 mL) and triethylamine (0.76 mL, 5.5 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 99:1) to furnish the title compound as a white solid (228 mg, 33%), m/z (ESI) C11H12Cl2N3 requires 256.0403 found [M+H]+ 256.0409.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]=[C:4]([S:15][CH3:16])[N:3]=1.O.[NH2:18][NH2:19]>CO>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([NH:18][NH2:19])[N:5]=[C:4]([S:15][CH3:16])[N:3]=1
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(Cl)n1
Reactant: NN
Solvent: O
Solvent: CO
Product: CSc1nc(Cl)c(-c2ccccc2)c(NN)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a cold (ice bath) stirred solution of 25 g (0.09 mole) of 4,6-dichloro-2-methylthio-5-phenylpyrimidine in 250 ml of methanol was added slowly 10 g (0.2 mole) of hydrazine hydrate. After one hour the mixture was allowed to warm to about 20° C., and was then stirred at 20° C. for about 16 hours. The precipitate was separated by filtration to provide 4-chloro-6-hydrazino-2-methylthio-5-phenylpyrimidine. Recrystallization twice from hexanes/cyclohexane provided white crystals, m.p. 134°-135° C. Analysis: Calculated for C11H11ClN4S: %C, 49.5; %H, 4.15; % N, 21.0; Found: %C, 49.4; %H, 4.0; %N, 20.9.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]([F:33])([F:32])[C:16]1[CH:17]=[C:18]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:29]2[CH2:28][CH2:27][N:26]([C:18]3[CH:17]=[C:16]([C:15]([F:33])([F:32])[F:14])[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=3)[CH2:31][CH2:30]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)c1cc(N2CCNCC2)cc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-[3,5-di(trifluoromethyl)phenyl]piperazine and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)sulfonyl]-4-[3,5-di(trifluoromethyl)phenyl]piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: COC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Yield: 82 %

Procedure:
9-(2,5-Dichlorobenzyl)-9H-β-carboline-3-carboxylic acid was prepared as described for the corresponding 9-unsubstituted compound (Hagen et al., Heterocycles 1986, 24:2845). A mixture of methyl 9-(2,5-dichlorobenzyl)-9H-β-carboline-3-carboxylate (15.0 g, 0.0389 mol), sodium hydroxide (2.0 g, 0.05 mol), water (75 mL), and 95% ethanol (200 mL) was refluxed for 1 hour. The mixture was concentrated in vacuo, and the residue dissolved in warm water (500 mL), and the pH adjusted to 3 using dilute HCl with vigorous stirring, resulting in the precipitation of a solid. The fine slurry was filtered, washed thoroughly with water, and dried in vacuo overnight at 70° C., and for another day at 85° C., affording 12.60 g (87%) of product. In another run, the product was isolated in 82% yield after recrystallization from hot acetic acid. The product had the following properties: 1H NMR (300 MHz, DMSO-d6) δ9.16 (s, 1H), 9.08 (s, 1H), 8.59 (d, J=8.0, 1H), 7.60-7.69 (m, 3H), 7.39-7.44 (m, 2H), 6.705 (d, J=2.3, 1H), 5.93 (s, 2H), 1.93 (s, 3H); LRMS calcd for C19H10Cl2N2O2 (M+H) 371, found 371.0.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:7]([N:4]1[CH2:5][CH2:6][CH:2]([N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[C:3]1=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C(Br)CCN1Cc1ccccc1
Reactant: COc1ccc(C2CCNCC2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCN(C3CCN(Cc4ccccc4)C3=O)CC2)cc1
Yield: 75.3 %

Procedure:
A solution of 3-bromo-1-benzyl-pyrrolidin-2-one (1.4 g, 5.1 mmol)(intermediate 3), 4-(4-methoxyphenyl)-piperidine (0.98 g, 5.1 mmol) and DIPEA (3.6 mL, 20.6 mmol) in acetonitrile (15 mL) was heated at 90° C. for 18 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (150 mL), washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated to yield 2.1 g of crude product, which was purified by flash chromatography on silica gel (24 g) using 100% EtOAc to yield 1-benzyl-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one (1.4 g, 71%). 1H NMR: 400 MHz, DMSO-d6: δ ppm 1.51-1.65 (m, 2H) 1.66-1.77 (m, 2H) 1.86-1.98 (m, 1H) 2.02-2.12 (m, 1H) 2.27-2.45 (m, 2H) 2.66-2.83 (m, 2H) 2.99-3.23 (m, 3H) 3.45-3.54 (m, 1H) 3.72 (s, 3H) 4.29-4.46 (m, 2H) 6.85 (d, J=9.04 Hz, 2H) 7.16 (d, J=9.04 Hz, 2H) 7.19-7.24 (m, 2H) 7.28 (s, 1H) 7.32-7.39 (m, 2H). LCMS: R.T. 1.76 min. LCMS (ES-API), 365.2 m/z (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([SH:14])=[N:12][N:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].[Cl-].[Na+]>CN(C)C=O>[O:24]([C:22]([NH:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([SH:14])=[N:12][N:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1)=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cccc(-n2nnnc2S)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-n2nnnc2S)c1)Oc1ccccc1
Yield: 92.8 %

Procedure:
After dissolving 391 g of 1-(3-aminophenyl)- 5-mercaptotetrazole hydrochloride in 800 ml of N,N-dimethylformamide in a nitrogen gas atmosphere, the mixture was cooled to a temperature below 0° C. After adding thereto 302 ml of pyridine, 294 g of phenyl chloroformate were added dropwise to the s-lution while cooling with stirring so that the liquid temperature was not over 0° C. After further stirring the mixture for one hour at a temperature below 0° C., the reaction mixture was added dropwise to 5 liters of a saturated aqueous sodium chloride solution followed by stirring for 30 minutes. Crystals formed were collected by filtration and washed with 2 liters of water to provide 495 g of the desired compound with a yield of 93%.