Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:55])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([OH:42])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:43]([F:54])[C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=2)[CH2:4][CH2:3]1.C1(C)C(S(O[CH2:66][CH2:67][C:68]([OH:71])([CH3:70])[CH3:69])(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1(C)C=CC=CC=1>[F:55][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([O:42][CH2:69][C:68]([CH3:70])([OH:71])[CH2:67][CH3:66])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[C@@H:43]([F:54])[C:44]2[CH:45]=[CH:46][C:47]([C:50]([F:52])([F:51])[F:53])=[CH:48][CH:49]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccccc1S(=O)(=O)OCCC(C)(C)O
Reactant: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(O)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCC(C)(O)COc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](OCc3ccc(OC)cc3)CC(C)(C)C4)CC2)nc1
Temperature: 80 °C
Reaction time: 2.8 h
Yield: 71.8 %

Procedure:
To 570 mg (0.741 mmol) of 2-[4-((5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)piperidin-1-yl]pyrimidin-5-ol, which was prepared by a method similar to that of Reference Example 14, 288 mg (1.11 mmol) of 3-hydroxy-3-methylbutyl toluenesulfonate and 198 mg (1.43 mmol) of potassium carbonate, 2 ml of N,N-dimethylformamide was added, and the reaction mixture was stirred at 80° C. for 2.8 hours. After completion of the reaction, toluene and water were added to the reaction solution to separate an organic phase. Further, the reaction mixture was extracted with toluene from the aqueous phase. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=78/22-50/50 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, then n-heptane was added thereto, and the precipitate was obtained by filtration to provide 455 mg of the title compound as a white solid (yield: 72%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2.[NH2:25][CH2:26][CH2:27][CH2:28][NH2:29].C1(C)C=CC=CC=1>O>[CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][CH:11]([NH:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2
Reactant: NCCCN
Reactant: CC1(C)C2CCC(C2)C1CCC(=O)CCC1C2CCC(C2)C1(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC(C2)C1CCC(CCC1C2CCC(C2)C1(C)C)NCCCN

Procedure:
1,5-Di-(3,3-dimethylnorborn-2-yl)-3-pentanone (6.04 g., 0.02 mole) and 1,3-diaminopropane (0.10 mole) in 150 ml. toluene is heated at reflux overnight with a Dean-Stark water separator. The cooled solution is concentrated under reduced pressure. The residue is dissolved in ethanol and hydrogenated with PtO2 at room temperature and 40 psi hydrogen pressure. The platinum catalyst is filtered off and the ethanol removed under vacuum. The residue is dissolved in ether and the ether solution washed several times with water to remove the excess 1,3-diaminopropane. The ether extracts are dried over anhydrous sodium sulfate and concentrated under vacuum to leave the diamine product, 1-[1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentyl]-1,5-diazapentane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]([Si](C)(C)C)[S:23][CH:24]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:4][C:3]=1[S:29]([NH2:32])(=[O:31])=[O:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[CH:22][S:23][CH:24]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:4][C:3]=1[S:29]([NH2:32])(=[O:30])=[O:31]
Reactant: Cc1cn(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(-c3csc([Si](C)(C)C)n3)cc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(-c3cscn3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a stirred solution of 2-fluoro-4-[4-methyl-2-[4-(2-trimethylsilylthiazol-4-yl)phenyl]-1H-imidazol-1-yl]benzenesulfonamide (crude, 0.634 mmol) in THF (3 mL) was added tetrabutylammonium fluoride (0.95 mL, 1.0 M solution in THF, 0.95 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was added water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (1/3). The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (0.116 g, 44.1% yield, via 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH:12]([CH3:16])[CH2:13][CH2:14]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH:12]([CH3:16])[CH2:13][CH2:14][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Reactant: CC(CCO)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(CCN(C(=O)OC(C)(C)C)S(C)(=O)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
The 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-3-methyl-1-butanol (97.2 mg, 0.259 mmol) obtained in Example 239, t-butyl N-methylsulfonylcarbamate (101 mg, 0.518 mmol) and triphenylphosphine (138 mg, 0.518 mmol) were dissolved in tetrahydrofuran (3 ml), followed by the addition of diisoopropyl azodicarboxylate (102 μl, 0.518 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride, water and brine, dried over magnesium sulfate and then concenetrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=3:2 eluate was concentrated, whereby the title compound (136 mg, 0.246 mmol, 95%) was obtained as a colorless amorphous substance.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:28]=[CH:27][C:13]3/[C:14](=[CH:23]/[C:24](O)=[O:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].O.[NH2:34][NH2:35].O>C1COCC1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:28]=[CH:27][C:13]3/[C:14](=[CH:23]/[C:24]([NH:34][NH2:35])=[O:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)O
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)NN
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 127.1 %

Procedure:
[step 1] (E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetic acid (130 mg, 0.31 mmol) obtained in Example 2 was dissolved in THF (1.5 mL), N,N′-carbonyldiimidazole (80 mg, 0.49 mmol) was added, and the mixture was stirred at room temperature for 10 min. Hydrazine monohydrate (60 μL, 1.24 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=90/10) to give (E)-[2-(2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetohydrazide (172 mg) quantitatively.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].[O:33]1[CH2:36][C:35](=O)[CH2:34]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:35]2[CH2:36][O:33][CH2:34]2)[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(NC1CCN(C2COC2)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
A solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.2 g, 0.35 mmol), oxetan-3-one (0.027 g, 0.38 mmol) and acetic acid (0.01 mL) in MeOH (5.0 mL) was stirred at ambient temperature for 30 min. After that NaBH3CN (0.022 g, 0.35 mmol) was added at 0° C. slowly lot wise over the period of 10 min and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to obtain a residue which was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether/pentane to afford the title compound as an off-white solid (0.05 g, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][CH:13]=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH3:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([N:23]2[CH2:27][CH2:26][C@@H:25]([N:28]3[CH2:32][CH2:31][CH2:30][C@@H:29]3[CH3:33])[CH2:24]2)[N:17]=1>>[CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][CH2:13][NH:22][C:21]2[C:16]([CH3:15])=[N:17][C:18]([N:23]3[CH2:27][CH2:26][C@@H:25]([N:28]4[CH2:32][CH2:31][CH2:30][C@@H:29]4[CH3:33])[CH2:24]3)=[CH:19][CH:20]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(CCC=O)CCOCC1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Product: COC(=O)C1(CCCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCOCC1

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 1 of Example 1, by condensing 4-(3-oxo-propyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (44 mg, 0.22 mmol) and 2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine to obtain 84 mg of a crude solid, which was used without purification.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[O:26][C:27]([CH3:55])=[C:28]([CH2:30][O:31][C:32]2[CH:52]=[CH:51][C:35]([CH2:36][O:37][C:38]3[CH:42]=[C:41]([CH:43]=O)[N:40]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:39]=3)=[CH:34][C:33]=2[O:53][CH3:54])[N:29]=1.[Cl-].[NH4+]>C(COC)OC.CO>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[O:26][C:27]([CH3:55])=[C:28]([CH2:30][O:31][C:32]2[CH:52]=[CH:51][C:35]([CH2:36][O:37][C:38]3[CH:42]=[C:41]([CH2:43][C:16]#[N:17])[N:40]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:39]=3)=[CH:34][C:33]=2[O:53][CH3:54])[N:29]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: COc1cc(COc2cc(CC#N)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.7 %

Procedure:
To a mixture of potassium t-butoxide (1.46 g) and dimethoxyethane (50 ml) was added a solution of p-toluenesulfonylmethyl isocyanide (1.33 g) in dimethoxyethane (50 ml) at −78° C. and the mixture was stirred for 5 min. Then a solution of 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazole-5-carbaldehyde (3.00 g) in dimethoxyethane (50 ml) was added. After stirring at said temperature for 1 hr, the mixture was stirred for 1 hr. while raising the temperature to room temperature. To the obtained mixture was added methanol (50 ml), and the mixture was refluxed for 2 hrs. After cooling, the reaction solution was poured into saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and [3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy-]-1-phenyl-1H-pyrazol-5-yl]acetonitrile (450 mg, yield 15%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 141–142° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[NH:8][C:7](=[O:14])[CH:6]=[CH:5]2.[H][H]>C(O)C.CN(C)C=O.[Ni]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: [H][H]
Reactant: O=c1ccc2cc(F)c(F)c(F)c2[nH]1
Agent: [Ni]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1CCc2cc(F)c(F)c(F)c2N1
Yield: 95.9 %

Procedure:
24.35 g of 6,7,8-trifluorocarbostyril in suspension in a mixture of 450 cm3 of ethanol and 150 cm3 of dimethylformamide are hydrogenated, with stirring, at about 50° C., in the presence of 5 g of Raney nickel under a pressure of 1 atmosphere until the absorption of hydrogen has ceased. The W-2 grade Raney nickel used is washed beforehand with 50 cm3 of an aqueous 2% acetic acid solution, twice 50 cm3 of water and 3 times 50 cm3 of ethanol. 250 cm3 of dimethylformamide are added to the reaction mixture and the mixture is filtered at about 50 C. through diatomaceous silica. The filtrate is concentrated under reduced pressure (20 kPa) at about 70° C. The dry extract is taken up in 150 cm3 of water, drained and washed with twice 50 cm3 of water. 23.6 g of 6,7,8-trifluoro-3,4-dihydrocarbostyril are obtained in the form of a light beige solid melting at 217° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9](Br)=[CH:8]2)=[O:4].[C:26]1([Sn](CCCC)(CCCC)CCCC)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2[C@H](C)c2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@H](C)c2ccccc2)c1O
Temperature: 120 °C
Yield: 63 %

Procedure:
A mixture of (R)-3-bromo-5-hydroxy-2-oxo-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (500 mg, 1.24 mmol), PhSnBu3 (0.49 mL, 1.49 mmol), and PdCl2(PPh3)2 (174 mg, 0.25 mmol) in DMF (10 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine and EtOAc were added. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (5-35% EtOAc/hexanes+1% AcOH) to give 313 mg of the title compound as a yellow solid. MS: (+) m/z 401.36 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:37]/[O:38][C:39]([C:42]([OH:44])=[O:43])([CH3:41])[CH3:40])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:32]([O-:34])=[O:33])=[C:15]([CH2:18][N+:19]4[N:20]([CH2:29][CH2:30][OH:31])[C:21]([NH2:28])=[C:22]([CH2:24][NH:25]C=O)[CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.Cl.C(OCC)(=O)C>CO>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:37]/[O:38][C:39]([C:42]([OH:44])=[O:43])([CH3:41])[CH3:40])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:32]([O-:34])=[O:33])=[C:15]([CH2:18][N+:19]4[N:20]([CH2:29][CH2:30][OH:31])[C:21]([NH2:28])=[C:22]([CH2:24][NH2:25])[CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(CNC=O)c(N)n3CCO)CS[C@H]12)c1nsc(N)n1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(CN)c(N)n3CCO)CS[C@H]12)c1nsc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 18.9 %

Procedure:
To a solution of 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-formamidomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (97 mg) in methanol (1 ml) was added concentrated hydrochloric acid (0.1 ml) at room temperature. The mixture was stirred at room temperature for 4.5 hours and poured into ethyl acetate. The resulting precipitate was collected by filtration and dried in vacuo. The obtained powder was dissolved in a phosphate buffer (pH 7), and the solution was adjusted to about pH 6 with saturated aqueous sodium hydrogencarbonate solution. The solution containing the objective compound was purified by preparative HPLC utilizing ODS column. The eluate containing the desired product was concentrated in vacuo. The concentrate was adjusted to about pH 2 with concentrated hydrochloric acid and chromatographed on Diaion® HP-20 (Mitsubishi Chemical Corporation) eluting with 20% aqueous 2-propanol. The eluate was concentrated in vacuo and lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-aminomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (17.5 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCc1ccc(C(F)(F)F)cc1)C1CCNCC1
Yield: 94.4 %

Procedure:
A mixture of tert-butyl N-(1-benzylpiperidin-4-yl)-N-[2-(4-trifluoromethylphenyl)ethyl]carbamate (0.437 g, 0.944 mmol) prepared in Reference Example 120 and 20% palladium hydroxide/carbon (100 mg) in ethanol (20 ml) was stirred at room temperature under an atmospheric pressure of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to afford tert-butyl N-(piperidin-4-yl)-N-[2-(4-trifluoromethylphenyl)ethyl]carbamate (0.332 g, yield 94%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH2:31][O:32][CH3:33])[C:12]1[C:13]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[N:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:33][O:32][CH2:31][N:11]1[C:12]2[C:13]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[N:14][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:16]=2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]1(=[O:10])=[O:9]
Reactant: COCN(c1cn(-c2ccccc2)nc1C(=O)N1CCOCC1)S(=O)(=O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: COCN1c2c(C(=O)N3CCOCC3)nn(-c3ccccc3)c2-c2ccccc2S1(=O)=O

Procedure:
A mixture of 2-bromo-N-(methoxymethyl)-N-[3(morpholin-4-ylcarbonyl)-1-phenyl-1H-pyrazol -4-yl] benzenesulfonamide (240 mg; 0.45 mmol; 1.00 eq.), palladium acetate (20 mg; 0.09 mmol; 0.20 eq.), triphenylphosphine (94 mg; 0.36 mmol; 0.80 eq.) and Cs2CO3 (584 mg; 1.79 mmol; 4.00 eq.) is flushed with N2 for 10 minutes. Toluene (50 mL) is added and the resulting mixture is stirred at reflux for 2 hours. After this time, reaction mixture is filtered through a short plug of celite, ished with ethyl acetate. Combined organic phase are ished with NaHCO3 then brine, dried over sodium sulfate and concentrated in vacuo and purified by flash chromatography to give the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.03 (dd, J=1.3, 7.5 Hz, 1H), 7.88-7.46 (m, 7H), 7.04-6.94 (m, 1H), 5.15 (s, 2H), 3.69 (s, 6H), 3.64-3.54 (m, 2H), 2.89 (s, 3H). HPLC (max plot) 83.4%; Rt 3.71 min. MS (ESI+) 423.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([N+:10]#[C-:11])=[CH:6]N(C)C)[CH3:2].C(N(CC)CC)C.[SH2:20]>O1CCCC1>[C:4]([C:5]1[N:10]=[CH:11][S:20][CH:6]=1)([O:3][CH2:1][CH3:2])=[O:12]
Reactant: S
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cscn1

Procedure:
A solution of 3-dimethylamino-2-isocyano-acrylic acid ethyl ester (1.0 g) and triethylamine (3.0 g) in tetrahydrofuran (30 mL) is treated with gaseous hydrogen sulfide until all starting material is consumed. The mixture is concentrated to an oil and purified by column chromatography using silica and 25% ethyl acetate-hexanes as the eluant. The purified material (0.61 g) is isolated as an oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19]>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:18](=[O:19])[NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[F:10])[CH2:2]2
Reactant: O=C=Nc1ccccc1F
Reactant: OC1CN2CCC1CC2
Product: O=C(Nc1ccccc1F)OC1CN2CCC1CC2
Yield: 79 %

Procedure:
3-Quinuclidinol and 2-fluorophenyl isocyanate were used. The reaction solution was evaporated under reduced pressure, and the residual solid was recrystallized from ethyl acetate to afford the title compound (79%) as a white solid: mp 124.0-126.0° C.; FAB LRMS m /z (relative intensity %) 265 (MH+, 22), 110 (100).