Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]3[C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>C1COCC1.CCO>[F:1][C:2]1[CH:12]=[C:11]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]3[C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=2)[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)O3)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(C2=CC(C)(C)Oc3ccc(C#Cc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a solution of ethyl 2-fluoro-4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)chromen-6-yl]-ethynyl]-benzoate (Compound 273, 82.0 mg, 0.180 mmol) in 2.0 mL THF and 2.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 70.0 mg (91%) the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 7.93 (1H, d, J=7.8 Hz), 7.41 (1H, dd, J=2.1, 8.3 Hz), 7.37-7.25 (6H, m), 7.18 (1H, d, J=2.0 Hz), 6.91 (1H, d, J=8.3 Hz), 5.77 (1H, s), 2.69 (2H, q, J=7.6 Hz), 1.49 (6H, s), 1.24 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N+:11]([O-:13])=[O:12].[Br:15]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([Br:15])=[C:6]([OH:10])[C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: BrBr
Reactant: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(Br)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
To a solution of 3-hydroxy-2-nitrobenzoic acid methyl ester (11 g) in chloroform (220 ml) was added dropwise bromine (18.7 g). The reaction mixture was heated at reflux for 16 hours. The reaction mixture was allowed to cool to ambient temperature and the reaction quenched by addition of aqueous sodium metabisulfite (22 g in 100 ml water) and the mixture was stirred for 15 minutes. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was crystallized from diethyl ether/heptane to give 4-bromo-3-hydroxy-2-nitro-benzoic acid methyl ester (6.6 g). 1H-NMR (400 MHz, CDCl3): 9.92 (s, 1H), 7.84 (d, 1H), 7.09 (d, 1H), 3.93 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([SH:27])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[C:3]2[C:10]([S:27][C:25]3[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[O:28][CH3:29])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: COc1ccc(F)cc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1Sc1cn(COCC[Si](C)(C)C)c2ncnc(Cl)c12
Temperature: 50 °C
Yield: 26 %

Procedure:
4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.49 mmol), 5-fluoro-2-methoxybenzenethiol (96 μl, 0.73 mmol), copper(I) iodide (139 mg, 0.73 mmol), potassium carbonate (135 mg, 0.98 mmol) and 2 ml dimethylformamide as solvent according to Preparation 86 but heating the reaction mixture at 50° C. overnight. The residue was purified using SP1® Purification System (0% to 15%, hexane-ethyl acetate) to give 56 mg (26% yield) of the title compound.
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[C:3]([N+]([O-])=NC#N)[CH:2]=1.CO.[Si](O)(O)(O)[OH:18]>Cl>[OH:18][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:1][CH:2]=1
Reactant: O[Si](O)(O)O
Reactant: N#CN=[N+]([O-])c1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CO
Product: O=C(O)c1ccc(O)cc1

Procedure:
Degradation of calvatic acid in 1 N HCl containing 10% of methanol under reflux for 15 hours followed by silicic acid chromatography gave p-hydroxy-benzoic acid, melting at 210°-211° C., which was identified by comparison with the infrared spectrum of an authentic sample. Elemental analysis: found: C, 61.03; H, 4.76; N, 0.0, m/e 138; calcd. for C7H6O3 : C, 60.87; H, 4.38, m.w., 138. The data on high resolution mass spectrum of calvatic acid methyl ester is as follows:
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[F:13][CH:14]([CH2:19][CH2:20][CH2:21][CH3:22])[C:15](OC)=[O:16]>C1COCC1>[F:13][CH:14]([CH2:19][CH2:20][CH2:21][CH3:22])[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(F)C(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(F)C(=O)CP(=O)(OC)OC
Reaction time: 0.17 h

Procedure:
Dimethyl methylphosphonate (8.38 g) was dissolved in dry THF (250 ml) and cooled to -78° C. n-Butyllithium (1.6-M, 42 ml) was added dropwise, and the reaction was stirred for 10 minutes. The above methyl fluorocaproate (200 g) in THF (10 ml) was added dropwise. After addition, the mixture was stirred at -78° C. for 45 minutes, and then at room temperature for additional 45 minutes. The crude product obtained after the conventional work-up was chromatographed (hexane/ethyl acetate=1/1). Yield; 5.04 g (62 g)
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[N:11]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=1)[C:12](=[O:31])[CH2:13][C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1)=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[F:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:11]2[C@@H:7]3[C@@H:6]([CH2:10][CH2:9][CH2:8]3)[C:4]([OH:3])=[C:13]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:17]=4[S:16](=[O:30])(=[O:29])[N:15]=3)[C:12]2=[O:31])=[N:34][CH:35]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cn1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccc(F)cn3)C1=O)N2
Temperature: 60 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A solution of cis-2-{(5-fluoro-pyridin-2-ylmethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentane-carboxylic acid ethyl ester (0.085 g, 0.146 mmol) in ethanol (2 mL) was treated with a 21% w/w solution of sodium ethoxide in ethanol (0.218 mL) and stirred for 2 h at 60° C. Glacial acetic acid (0.200 mL) was added, the solvents were removed in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-{3-[1-(5-fluoro-pyridin-2-ylmethyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.052 g, 0.097 mmol, 66.5%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.47-1.69 (3H, m), 1.96-2.14 (3H, m), 3.06 (3H, s), 3.95-4.01 (1H, m), 4.61 (1H, bs), 4.96 (1H, d, J=16.5 Hz), 7.46-7.52 (2H, m), 7.56-7.58 (2H, m), 7.67-7.72 (1H, m), 8.51 (1H, d, J=3.5 Hz), 10.18 (1H, s). LC-MS (ESI) calcd for C22H22FN5O6S2 535.10, found 536.4 [M+H+].
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].[OH-].[NH4+].Cl>O.CO.N1C=CC=CC=1>[OH:8][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][NH:2][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:12]=[CH:11][C:9]=1[OH:10]
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)NCCc1ccc(O)c(O)c1
Reaction time: 5 h

Procedure:
Dissolve 15.0 g. of dopamine hydrochloride in 200 ml. of pyridine. With stirring, add 28.8 g. of pivalyl chloride (α,α-dimethylpropionylchloride) portionwise over a 2-hour period at room temperature. Stir at room temperature overnight. Add methanol (200 ml.), water (75 ml.) and concentrated ammonium hydroxide solution (50 ml.) to the reaction mixture and allow the clear solution to stand for 5 hours at room temperature. Pour the solution into 2 liters of 2N-hydrochloric acid and ice with vigorous agitation. Extract the oily precipitate with ethyl acetate. Wash the extract with saturated aqueous sodium bicarbonate solution, dry over sodium sulfate and evaporate to a residue. Remove the last traces of ethyl acetate in vacuo and crystallize the product from a 9:1 toluene:ethanol mixture to obtain the title product m.p. 143.5°-146°C.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[O:20][CH:21]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:15][CH2:16][C:17]1[CH:18]=[C:19]([Si:22]([CH2:25][CH3:26])([CH2:27][CH3:28])[CH2:23][CH3:24])[O:20][CH:21]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC[Si](CC)(CC)c1cc(CN)co1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NCc1coc([Si](CC)(CC)CC)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Dodecanoyl chloride (109 mg, 0.49 mmol) was added to a solution of 4-aminomethyl-2-triethylsilylfuran (Compound 29, 70 mg, 0.33 mmol) and triethylamine (69 microliter, 0.49 mmol) in tetrahydrofuran (3 ml) at room temperature. After stirring at room temperature overnight (ca. 15 hours), most of the solvent was evaporated and the residue was purified by chromatography on preparative silica thin layer plates (developed with 50% ethyl ether/hexane) to give the title amide as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][C:6]=1[NH2:28])C.[OH-].[K+].Cl>C(O)C.O>[NH2:28][C:6]1[CH:7]=[C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:9]=[CH:10][C:5]=1[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.7 %

Procedure:
In a solution of 0.6 g of crude 2-amino-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]benzoic acid ethyl ester in 7 ml of ethanol, a solution of 0.5 g of potassium hydroxide in 2.0 ml of water was added, and stirred at room temperature for 18 hours. After the completion of the reaction, 20 ml of ice water was added in the reaction mixture, adjusted to pH 2 to 3 with concentrated hydrochloric acid, and then extracted with ethyl acetate (20 ml×2). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.6 g of crude aimed product as yellow oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:14]([C:16]([O:20]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C[C@@H](N)CC1SC=CC=1>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]([C:16]([NH2:14])=[O:20])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: c1ccc(-c2ccccc2)cc1
Agent: CN(C)C[C@@H](N)Cc1cccs1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1-c1ccccc1
Reaction time: 2 h
Yield: 45 %

Procedure:
Biphenyl acid 10 (40 mg, 0.064 mmol, 1 eq) and HBTU (49 mg, 0.13 mmol, 2 eq) were dissolved in DMF (1 mL) followed by the addition of (S)-N1,N1-dimethyl-3-(thiophen-2-yl)propane-1,2-diamine (23 mg, 0.13 mmol, 2 eq). The reaction mixture was stirred for 2 h, diluted with EtOAc and quenched with a saturated aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford an oil. The crude oil was purified by silica gel chromatography (2-5% MeOH/DCM, 0.1% Et3N) to afford 23 mg of biphenyl amide 251. Yield 45%.
Reaction SMILES: C([O:8][C:9]1[N:10]([C:19]2[N:20]=[C:21]([NH2:27])[NH:22][C:23](=[O:26])[C:24]=2[N:25]=1)[C@@H:11]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1)C1C=CC=CC=1>CO.O.[Pd]>[OH:8][C:9]1[N:10]([C:19]2[N:20]=[C:21]([NH2:27])[NH:22][C:23](=[O:26])[C:24]=2[N:25]=1)[C@@H:11]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1
Reactant: Nc1nc2c(nc(OCc3ccccc3)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1nc2c(nc(O)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
The final stage of the synthesis is accomplished according to the published procedure of Lin et al. (J. Med. Chem. 28:1194-1198, 1985). A solution of 8-(benzyloxy)-2'-deoxyguanosine (0.20 g, 0.54 mmol) in a mixture of methanol (8 mL) and water (8 mL) is hydrogenated over 10% palladium on carbon (0.3 g) at 50 psi and room temperature for 18 hours. The catalyst is removed by filtration and the solvent evaporated to dryness to yield 8-hydroxydeoxyguanosine.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12](Cl)=[O:13])[CH2:9][CH3:10]>N1C=CC=CC=1>[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([O:7][CH2:1][CH:2]([O:6][C:12](=[O:13])[CH:11]([CH2:15][CH2:16][CH3:17])[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][O:5][C:12](=[O:13])[CH:11]([CH2:15][CH2:16][CH3:17])[CH2:8][CH2:9][CH3:10])=[O:13])[CH2:9][CH3:10]
Reactant: OCCC(O)CO
Reactant: CCCC(CCC)C(=O)Cl
Solvent: c1ccncc1
Product: CCCC(CCC)C(=O)OCCC(COC(=O)C(CCC)CCC)OC(=O)C(CCC)CCC

Procedure:
Into a perfectly clean and dry flask were introduced 106.1 g (1 mol) of rectified 1,2,4-butanetriol and 1600 ml of anhydrous pyridine. While stirring, 507.4 g (3.12 mols) of di-n-propylacetyl chloride were added in 60 to 90 minutes care being taken to maintain the temperature below 30° C. The reaction medium was then stirred at room-temperature for 72 hours. The subsequent operations of purification were identical to those carried out in the foregoing Example 13.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:19][CH2:20][Mg+].[Br-]>C1COCC1>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([OH:16])[CH2:19][CH3:20])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC[Mg+]
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reaction time: 2 h

Procedure:
To a solution of 6-(4-trifluoromethyl-phenyl)-pyridine-3-carbaldehyde (2.1 g, 8.3 mmol) in THF (20 mL) is added EtMgBr (3.0 M in Et2O, 3.2 mL, 9.6 mmol) at 0˜5° C., stirred for 2 hrs, quenched by NH4Cl aq., extracted with ethyl acetate, dried and concentrated giving 1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propan-1-ol (1.8 g) and [6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (0.29 g).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][N:14]([CH3:55])[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:54])[CH2:25][N:26]2[C:31](=[O:32])[C:30]3[CH:33]=[C:34]([CH2:36][CH3:37])[S:35][C:29]=3[N:28]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([C:45]4[C:46]([C:51]#[N:52])=[CH:47][CH:48]=[CH:49][CH:50]=4)=[CH:41][CH:40]=3)[C:27]2=[O:53])=[CH:20][CH:19]=1>O.C(OCC)(=O)C>[CH3:55][N:14]([CH3:13])[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:54])[CH2:25][N:26]2[C:31](=[O:32])[C:30]3[CH:33]=[C:34]([CH2:36][CH3:37])[S:35][C:29]=3[N:28]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=4[C:51]4[NH:3][C:4](=[O:7])[O:5][N:52]=4)=[CH:43][CH:44]=3)[C:27]2=[O:53])=[CH:20][CH:19]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OCCN(C)C)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OCCN(C)C)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.38 g), sodium hydrogencarbonate (0.58 g) and dimethyl sulfoxide (4 mL) was stirred at 50° C. for 30 min, 4′-{[3-(2-{4-[2-(dimethylamino)ethoxy]phenyl}-2-oxoethyl)-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.41 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.26 g, 57%).
Reaction SMILES: [CH:1]([N:3]1[CH2:7][C@H:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:30])[CH:21]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C@H:5]([C:31](O)=[O:32])[CH2:4]1)=[O:2].[NH2:34][OH:35]>>[CH:1]([N:3]1[CH2:7][C@H:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:30])[CH:21]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:11])[C@H:5]([C:31]([NH:34][OH:35])=[O:32])[CH2:4]1)=[O:2]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C=O)C[C@H]3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C=O)C[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 52 %

Procedure:
According to the procedure of Example 17, Step 5, the reaction of 175 mg of cis-1-formyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid with hydroxylamine provided 76 mg (52% yield) of cis-1-formyl-N-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxamide. MS: 485.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:64]=[CH:63][C:62]([C:65]2([NH2:68])[CH2:67][CH2:66]2)=[CH:61][CH:60]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:68][C:65]3([C:62]4[CH:63]=[CH:64][C:59]([C:58]([F:57])([F:69])[F:70])=[CH:60][CH:61]=4)[CH2:67][CH2:66]3)=[O:20])=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)O
Reactant: NC1(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)NC1(c2ccc(C(F)(F)F)cc2)CC1
Yield: 13.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoic acid (Intermediate-15, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropyl ethyl amine (2.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[4-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-13, 0.066 g, 0.320 mmol) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.37 (s, 4H), 3.95 (s, 3H), 7.42 (d, J=7.8 Hz, 2H), 7.50 (t, J=8.7 Hz, 1H), 7.63 (t, J=7.8 Hz, 4H), 7.73 (t, J=12.3 Hz, 3H), 8.85 (s, 1H), 12.50 (br s, 1H); MS (m/z): 546.99 (M+).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@@H:5]1[CH2:9][S:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:14][C:13]=3[NH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[N:6]1.O1CCCC1.[BH4-].[Li+].O>O1CCCC1>[CH:25]1([NH:24][C:13]2[CH:14]=[C:15]([CH2:19][S:20]([CH3:23])(=[O:21])=[O:22])[CH:16]=[C:17]3[C:12]=2[NH:11][C:10]([C:7]2[S:8][CH2:9][C@@H:5]([CH2:4][CH2:3][OH:2])[N:6]=2)=[CH:18]3)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)C[C@@H]1CSC(c2cc3cc(CS(C)(=O)=O)cc(NC4CCCC4)c3[nH]2)=N1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCO)CS3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.3 %

Procedure:
The compound (720 mg, 1.60 mmol) prepared in Example 68 was dissolved in tetrahydrofuran (20 ml). 2 M lithium borohydride tetrahydrofuran solution (1.6 ml, 3.2 mmol) was added thereto, and the mixture was stirred for 3 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give the title compound (292 mg, Yield 43%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1COCC1.O.[OH-].[Li+]>CO>[CH3:1][C:2]1[C:3]([C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)COc1ccc(-c2noc(-c3ccccc3)c2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(-c2ccc(OCC(=O)O)cc2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
To a solution of the product of step 1 (1.4 gm, 4.15 mmoles) in a mixture of methanol (10 ml), THF (30 ml) and H2O (10 ml), lithium hydroxide (0.35 gm, 8.30 mmoles) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water and acidified with 1N HCl. The solid separated which was filtered, washed with water & dried over P2O5 under vacuum to give 1.25 g of title product as pale brown solid.