Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=1>O.C1(C)C=CC=CC=1.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>[F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Yield: 97.8 %

Procedure:
3-Fluorophenylboronic acid (39.5 g, 0.282 mol), a solution of K2CO3 (150 g) in water (700 mL), [Bu4N]Br (3.5 g, 0.0107 mol), and Pd(PPh3)4 (12.4 g, 0.0107 mol) were added to a solution of 6-chloronicotinic acid (37.0 g, 0.235 mol) in toluene. The reaction mixture was stirred under reflux for 20 h. After cooling, the reaction mixture was filtered and acidified with 2 M HCl to pH 3. The formed precipitate was separated by filtration and dried to give 6-(3-fluorophenyl)nicotinic acid (yield 97%, 49.9 g). 1H NMR (400 MHz, DMSO-d6) □ ppm 7.29 (td, J=8.46, 2.42 Hz, 1H) 7.50-7.56 (m, 1H) 7.93 (dd, J=10.47, 2.15 Hz, 1H) 7.97 (d, J=7.79 Hz, 1H) 8.11 (d, J=8.06 Hz, 1H) 8.30 (dd, J=8.32, 2.15 Hz, 1H) 9.11 (d, J=1.88 Hz, 1H), 13.48 (bs, 1H).
Reaction SMILES: [N:1]1([C:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH:14]=O)[NH:11][C:12]=2[CH3:13])=[O:7])[CH:5]=[CH:4]N=[CH:2]1.[O:17]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28]CNCC2)[CH2:19][CH2:18]1.[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])[CH2:33]2>C1COCC1>[CH3:16][C:9]1[C:8]([C:6]([N:1]2[CH2:2][CH2:28][CH:23]([N:20]3[CH2:19][CH2:18][O:17][CH2:22][CH2:21]3)[CH2:4][CH2:5]2)=[O:7])=[C:12]([CH3:13])[NH:11][C:10]=1/[CH:14]=[C:33]1\[C:34](=[O:39])[NH:35][C:36]2[C:32]\1=[CH:31][C:30]([F:29])=[CH:38][CH:37]=2
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)n1ccnc1
Reactant: C1CC(N2CCOCC2)CCN1
Solvent: C1CCOC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)N1CCC(N2CCOCC2)CC1
Temperature: 66 °C
Reaction time: 68 h
Yield: 68.5 %

Procedure:
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (11.3 g, 51.9 mmol), 4-morpholinopiperidine (15.0 g, 88.2 mmol), 5-fluorooxindole (7.84 g, 51.9 mmol), and THF (126 ml) were mixed and heated to 66° C. After stirring for 68 h at 66° C., the mixture was cooled to room temperature and filtered. The cake was washed with 4×20 ml THF and dried overnight at 70° C. under house vacuum. (3Z)-3-({3,5-dimethyl-4-[(4-morpholin-4-ylpiperidin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-5-fluoro-1,3-dihydro-2H-indol-2-one 16.09 g was obtained in 68% yield.
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]2[NH:22][C:2]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=4[CH2:4][C:3]=3[C:18]=2[CH:17]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: Cl
Product: O=C(O)c1cccc2c1Cc1c-2[nH]c2ccc(Cl)cc12
Yield: 14.3 %

Procedure:
In a manner similar to Example 17, 1-oxo-indan-4-carboxylic acid (1.00 g, 5.68 mmol) and 4-chlorophenylhydrazine hydrochloride (1.03 g, 5.75 mmol) were converted to the title compound (0.230 g, 14%) as a pale brown solid: mp>300° C.; 1H NMR (DMSO-d6,): δ 4.00 (s, 2H), 7.10 (d of d, 1H), 7.46 (d, 1H), 7.51 (d, 1H), 7.66 (d, 1H), 7.78-7.81 (m, 2H), 11.83 (s, 1H), 13.57 (s, 1H); MS [EI, m/z]: 283 [M]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([F:10])[F:9].C([Li])CCC.CN(C)[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1.O>[F:9][CH:8]([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: FC(F)c1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccccc1C(F)F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
After dissolving 1-bromo-2-difluoromethylbenzene (3.23 g) in tetrahydrofuran (65 ml), the mixture was cooled to −78° C. After then adding n-butyllithium (2.64 M solution in hexane, 6.5 ml) and stirring for 30 minutes, N,N-dimethylformamide (2.4 ml) was added and stirring was continued for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (991 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][C:31]=1[CH2:32]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][C:31]=1[CH2:32][N:8]([C:9]1[N:10]=[CH:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)cn1
Reactant: BrCc1cc(Br)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N(Cc2cc(Br)ccc2OCc2ccccc2)C(=O)OC(C)(C)C)cn1
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of ethyl 5-(tert-butoxycarbonylamino)pyrazine-2-carboxylate (10.7 g 0.04 mol) in DMF (160 ml) at 20° C., under argon atmosphere, was added sodium hydride dispersion (50% in oil, 1.85 g, 0.04 mol) and stirred for 1 hour until effervescence ceased. Next was added 2-benzyloxy-5-bromobenzylbromide (14.3 g, 0.04 mol) and stirring continued at 20° C. under argon for 2 hours. The solvent was evaporated at reduced pressure and the residue partitioned between dichloromethane (500 ml) and water (250 ml), the organic layer was dried over magnesium sulphate and evaporated at reduced pressure to give a crude solid (21 g). Purification was by chromatography on silica, eluting with 5% ethyl acetate in dichloromethane to give ethyl 5-(N-(2-benzyloxy-5-bromobenzyl)-N-tert-butoxycarbonylamino)pyrazine-2-carboxylate as a white solid (16 g, mp 116°-7° C.).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:25]([O:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)(=[O:27])[CH3:26]>>[C:25]([O:28][CH:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[C:10]4[C:5](=[CH:6][C:7]([C@H:11]5[C@@:13]6([C:21]7[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=7)[NH:15][C:14]6=[O:24])[CH2:12]5)=[CH:8][CH:9]=4)[NH:4][N:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCC(OC(C)=O)CC5)cc4)n[nH]c3c1)C(=O)N2
Yield: 40.4 %

Procedure:
The title compound was synthesized according to the method described for example A45 except reacting a (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (76 mg, 0.18 mmol) with 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate (67 mg, 0.19 mmol). Crude product was purified by flash chromatography using EtOAc/Hexanes (2:3 to 1:0) to give the title compound as a yellow solid (38 mg, 41%). MS ESI 523.3 [M+H]+, calcd for [C31H30N4O4+H]+ 523.23.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:23]1([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][N:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][CH:28]([N:23]5[CH:27]=[CH:26][N:25]=[N:24]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1cn(C2CCNC2)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: Cc1c(F)c(N2CCC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 48.1 %

Procedure:
1-Cyclopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (30 mg, 0.1 mmol) was reacted with 35 mg (0.2 mmol) of 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride in 2 ml of dry pyridine under nitrogen in the presence of 30.4 mg (0.2 mmol) of DBU under reflux conditions. The solvent was removed under reduced pressure and to the orange viscous oil water was added and the solid was collected which was further purified from methanol to yield 20 mg of the desired product, m.p. 228°-230° C. 1H NMR (TFA) δ: 9.28 (s, 1H), 8.68 (s, 1H), 8.57 (d, 1.4Hz, 1H), 5.9-5.75 (m, 4.14 (m, 5H), 3.1-2.72 (m, 5H), 1.7-1.2 (m, 4H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[CH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][C:38]([Cl:44])=[CH:39][CH:40]=3)[N:35]=2)[CH:27]=1)[OH:25])(=[O:15])[CH3:14].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:44][C:38]1[CH:37]=[C:36]2[C:41]([CH:42]=[CH:43][C:34]([CH:33]=[CH:32][C:28]3[CH:27]=[C:26]([C@H:24]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23][CH2:22][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:13](=[O:15])[CH3:14])[CH:31]=[CH:30][CH:29]=3)=[N:35]2)=[CH:40][CH:39]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccccc1CC[C@@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccccc1CC[C@@H](OS(C)(=O)=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
At -40° C., methanesulfonyl chloride (1.25 mL, 16.2 mmol) and Et3N (2.8 mL, 20 mmol) were added successively to a solution of the hydroxyketone of Step 4 (6.157 g, 13.44 mmol) in 135 mL of CH2Cl2 and the mixture was stirred at -40° C. for 30 min., then at 0° C. for an hour. A saturated solution of NaHCO3 was added and the title mesylate was extracted into CH2CL2, dried over Na2SO4, concentrated and the remaining traces of water were co-evaporated twice with toluene. This mesylate was used as such in Step 7.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[C:5](=[O:17])[O:6][C:7]12[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:18]1([C:24]2[CH:25]=[N:26][C:27]([NH:30][C:31](=O)[O:32]C3C=CC=CC=3)=[N:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[C:5](=[O:17])[O:6][C:7]12[CH2:12][CH2:11][N:10]([C:31]([NH:30][C:27]2[N:26]=[CH:25][C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:29][N:28]=2)=[O:32])[CH2:9][CH2:8]1
Reactant: O=C(Nc1ncc(-c2ccccc2)cn1)Oc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2cccc(F)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1OC2(CCN(C(=O)Nc3ncc(-c4ccccc4)cn3)CC2)c2cccc(F)c21
Temperature: 60 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A mixture of 4-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (150 mg), phenyl N-(5-phenyl-2-pyrimidinyl)carbamate (170 mg) and triethylamine (0.24 mL) in chloroform (2 mL) was stirred at 60° C. for 3 hours. The concentration of the reaction mixture left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate/methanol=1/1/0˜8/8/1˜6/6/1) followed by recrystallization from ethyl acetate-hexane to give the subject compound(190 mg)as colorless crystals (melting point 247-249° C.).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[CH:12]=[CH:11]2)[CH:5]=[CH:4][N:3]=[CH:2]1.I.CS[C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[NH:26]>C(O)C.C(OCC)C.[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[NH:26])[CH:17]=3)[CH:12]=[CH:11]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc2ccn(CCCCn3ccnc3)c2c1
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: N=C(Nc1ccc2ccn(CCCCn3ccnc3)c2c1)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
1-(4-(1H-imidazol-1-yl)butyl)-6-nitro-1H-indole (compound 166, 145 mg, 0.510 mmol) was dissolved in anhydrous ethanol (7 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (54.2 mg, 0.051 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of (10% 2M NH3 in methanol/90% dichloromethane) shows complete conversion to compound 167, 1-(4-(1H-imidazol-1-yl)butyl)-1H-indol-6-amine, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (7 mL) and the ethanolic solution of the amine 167 is charged to a small, argon purged flask fitted with a magnetic stir bar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (189.1 mg, 0.663 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 20 hours, at which time the solution was diluted with diethyl ether (100 ml) resulting in the formation of a sticky solid which could not be isolated via filtration. As a result the product was washed off the funnel with methanol, combined with the filtrate and solvents evaporated to leave a crude residue. The residue was partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated and the residue purified via chromatography on silica gel (2.5% 2M NH3 in methanol/97.5% dichloromethane) to yield yellow solid, compound 168 (101 mg, 54.5% yield); 1H-NMR (DMSO-d6) δ 7.74 (d, 1H, J=3.0), 7.60 (d, 1H, J=5.2), 7.56 (s, 1H), 7.45 (d, 1H, J=8.3), 7.21 (d, 1H, J=3.0), 7.13-7.06 (m, 2H), 6.92 (s, 1H), 6.85 (s, 1H), 6.59 (d, 1H, J=8.0), 6.42-6.30 (br, 2×m, 3H), 4.17-4.06 (m, 2H), 3.99-3.92 (m, 2H), 1.75-1.58 (m, 4H); MS (ESI+): 364 (M+1, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[S:10][C:9]=2[CH:21]=O)=[CH:4][CH:3]=1.Cl.[O:24]([NH2:26])[CH3:25]>>[CH3:25][O:24][N:26]=[CH:21][C:9]1[S:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[C:12]([CH3:13])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: Cc1c(-c2ccc(O)cc2)sc(C=O)c1-c1ccc(O)cc1
Reactant: CON
Agent: Cl
Product: CON=Cc1sc(-c2ccc(O)cc2)c(C)c1-c1ccc(O)cc1
Yield: 62.1 %

Procedure:
Starting from 3,5-bis(4-hydroxyphenyl)-4-methylthiophene-2-carbaldehyde (0.86 g, 2.8 mmol) in place of 3-(3-methoxyphenyl)-5-(4-methoxyphenyl)-4-methylthiophene-2-carbaldehyde and methoxylamine hydrochloride (0.25 g, 3.0 mmol) in place of hydroxylamine hydrochloride, the title compound (0.59 g, 62%, m.p. 219-25° C.) was synthesized in essentially the same manner as described in Example 16, Step 1. Contains 6% E form as determined by NOE.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([OH:13])=[C:7]([CH2:14][C:15]([CH3:17])=[CH2:16])[C:6]=1[CH3:18])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]2[O:13][C:15]([CH2:17][OH:27])([CH3:16])[CH2:14][C:7]=2[C:6]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: C=C(C)Cc1c(C)c(OC(C)=O)c(C)c(C)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)(CO)O2
Reaction time: 1 h
Yield: 87.3 %

Procedure:
In methylene chloride (100 ml) was dissolved 4-acetoxy-2-(2-methyl-2-propenyl)-3,5,6-trimethylphenol [30 g (40.3 mmol)]. To the solution was added at 0° C., in limited amounts, m-chloroperbenzoic acid [16.7 g (67.8 mmol)]. The reaction mixture was stirred for one hour, and there was added triethylamine (30 ml), followed by stirring for further one hour. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, and then dried, followed by distilling off the solvent. The residue was crystallized from isopropyl ether-hexane to obtain the desired 5-acetoxy-2-hydroxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran [9.3 g (yield 87.4%, m.p. 98°-99° C.)].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][S:23][CH3:24])[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]CC)=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][S:23][CH3:24])[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)CC1CCC(N(CCSC)C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSCCN(C(=O)OC(C)(C)C)C1CCC(CC(=O)O)CC1
Reaction time: 3.75 h

Procedure:
To a solution of ethyl 2-[4-[tert-butoxycarbonyl(2-methylsulfanylethyl)amino]cyclohexyl]acetate (2.11 g, 5.89 mmol) in methanol (10 mL) and THF (10 mL) was added NaOH (10 mL, 1M aqueous). The resulting solution was stirred for 3.75 hours then acidified with HCl (2M, aqueous to pH 2). The mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by silica chromatography (25 g silica; eluted with 20-60% ethyl acetate in hexanes) to give the title compound as a 6.9:1 mixture of trans to cis isomers.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][CH2:65][NH:64][C:63]2=[O:67])[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[CH:18][C@:19]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][CH2:65][NH:64][C:63]4=[O:67])[CH2:45]3)([CH3:42])[C@H:20]12)[CH3:39]
Reactant: O=C1NCCC1[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C[C@@](C)(S[C@H]3C[C@@H](C4CCNC4=O)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H]12
Yield: 75.6 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (180 mg, 0.30 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-3-yl)pyrrolidine (110 mg, 0.30 mmol) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (161 mg, yield: 74.9%).
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=3)[NH:18][CH:17]=2)[CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].O.NN>CO.O.[Ni]>[NH2:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:13]1[CH2:14][CH2:15][CH:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[CH2:12]1
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(N)cc23)C1
Yield: 97.1 %

Procedure:
To a solution of tert-butyl ethyl(3-(5-nitro-1H-indol-3-yl)cyclopentyl)carbamate (1.40, g 3.75 mmol) in dry MeOH (15 mL) was added Raney-Ni (0.1 g as a slurry in water) and hydrazine hydrate (1.9 mL, 37.5 mmol). The resulting mixture was immersed in a preheated oil bath and refluxed for 15 min. until the solution became clear. The reaction was cooled and filtered trough celite, washed with MeOH (20 mL) and the solvent evaporated. The crude was purified on column chromatography (2% 2N NH3 in MeOH: 98% CH2Cl2) to give the title compound as a brownish solid (1.25 g, quantitative). 1H-NMR (CDCl3) δ 1.11-1.19 (m, 6H), 1.49 (s, 18H), 1.67-1.89 (m, 6H), 1.96-2.12 (m, 4H), 2.13-2.22 (m, 2H), 2.26-2.35 (m, 2H), 3.10-3.28 (m, 4H), 3.37-3.58 (m, 4H), 4.44-4.59 (m, 2H), 6.64 (dd, 1H, J=1.8, 9.0 Hz), 6.67 (dd, 1H, J=2.1, 8.4 Hz), 6.91 (d, 1H, J=2.4 Hz), 6.92 (d, 1H, J=2.1 Hz), 7.14 (d, 1H, J=2.1 Hz), 7.17 (d, 1H, J=2.1 Hz), 7.73 (brs, 2H, NH); E1-MS (m/z, %) 343 (M+, 100).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH3:15][O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2C(O)=O)[CH2:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CN([CH:54]=[O:55])C>>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:54](=[O:55])[C:31]2[CH:30]=[CH:26][C:25]([N:22]3[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][O:16][CH3:15])[CH2:24][CH2:23]3)=[CH:33][CH:32]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: CN(C)C=O
Reactant: COCCN1CCN(c2ccccc2C(=O)O)CC1
Reactant: N#CCNC(=O)C1(N)CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: COCCN1CCN(c2ccc(C(=O)NC3(C(=O)NCC#N)CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (1.0 mmol), [4-(2-methoxy-ethyl)-piperazin-1-yl]-benzoic acid hydrochloride (1.0 mmol), HOBT (1.0 mmol), WSCD (1.0 mmol) and triethylamine (1.0 mmol) are dissolved in DMF (4 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH=92.5:7.5 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale powder with mp. 166-168° C., Rf=0.37 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C1(C)C=CC=CC=1>[CH3:8][N:9]([CH2:10][CH2:11][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN(CCN1CCOCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-[methyl-(4-nitro-phenyl)-amino]-ethyl ester TFA salt (74 mg, 0.21 mmol) in toluene (1 mL) is added triethylamine (50 μL) and morpholine (55 μL, 0.63 mmol). The mixture is shaken in 70° C. block shaker overnight. The reaction mixture is concentrated and purified by reverse phase high performance liquid chromatography to give methyl-(2-morpholin-4-yl-ethyl)-(4-nitro-phenyl)-amine as a di-TFA salt (80 mg, 77%).