Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:18])[N:11]2[C:16]=1[C:15](=[O:17])[NH:14][CH:13]=[N:12]2.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:18][C:10]1[N:11]2[C:16]([C:15](=[O:17])[NH:14][CH:13]=[N:12]2)=[C:8]([C:3]2[CH:4]=[N:5][N:6]([CH3:7])[C:2]=2[C:24]2[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=2)[N:9]=1
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(=O)[nH]cnn12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [Na+]
Solvent: CCO
Product: Cc1nc(-c2cnn(C)c2-c2ccc(C(F)(F)F)cc2)c2c(=O)[nH]cnn12
Temperature: 100 °C

Procedure:
5-(5-Bromo-1-methyl-1H-pyrazol-4-yl)-7-methyl imidazo[5,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.647 mmol), [4-(trifluoromethyl)phenyl]boronic acid (96%, 128 mg, 0.647 mmol), tetrakis(triphenylphosphine)palladium(0) (60.1 mg, 0.052 mmol) and sodium carbonate (206 mg, 1.94 mmol) were combined in ethanol (4 mL) and subjected to microwave irradiation at 130° C. for 45 minutes, then heated at 100° C. for 18 hours. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were concentrated in vacuo and purified via silica gel chromatography (Gradient: 50% to 100% [5% methanol/5% triethylamine/90% ethyl acetate] in heptane) to provide the product. Yield: 90 mg, 0.24 mmol, 37%. LCMS m/z 375.4 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.47 (s, 3H), 3.84 (s, 3H), 7.56 (br d, J=8 Hz, 2H), 7.63 (s, 1H), 7.71 (br d, J=8 Hz, 2H), 7.98 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[C:33](F)=[O:34])=[O:27])([CH3:24])([CH3:23])[CH3:22]>O1CCCC1.C(OCC)(=O)C>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[C:33](=[O:34])[NH:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)F
Reactant: CCOC1OC(=O)C=C1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC1OC(=O)C=C1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
To a solution of 4-amino-5-ethoxy-5H-furan-2-one (0.08 g, 0.58 mmol) in tetrahydrofuran (10 mL) at −78° C. under nitrogen was dropwise added a solution of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.64 mL, 0.64 mmol). The reaction was stirred 3 h at 0° C. A solution of 2-fluorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.77 mmol) in tetrahydrofuran (3 mL) was added dropwise. The reaction was stirred for 16 h at room temperature. The mixture was diluted with ethyl acetate, was washed with 10% sodium bisulfate, saturated sodium bicarbonate, and brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 35:65 ethyl acetate:hexanes afforded (R )-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.05 g, 26% yield). Also isolated was starting 4-amino-5-ethoxy-5H-furan-2-one (0.03 g, 36% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][C:9](=[O:16])[O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[N:4][N:5]([CH3:7])[CH:6]=1.O[CH:18]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[Br:1][C:2]1[C:3]([N:8]([C:9]([O:10][CH2:11][C:12]([Cl:14])([Cl:13])[Cl:15])=[O:16])[C@H:18]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:20])[CH2:31][CH:32]([CH3:34])[CH3:33])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(NC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: COc1ccc(COC(=O)C(O)CC(C)C)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c2nn(C)cc2Br)cc1
Reaction time: 48 h

Procedure:
To 2,2,2-trichloroethyl 4-bromo-1-methyl-1H-pyrazol-3-ylcarbamate (2.402 g, 6.83 mmol), 4-methoxybenzyl 2-hydroxy-4-methylpentanoate (3.45 g, 13.67 mmol) and triphenyl phosphine (3.58 g, 13.67 mmol) in dry DMF (50 mL) under dry nitrogen was added dropwise diisopropyl azodicarboxylate (2.7 mL, 13.67 mmol) over 45 minutes and the reaction mixture stirred for 2 days. Water was added and the product extracted with ether (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8) to afford 4-methoxybenzyl N-(4-bromo-1-methyl-1H-pyrazol-3-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:8][CH:9]=2)[C:4]([S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3]1.[CH:38]([NH2:41])([CH3:40])[CH3:39]>C1COCC1>[CH:38]([NH:41][CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[C:4]2[S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])([CH3:40])[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3C)cc1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NCCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2C
Temperature: 80 °C
Reaction time: 21 h
Yield: 57.9 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.433 g, 0.807 mmol) and isopropylamine (1.0 mL, 12 mmol) in THF (10 mL) was stirred at 80° C. in a sealed tube for 15 hours. Additional isopropylamine (1.0 mL, 12 mmol) was added, and the reaction mixture was stirred at 80° C. for 21 hours. It was allowed to cool to room temperature, and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.25% ammonium hydroxide/2.5% methanol in chloroform. Drying at 63° C. in vacuo for 30 minutes yielded isopropyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol -5-yloxy]-ethyl}-amine as a yellow semi-solid 0.198 g, 57.9%). This was dissolved in chloroform, and ethereal hydrochloride was added. The precipitate was filtered and dried at 85° C. in vacuo for 13 hours to give the hydrochloride as an off-white solid (0.180 g): MP: 274-6° C. (dec).; Mass Spectrum (+EI, [M+H]+) m/z 424.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]1[O:24][C:17]2([CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[O:16][CH2:15]1>C(Cl)CCl>[O:16]1[C:17]2([CH2:22][CH2:21][CH:20]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)[CH2:19][CH2:18]2)[O:24][CH2:14][CH2:15]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: ClCCCl
Product: Fc1ccc(N2CCN(C3CCC4(CC3)OCCO4)CC2)cc1
Reaction time: 18 h

Procedure:
A mixture of 11.5 gm of 1-(4-fluoro-phenyl)-piperazine 10.0 gm of 1,4-cyclohexanedione mono-ethylene ketal (available from Aldrich) and 27.2 gm NaB(OAc)3 in 250 ml dichloroethylene was kept for 18 hours at ambient temperature. The solvents were removed and the residue partitioned between ethyl acetate (200 ml) and 2N NaOH (200 ml). The ethyl acetate layer is washed with 2×20 ml water and dried over Na2SO4. The crude 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-(4-fluoro-phenyl)-piperazine (20.1 gm of a solid) obtained after removing the solvents had a melting point of 116-118° C. A sample of this material (C18H25FN2O2) showed an elemental analysis of C, 67.24%, H, 8.22%. N, 8.98%.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([OH:24])=O)=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([NH:35][C:22](=[O:24])[CH:21]([O:25][CH2:26][CH3:27])[CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1][CH2:2][CH2:3]2)=[CH:19][CH:18]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)O
Reactant: NCc1ccccc1
Product: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)NCc1ccccc1
Yield: 71 %

Procedure:
The title compound (0.22 g, 74%) was prepared as a white solid from 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.25 g, 0.65 mmol) obtained in example 29 and benzylamine (0.076 g, 0.71 mmol) by an analogous procedure to that described in example 32. mp : 92-93° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].Br[CH2:13][CH2:14][CH2:15][Cl:16]>CO>[Cl:16][CH2:15][CH2:14][CH2:13][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: ClCCCBr
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Na]
Solvent: CO
Product: O=[N+]([O-])c1ccc(SCCCCl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
4-Nitrothiophenol (80%, 25.0 g, 129 mmol) was added to a solution formed by adding sodium (5.55 g, 242 mmol) to methanol (500 mL) maintained at 0° C. After 0.5 h the reaction was warmed to ambient temperature and 1-bromo-3-chloropropane (50.7 g, 322 mmol) was added in one portion. The reaction mixture was stirred overnight and filtered. The filtrate was reduced to half volume and the solid which formed was collected by filtration. Recrystallization from methanol afforded 15.4 g (51%) of yellow solid, mp 50°-52° C.
Reaction SMILES: FC(F)(F)C1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2C=1.Br[CH2:15][C:16](=O)[C:17]([CH3:20])([CH3:19])[CH3:18].C(O)C>[Pt](=O)=O.CO>[CH3:18][C:17]([C:16]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:15]=1)([CH3:20])[CH3:19]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: CC(C)(C)C(=O)CBr
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CO
Product: CC(C)(C)c1cn2c(n1)CNCC2

Procedure:
2-(1,1-Dimethylethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was prepared in an analogous manner to that described above for 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Intermediate 4) but starting from 1-bromo-3,3-dimethyl-2-butanone instead of 3-bromo-1,1,1-trifluoro-2-propanone and using platinum (IV) oxide and ethanol in the place of 10% palladium on carbon paste and methanol for the hydrogenation step.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:18]=1[CH3:34].Cl.O1CCOCC1>CN1C(=O)CCC1>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:19]1[C:18]([CH3:34])=[C:17]([NH:1][C:2]2[CH:9]=[C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: N#Cc1ccc(N2CCOCC2)cc1N
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1C#N

Procedure:
Prepared according to Procedure K, Method 2 using 2-amino-4-morpholinobenzonitrile (82 mg, 405 μmol), 4-chloro-2-(2-fluorophenyl)-3-methylquinoline (110 mg, 405 μmol) and 4N hydrochloric acid solution in dioxane (0.010 mL, 40 μmol) in NMP (0.50 mL) to afford product as a tan solid upon purification by chromatography on silica gel, eluting with EtOAc gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.11 (1H, d, J=8.6 Hz), 7.90 (1H, d, J=8.6 Hz), 7.61-7.74 (1H, m), 7.45-7.61 (2H, m), 7.32-7.45 (2H, m), 7.26 (1H, t, J=7.4 Hz), 7.08 (1H, t, J=9.2 Hz), 6.55 (1H, br. s.), 6.31 (1H, dd, J=8.8, 2.5 Hz), 5.76 (1H, br. s.), 3.54-3.73 (4H, m), 2.88-3.11 (4H, m), 2.04-2.23 (3H, m). Mass Spectrum (ESI) m/e=439.1 (M+1).
Reaction SMILES: C(OC([NH:11]/[C:12](=[N:20]\C(=O)OCC1C=CC=CC=1)/[NH:13][C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.[H][H]>CCO.C1COCC1.[OH-].[OH-].[Pd+2]>[CH3:19][N:18]1[C:14]([NH:13][C:12]([NH2:20])=[NH:11])=[CH:15][CH:16]=[N:17]1
Reactant: [H][H]
Reactant: Cn1nccc1N/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1nccc1NC(=N)N
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a stirred solution of 180 (1.00 g, 2.45 mmol) in EtOH/THF (1:1, 35 mL) at RT was added Pearlman's Catalyst (0.172 g, 0.245 mmol). The mixture subjected to a vacuum/purge cycle three times with hydrogen gas and then maintained under 1 atmosphere balloon of hydrogen pressure. After stirring overnight and the reaction was filtered through GF/F filter paper with EtOH and the filtrate was concentrated to afford 0.31 g (90%) of 1-(1-methyl-1H-pyrazol-5-yl)guanidine (182) as a clear glass which was used without further purification: MS m/z (APCI-pos) M+1=140.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][C@H:20]([C:31]1[NH:35][C:34]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:33]=2[N:32]=1)[CH2:21][CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH:16]=[CH:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][C@H:20]([C:31]1[NH:35][C:34]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:33]=2[N:32]=1)[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CC(C)(C)OC(=O)CCC[C@H](Nc1ncnc2cc(C(=O)N3CC=CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC[C@H](Nc1ncnc2cc(C(=O)N3CC=CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 8c from 6-chloro-4-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-4-(tert.-butyloxycarbonyl)-butylamino]-7-(2,5-dihydropyrrol-1-yl-carbonyl)-quinazoline and trifluoroacetic acid in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH2:11](N1[C@H](C)CN([C@H](C2C=C(C=CC=2)C(Cl)=O)C2C=CC=C(O[Si](C(C)(C)C)(C)C)C=2)[C@@H](C)C1)C=C>>[CH3:11][NH:4][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:5]=1[Cl:10]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Product: CNc1c(Cl)cc(Cl)cc1Cl

Procedure:
N-Methyl-2,4,6-trichloroaniline [NMR (200 MHz, CDCl3): δ 2.82 (s, 3H); 5.11 (s, 1H); 7.46 (s, 2H)] was prepared from 2,4,6-trichloroaniline, coupled with 3-((αR)-α-((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2,4,6-trichlorophenyl) as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:16][CH:17]3[O:21][CH2:20][CH2:19][O:18]3)[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1>CN1CCCC1=O.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:16][CH:17]3[O:21][CH2:20][CH2:19][O:18]3)[CH2:14][N:13]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=3)[C:12](=[O:15])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cccc(Br)n1
Reactant: O=C1CC[C@](CC2OCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(N2C[C@@](CC3OCCO3)(c3ccc(Cl)c(Cl)c3)CCC2=O)n1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
A mixture of (5S)-5-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-2-piperidinone (WO 9807722) (6.5 g, 19.7 mmol), potassium carbonate (3.05 g, 21.7 mmol), copper (I) iodide (400 mg, 2.1 mmol) and 2-bromo-6-methylpyridine (10.2 g, 60 mmol) in 1-methyl-2-pyrrolidinone (200 ml) was stirred at 140° C. for 24 hours. The cooled mixture was partitioned between ethyl acetate and 10% aqueous ammonia, and the layers separated. The aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with water, then brine (3×), dried (MgSO4) and evaporated under reduced pressure to give a gum. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 100:0) to afford the title compound as a brown solid, 3.02 g.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[O:10]=[C:11]([CH3:14])[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:11]([C:12]1[CH2:13][O:4][C:3]2[C:2]([CH:1]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:10])[CH3:14]
Reactant: O=Cc1ccccc1O
Reactant: C=CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)C1=Cc2ccccc2OC1

Procedure:
1.22 g (10 mmol) of salicylaldehyde together with 0.66 g (10 mmol) of 3-oxo-l-butene are added at room temperature to a suspension of 0.14 g (1 mmol) of potassium carbonate in 50 ml of 2-butanone. The mixture is brought to reflux with stirring and this temperature is maintained for 4 hours. The procedure is then as in Example 1, stage A. The final chromatography is replaced by a recrystallization in hexane.
Reaction SMILES: C[O:2][C:3]([CH:5]1[O:9][C:8](=[O:10])[NH:7][CH:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[BH4-].[Na+].O.Cl>C(O)C>[CH2:11]([C@H:6]1[C@@H:5]([CH2:3][OH:2])[O:9][C:8](=[O:10])[NH:7]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C1OC(=O)NC1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Reaction time: 2 h

Procedure:
150 g of the 98:2 mixture of the (4S,5S) and (4S,5R) isomers of 4-benzyl-2-oxo-oxazolidine-5-carboxylic acid methyl ester were added at 15°-20° over a period of 1.5 hours to a stirred solution of 20.8 g of sodium borohydride in 360 ml of ethanol and then stirred for a further 2 hours. The suspension was combined at 20° with 540 ml of water and the pH value adjusted to 7 with 165 ml of 3N hydrochloric acid. The suspension was stirred at room temperature for 2.5 hours, left to stand for 18 hours at 4° and then filtered. The residue was washed with water and dried and yielded 111.6 g (84%) of 99% (4S,5S)-4-benzyl-5-hydroxymethyl-oxazolidin-2-one, melting point 167.3°-168.9°, [α]D20 : -79.4° (1% in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2ccc(Cl)cc2[N+](=O)[O-])cc1
Yield: 92.4 %

Procedure:
The title compound was prepared from 4-chloro-2-nitro-benzoic acid (6.0 g, 30 mmol) and p-anisidine (4.0 g, 33 mmol) using the procedure of step 1 of the Example 1 to provide the title compound (8.5 g, 90%).
Reaction SMILES: [NH2:1][CH3:2].[Li]CCCC.C(O[C:11]([C:13]1[N:14]=[N:15][S:16][C:17]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:12])C.[NH4+].[Cl-]>C1CCCCC1.CCOC(C)=O>[CH3:2][NH:1][C:11]([C:13]1[N:14]=[N:15][S:16][C:17]=1[NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:12]
Reactant: CCOC(=O)c1nnsc1Nc1ccccc1
Reactant: CN
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1nnsc1Nc1ccccc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2 M NH2CH3 in cyclohexane (2 mL) at −40° C. was added 0.8 mL of 2 M n-BuLi in cyclohexane under argon. A white precipitate was immediately observed. The mixture was stirred at −30° C. for 0.5 hours, and 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester (60 mg, 0.24 mmole) in 1 mL of cyclohexane was slowly added. Greenish solution was immediately obtained. The reaction was slowly warmed up to room temperature and TLC showed a total disappearance of the starting material. A mixture of 7 mL of saturated NH4Cl solution and 7 mL of EtOAc was added to the ice-cooled flask and the solution was stirred for 30 minutes. The aqueous layer was neutralized to pH ˜7 and then extracted with EtOAc. The organic layer was absorbed with silica gel, loaded to a 53 g silica gel column, and eluted with hexane:EtOAc=5:1. A 25 mg white powder was obtained (45%). 1H NMR (ppm, DMSO-d6): 11.00 (br. s, 1H), 8.92 (br. q, 1H), 7.46 (t, 2H), 7.34 (d, 2H), 7.20 (t, 1H), 2.85 (d, 3H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23][CH2:24][C:25]([OH:27])=O.[NH2:28][C@@H:29]1[C:36](=[O:37])[N:35]2[C@@H:30]1[S:31][CH2:32][C:33](/[CH:41]=[C:42]1/[C:43](=[O:51])[N:44]([CH2:47][CH:48]3[CH2:50][CH2:49]3)[CH2:45][CH2:46]/1)=[C:34]2[C:38]([OH:40])=[O:39]>CN(C)C=O>[CH:48]1([CH2:47][N:44]2[CH2:45][CH2:46]/[C:42](=[CH:41]\[C:33]3[CH2:32][S:31][C@H:30]4[N:35]([C:36](=[O:37])[C@H:29]4[NH:28][C:25](=[O:27])[CH2:24][S:23][C:14]4[CH:15]=[CH:16][C:17]5[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH:13]=4)[C:34]=3[C:38]([OH:40])=[O:39])/[C:43]2=[O:51])[CH2:50][CH2:49]1
Reactant: O=C(O)CSc1ccc2ccccc2c1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(CSc1ccc2ccccc2c1)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12

Procedure:
With 167.0 mg (1.03 mmol) 1,1′-carbonyldiimidazole, 225.0 mg (1.03 mmol (naphthalen-2-ylsulfanyl)-acetic acid and 300.0 mg (0.86 mmol) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 4 ml N,N-dimethylformamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])[CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])[CH2:18][CH2:17]1>>[F:32][C:31]([F:34])([F:33])[C:30]([C:12]1[CH:13]=[CH:14][C:15]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[C:10]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:11]=1)([OH:39])[C:35]([F:38])([F:37])[F:36]
Reactant: OB(O)c1ccsc1
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2-c2ccsc2)CC1

Procedure:
Following the procedure outlined for Example 69, 3-thiopheneboronic acid (17.8 mg, 0.139 mmol, Sigma-Aldrich, St. Louis, Mo.) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol, the reaction mixture was filtered, concentrated, and the residue was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini-NX (C18 110 A column (100×21 mm, 5 μm) eluting with 0.1% NH4OH in CH3CN/H2O (5% to 95% over 8 min)) to afford 1,1,1,3,3,3-hexafluoro-2-(3-(3-thiophenyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=6.2 Hz, 1H), 7.69-7.62 (m, 2H), 7.53 (m, 3H), 7.38-7.29 (m, 2H), 7.19 (d, J=9.7 Hz, 1H), 2.99-2.94 (m, 4H), 2.93-2.87 (m, 4H). m/z (ESI, +ve ion) 557.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.50 μM; GK-GKRP EC50 (LC MS/MS)=1.90 μM.