Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].[OH-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CCc1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CCc1ccc(F)cc1F
Temperature: 80 °C

Procedure:
33 g (0.154 mol) of ethyl 3-(2,4-difluorophenyl)propanoate are suspended in 250 ml of water. 60 ml of 10N sodium hydroxide solution and 30 ml of 40% tetrabutylammonium hydroxide solution are then added. The mixture is stirred vigorously and warmed. Everything has dissolved at about 50° C. The mixture is warmed further to 80° C. and then cooled to 5° C. On dropwise addition of 80 ml of concentrated hydrochloric acid, white crystals precipitate, which are filtered off and washed with ice-water. After drying in vacuo, 28.1 g (98% of theory) of white crystals of melting point 107°-108° C., which does not change even after recrystallization from 50% ethanol, are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C@@H:28]([NH:33][C:34]([CH2:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1)=[O:35])[C:29]([F:32])([F:31])[F:30]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:42][CH2:41][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][C:34](=[O:35])[NH:33][C@H:28]([CH3:27])[C:29]([F:32])([F:30])[F:31])=[CH:44][CH:43]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C[C@@H](NC(=O)Cc1ccc(CN)cc1)C(F)(F)F
Product: C[C@@H](NC(=O)Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C(F)(F)F
Yield: 44.7 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (84 mg, 0.196 mmol) and (R)-4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzylamine (102 mg, 0.39 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain (R)-7-chloro-6-{4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (47 mg, 45%). MS (ES+) m/z: 536 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH:9]([CH3:22])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([O:20]C)[CH:12]=1)=O)(C)(C)C.[ClH:23].N1C=CC=CC=1>ClCCl.[OH-].[NH4+]>[ClH:23].[OH:20][C:13]1[CH:12]=[C:11]([CH2:10][CH:9]([NH2:8])[CH3:22])[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=1
Reactant: COc1cc(CC(C)NC(=O)OC(C)(C)C)c2occc2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(N)Cc1cc(O)cc2ccoc12
Temperature: 170 °C

Procedure:
A mixture of 0.73 gm (2.38 mMol) N-tert-butoxycarbonyl 1-(5-methoxybenzofur-7-yl)-2-aminopropane and 3.30 gm (28.52 mMol) pyridine hydrochloride were heated at 170° C. in a sealed tube for 15 hours. The mixture was cooled and the residue was dissolved in dichloromethane containing 10% methanol and 1% ammonium hydroxide. The solution was concentrated under reduced pressure and the pyridine remaining in the residue was removed azeotropically by diluting the residue with water and concentrating three times. The residue was crystallized from ethanol:diethyl ether. The 1-(5-hydroxybenzofur-7-yl)-2-aminopropane was recovered in the second crop and the filtrate. 0.045 gm (0.24 mMol) was treated with hydrochloric acid in diethyl ether to provide the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[CH:3]=[N:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:4]1[CH:3]=[N:2][NH:1][CH:5]=1)=[O:8]
Reactant: O=C(O)c1cn[nH]c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cn[nH]c1

Procedure:
A N,N-dimethylformamide solution (3 mL) of 4-pyrazolecarboxylic acid (150 mg, 1.34 mmol), N,O-dimethylhydroxylamine hydrochloride (261.4 mg, 2.68 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (513.8 mg, 2.68 mmol), 1-hydroxybenzotriazoleimidazole anhydride (54.2 mg, 0.40 mmol), and triethylamine (0.38 mL, 2.68 mmol) was stirred for 1 day. After completion of the reaction, the reaction solution was mixed with ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step (142.7 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[O:14]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][CH:4]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCC(=O)c1ccc(Sc2ccccc2)cc1
Temperature: 110 °C
Yield: 75.5 %

Procedure:
4-(4-Fluoro-phenyl)-4-oxo-butyric acid (10.0 g, 51 mmol), thiophenol (5.2 g, 51 mmol), thiophenol (5.2 g, 51 mmol) and powdered potassium carbonate (13.8 g, 100 mmol) were added to 25 mL of dimethyl sulfoxide (DMSO). The reaction mixture was heated to 110° C. for 2 hours, then cooled and diluted by addition of 250 mL water. The aqueous mixture was extracted three times with 100 mL of EtOAc, and the combined organic layers were dried (MgSO4), and evaporated under reduced pressure to yield 11 g (38.5 mmol, 75.5%) of 4-oxo-4-(4-phenylsulfanyl-phenyl)-butyric acid as a crude solid. MS: 287 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[C:16]([NH:23][CH2:24][CH2:25]Br)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:25][CH2:24][NH:23][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1H-Indole-6-carboxylic acid methyl ester (0.503 g, 2.87 mmol) and DMF (9.0 mL) under argon was cooled to 0° C. for 10 min. Sodium hydride (˜48%, 0.190 g, 3.80 mmol) was added and reaction warmed to room temperature for 30 min. 2-(Boc-amino)ethyl bromide (0.787 g, 3.52 mmol) was added and the reaction stirred for 17 hr. The reaction was quenched with H2O and extracted with ethyl acetate (3×). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0-50% EtOAc:Hexane). ESI-MS m/z 319 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](O)=[C:7]([Br:12])[N:6]=1)=[O:4].O=P(Cl)(Cl)[Cl:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Cl:15])=[C:7]([Br:12])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(O)c(Br)n1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cnc(Cl)c(Br)n1
Yield: 29 %

Procedure:
A mixture of 6-bromo-5-hydroxy-pyrazine-2-carboxylic acid methyl ester and 9.75 mL (10.7 mmol) POCl3 was refluxed for 3 h and subsequently quenched with 200 g ice. The mixture was extracted with DCM, the combined organic phases were dried with MgSO4 and evaporated to dryness the residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product fractions were combined and evaporated to dryness to yield 0.95 g (29%) of the title compound as light yellow solid. 300-MHz-1H-NMR (DMSO): δ=9.00 (s, 1H, 3-H), d=4.04 (s, 3H, OMe).
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:32][CH:31]([C:33](O)=[O:34])[CH2:30]2)=[CH:25][CH:24]=1)=[O:21].[CH2:36]1[C:44]2[C:39](=[CH:40]C=CC=2)[CH2:38][N:37]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:38][CH:39]([CH3:40])[CH2:44][CH2:36][NH:37][C:33]([CH:31]1[CH2:30][N:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])=[CH:28][CH:27]=2)[CH2:32]1)=[O:34]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-methylbutan-1-amine for 3-phenylpropan-1-amine and 1-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)phenyl)azetidine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.13 (s, 1H), 7.90 (t, J=5.5 Hz, 1H), 7.42 (d, J=4.8 Hz, 1H), 7.34-7.27 (m, 2H), 6.41-6.34 (m, 2H), 4.79-4.73 (m, 4H), 3.94-3.85 (m, 2H), 3.76-3.69 (m, 2H), 3.47-3.36 (m, 1H), 3.13-3.04 (m, 2H), 1.65-1.48 (m, 1H), 1.35-1.24 (m, 2H), 0.87 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 408 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:29])[C:7]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([C:26]#[N:27])[C:24]#[N:25])=[CH:19][CH:18]=2)=[CH:10][C:9]=1[CH3:28].C[O-].[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[C:7](=[C:8]2[C:9]([CH3:28])=[CH:10][C:11](=[CH:15][CH:16]=[C:17]3[CH:22]=[CH:21][C:20](=[C:23]([C:24]#[N:25])[C:26]#[N:27])[CH:19]=[CH:18]3)[CH:12]=[C:13]2[CH3:14])[C:6]([CH3:29])=[CH:5][N:4]([CH2:13][CH:8]([CH2:7][CH2:2][CH3:1])[CH2:9][CH2:10][CH2:11][CH2:15][CH3:16])[CH:3]=1
Reactant: Cc1cncc(C)c1-c1c(C)cc(C=Cc2ccc(C(C#N)C#N)cc2)cc1C
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCCC(CCC)CN1C=C(C)C(=c2c(C)cc(=CC=c3ccc(=C(C#N)C#N)cc3)cc2C)C(C)=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 131.3 %

Procedure:
To a solution of 2-propyl-1-heptanol (0.81 g, 5.1 mmol) in dry CH2Cl2 (15 mL) was added dropwise a solution of trifluoromethanesufonic anhydride (1.77 g, 6.10 mmol) in the same solvent (5 mL). After stirring at room temperature for 20 min, the reaction mixture was poured into ice (40 mL), and neutralized with saturated aqueous NaHCO3 solution. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give nearly pure 2-propyl-1-heptyl triflate as purple liquid (1.40 g, 94.1%). Next, 2-propyl-1-heptyl friflate (0.319 g 1.10 mmol ) was added dropwise to a solution of 19 (0.377 g, 1.00 mmol) in dry CH2Cl2 (20 mL). The reaction mixture was stirred at room temperature for 4 h. A solution of sodium methoxide in methanol (2.4 mL, 0.5 M) was then added dropwise to the resulting solution of pyridinium salt 20. The color of the mixture immediately changed from yellow to red. After stirring at room temperature for 10 min, the solvent was removed under reduced pressure. The resulting purple solid was then partitioned between water (50 mL) and CH2Cl2 (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 4:100 methnol: CH2Cl2, to give 0.340 g (65.7%) of the title compound as purple solid: mp 161-162° C.; 1H NMR (400 MHz, DMSO-d6): δ 9.039 (s, 2H), 7.418 (s, 2H), 7.286 (d, 2H, J=8.0 Hz), 7.145 (d, 1H, J=16.4 Hz), 6.919 (d, 1H, J=16.4 Hz ), 6.739 (d, 2H, J=7.6 Hz), 4.453 (m, 2H, J=5.2Hz), 2.125 (m, 1H), 2.074 (s, 6H), 1.859 (s, 6H), 1.319-1.219 (m, 12H), 0.849 (m, 6H); 13C NMR (125 MHz, DMSO-d6): δ 157.523, 142.592, 141.882, 138.688, 136.859, 133.320, 131.364, 129.981, 126.942, 125.704, 125.468, 121.582, 118.070, 64.195, 38.546, 32.695, 31.366, 30.156, 29.419, 25.061, 21.894, 19.010, 18.855, 16.581, 14.215, 13.942; MS (high resolution, EI): m/z 517.3451 [M+]; calcd, 517.3457; Anal. Calcd. for C36H43N3·1/3 H2O: C, 82.56; H, 8.40; N, 8.02. Found; C, 82.59; H, 8.11;N, 8.36.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[CH:27][C:28]=1[CH3:29].N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:26]1/[C:25]([OH:30])=[CH:24][C:23](=[NH:22])[C:28]([CH3:29])=[CH:27]/1
Reactant: Cc1ccc(O)cc1N
Reactant: Nc1c(N)n2n(c1=O)CCC2
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: CC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(O)=CC1=N

Procedure:
0.05 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 3-amino-4-methylphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].Cl.[NH2:14][NH2:15].C(N(CC)CC)C>C(O)C>[F:6][C:5]([F:8])([F:7])[C:4]1[CH:3]=[C:2]([NH2:1])[NH:14][N:15]=1
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cc(C(F)(F)F)n[nH]1

Procedure:
To a solution of (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one, (Compound [XXIV]) (7.00 g, 38.2 mmol, 1.0 eq.) in ethanol (150 mL) in a 250 mL round bottom flask was added hydrazine hydrochloride (2.75 g, 40.16 mmol, 1.05 eq.) followed by triethylamine (4.05 g, 40.16 mmol, 1.05 eq.). The reaction mixture was heated to reflux for 16 hours. After cooling and concentration, the residue was purified by silica gel chromatography using CHCl3-MeOH (10%) as the eluant to give Compound [XXV]: LCMS m/e 152 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 5.32 (s, 2H) 5.51 (s, 1H) 12.12 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:14](OCC)=O)[N:8]2[CH2:11][C:12]#[N:13])=[CH:4][C:3]=1[CH3:19].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C(OCC)(=O)C>CCOCC>[Cl:1][C:2]1[C:3]([CH3:19])=[CH:4][C:5]2[CH:6]=[C:7]3[CH2:14][NH:13][CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1cc2cc(C)c(Cl)cc2n1CC#N
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cc2cc3n(c2cc1Cl)CCNC3
Reaction time: 70 h
Yield: 19.4 %

Procedure:
Ethyl 6-chloro-1-(cyanomethyl)-5-methylindole-2-carboxylate (1.75 g, 6.3 mmol) was added portionwise over 2 min to a stirred solution of lithium aluminium hydride (0.61 g, 16 mmol) in ether (50 mL) at room temperature under Ar. The reaction was then heated to reflux and stirred for 70 h. The mixture was cooled to room temeperature, a further portion of lithium aluminium hydride (0.61 g) was added and the reaction was heated to reflux and stirred for 18 h. The mixture was allowed to cool and then poured into aqueous potassium sodium tartrate solution (200 mL) and ethyl acetate (150 mL). The mixture was filtered through celite and the aqueous and organic layers were separated. The aqueous was extracted with ethyl acetate (2×100 mL) and the combined organic extracts were washed with brine (1×100 mL) dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol, (100:0)→(9:1)] to give the product as a yellow solid (0.27 g, 19%). IR νmax (Nujol)/cm−1 3351, 3190, 2922, 2731, 1734, 1647, 1615, 1562, 1543, 1457, 1416, 1378, 1350, 1316, 1304, 1261, 1246, 1223, 1182, 1157, 1134, 1116, 1028, 983, 972, 962, 902, 883, 835, 800, 782, 732, 700, 666, 632, 617, 558, 510 and 496; NMR δH (400 MHz; CDCl3) 7.35 (1H, s), 7.25 (1H, s), 6.06 (1H, m), 4.16 (2H, s), 3.91 (2H, t, J 5.5 Hz), 3.31 (2H, t, J 5.5 Hz), 2.42 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19](=[O:24])NCOC)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH2:25]([Mg]Br)[CH3:26]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:24])[CH2:25][CH3:26])=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: COCNC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: C1CCOC1
Product: CCC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
2-[(Methoxymethylcarbamoyl)methoxy]pyrimidine-5-carboxylic acid (4-fluorophenyl)amide (prepared as in Example 4, 60 mg, 0.18 mmol) was suspended in 1.8 mL THF and cooled to 0° C. Ethyl magnesium bromide (1 M in THF, 0.45 mL, 0.45 mmol) was added dropwise while maintaining internal reaction temperature between 0° C. and 5° C. The reaction mixture was warmed to ambient temperature and held for 1 h. The reaction mixture was cooled back to 0° C. and a second addition (0.45 mL, 0.45 mmol) of Grignard reagent was performed. The reaction was warmed to ambient temperature and held for 2.5 hours. The reaction was quenched with 0.1 M HCl and diluted with ethyl acetate. The organic layer was separated, dried using Na2SO4 and concentrated to 36 mg of yellow oil. The crude material was purified by SiO2 chromatography to deliver 8 mg (15% yield) of the titled compound. ESI-MS m/z 304 (MH+), 302 (M−H−).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:19]2=[O:43])=[CH:15][CH:14]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ncccc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ncccc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 4.1 g of 5-{4-(1-methyl-1H-imidazo[4,5-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 31) and 160 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 1.45 g of the title compound, melting at 231-232° C.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)[S:6]1(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>O1CCCC1>[C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)[S:6]1(=[O:20])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)C=C(c2ccc(CO)cc2)S1(=O)=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C(=O)CC(c2ccc(CO)cc2)S1(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
A solution of 20-A of Example 1.20 (420 mg, 1.4 mmol) in tetrahydrofuran (8.4 mL) at 0° C. was treated with lithium tetrahydroborate (0.71 mL, 1.4 mmol, 2 M in tetrahydrofuran). The reaction mixture was stirred at 0° C. for 30 min and quenched with acetic acid (1 mL). The reaction mixture was concentrated and purified by preparative LCMS to yield 4.15-C (359 mg, 85%). LCMS found for C14H20NO4S (M+H)+: m/z=298.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[N:13]=[C:12]([Cl:18])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:10]2[Cl:25].[C:26]([CH:34]1[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[Cl:18][C:12]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:10]([Cl:25])[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]([C:26]([OH:33])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:34]3[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]3)[CH:8]=2)[N:13]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccccc2)CC1
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(O)(c2ccccc2)c2cc(C)c3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)CC1
Reaction time: 0.03 h

Procedure:
A solution of n-butyllithium (1.6 M in hexanes, 0.5 mL, 0.8 mmol) was added dropwise by syringe to a solution of 6-bromo-2,4-dichloro-8-methyl-3-phenylquinoline (0.32 g, 0.88 mmol, Intermediate 3) in dry deoxygenated THF (10 mL) at −78° C. After 2 minutes, a solution of 1-(4-benzoylpiperidin-1-yl)ethanone (0.203 g, 0.88 mmol, Intermediate 4) in dry THF (4 mL) was added dropwise by syringe. An additional 2 mL of THF was used to complete the quantitative addition. After 10 minutes, the flask was removed from the dry-ice bath and placed into an ice-water bath. After 1 hour, the reaction was quenched with saturated aqueous ammonium chloride solution and the mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was further extracted with EtOAc and washed with saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-100% EtOAc-DCM) to provide the title compound. MS m/e 519.1 (M+H)+.
Reaction SMILES: C([N:11]1[CH2:15][CH2:14][C:13]([CH2:22][CH2:23][N:24]2[CH2:30][CH2:29][CH2:28][N:27]([C:31]3[N:35]([CH2:36][CH2:37][O:38][CH2:39][CH3:40])[C:34]4[CH:41]=[CH:42][CH:43]=[CH:44][C:33]=4[N:32]=3)[CH2:26][CH2:25]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12]1)(OCC1C=CC=CC=1)=O.[Cl:45]CCl.Cl.O1CCOCC1>C(O)C.[Pd].[OH-].[Pd+2].[OH-].CCOCC>[ClH:45].[CH2:39]([O:38][CH2:37][CH2:36][N:35]1[C:34]2[CH:41]=[CH:42][CH:43]=[CH:44][C:33]=2[N:32]=[C:31]1[N:27]1[CH2:28][CH2:29][CH2:30][N:24]([CH2:23][CH2:22][C:13]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15][NH:11][CH2:12]2)[CH2:25][CH2:26]1)[CH3:40]
Reactant: ClCCl
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)OCc4ccccc4)C3)CC2)nc2ccccc21
Agent: [Pd+2]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reaction time: 72 h

Procedure:
Alternately, combine 1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (1.23 g, 2.06 mmol) in ethanol (20 mL). Add 10% palladium-on-carbon (0.2 g) and palladium hydroxide (0.2 g). Hydrogenate on a pressure apparatus at 50 psi. After 72 hours, remove the catalyst by filtration, and evaporate in vacuo to give a residue. Combine the residue and dichloromethane (50 mL). Add a solution of hydrochloric acid an dioxane (1.01 mL, 4 M, 4.0 mmol) and stir. After 3 hours, add dither ether (180 mL) to give a solid. Collect the solid by filtration and dry to give 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt: mp; 117-126° C.