Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1C=CC=C1CC(NC1C(=O)N2C(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=C(O)CS[C@H]12)=O.FC1C=CC(S(Cl)(=O)=O)=CC=1.C1OC1C.[S:48]1[CH:52]=[CH:51][CH:50]=[C:49]1[CH2:53][C:54]([NH:56][CH:57]1[C:88](=[O:89])[N:59]2[C:60]([C:75]([O:77]CC3C=CC([N+]([O-])=O)=CC=3)=[O:76])=[C:61]([O:64][S:65]([C:68]3[CH:73]=[CH:72][C:71]([F:74])=[CH:70][CH:69]=3)(=[O:67])=[O:66])[CH2:62][S:63][C@H:58]12)=[O:55]>CC(N(C)C)=O.CO.C1COCC1.[Pd]>[S:48]1[CH:52]=[CH:51][CH:50]=[C:49]1[CH2:53][C:54]([NH:56][CH:57]1[C:88](=[O:89])[N:59]2[C:60]([C:75]([OH:77])=[O:76])=[C:61]([O:64][S:65]([C:68]3[CH:73]=[CH:72][C:71]([F:74])=[CH:70][CH:69]=3)(=[O:67])=[O:66])[CH2:62][S:63][C@H:58]12)=[O:55]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OS(=O)(=O)c3ccc(F)cc3)CS[C@H]12
Agent: [Pd]
Agent: CC1CO1
Agent: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(OS(=O)(=O)c3ccc(F)cc3)CS[C@H]12

Procedure:
By following the sulfonation and de-esterification procedures described in Example 4 p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate was reacted with 4-fluorobenzenesulfonyl chloride in DMAC in the presence of propylene oxide and the recovered sulfonation product, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-(4-fluorobenzenesulfonyloxy)-3-cephem-4-carboxylate was hydrogenated in methanol-THF over prereduced 5 percent palladium on carbon catalyst to provide the product, 7-[2-(2-thienyl)acetamido]-3-(4-fluorobenzenesulfonyloxy)-3-cephem-4-carboxylic acid.
Reaction SMILES: [OH-].[Na+].CO.[N:5]1([C:10]2[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6]1.Cl>C(OCC)(=O)C.O1CCCC1>[N:5]1([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=[CH:9]1
Reactant: COC(=O)c1ccnc(-n2cccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccnc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 mL of 2.0 mol/L aqueous sodium hydroxide was added to a mixed solution of 4.0 mL of methanol and 4.0 mL of tetrahydrofuran containing 0.47 g of methyl 2-(1H-pyrrol-1-yl)pyridine-4-carboxylate and stirred at room temperature for 1 hour. 5.0 mL of 1.0 mol/L hydrochloric acid and ethyl acetate were added to the reaction mixture sequentially. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated, under reduced pressure. Diisopropyl ether was added to the obtained residue and a solid substance was removed by filtration to obtain 0.39 g of 2-(1H-pyrrol-1-yl)pyridine-4-carboxylic acid as white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([O:1][CH2:2][C@H:3]2[C@@H:8]([CH2:9][O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][CH:6]=[CH:5][CH2:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: OC[C@@H]1CC=CC[C@@H]1COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CC=CC[C@@H]2COCc2ccccc2)cc1
Reaction time: 8 h
Yield: 84.2 %

Procedure:
The alcohol/benzyl ether (2) (10 g) ml of dry pyridine is added slowly at 0° C. to p-toluenesulphonyl chloride (10.4 g) in pyridine (60 ml). The mixture is kept overnight at room temperature and is then quenched by pouring over crushed ice with vigorous shaking. The product is extracted with ether, washed consecutively with water, 0.1M sodium carbonate and brine, dried (MgSO4), and concentrated in vacuo at room temperature. The crude product is purified on a silica gel column, eluting with benzene-ethyl acetate (95%: 5% v/v) to give the title compound (14 g, 90%). The i.r. spectrum shows the absence of a hydroxyl group.
Reaction SMILES: O=C1[CH:6]([C:7](O)([OH:12])[C:8]([F:11])([F:10])[F:9])[CH2:5][CH2:4][O:3]1.Cl.C(O)(=O)C>O>[F:9][C:8]([F:11])([F:10])[C:7](=[O:12])[CH2:6][CH2:5][CH2:4][OH:3]
Reactant: O=C1OCCC1C(O)(O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCCO)C(F)(F)F
Yield: 125.1 %

Procedure:
A 500 mL three neck round bottom flask, fitted with reflux condenser, heating mantle, and magnetic stirrer was charged with 61.5 g(0.31M) of 2,3,4,5-tetrahydro-2-oxo-3-(2,2,2-trifluoro-1,1-dihydroxyethyl)furan, 6.4 mL of concentrated HCl, 10 mL of water, and 80 mL of acetic acid. The reaction mixture was heated at 125 C. overnight. An additional 3.0 mL of concentrated HCl and 5.0 mL of water was added and the reaction mixture was heated for an additional 10 hour. The reaction was partitioned between water and ethyl ether while the water layer was neutralized with solid sodium bicarbonate (100 g). The ether solution was washed with water (2×20 mL), dried (anhydrous MgSO4), and solvent removed under reduced pressure to give 60 g(45%) of a pale yellow oil. nmr(CDCl3)-L 2.15m,4H), 4.03(m,1H), 4.20(m,1H).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH2:13][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:10]2)=[CH:5][CH:4]=1.[CH:33]([C:35]1[CH:36]=[C:37]([CH:41]([S:49][CH2:50][CH2:51][C:52](=[O:56])[N:53]([CH3:55])[CH3:54])[S:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[CH:38]=[CH:39][CH:40]=1)=O.C([O-])(=O)C.[NH4+]>C1COCC1.CCCCCC>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[CH:33][C:35]3[CH:36]=[C:37]([CH:41]([S:49][CH2:50][CH2:51][C:52](=[O:56])[N:53]([CH3:55])[CH3:54])[S:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[CH:38]=[CH:39][CH:40]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=O)c1
Reactant: Clc1ccc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1
Agent: CC(=O)[O-]
Agent: [Br-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-chloroquinolin-2-ylmethyltriphenylphosphonium bromide (809 mg, 1.56 mmol.) (Example 4, Step 2) in THF (15 mL) at -78° C., was added a solution of n-Buli (1.6M) in hexane (0.89 mL, 1.43 mM). The mixture was stirred for 0.5 hrs at -78° C. Then, (-)-methyl 5-(3-formylphenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate (step 7) (480 mg, 1.3 mmol.) in THF (4 mL) was slowly added. The mixture was stirred for 0.5 hr at -78° C. and then warmed up to room temperature and stirred for an additional 2 hrs. A solution of 25% ammonium acetate was added, the mixture was extracted with ethyl acetate, and the extracts were washed with brine (3×), dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[NH:8][C:9]3[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[C:12]([O:20][CH3:21])[C:10]=3[N:11]=2)=[CH:4][CH:3]=1.[CH3:24][N:25](C)C=O>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:24]([C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[NH:8][C:9]3[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[C:12]([O:20][CH3:21])[C:10]=3[N:11]=2)=[CH:4][CH:3]=1)#[N:25]
Reactant: COC(=O)c1ccc(OC)c2nc(Cc3ccc(Br)cc3)[nH]c12
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC)c2nc(Cc3ccc(C#N)cc3)[nH]c12
Temperature: 100 °C

Procedure:
A solution of methyl 2-(4-bromobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylate [1.4 g, Reference Example 3(1)] in dry dimethylformamide was treated with tetrakis(triphenylphosphine) palladium (0) (0.266 g) and zinc cyanide (0.275 g). The reaction mixture was heated at 100° C. for 12 hours then cooled to room temperature. The mixture was diluted with ethyl acetate and then washed with ammonium hydroxide (2N), then with water and then with brine. The organic solution was dried over magnesium sulphate then evaporated. The residue was subjected to flash chromatography on silica to give the title compound (0.88 g). NMR (CDCl3): δ 3.85(s, 3H), 4.00(s, 3H), 4.40(s, 2H), 6.70(d, 1H), 7.40(d, 2H), 7.65(d, 2H), 7.85(1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[CH2:8][CH2:7][CH2:6][C:5]2=1.[ClH:25]>CO>[ClH:25].[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@H:9]([NH:15][CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3NC1Cc2ccccc2C1
Agent: Cl
Solvent: CO
Product: Brc1ccc2[nH]c3c(c2c1)CCC[C@H]3NC1Cc2ccccc2C1

Procedure:
(1R)-6-Bromo-N-(2,3-dihydro-1H-inden-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of racemic 6-bromo-N-(2,3-dihydro-1H-inden-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine by Super critical Fluid Chromatography (hereinafter “SFC”) (Diacel AD-H, Chiral Technologies, 30% methanol, 3000 psi, 40° C., 2 mL/min, retention time: 16.6 min.) The oil obtained was converted to the HCl salt to give a white solid. 1H-NMR (DMSO-d6): δ 11.4 (s, 1H), 9.61 (s, 1H), 9.42 (s, 1H), 7.69 (s, 1H), 7.36 (d, 1H), 7.35-7.19 (m, 5H), 4.68 (t, 1H), 4.32 (m, 1H), 3.47 (dd, 1H), 3.32 (m, 3H), 2.74 (m, 1H), 2.65 (m, 1H), 2.18 (m, 2H), 2.01 (m, 1H), 1.87 (m, 1H); MS m/z 379, 381 (ES-1).
Reaction SMILES: [N+:1](=[C:3]([C:17]([CH3:19])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-:2].C(N(CC)CC)C.FC(S(O[Si:35]([CH3:38])([CH3:37])[CH3:36])(=O)=O)(F)F>C(Cl)Cl>[N+:1](=[C:3]([C:17]([O:18][Si:35]([CH3:38])([CH3:37])[CH3:36])=[CH2:19])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a suspension of p-nitrobenzyl α-diazoacetoacetate (236 mg, 1 mmole) and triethylamine (0.15 ml, 1.08 mmole) in CH2Cl2 (2 ml) was added at 0°-5° C. trimethylsilyl trifluoromethylsulfonate (0.22 ml) under a nitrogen atmosphere and the mixture was stirred for 30 minutes. To this clear yellow solution was added dry hexanes (30 ml) and the reaction mixture was stirred for 10 minutes. After removing the oily deposit, the hexanes solution was evaporated in vacuo to yield yellow solid which was redissolved in dry hexanes (50 ml). The insoluble material was filtered over Celite and the filtrate was evaporated in vacuo to obtain 277 mg (0.90 mmole, yield 90%) of the title compound as yellow crystals: ir (film) νmax : 2100 (N2), 1705 (ester), 1520 and 1345 cm-1 (NO2); 1Hmr (CDCl3) δ: 0.27 (9H, s, --SiMe ), 4.23 (1H, d, J=2 Hz, vinyl proton), 4.93 (1H, d, J=2 Hz, vinyl proton), 5.32 (2H, s, --CO2CH2Ar), 7.48 (2H, "d", J=9 Hz, aromatic protons) and 8.23 ppm (2H, "d", J=9 Hz, aromatic protons).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7](O)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:42]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]=2[C:32]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[CH2:31][CH2:30]2)=[O:33])=[CH:5][CH:4]=1
Reactant: O=C(c1cc2ccccc2[nH]1)N1CCN(c2ccccc2Cl)CC1
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(c2ccc(OC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Yield: 80 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 4,4'-dimethoxybenzhydrol (2.37 g, 9.71 mmol) and 1-(2-chlorophenyl)-4-(indol-2-ylcarbonyl)piperazine (3.0 g, 8.83 mmol) to give 4.0 g (yield: 81%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]>CN1CCCC1=O>[C:38]([O:37][C:36](=[O:42])[NH:35][C@H:30]1[CH2:31][CH2:32][CH2:33][CH2:34][C@H:29]1[NH:28][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:3]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: Cc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 150 °C
Yield: 36.1 %

Procedure:
6-Chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (130 mg, 0.49 mmol), N,N-diisopropylethylamine (0.17 mL, 0.986 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (211 mg, 0.986 mmol) were dissolved in N-methylpyrrolidinone (2 mL) and heated at 150° C. for 2 d. The reaction mixture was cooled and concentrated in vacuo, then diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) gave {(1S,2R)-2-[6-carbamoyl-5-(6-methyl-pyridin-2-ylamino)-pyridazin-3-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (78 mg, 35%) as a light brown amorphous residue. LCMS (EI/CI) m/z: 442 [M+H].
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11](OB(O)O)=[C:10]([F:19])[CH:9]=1.[F:20][C:21]1[CH:28]=[C:27](Br)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:27]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:20])[CH:28]=2)=[C:10]([F:19])[CH:9]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: OB(O)Oc1c(F)cc(CCC2OCCO2)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2c(F)cc(CCC3OCCO3)cc2F)cc1F
Yield: 66 %

Procedure:
To 300 ml of DMF were added 14 g (54 mmol) of 4-(1,3-dioxolan-2-ylethyl)-2,6-difluorophenylboric acid obtained in Step 2 of Example 1, 10 g (50 mmol) of 2-floro-4-bromobenzonitrile, 20 g (198 mol) of triethyl amine, 0.50 g (2.2 mmol) of palladium acetate, and 0.50 g (3.8 mmol) of triphenylphosphine, and the mixture was refluxed for 7 hours. The solvent was distilled off under reduced pressure. To the residue were added 700 ml of methylene chloride and 300 ml of a 10% aqueous ammonia, and the mixture was stirred. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (eluting solvent: toluene/ethyl acetate=5/1). The solvent was distilled under reduced pressure and the residue was washed with ethanol and then dried under reduced pressure to afford 11 g (33 mmol) of 1-(1,3-dioxolan-2-ylethyl)-3,5-difluoro-4-(3-fluoro-4-cyanophenyl)benzene.
Reaction SMILES: [O:1]=[C:2]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:7]1.[BH4-].[Na+]>CO>[OH:1][CH:2]([C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:7]1
Reactant: O=C(CCCN1CCCC(c2cccc(O)c2)C1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1cccc(C2CCCN(CCCC(O)c3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.3 %

Procedure:
A mixture of 230 mg (5 mmole) of 1-(4-oxo-4-[4-fluorophenyl]butyl)-3-(3-hydroxyphenyl)piperidine and 193 mg (5 mmole) of sodium borohydride in 20 ml of methanol was stirred at room temperature overnight. The solvent was removed by evaporation in vacuo, and the residue was partitioned between ethyl acetate and water. The layers were separated, the aqueous phase was further extracted with ethyl acetate, and all the ethyl acetate phases were combined. The resulting ethyl acetate solution was washed with water, followed by saturated sodium chloride, and then it was dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on 150 ml of silica gel, eluting with chloroform/methanol (9:1). The product-containing fractions were combined and evaporated in vacuo to give 125 mg (67% yield) of the title compound as a foam, containing chloroform of solvation.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH:20]=4)[CH:11]=[C:10]([C:25]([NH:27][CH2:28][C:29]4[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=4[CH3:35])=[O:26])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH:15]4[CH2:16][C:17]([CH3:23])([CH3:24])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]4)[CH:11]=[C:10]([C:25]([NH:27][CH2:28][C:29]4[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=4[CH3:35])=[O:26])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC(C)(C)NC(C)(C)C3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-4-carboxamide (0.15 g, 0.29 mmol) in MeOH (2 mL), 10% Pd/C in catalytic amount was added and stirred it at room temperature under a hydrogen balloon for 3 hr. On completion of reaction, reaction mixture was filtered through a celite bed and the filtrate concentrated under reduced pressure to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-indazole-4-carboxamide (0.09, 66.4%). LCMS: 504.25 (M+1)+; HPLC: 99.77% (@ 254 nm) (Rt;5.460); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H), 8.43 (t, 1H, J=5.2 Hz), 8.26 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 5.89 (s, 1H), 5.22-5.18 (m, 1H), 4.36 (d, 2H, J=5.2 Hz), 3.33 (1H merged with DMSO peak), 2.22 (s, 3H), 2.12 (s, 3H), 2.09 (m, 2H), 1.99-1.87 (m, 4H), 1.73-1.66 (m, 4H), 1.52 (m, 2H), 1.32 (s, 6H), 1.18 (s, 6H).
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][C:57]=2[CH3:58])[CH:53]([NH:59][C:60](=[O:74])[CH2:61][C:62]2[N:63]=[C:64]([C:67]4[C:72]([OH:73])=[CH:71][CH:70]=[CH:69][N:68]=4)[S:65][CH:66]=2)[C:52]3=[O:75])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[OH:73][C:72]1[C:67]([C:64]2[S:65][CH:66]=[C:62]([CH2:61][C:60]([NH:59][CH:53]3[C:52](=[O:75])[N:51]4[CH:54]3[S:55][CH2:56][C:57]([CH3:58])=[C:50]4[C:48]([OH:49])=[O:47])=[O:74])[N:63]=2)=[N:68][CH:69]=[CH:70][CH:71]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(-c4ncccc4O)n3)C2SC1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ncccc4O)n3)C2SC1
Yield: 92.8 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8l (167 mg, 0.279 mmol), Et3SiH (0.446 mL, 2.79 mmol), and trifluoroacetic acid (0.860 mL, 11.2 mmol) in dry ClCH2CH2Cl (6 mL) am 0° C. under nitrogen to give 9l (112 mg, 93%) as a yellowish solid after crystallization from THF/CH2Cl2 /hexane. mp 180° C. (dec); IR (KBr) 3540-2540 (br), 3280, 1774, 1725, 1661 cm-1 ; 1H NMR (DMSO-d6) δ1.97 (3H, s, CH3),3.30 (1H, d, J=18.0Hz), 3.51 (1H, d J=18.0 Hz), 3.79 (2H, s, CH2), 4.99 (1H, d, J=4.6 Hz), 5.56 (1H, dd, J=8.1 and 4.6 Hz), 7.37 (1H, dd, J=8.4 and 4.3 Hz), 7.44 (1H, dd, J=8.4 and 1.0 Hz), 7.58 (1H, s), 8.14 (1H, dd, J=4.3 and 1.0 Hz), 9.11 (1H, d, J=8.1 Hz, NH), 11.64 (1H, s, OH), 13.12 (1H, br s, CO2H); FDMS m/z 432 (M+), 433 (M+ +1); Anal. Calcd for C18H16N4O5S2 : C, 49.99; H, 3.73; N, 12.95. Found: C, 50.24; H, 3.58; N, 12.68.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:27][CH:28]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[CH:29]([OH:41])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH3:40])[CH:34]=1>CN(C=O)C>[F:49][C:47]1[CH:48]=[C:43]([CH:44]=[C:45]([F:50])[CH:46]=1)[CH2:42][C@H:28]([NH:27][C:1]([C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)=[O:12])[C@H:29]([OH:41])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH3:40])[CH:34]=1
Reactant: CCc1cccc(CNCC(O)C(N)Cc2cc(F)cc(F)c2)c1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc3c(c2)OCO3)c1
Reaction time: 8 h

Procedure:
To a solution of piperonylic acid (0.500 g, 3.01 mmol), EDC (0.867 g, 4.52 mmol), HOBT (0.611 g, 4.52 mmol) in anhydrous DMF (10 mL) was added a solution of TEA (1.67 mL, 12.04 mmol), 3-Amino-4-(3,5-difluoro-phenyl)-1-(3-ethyl-benzylamino)-butan-2-ol (1.693 g, 3.01 mmol), and anhydrous DMF (5 mL). Reaction mixture was stirred under nitrogen overnight. Quenched reaction mixture with 10% sodium bicarbonate (aq.) then extracted with ethyl acetate. Washed organic layer with 1N HCl, followed by a wash with 10% sodium bicarbonate (aq.). Dried organic layer over magnesium sulfate, filtered, then concentrated in vacuo, yielding the product. (ES+: 483.2)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[CH:14]=[N:15]O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH:10]([CH3:11])[CH3:12])[CH3:9])[C:4](=[O:13])[C:3]=1[C:14]#[N:15]
Reactant: CC(C)C(C)n1ccc(Cl)c(C=NO)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)C(C)n1ccc(Cl)c(C#N)c1=O
Temperature: 90 °C
Yield: 100.4 %

Procedure:
To a solution of 4-chloro-3-((hydroxyimino)methyl)-1-(3-methylbutan-2-yl)pyridin-2(1H)-one obtained in Step D (328 mg) in acetonitrile (3.0 mL) was added phosphorus oxychloride (0.126 mL) at room temperature. The reaction mixture was heated at 90° C. for 30 min, and cooled to room temperature. The reaction mixture was poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (305 mg).
Reaction SMILES: ClC1C2C(=CC(OC)=C(OC)C=2)N=CC=1.O[C:17]1[C:18]([CH:24]=[O:25])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:23][C:20]1[N:19]=[C:18]([CH:24]=[O:25])[CH:17]=[CH:22][CH:21]=1
Reactant: Cc1ccc(O)c(C=O)n1
Agent: CN(C)c1ccncc1
Agent: COc1cc2nccc(Cl)c2cc1OC
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(C=O)n1
Temperature: 150 °C
Reaction time: 3 h
Yield: 13.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (330 mg), 3-hydroxy-6-methyl-2-pyridinecarbaldehyde (200 mg), and 4-dimethylaminopyridine (360 mg) were suspended in o-dichlorobenzene (7 ml), and the suspension was stirred at 150° C. for 3 hr. The reaction solution was cooled to room temperature and was then purified by column chromatography using acetone-chloroform to give 3-[6,7-dimethoxy-4-quinolyl]oxy}-6-methyl-2-pyridinecarbaldehyde (24 mg, yield 5%).