Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:30]([CH3:31])=[CH:29][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:26]([CH3:27])=[CH:25][N:24]([CH3:28])[C:21]4=[N:22][CH:23]=3)[S:17][C:13]=2[C:12]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2N=C(C3C=C4C(C)=CNC4=NC=3)SC=2C=1C1C=CC(Cl)=CC=1)C(OC)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:30]([CH3:31])=[CH:29][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:26]([CH3:27])=[CH:25][N:24]([CH3:28])[C:21]4=[N:22][CH:23]=3)[S:17][C:13]=2[C:12]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(c3)c(C)cn4C)sc2c1-c1ccc(Cl)cc1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4[nH]cc(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc2nc(-c3cnc4c(c3)c(C)cn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Preparation (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetate: To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate (12 mg, 0.022 mmol) in DMF (5 mL) was added cesium carbonate (11 mg, 0.033 mmol). The reaction solution was stirred at room temperature for 5 minutes, iodomethane (4.7 mg, 0.033 mmol) was added. The reaction solution was stirred for 30 minutes and quenched with water. Volatiles were removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to give crude product which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C30H30ClN3O3S: 548.17 (M+H+); Found: 548.4 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.C(B(CC)[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)C.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:2]2[C:10]3[N:9]=[C:8]([N:11]4[CH2:12][CH2:13][N:14]([C:17]5[C:22]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:15][CH2:16]4)[NH:7][C:6]=3[CH:5]=[C:4]([C:27]([F:30])([F:28])[F:29])[CH:3]=2)[CH:35]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: FC(F)(F)c1cc(-c2cccnc2)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reaction time: 0.67 h

Procedure:
A mixture of 4-bromo-6-trifluoromethyl-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1H-benzoimidazole (99 mg, 0.2 mmol, Example 7), diethyl(3-pyridyl)borane (37 mg, 0.25 mmol, Aldrich), Pd(PPh3)4 (23 mg, 0.02 mmol, Aldrich), Na2CO3 (32 mg, 0.3 mmol) and dimethoxyethane (1 mL) was subjected to microwave irradiation at 200° C. with stirring for 40 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 60% EtOAc/hexane, to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 493 (M+1).
Reaction SMILES: C([C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([NH:19][CH:20](C)C)=[O:18])(=O)C1C=CC=CC=1.Cl.N[OH:25]>C(O)C>[NH:16]1[C:10]2[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:20]=[N+:19]([O-:25])[C:17]1=[O:18]
Reactant: NO
Reactant: CC(C)NC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccccc2c[n+]1[O-]

Procedure:
A stirred mixture of 6.34 g (0.02 mole) of 1-(2-benzoyl-4-chlorophenyl)-3-isopropylurea and 4.17 g (0.06 mole) of hydroxylamine hydrochloride in 100 ml of ethanol was refluxed for 48 hr, and then cooled. The suspended crystals were collected on a filter, washed with alcohol, and then dried in air to give 4.60 g (84%) of 6-chloro-4-phenyl-(2(1H)-quinazolinone 3-oxide as yellow crystals, mp 267°-269° (dec.).
Reaction SMILES: C[C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][O:3]1.OS(O)(=O)=O.N.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:23]O>C1(C)C=CC=CC=1>[O:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[C:7]([O:9][CH3:23])=[O:8]
Reactant: CO
Reactant: CC1(C(=O)O)CCCO1
Agent: N
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCO1
Temperature: 95 °C

Procedure:
To a mixture of methyl tetrahydrofuran-2-carboxylic acid (11.6 g, 100 mmol), MeOH (20 mL), and toluene (30 mL) was slowly added concentrated H2SO4 (6 g). The resulting biphasic mixture was heated in a sealed pressure vessel for 1 hour at 95° C. The reaction was then cooled to 0° C. and 7N NH3 in MeOH was added until the pH reached between 7 and 9. Na2SO4 was then added, and the reaction was passed through short plug of silica gel, eluting with DCM. The resulting mixture was distilled at 64° C. under vacuum to afford the product as a clear liquid.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[C:12]([F:13])=[C:11]([F:14])[CH:10]=[CH:9][C:8]=2OS(C(F)(F)F)(=O)=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(C(C)C)CC)(C)C.C([O-])(=O)C.[K+]>CN(C=O)C.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[F:14][C:11]1[CH:10]=[CH:9][C:8]2[CH:4]3[CH2:5][CH:1]([CH2:6][C:7]=2[C:12]=1[F:13])[CH:2]=[CH:3]3
Reactant: O=S(=O)(Oc1ccc(F)c(F)c1CC1CC=CC1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2c(c1F)CC1C=CC2C1
Temperature: 100 °C
Yield: 57.8 %

Procedure:
Trifluoro-methanesulfonic acid 2-cyclopent-3-enylmethyl-3,4-difluoro-phenyl ester (340 mg, 0.99 mmol), was dissolved In DMF (5 mL) under a N2 atmosphere and treated with diisopropylethylamine (0.28 mL, 1.5 mmol), potassium acetate (981 mg, 10.0 mmol) and tri-o-tolylphosphine (12 mg, 0.04 mmol). This mixture was stirred and degassed (3 vacuum/N2 purge cycles) and then treated with palladium acetate (5 mg, 0.02 mmol). After 20 min. the mixture was warmed to 100° C. for 18 hours, cooled and poured into brine (50 mL). The resulting mixture was extracted with hexanes (4×25 mL) and the combined organic layer was washed with a sat. aq. NaHCO3 soln. (10 mL), water (H2O) (10 mL), brine (10 mL), dried (magnesium sulfate (MgSO4)), filtered and and chromatographed on silica gel to provide an oil (110 mg, 60%). (TLC hexanes Rf 0.58). 1H NMR (CDCl3) δ6.80 (ddd, J=6.6,8.1,8.3 Hz, 1H), 6.68 (m, 1H), 6.17 (dd, J=5.5,2.8 Hz, 1H), 5.77 (dd, J=5.5,2.8 Hz, 1H), 3.29 (br s, 1H), 2.96 (br s, 1H), 2.84 (AB dd, J=17.9,5.0 Hz, 1H), 2.54 (AB d, J=17.9 Hz, 1H), 2.19 (m, 1H), 1.77 (d, J=10.5 Hz, 1H). GCMS m/e 192 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH2:16][C:17]1[C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[C:32]4[C:37](=[CH:38][CH:39]=3)[N:36]=[C:35]([C:40]([O:42]C)=[O:41])[CH:34]=[CH:33]4)=[CH:26][CH:25]=2)=[C:20]([CH:44]([CH3:46])[CH3:45])[O:19][N:18]=1)C(=O)C(F)(F)F.O1CCCC1.[OH-].[Na+].Cl>O.CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][CH2:16][C:17]1[C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[C:32]4[C:37](=[CH:38][CH:39]=3)[N:36]=[C:35]([C:40]([OH:42])=[O:41])[CH:34]=[CH:33]4)=[CH:26][CH:25]=2)=[C:20]([CH:44]([CH3:46])[CH3:45])[O:19][N:18]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CN(C(=O)C(F)(F)F)c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(CNc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 90 °C
Yield: 94.8 %

Procedure:
To a solution of methyl 6-[4-({[3-{[(2,6-dichlorophenyl)(trifluoroacetyl)amino]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (10 mg, 0.015 mmol) in 1:1 tetrahydrofuran:methanol (0.75 mL) was added 1 N sodium hydroxide (0.37 mL, 0.37 mmol). The solution was heated in a microwave reactor at 90° C. for 10 minutes. The solution was concentrated and the residue was taken up with ethyl acetate. Then 1 N hydrochloric acid (0.37 mL, 0.37 mmol) was added followed by water. The layers were separated and the aqueous layer was extracted one more time with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated to afford 6-[4-({[3-{[(2,6-dichlorophenyl)amino]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (8 mg, 100%). 1H-NMR (400 MHz, CDCl3) δ 8.46 (d, J=9 Hz, 1H), 8.31-8.24 (m, 2H), 8.11-8.07 (m, 2H), 7.69 (d, J=9 Hz, 2H), 7.25-7.20 (m, 2H), 7.07 (d, J=9 Hz, 2H), 6.84-6.80 (m, 1H), 4.96 (s, 2H), 4.60 (s, 2H), 3.24 (septet, J=7 Hz, 1H), 1.36 (d, J=7 Hz, 6H). HRMS (ESI) C30H25Cl2N3O4 calculated: 562.1300 (M+H)+, found: 562.1292 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])[CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH2:7][C:6]1=[O:25])(O)=[O:2].[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].ON1C2C=CC=CC=2N=N1.O>CN(C=O)C>[F:26][C:27]([F:35])([F:36])[C:28]1[CH:29]=[C:30]([NH:31][C:1]([CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[NH:20][C:19]4=[O:24])[CH:11]=[CH:12][C:13]=3[O:15][CH3:16])[CH2:8][CH2:7][C:6]2=[O:25])=[O:2])[CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC(=O)O)C(=O)CC2
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC(=O)Nc1cccc(C(F)(F)F)c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg of 5-(1-carboxymethyl-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione was dissolved in 5 ml of DMF. 0.35 ml of 3-trifluoromethyl aniline, 0.32 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(WSC), and 0.25 g of 1-hydroxybenzotriazole (HOBT) were added to the solution, followed by stirring at room temperature overnight. Water was added to the reaction liquid, and the solid thus obtained was separated by filtration. The solid was dissolved in methylene chloride, washed with sodium chloride solution, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1), giving 412 mg of 5-{1-[N-(3-trifluoromethylphenyl)amino]carbonylmethyl-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([NH:9][S:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1cnc(N)c(C)c1
Solvent: c1ccncc1
Product: Cc1cnc(NS(=O)(=O)c2ccc(F)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To a stirred solution of 3,5-dimethylpyridin-2-amine (129 mg, 1.056 mmol) in pyridine (5 mL) at room temperature, was added 4-fluorobenzene-1-sulfonyl chloride (205 mg, 1.056 mmol). The reaction mixture was stirred at 20° C. for 30 minutes, then left to stand for 16 hours. Additional 4-fluorobenzene-1-sulfonyl chloride (205 mg, 1.056 mmol) was then added and the reaction stirred for an additional 4 hours. The reaction mixture was concentrated in vacuo and purified by passing through an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol, followed by a sulphonic acid (SCX) SPE cartridge eluting with methanol then 2M ammonia/methanol. Concentration of the product-containing fractions provided the title compound (84.1 mg) as a yellow oil. LCMS (2 min, formic) Rt 0.89 min, m/z (ES+) 281 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2.Cl.N([O-])=O.[Na+].O>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2
Reactant: COc1ccc(N)c(-c2ccc3cc(OC)c(OC)cc3c2)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2ccc(-c3ccccc3N)cc2cc1OC
Reaction time: 8 h
Yield: 28.6 %

Procedure:
6-(2-Amino-5-methoxyphenyl)-2,3-dimethoxynaphthalene (33) (60 mg, 0.20 mmol) was dissolved in acetic acid (1.5 mL) and concentrated hydrochloric acid (0.3 mL). The solution was cooled in an ice bath and diazotized by dropwise addition of a solution of sodium nitrite (0.12 g in 1.2 mL water). The resulting diazonium solution was allowed to rise to room temperature slowly and left overnight. To the resulting red solution with some precipitate, 50 mL water was added and then extracted with ethyl acetate (40 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. Dried with anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 35:65 hexanes:ethyl acetate to give the pure 5 (16 mg) in 26% yield; mp 215-217° C.; IR (KBr) 2987, 1617, 1504, 1486, 1394, 1277, 1231, 1167 cm−1; UV (MeOH) 288, 262, 232 nm (log ε=4.71, 4.66, 4.58); 1H NMR (CDCl3) δ4.07 (3H, s), 4.09 (3H, s), 4.22 (1H, s), 7.29 (1H, s), 7.46 (1H, dd, J1=9.1, J2=2.6), 7.72 (1H, J=2.5), 7.99 (1H, d, J=8.9), 8.20 (1H, d, J=9.0), 8.60 (1H, d, J=9.1), 9.17 (1H, s); 13C NMR δ56.31, 56.51, 56.90, 100.27, 104.61, 107.73, 117.00, 118.66, 121.31, 124.25, 126.98, 129.09, 131.40, 133.34, 141.76, 143.70, 151.23, 151.31, 161.95; HRMS (EI) calcd for C19H16N2O3 m/z: 320.1161; found: 320.1144.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:16][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Product: CCCCNc1ccc2n[nH]c(=O)n2n1

Procedure:
17 g. of 6-chloro-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one (0.1 mol.) and 150 ml. of n-butylamine are refluxed for 5 hours. The clear solution is evaporated in vacuo and the oily residue is dissolved in 250 ml. of water. After treating with charcoal, the aqueous solution is acidified with dilute hydrochloric acid to give 18.6 g. (90%) of 6-butylamino-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one, which, after recrystallization from a mixture of acetonitrile and methanol (1:1), melts at 259°-261° .
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:36](I)[C:37]([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:27]=2)[C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CC(C(=O)Nc2ccc(I)cc2)c2ccc(O)cc2)cc1
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC(C(=O)Nc2ccc(I)cc2)c2ccc(OCC(C)(C)C)cc2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 4-[2-(4-hydroxy-phenyl)-2-(4-iodo-phenyl-carbamoyl)-ethyl]-benzoic acid methyl ester (Step D, 0.6 g, 1.60 mmol) in DMF (15 mL) at rt were added Cs2CO3 (2.07 g, 6.38 mmol) and Neopentyliodide (2.53 g, 12.7 mmol). The reaction mixture was heated at 80° C. for 14 h and cool to rt and after completion of the reaction, the solvent was removed under reduced pressure and poured into H2O (50 mL). The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was recrystallization in hexanes to afford 4-[2-(4-(2,2-dimethylpropoxy)-phenyl)-2-(4-iodo-phenyl-carbamoyl)-ethyl]-benzoic acid methyl ester as a yellow solid. (1.6 g, 88%): 1H NMR (300 MHz, CDCl3): δ 10.15 (s, 1H, NH), 7.80 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.35-7.26 (m, 6H), 6.82 (d, J=8.7 Hz, 2H), 3.93 (t, J=7.2 Hz, 1H), 3.77 (s, 3H), 3.54 (s, 2H), 3.35 (dd, J=9.0, 13.5 Hz, 1H), 2.98 (dd, J=6.6, 13.8 Hz, 1H), 0.94 (s, 9H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate/hexanes (1:3); Rf=0.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([OH:26])([C@H:17]([O:19]C1CCCCO1)[CH3:18])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@:10]([OH:26])([C@H:17]([OH:19])[CH3:18])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: C[C@@H](OC1CCCCO1)C(O)(Cn1cncn1)c1cc(F)c(F)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@H](O)[C@](O)(Cn1cncn1)c1cc(F)c(F)cc1F
Temperature: 55 °C
Yield: 63.1 %

Procedure:
A mixture of (3R)-2-(2,4,5-trifluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (740 mg) and pyridinium p-toluene sulfonate (PPTS, 200 mg) in ethanol (15 ml) was heated at 55° C. for 7 h. The reaction mixture was partitioned between ethyl acetate and water. The water layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, and concentrated to dryness in vacuo. Purification of the residue by silica gel chromatography, using dichloromethane:methanol (20:1) as an eluent, gave (2R,3R)-2-(2,4,5-trifluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (361 mg, 63%) as white amorphous.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH:10]([NH:25]C(OC(C)(C)C)=O)[C:9]1=[O:33])=[O:6])([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>C(Cl)(Cl)Cl>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH:10]([NH2:25])[C:9]1=[O:33])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)CN1C(=O)C(N)CN(C(=O)C(C)(C)C)c2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
1-tert-Butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1 g) was dissolved in chloroform (10 ml), 4N HCl-dioxane (5 ml) was added to the solution, and the mixture was stirred at 50° C. for one hour. After the reaction mixture was allowed to cool, crystals so precipitated were collected by filtration. The crystals were neutralized with saturated aqueous sodium bicarbonate, and extracted with methylene chloride, dried over anhydrous sodium sulfate, to thereby obtain 720 mg of the titled compound (Yield: 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].C([N:39]1[CH2:44][CH2:43][O:42][C@@H:41]([CH2:45][NH2:46])[CH2:40]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:46][CH2:45][C@@H:41]2[O:42][CH2:43][CH2:44][NH:39][CH2:40]2)=[O:19])[CH:8]=1)=[O:5]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Reactant: NC[C@H]1CN(Cc2ccccc2)CCO1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=C(NC[C@H]1CNCCO1)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to the method described for Example 3 using 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105) and (S)-(4-benzylmorpholin-2-yl)methanamine. The residue was dissolved in DCM and treated with 1-chloroethyl chloroformate (37.2 μL, 0.192 mmol) and stirred at room temperature for 4 hours. The reaction was concentrated in vacuo, methanol (4 mL) was added, and the resulting solution stirred for 2 hours at 65° C. The reaction was concentrated in vacuo, and the residue purified by elution through an SCX cartridge followed by silica gel column chromatography eluting with 2% NH3(aq) and 8% propan-2-ol in dichloromethane.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH:11]=2)=[C:6]([O:22][CH3:23])[CH:5]=1)([CH3:3])[CH3:2]>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[C:6]([O:22][CH3:23])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)C)ccc1-c1coc2c(C)c(C)cc(C)c12
Solvent: CO
Product: COc1cc(C(C)C)ccc1C1COc2c(C)c(C)cc(C)c21
Yield: 79 %

Procedure:
Using 3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-1-benzofuran obtained in Reference Example 188, the title compound was synthesized in the same manner as in Reference Example 199. Yield 79%. Melting point: 102-103° C. (methanol).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([Cl:19])=[N:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:20][C:21](=[O:34])[NH:22][C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH3:31])=[CH:25][C:24]=2[O:32][CH3:33])[C:9]1=[O:35])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:19][C:15]1[C:12]2[C:13](=[O:14])[N:8]([CH2:7][C:6]([OH:36])=[O:5])[C:9](=[O:35])[N:10]([CH2:20][C:21](=[O:34])[NH:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH3:31])=[CH:25][C:24]=3[O:32][CH3:33])[C:11]=2[CH:18]=[CH:17][N:16]=1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3c(Cl)nccc32)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3c(Cl)nccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vial containing a solution of {5-Chloro-1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-pyrido[4,3-d]pyrimidin-3-yl}-acetic acid tert-butyl ester (Intermediate T) (10.1 mg, 0.019 mmol) in DCM (1 ml), TFA (1 ml) is added. The reaction mixture is stirred at RT for 2 hours, transferred to a 10 ml round bottomed flask, diluted with a minimal amount of DCM and concentrated in vacuo. The residue is taken up in a minimal amount of DCM and concentrated in vacuo. This process is repeated once with DCM, twice with EtOAc, and once with MeOH, the solvent being concentrated in vacuo each time, finally giving the title compound.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][NH:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:28])[C@H:13]([CH:25]([CH3:27])[CH3:26])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[Li+].[OH-].Cl>C1COCC1>[C:15]([NH:14][C@H:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([NH:5][CH2:4][C:3]([OH:30])=[O:2])=[O:29])=[O:28])[CH:25]([CH3:27])[CH3:26])([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: COC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC(=O)O
Reaction time: 8 h

Procedure:
To a solution of N-Cbz-valylprolylglycine methyl ester (Cbz-NH-[VPG]-CO2CH3) (4.2 g, 10 mmol) in THF (20 mL) is added a 1M aqueous solution of LiOH (11 mL, 11 mmol) and the solution is stirred overnight. The resulting solution is acidified to pH about 7 with 1M HCl and the contents of the flask partitioned between water (30 mL) and ethyl acetate (30 mL). The organic phase is extracted with brine, dried over Na2SO4 then concentrated in vacuo to afford the desired compound.