Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[C:7]([C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=O)[CH:6]=[CH:5]2>[Pd].C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[C:7]([CH2:13][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:5]2
Reactant: Cc1cc2ccc(C(=O)CCC(=O)O)cc2cc1C
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc2ccc(CCCC(=O)O)cc2cc1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The β-isomer, 3-(6,7-dimethyl-2-naphthoyl)propanoic acid (6.58 g, 0.026 mole) was dissolved into 200 ml of THF in a hydrogenation pressure bottle. To the solution was carefully added 30% Pd/C (700 mg). The whole mixture was shaken for 15 hrs under H2 (40 psi) at room temperature. After releasing pressure, Pd/C was removed by passing the THF solution through the celite pad. The solution was concentrated to afford 4-(6,7-Dimethyl-2-naphthyl)butanoic acid as a gray solid material (6.21 g, 0.026 mole, 100% yield). mp 141.0°-142.0° C., 1H NMR (CDCl3)δ 1.98-2.12 (m,2H), 2.36-2.41 (m,8H), 2.81 (t, J=7.4 Hz,2H), 7.22 (d, J=8.3 Hz,1H), 7.49-7.55 (m,3H), 7.65 (d, J=8.3 Hz,1H), IR (KBr) cm-1 3700-3450,2920,1698, Anal. Calcd for C16H 18 O2 : C, 79.31; H, 7.49. Found: C, 79.28; H, 7.49.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].Cl.[F:15][C:16]1([F:23])[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1>>[F:15][C:16]1([F:23])[CH2:21][CH2:20][CH:19]([NH:22][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=2)=[O:13])[CH2:18][CH2:17]1
Reactant: NC1CCC(F)(F)CC1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: Cl
Product: O=C(O)c1ccc(C(=O)NC2CCC(F)(F)CC2)nc1

Procedure:
The title compound was synthesized in two steps. The first as described for Intermediate example I-97, starting from 5-(methoxycarbonyl)pyridine-2-carboxylic acid and 4,4-difluorocyclohexylamine hydrochlorid, and the second as described for Intermediate example I-98 at 55° C., starting from the product received in the first step which was first purified by column chromatography using a gradient of ethyl acetate in heptane. Total yield (two steps) 65%; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (dd, 1 H), 8.89 (d, 1 H), 8.43 (dd, 1 H), 8.13 (dd, 1 H), 3.95-4.07 (m, 1 H), 1.68-2.11 (m, 8 H); MS (ESI) m/z 285[M+H+], m/z 283[M−H+];
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9](OCC)=[O:10])=[C:4]([F:14])[CH:3]=1.[NH3:15]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([NH2:15])=[O:10])=[C:4]([F:14])[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1[nH]c(=O)c(Br)cc1F
Solvent: CCO
Product: NC(=O)c1[nH]c(=O)c(Br)cc1F
Temperature: 45 °C

Procedure:
In a round bottom flask charged with ethyl 5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxylate (4, 0.8 g, 3.03 mmol) at 0° C. was added liquid ammonia (15 mL, 3.03 mmol) in ethanol (5 mL). The stirred reaction mixture was warmed to 45° C. for 2 h. After the ester was completely consumed liquid ammonia and ethanol was evaporated under reduced pressure. Methanol was added and the mixture was refluxed for 2 h and filtered while hot. The volume of the filtrate was reduced by ⅔ and to the remaining methanol was added diethyl ether until solid precipitated. The solid was filtered and dried under vacuum to afford 5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxamide (5) as a light brown solid. Yield: 0.6 g, 85%; 1H NMR (400 MHz, DMSO-d6) δ 7.88-7.86 (m, 1H), 7.67 (s, 1H), 7.50 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:24]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=3[CH3:33])=[C:23]([F:34])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH:19]([OH:22])CO)[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.C1COCC1.P([O-])([O-])([O-])=O.I([O-])(=O)(=O)=O.[Na+]>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:24]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=3[CH3:33])=[C:23]([F:34])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH:19]=[O:22])[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1cc(Br)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CCCC(O)CO)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CCCC=O)c1F
Reaction time: 16 h
Yield: 82.3 %

Procedure:
To a mixture of 6-(4-bromo-2-methyl-phenylamino)-3-(4,5-dihydroxy-pentyl)-7-fluoro-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11m (0.244 g, 0.456 mmol), THF (5 mL) and pH 7 phosphate buffer (3 mL) is added sodium periodate (0.195 g, 0.911 mmol). After 16 hours, the reaction mixture is diluted with ethyl acetate and washed with NaHCO3, and brine. The organic layer is dried (Na2SO4) and concentrated under reduced pressure to give an orange solid. Purification by FCC eluted with 4:1 methylene chloride/MeOH yields 0.189 g (82%) pure desired product as a yellow solid: MS APCI (+) m/z 505, 503 (M+1 Br pattern) detected; MS APCI (−) m/z 503, 501 (M−1 Br pattern) detected.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:44]2[CH:43]=[N:42][C:41]([CH:39]=[O:40])=[N:46][CH:45]=2)[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ncccn1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(-c3cnc(C=O)nc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-N-methylpyrimidine-2-carboxamide.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[CH2:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:17]1[C:11]2[CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[C:7]([N:1]3[CH2:2][CH2:3][N:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:5][CH2:6]3)=[N:13][C:12]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccc2c(c1)Cc1ccccc1C(N1CCNCC1)=N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C2=Nc3ccccc3Cc3ccccc32)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
A mixture of 3.33 g of 6-(1-piperazinyl)-11H-dibenz[b,e]azepine, 1.63 g of ethyl chloroformate and 1.66 g of potassium carbonate in 20 ml of N,N-dimethylformamide was stirred at 80° C. for 3 hrs. Ice water was added to the reaction mixture and extracted with ether. The ether layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (1:2) as an eluent to give 3.14 g of colorless crystals, which were recrystallized from isopropyl ether to give colorless prisms, mp 137°-138° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:3]=1[CH3:26].[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[N:37][CH:38]=2)[CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:39][C:35]1[CH:36]=[N:37][CH:38]=[C:33]([N:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[CH:34]=1)=[C:3]([CH3:26])[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:5]2
Reactant: Cc1c(N2CCC[C@H]2C(=O)OC(C)(C)C)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCC[C@H]2C(=O)OC(C)(C)C)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using (S)-tert-butyl 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidine-2-carboxylate (260 mg, 0.68 mmol) and 5-morpholinopyridin-3-amine in toluene to give (S)-tert-butyl 1-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)pyrrolidine-2-carboxylate. 1H NMR (CDCl3) δ ppm 7.80 (1H, d, J=2.2 Hz), 7.65-7.75 (2H, m), 7.07-7.17 (1H, m), 6.90 (1H, br. s.), 6.60 (1H, ddd, J=13.1, 8.8, 2.5 Hz), 4.71 (1H, t, J=7.0 Hz), 3.83-3.94 (1H, m), 3.77-3.83 (4H, m), 3.67-3.77 (1H, m), 3.15-3.26 (4H, m), 2.28-2.43 (1H, m), 2.21 (3H, s), 2.08-2.19 (1H, m), 1.90-2.06 (2H, m), 1.45 (9H, s). Mass Spectrum (ESI) m/e=526.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][NH:27]2)=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][N:27]2[C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)=[CH:23][CH:22]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Fc1ccc2c(c1)NCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3ccc(F)cc32)nc(N2CCOCC2)cc1=O
Yield: 37.6 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 205 mg of 6-fluoroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 140 mg of 2-[2-(6-fluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a very pale pink powder, the characteristics of which are the following:
Reaction SMILES: [CH:1]([C:4]1([CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])SCCCS1)([CH3:3])[CH3:2].C[OH:16]>C(#N)C>[OH:14][CH:10]([CH2:11][CH2:12][CH3:13])[C:4](=[O:16])[CH:1]([CH3:3])[CH3:2]
Reactant: CO
Reactant: CCCC(O)C1(C(C)C)SCCCS1
Solvent: CC#N
Product: CCCC(O)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of (101) (5.0 g, 21.4 mmol) in acetonitrile (270 mL) was added under vigorous stirring a solution of Hg(ClO4)2 in methanol (30 mL). The resulting mixture was stirred at room temperature for 2 h. After filtration, the filtrate was carefully concentrated under reduced pressure without heating. Purification of the residue using silica gel flash column chromatography (10% ethyl acetate/hexane) provided 2.8 g (91%) of the title compound as colorless liquid. 1H NMR (CDCl3, 400 MHz): δ 0.91 (t, J=7.2 Hz, 3H), 1.09 (d, J=7.2 Hz, 3H), 1.10 (d, J=7.2 Hz, 3H), 1.35-1.46 (m, 4H), 1.75 (m, 1H), 2.80 (m, 1H), 3.45 (d, J=5.2 Hz, 1H), 4.29 (m, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][CH2:26]I>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([CH2:26][CH2:25][CH2:24][Cl:23])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC1CNCCO1
Reactant: ClCCCI
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CN(CCCCl)CCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
A solution of 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine (2.1 g, 9.07 mmol) in DCM (20 mL) was treated with triethylamine (3.8 mL, 27.2 mmol) and 1-chloro-3-iodopropane (1.95 mL, 18.1 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure then purified by MPLC (ISCO, 0% MeOH/100% DCM to 25% MeOH/75% DCM). The product was isolated as an oil (560 mg, 20%): HPLC MS RT=2.66 min, MH+=308.4, 310.4; 1H NMR (DMSO-d6) δ: 3.79-3.69 (1H, m), 3.63 (2H, t) 3.59-3.52 (1H, m), 3.50-3.36 (3H, m), 2.73 (1H, d), 2.61 (1H, d), 2.35 (2H, t), 1.94 (1H, td), 1.83 (2H, qt), 1.73 (1H, t), 0.83 (9H, s), 0.00 (6H, s).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][C@@H:12]([CH3:14])[C@@H:11]3[O:15][C:16](=[O:18])[NH:17][C@@H:10]3[CH2:9]2)=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:14][C@@H:12]1[CH2:13][NH:8][CH2:9][C@H:10]2[NH:17][C:16](=[O:18])[O:15][C@@H:11]12
Reactant: COc1ccc(CN2C[C@@H](C)[C@@H]3OC(=O)N[C@@H]3C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CNC[C@H]2NC(=O)O[C@@H]12
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (3aR,7R,7aS)-5-(4-methoxybenzyl)-7-methylhexahydrooxazolo[4,5-c]pyridin-2(3H)-one (1.0 equiv.) in methanol, at a concentration of 0.1M, was added 20% palladium hydroxide on carbon (0.3 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 2 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding (3aR,7R,7aS)-7-methylhexahydrooxazolo[4,5-c]pyridin-2(3H)-one (99%). LCMS (m/z): 157.1 (MH+).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12](I)[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:12]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH2:13][CH2:14][CH3:15]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1cc(C=O)ccc1OC
Temperature: 25 °C

Procedure:
Isovanillin (6.00 g, 39.4 mM), butyl iodide (5.7 ml, 49.3 mM), and anhydrous potassium carbonate (6.8 g, 49.3 mM) were dissolved in dried dimethylformamide (50 ml) and stirred at room temperature for one night, then the solution was diluted with ethyl acetate (300 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to obtain a residue as a light yellow oil. The residue was purified by flash chromatography (SiO2: eluted by 20% ethyl acetate/hexane solution). The solvent was removed in vacuo and the resultant product was dried to obtain 3-butoxy-4-methoxy-3-benzaldehyde 8.09 g (yield 99.0%) as a light yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:25][C:26](=[O:28])[CH3:27])([CH2:23][OH:24])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:12]=2)[CH2:7][CH:6]1O.C1(C)C(S(O)(=O)=O)=CC=CC=1.O.C(=O)(O)[O-]>C1(C)C=CC=CC=1>[OH:24][CH2:23][C:3]([NH:25][C:26](=[O:28])[CH3:27])([CH2:2][OH:1])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:12]=2)[CH2:7][CH:6]=1
Reactant: CCCCCCCCc1ccc2c(c1)CC(O)C2CC(CO)(CO)NC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc2c(c1)CC=C2CC(CO)(CO)NC(C)=O

Procedure:
Compound 18 (85 mg, 022 mmol) is dissolved in toluene (10 mL), toluenesulphonic acid (˜5 mg) is added, and the reaction heated to reflux for 3 hours with continuous removal of water from the condensed azeotrope. The reaction is cooled, then poured into aqueous bicarbonate (5% w/w, 10 mL) and the aqueous layer extracted with ether (5 mL) twice. The organic layers are combined and removed in vacuo to provide the crude residue that upon silica gel chromatography provide 19.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:3]1.[C:18]1([Mg]Cl)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[OH:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH:4]([N:7]2[C:8](=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]2=[O:16])[CH2:3]1
Reactant: Cl[Mg]c1ccccc1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)(c2ccccc2)C1
Reaction time: 2 h
Yield: 27.5 %

Procedure:
A solution of Example 58A (1.00 g, 4.36 mmol) and THF (20 mL) was cooled to <−70° C. and phenylmagnesium chloride (2.40 mL, 4.80 mmol) was added at <−70° C. After 2 hours, saturated aqueous NH4Cl (20 mL) was added and the mixture was extracted with MTBE (50 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was puridifed by flash column chromatography (0-20% EtOAc/hexanes, gradient elution), to provide the title compound (370 mg, 1.20 mmol, 27.6% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[C:21]([CH2:27][OH:28])[C:20]=1[CH3:29])=[O:17])(=[O:10])=[O:9].Cl[C:32]1C(C)=N[O:35][C:36]=1NS(C1C=CSC=1C(NC1C(C)=CC(C)=C(C(OC)=O)C=1C)=O)(=O)=O>>[Cl:1][C:2]1[C:3]([CH3:30])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[C:21]([CH2:27][O:28][C:36](=[O:35])[CH3:32])[C:20]=1[CH3:29])=[O:17])(=[O:10])=[O:9]
Reactant: Cc1cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C)c1CO
Reactant: COC(=O)c1c(C)cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c1C
Product: CC(=O)OCc1c(C)cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c1C

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylamino-carbonyl)thiophene-3-sulfonamide; and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4, 6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(diethyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M28) (0.53 g, 0.827 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (210 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21](O)=[O:22])[C:15](=[O:24])[C@@H:14]2[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:28]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]([N:32]3[CH2:33][CH2:34][C:29]4([CH2:27][CH2:28]4)[C@H:30]([OH:35])[CH2:31]3)=[O:22])[C:15](=[O:24])[C@@H:14]2[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O[C@@H]1CNCCC12CC2
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H]1C(=O)N(CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Yield: 55.3 %

Procedure:
To a solution of 3-{(S)-4-[(E)-3-(3-chloro-4-fluoro-phenyl)-acryloyl]-3-methyl-2-oxo-piperazin-1-yl}-propionic acid (50 mg, 0.14 mmol), (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 24 mg, 0.15 mmol) and 4-methylmorpholine (41 mg, 0.41 mmol) in N,N-dimethylformamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (77 mg, 0.20 mmol) at room temperature, then after 16 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; dichloromethane→dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (37 mg, 54%). White solid, MS: 478.2 (M+H, Cl)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:24])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]=1[CH3:23]>C1COCC1.CO>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([CH2:6][C:5]([OH:24])=[O:4])=[C:8]1[CH3:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccccc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccccc1
Reaction time: 5.5 h

Procedure:
1M Aqueous NaOH (364 μL, 0.364 mmol) is added to a stirring solution of (1-benzyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid methyl ester (65 mg, 0.22 mmol) in 5:1 THF/MeOH (2.4 mL). After 5.5 hours, the reaction is evaporated, and partitioned between water and EtOAc. The aqueous layer is acidified to pH 3, and the resulting precipitate collected by filtration to furnish 1-benzyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid; MH+=281.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[Cl:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: ClCc1ccccc1
Product: O=C(O)c1ccc(OCc2ccccc2)c(Cl)c1
Yield: 55.5 %

Procedure:
Using 3-chloro-4-hydroxybenzoic acid 1/2 hydrate (25 g, 0.14 mole) and benzyl chloride (52.3 g, 0.41 mole), the reaction was carried out in the same manner as described in Synthesis Example 1, (1) to give 20.4 g of 4-benzyloxy-3-chlorobenzoic acid as white crystals having a m.p. of 211°-213° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[C@H:11]([OH:14])[C@@H:10]([OH:15])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([OH:14])[C@@H:10]([OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H](O)[C@@H](O)C(=O)N1Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a mixture of (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (44 g, 199 mmol, 1.0 eq) and THF (176 mL) at 20° C. (vessel jacket temperature) was added borane-tetrahydrofuran complex (1.0 mol/L) in THF (800 mL, 800 mmol, 1.0 mol/L, 4.0 eq) at a rate to maintain the temperature between 20° C. and 25° C. Over 1 hr, the jacket temperature was ramped to 60° C. and then held for 1 hr. Upon completion, the reaction was cooled to 30° C. and quenched by the slow dropwise addition of MeOH (97 mL, 12 eq) to the mixture at a rate to control off gassing. The reaction mixture was then heated to reflux and concentrated to a low stir volume. The reaction solvent THF was then replaced by a constant volume displacement with MeOH (total of 1.5 L). Once the THF content had been reduced to less than 1 wt %, MeOH was replaced by a constant volume displacement with EtOAc (total of 1.5 L) to reduce the MeOH content to less than 1 wt %. The total volume of EtOAc was then readjusted to about 250 mL (6 vol) and then cooled to 5° C. to crystallize the product. The desired product was isolated by filtration, washed with cold EtOAc (88 mL) and dried to give title compound (27.0 g, 140 mmol, 70%). A second crop of product was isolated by concentration of the combined filtrate and cake wash to half volume, which was then cooled to 5° C., filtered and washed with cold EtOAc (50 mL) to afford additional title compound (4.5 g, 23 mmol, 12%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.26 (m, 4 H) 7.25-7.20 (m, 1 H) 4.48 (d, J=4.8 Hz, 2 H) 3.38-3.31 (m, 2 H), 3.57 (d, J=13.0 Hz, 1 H) 3.46 (d, J=13.0 Hz, 1 H) 2.74 (dd, J=9.4, 5.9 Hz, 2 H) 2.30 (dd, J=9.4, 4.4 Hz, 2 H). m/z (EI+) for C11H15NO2 194.2 (M+H)+.