Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[N:14][C:15]([C:17](=[N:19]O)[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:5][CH:4]=1.[Cl-].[NH4+]>CO.CC(O)=O.[Zn]>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[N:14][C:15]([CH:17]([NH2:19])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cnc3cc(C(C)=NO)ncc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(Cn2cnc3cc(C(C)N)ncc32)cc1
Temperature: 60 °C
Yield: 65.6 %

Procedure:
A mixture of 1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethanone oxime (320 mg, 1.08 mmol), zinc (3.53 g, 54.00 mmol), and ammonium chloride (2.89 g, 54.00 mmol) in MeOH (10 mL) and HOAc (2 mL) was heated at 60° C. for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added an aqueous solution of ammonia (50 mL) and the resulting mixture was extracted with DCM (50 mL×3). The combined extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with CH2Cl2:MeOH:Et3N (10:1:0.2) to afford 200 mg (66%) of 1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethanamine as a colorless oil. MS (ESI): m/z=283.2[M+1]+.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:9]=1.[Cl-:22].[NH4+:23]>CO>[ClH:22].[NH:23]=[C:3]1[NH:9][CH:8]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: COC(=O)c1ccccc1CCC1CCCCC(OC)=N1
Reactant: [Cl-]
Solvent: CO
Product: COC(=O)c1ccccc1CCC1CCCCC(=N)N1
Product: Cl

Procedure:
The title product of Example 83 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([N:29]([CH2:32][CH3:33])[CH2:30]C)[CH3:28].ClC(OC1C=CC=CC=1)=[O:36].C(NCC)C>O1CCCC1>[C:1]1([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:30]([N:29]([CH2:32][CH3:33])[CH2:27][CH3:28])=[O:36])[CH:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(Nc2ccc3c(ccn3C(=O)Nc3ccccc3)c2)ccn1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCN(CC)C(=O)Nc1cc(Nc2ccc3c(ccn3C(=O)Nc3ccccc3)c2)ccn1
Yield: 2.5 %

Procedure:
5-(2-Aminopyridin-4-ylamino)indole-1-carboxylic acid phenylamide (69 mg, 0.20 mmol) was dissolved in tetrahydrofuran (14 ml); triethylamine (0.055 ml, 0.40 mmol) was added thereto; and phenyl chloroformate (0.038 ml, 0.30 mmol) was added thereto while cooling with ice and stirring. A portion of 7.0 ml of the reaction mixture was transferred to another vessel and concentrated under reduced pressure. After the residue was dissolved in N,N-dimethylformamide (1.0 ml), the similar reaction to Example 27 was performed by use of diethylamine (0.031 ml, 0.30 mmol). The obtained crude product was purified by TLC plate (Fuji Silysia NH, developing solvent: ethyl acetate) to yield the title compound (2.0 mg, 0.005 mmol) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:13](=O)[O:12][C:10](=O)[C:9]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:8]23)=[CH:4][CH:3]=1.I.CSC(=N)[NH:25][CH2:26][CH:27]=[CH2:28].C(=O)([O-])[O-].[Na+].[Na+].C(#[N:38])C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:8]3[C:9](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10](=[O:12])[N:38]=[C:13]2[NH:25][CH2:26][CH:27]=[CH2:28])=[CH:19][CH:20]=1
Reactant: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Reactant: CC#N
Reactant: C=CCNC(=N)SC
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=CCNc1nc(=O)c2ccccc2n1Cc1ccc(F)cc1

Procedure:
A suspension of 13.5 g. of N-(4'-fluorobenzyl)isatoic anhydride, 130 g. of S-methyl-N-allylthiopseudourea hydroiodide and 75 g. of powdered sodium carbonate in 500 ml. of acetonitrile is heated with stirring at reflux for 1.5 hours. The excess sodium carbonate is filtered off and the solvent evaporated to dryness. The residue is dissolved in methylene chloride, filtered to remove insolubles and the filtrate evaporated to dryness. The residue is dissolved in 500 ml. of diglyme and the resulting solution heated at reflux for 1.5 hours. After cooling, methylene chloride is added to obtain a precipitate which is recovered by filtering, washed twice with methylene chloride and once with ether, dried, dissolved in methanol, filtered and concentrated on a steam bath to obtain a precipitate which is recovered by filtering, washed with methanol and dried under reduced pressure to obtain 1-(4'-fluorobenzyl)-2-allylamino-quinazolin-4(1H)-one, m.p. 155°-157°C. (additional quantities of the title compound are recovered from the mother liquid).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:5][C:6]2[C:11]([CH2:12][CH:13]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[N:14]=[C:15]=S)[CH3:2].[N:17]([CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:22])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH2:5][C:6]2[C:7]([NH:14][C:15]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=4)=[CH:20][N:17]=3)=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:12][CH:13]=1)[CH3:2]
Reactant: CCOC1=CCc2cccc(N=C=S)c2C1
Reactant: [N-]=[N+]=NCC(=O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Temperature: 25 °C
Yield: 21.8 %

Procedure:
A solution of the product of Example 1F (398 mg, 1.72 mmol), the product of Example 1G (473 mg, 2.07 mmol), and triphenyl phosphine (542 mg, 2.07 mmol) in dioxane (9 mL) was heated at 85° C. for 30 min. The solution was cooled to room temperature and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with 25% ethyl acetate-hexane to afford the title compound as a yellow solid (150 mg, 22%). 1H NMR (DMSO-d6) δ 9.38 (s, 1H), 7.76 (m, 4H), 7.65 (d, 1H, J=8.5 Hz), 7.62 (s, 1H), 7.18 (t, 1H, J=8.2 Hz), 6.97 (d, 1H, J=8.4 Hz), 4.85 (m, 1H), 3.79 (q, 2H, J=6.7 Hz), 3.49 (m, 2H), 3.36 (m, 2H), 1.26 (t, 3H, J=6.8 Hz); MS (ESI+) m/z 401 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15](O)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.3 %

Procedure:
To a solution of 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)-methyl]-2-pyridinecarboxylic acid (81 mg) in dichloromethane (2 ml) and tetrahydrofuran (2 ml) was added benzenesulphonamide (50 mg), 4-dimethyl-aminopyridine (3.5 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (61 mg) and the mixture stirred at ambient temperature for 5 hours. Solvent was removed in vacuo and water (5 ml) added. The mixture was extracted with ether (2×5 ml) and the combined extracts dried (MgSO4) and concentrated in vacuo. The residue was purified by mass-directed autopreparation to afford the title compound (46 mg, 42%) as a white solid. LC/MS [MH+]=545/547, Rt=3.89 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-2-methylpropanoate (6 g, 29 mmol), KOH (3 g, 57 mmol) and 100 mL EtOH/H2O (4:1) was refluxed for 4 hours. The mixture was cooled to room temperature. The mixture was extracted with EtOAc and the organic layer discarded. The water layer was acidified with concentrated HCl, extracted with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 3.1 g of the product as a white solid. MS m/e=211 (M−1)−.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([N+]([O-])=O)[C:10]([F:17])=[CH:9][N:8]=1.[OH-:18].[Na+]>ClCCl>[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([Cl:3])[C:10]([F:17])=[CH:9][N+:8]=1[O-:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ncc(F)c([N+](=O)[O-])c1C
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Cl)c(F)c[n+]([O-])c1C

Procedure:
Phosphoryl chloride (8.6 ml) in dichloromethane (50 ml) was added to a stirred solution of 2,3-dimethyl-4-nitro-5-fluoropyridine (5.8 g) in dichloromethane (100 ml). The reaction mixture was heated under reflux for 4 hours. After cooling and pouring onto ice, the mixture was basified (NaOH) to pH 12 and extracted with dichloromethane. After drying (K2CO3) and removal of solvent, the crude product was purified by column chromatography (silica gel, 2%MeOH/CHCl3) to give 2,3-dimethyl-4-chloro-5-fluoropyridine-N-oxide (4.11 g) m.p. 137°-39°.
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].Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.O>[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH:6][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C[C@H](NC(=O)c1ccncc1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of L-aspartic acid dimethyl ester hydrochloride (2.0 g, 10 mmol) in chloroform (100 mL) was added isonicotinoyl chloride hydrochloride (1.8 g, 10 mmol) and triethylamine (3.0 mL, 21.5 mmol). The reaction mixture was refluxed for 2 h, and then stirred at room temperature for 24 h. The solution was filtered and the filtrate was evaporated to give a whitish oil. This residue was dissolved in 20 mL H2O, and was then extracted with ethyl acetate (2×100 mL). The organic phases were combined, washed with H2O (50 mL), and dried over Na2SO4. Removal of ethyl acetate gave a whitish oil, isonicotinoyl aspartic acid dimethyl ester. Electrospray MS: m/z=267 (M+1, [C12H14N2O5]+) 1H NMR (CDCl3): 2.91-3.17 (m, 2H, CH2), 3.69 (s, 3H, COOCH3), 3.78 (s, 3H, COOCH3), 4.99-5.05 (m, 1H, CH), 7.38-7.41 (d, 1H, NH), 7.62-7.65 (m, 2H, py), 7.82-7.84 (m, 2H, py).
Reaction SMILES: C(OC([N:7]1[C@H:11](/[CH:12]=[CH:13]\[C:14]2[N:15]3[CH:21]=[N:20][CH:19]=[C:16]3[S:17][CH:18]=2)[CH2:10][C@H:9]([S:22][C:23]2[C@H:24]([CH3:40])[C@@H:25]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:26]3[C:27]=2[C:28]([O:30]CC=C)=[O:29])[CH2:8]1)=O)C=C.CNC1C=CC=CC=1>ClCCl.CN(C=O)C.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>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:26]2[C:27]([C:28]([OH:30])=[O:29])=[C:23]([S:22][C@H:9]3[CH2:10][C@@H:11](/[CH:12]=[CH:13]\[C:14]4[N:15]5[CH:21]=[N:20][CH:19]=[C:16]5[S:17][CH:18]=4)[NH:7][CH2:8]3)[C@H:24]([CH3:40])[C@H:25]12)[CH3:37]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](/C=C\c3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CNc1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](/C=C\c4csc5cncn45)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
Allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[2 (Z)-(imidazo[5,1-b]thiazol-3-yl)ethenyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (80 mg) is dissolved in 1 ml of dichloromethane and 1 ml of DMF. N-Methylaniline (0.060 ml) and 40 mg of tetrakis(triphenylphosphine)palladium(0) are added thereto, and the mixture is stirred in an argon atmosphere at room temperature for 30 min. The reaction mixture is concentrated under reduced pressure. Ethyl acetate is added to the concentrate, and the resultant precipitate is collected by filtration and then purified by column chromatography on Cosmosil 40C18-PREP and Amberlyst A-26 (Cl− form) to give 11.9 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([C:31](=[O:33])[NH2:32])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]S(C(F)(F)[F:39])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([F:39])=[C:17]([C:31](=[O:33])[NH2:32])[N:18]3[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2cc(C(N)=O)n3Cc2ccc(F)cc2)CC1
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2c(F)c(C(N)=O)n3Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
4-[2-Carbamoyl-1-(4-fluoro-benzyl)-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.0155 gm, 0.034 mmol) was dissolved in dichloromethane and 1-fluoro-2,4,6-trimethylpyridinium triflate (85%, 0.012 gm, 0.035 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was transferred onto two preparative thin layer chromatography plates and eluted with 1/1 ethyl acetate/hexane, then further purified on two analytical thin layer chromatography plates (1/1 ethyl acetate/hexane), and then additionally purified on two more analytical plates (35/65 ethyl acetate/hexane) to give 4-[2-carbamoyl-3-fluoro-1-(4-fluoro-benzyl)-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.009 gm, 56% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[N+:7]([O-:9])=[O:8].[CH3:10][C@H:11]1[CH2:13][O:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1[N:6]([CH2:10][C@@H:11]([OH:12])[CH3:13])[N:5]=[CH:4][C:3]=1[N+:7]([O-:9])=[O:8]
Reactant: C[C@H]1CO1
Reactant: Cc1[nH]ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1c([N+](=O)[O-])cnn1C[C@H](C)O
Temperature: 30 °C
Reaction time: 168 h
Yield: 9 %

Procedure:
To a solution of 5-methyl-4-nitro-1H-pyrazole (2.5 g, 19.7 mmol) in acetonitrile (100 mL) was added (S)-2-methyloxirane (1.37 g, 23.6 mmol) and cesium carbonate (19.3 g, 59.1 mmol). The mixture was stirred at 30° C. for 7 days, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC and then chiral-HPLC to give (S)-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol (0.33 g) as a yellowish solid. MS (ES+) C7H11N3O3 requires: 185, found: 186 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16].[CH3:22][O:23][CH:24]=O.S(OC)(OC)(=O)=O>CN(C=O)C.O>[OH:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[C:14](=[CH:22]\[O:23][CH3:24])/[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)Cc1ccccc1Oc1cccc(O)c1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(O)c1
Reaction time: 0.75 h

Procedure:
To a suspension of sodium hydride (0.558 g, 0.023 moles in DMF (20 ml) was added dropwise a solution of methyl 2-(3-hydroxyphenoxy)phenylacetate (D) (2.0 g; 0.0077 mol) in DMF (10 ml) and methylformate (10 g; 0.167 mol) After stirring for 45 minutes, water (100 mls) was added and the mixture was extracted with ether (50 mls). The aqueous layer was acidified with hydrochloric acid to pH 3-4 and the mixture was extracted with ether (2×40 mls). The combined ether extracts were washed with water (3×30 mls) and saturated brine (1×30 ml), and then dried. The ether was evaporated off and the residue was dissolved in DMF (20 ml), and anhydrous potassium carbonate. (0.64 g; 0.0046 moles) and dimethyl sulphate (0.55 g; 0.0044 moles) was added. The mixture was stirred at ambient temperature for 1 hour, then water (100 ml) was added, and the mixture was extracted with ether (2×40 ml). The combined ether extracts were washed with water (3×20 ml) and saturated brine (20 ml), dried, filtered, evaporate to dryness, then chromatographed using a mixture of ether and hexane as eluant to give (E)-methyl 2-[2-(3-hydroxyphenoxy)phenyl]-3-methoxypropenoate (E) as an amber gum which, on trituration with a mixture of hexane and dichloromethane, gave a white solid, [0.7 g, 30% yield from methyl 2-(3-hydroxyphenoxy)phenylacetate (D)] m.p. 115°-116° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1([CH2:18][CH3:19])[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:7][C:6]1=O.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28]N>>[CH2:18]([C:5]1([CH2:4][C:3]([OH:2])=[O:20])[C:6]2[NH:28][C:23]3[C:24](=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[C:7]=2[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:9][CH2:10]1)[CH3:19]
Reactant: C=CCCCCC1CCC(CC)(CC(=O)OC)C(=O)C1
Reactant: Cc1ccccc1NN
Product: C=CCCCCC1CCC(CC)(CC(=O)O)c2[nH]c3c(C)cccc3c21

Procedure:
The title compound was prepared from 1-ethyl-4-(5-hexenyl)-2-oxocyclohexaneacetic acid methyl ester (isomer B) and 2-methylphenylhydrazine as described in Example 1, m.p. 111°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].C=O.[C:12]([BH3-])#N.[Na+]>CO>[CH3:12][N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1CCCN1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCN1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl pyrrolidine-2-carboxylate 10b crude product (5 g) was dissolved in 100 mL of methanol. The solution was cooled to 0˜5° C. in an ice-water bath, followed by addition of 13 mL of 40% formaldehyde. The reaction mixture was warmed up to room temperature and stirred for 2 hours, then cooled to 0˜5° C. in an ice-water bath, and sodium cyanoborohydride (5.45 g, 87.20 mmol) was added in batches. The reaction mixture was warmed up to room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure and added with 5 mL of water, extracted with dichloromethane (5 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain methyl 1-methylpyrrolidine-2-carboxylate 10c (4.7 g, yield 70.1) crude product as a brown oil.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C.[CH2:54]([C:56]1[S:67][C:59]2=[N:60][C:61]([CH:65]=O)=[CH:62][C:63](=[O:64])[N:58]2[N:57]=1)[CH3:55].C(N1C(C)=C(C=O)C(C)=N1)C>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:65][C:61]3[N:60]=[C:59]4[S:67][C:56]([CH2:54][CH3:55])=[N:57][N:58]4[C:63](=[O:64])[CH:62]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn2c(=O)cc(C=O)nc2s1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: CCn1nc(C)c(C=O)c1C
Product: CCc1nn2c(=O)cc(CC3=C(O)CC(CCc4ccc(C(C)(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nc2s1

Procedure:
The title compound was prepared on a 0.5-mmol scale analogously to example B(19): except using 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile from step 3 of example A(84) in place of 6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 2-ethyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-7-carbaldehyde from step 2 below in place of 1-ethyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde. Yield: 10 mg (4%). 1H NMR (300 MHz, DMSO-d6): δ 1.29 (t, 3H), 1.35–1.7 (s, m overlap, 14H), 1.99 (m, 2H), 2.38 (m, 1H), 2.63 (m, overlap, 3H), 2.75 (d, 1H), 3.03 (q, 2H), 3.48 (ABq, 2H), 6.06 (s, 1H), 7.10 (m, overlap, 2H), 7.35 (m, 1H), 10.98 (s, 1H). LC-MS (APCI) calcd for C30H33FN2O3S: 564.22, found (M+H+): 565.2 m/z.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH3:18][O:19][CH2:20][CH2:21][NH2:22].CCN(C(C)C)C(C)C>CC#N>[F:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:2]([NH:22][CH2:21][CH2:20][O:19][CH3:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCNc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
A mixture of 2-(2-chloro-6-fluoro-3-nitrophenyl)pyridine* (618 mg, 2.6 mmol), 2-methoxyethylamine (0.23 mL, 2.6 mmol) and DIPEA (0.48 mL, 2.7 mmol) in MeCN (5 mL) was stirred for 1.5 h at 0° C. After warming to RT, the volatiles were removed in vacuo. The resulting residue was purified by column chromatography (Si—PPC, gradient 0-70% EtOAc/cyclohexane) to afford the title compound as a yellow oil (414 mg, 54%). LCMS (Method C): RT 2.95 min [M+H]+ 292. 1H NMR (CDCl3, 400 MHz): δ 8.73 (1H, ddd, J=5.0, 2.0, 1.0 Hz), 8.47 (1H, bs), 8.26 (1H, dd, J=9.5, 6.0 Hz), 7.79 (1H, ddd, 8.0, 8.0, 2.0 Hz), 7.45-7.43 (1H, m), 7.32 (1H, ddd, J=7.5, 5.0, 1.0 Hz), 6.52 (1H, dd, 9.5, 8.0 Hz), 3.29-3.26 (2H, m), 3.28 (3H, s), 2.63-2.60 (2H, m)
Reaction SMILES: [CH3:1][NH:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:6][CH3:7])[CH2:4][OH:5].[Li]CCCC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25].C(O)(=O)C>C1COCC1>[CH3:7][CH2:6][C:3]([NH:2][CH3:1])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][O:5][C:24]([C:23]1[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:21]([O:20][CH3:19])[CH:22]=1)=[O:25]
Reactant: CCC(CO)(NC)c1ccccc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(NC)c1ccccc1
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
To a solution of 1.84 g of 8 (10.3 mmol) in 28 mL of anhydrous THF were added dropwise, at −78° C., 4.11 mL of n-BuLi (2.5 mol/L in hexanes). After 15 minutes, a solution of 2.31 g (10.01 mmol) of 3,4,5-trimethoxybenzoyl chloride in 15.8 mL of anhydrous THF was added. The reaction mixture was then allowed to warm to −30° C. (ca 1 h) and 19 mL of acetic acid were cautiously added. Solvents were removed under vacuum and 55 mL of diethyl ether and 55 mL of water were added to the previously obtained oil. After stirring until complete dissolution, the resulting mixture was then decanted and the aqueous layer alcalinized completely with solid Na2CO3 and re-extracted with diethyl ether. The organic layers were washed twice with a saturated aqueous solution of sodium carbonate and with brine and then dried over sodium sulphate. Diethyl ether was evaporated under vacuum and the ester 9 was purified by chromatography on silica gel column (ethyl acetate/n-hexane, 7:3) to give 1.4 g of pure N-desmethyltrimebutine 9 (49% yield) as a yellow pale oil. MS(ESI), m/e 374.1 (M+).