Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:26]1([C:32]2[O:33][C:34]([CH3:50])=[C:35]([CH2:37][CH2:38]OS(C3C=CC(C)=CC=3)(=O)=O)[N:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:38][CH2:37][C:35]4[N:36]=[C:32]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:33][C:34]=4[CH3:50])=[CH:9][CH:8]=3)[C:4]([OH:3])=[O:25])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C)(Oc2ccc3c(c2)OCO3)C(=O)O)cc1

Procedure:
Standard Procedure (B) was utilized to prepare the title compound from 2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.96-7.93 (m, 2H), 7.44-7.41 (m, 3H), 7.13 (d, 2H, J=8.79 Hz), 6.78 (d, 2H, J=8.79 Hz), 6.60 (d, 1H, J=8.79 Hz), 6.41 (d, 1H, J=2.44 Hz), 6.32 (dd, 1H, J=8.79 Hz, J=2.44 Hz), 5.88 (d, 2H, J=0.98 Hz), 4.17 (t, 2H, J=6.35 Hz), 3.15 (d, 1H, J=14.16 Hz), 3.04-3.00 (m, 3H), 2.38 (s, 3H), 1.30 (s, 3H); HRMS (ES+) m/z exact mass calcd for C29H28NO7 502.1866, found 502.1881.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]2[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)[CH:17]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].C(N(CC)CC)C>ClCCl>[C:38]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]4[CH:37]=[CH:36][C:27]5[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=5[CH:25]=4)[CH:17]=3)=[C:4]([CH3:15])[CH:5]=2)[CH2:14][CH2:13]1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCNCC5)cc4C)c3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(C(C)=O)CC5)cc4C)c3)ccc21
Reaction time: 2 h
Yield: 46 %

Procedure:
(S)-Methyl 2-(6-((2′,6′-dimethyl-4′-(piperidin-4-yloxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 4a (20 mg, 0.04 mmol) was dissolved in 2 mL of dichloromethane, followed by addition of acetic anhydride (5 mg, 0.05 mmol) and triethylamine (12 mg, 0.12 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the title compound (S)-methyl 2-(6-((4′-((1-acetylpiperidin-4-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 6a (10 mg, yield 47.0%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.S(Cl)([Cl:32])=O>>[Cl:32][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCN(C)CC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Yield: 53 %

Procedure:
6-Methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-3,4-dihydroquinazolin-4-one (2.15 g, 6.48 mmol) was suspended in thionyl chloride (25 ml) and DMF (0.18 ml) and stirred under reflux for 2 hours. The thionyl chloride was evaporated under vacuum and the residue azeotroped twice with toluene. The residue was taken up in water, basified with saturated with aqueous sodium hydrogen carbonate solution and the aqueous solution extracted 4 times with dichloromethane. The combined extracts were washed with water and brine then filtered through phase separating paper. The filtrate was evaporated under vacuum and the residue purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1) to give a solid which was triturated with a little acetone, filtered and dried to give 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (1.2 g, 53%). This was used without further purification.
Reaction SMILES: C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[N:23]1([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:32]3=[N:33][CH:34]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C([O-])(O)=O.[Na+]>C1COCC1>[N:23]1([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(N3CCOCC3)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: c1cc2cc(N3CCOCC3)cnc2[nH]1
Temperature: 60 °C
Reaction time: 6 h
Yield: 35.5 %

Procedure:
Ethylenediamine (0.090 mL, 1.35 mmol) and 1M solution of TBAF in THF (2.70 mL, 2.70 mmol) were added to a solution of 52 (0.300 g, 0.90 mmol) in THF (5 mL). The mixture was stirred at 60° C. for 6 hours. More 1.0 M TBAF solution (1.80 ml, 1.80 mmol) was added and stirring was continued at 60° C. for 42 hours. The mixture was cooled, and poured into saturated aqueous NaHCO3 solution and extracted with AcOEt. The organic layer was washed with brine, dried (MgSO4), and concentrated to afford a tan solid. The solid was recrystallized from AcOEt to afford 53 (0.065 g) as a pale yellow crystalline solid. The mother liquors were concentrated and successively purified by means of SGC with AcOEt: MeOH as eluent and preparative TLC with CH2Cl2:MeOH as eluent to afford additional 53 (0.060 g, total yield: 0.125 g, 68%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.05-3.09 (m, 4H), 3.83-3.87 (m, 4H), 6.36 (dd, J=0.35, 0.20 Hz, 1H), 7.22 (dd, J=0.33, 0.25 Hz, 1H), 7.45 (d, J=0.25 Hz, 1H), 8.07 (d, J=0.25 Hz, 1H), 8.97 (bs, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CS(C)=O.O>[C:17]([N:24]1[CH2:25][CH2:26][N:27]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:28][CH2:29]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a suspension of 1-fluoro-4-nitrobenzene (1.4 mL, 13 mmol) and potassium carbonate (2.5 g, 18 mmol) in DMSO (10 mL) was added 1-Boc-piperazine (2.75 g, 14.8 mmol). The mixture was stirred at 100° C. for 2 hours. After cooing down, the mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried with sodium sulfate (Na2SO4), and concentrated in vacuo to afford a yellow solid. Recrystallization from EtOAC/hexanes gave 4.0 g of 1-(4-Boc-piperazin-1-yl)-4-nitrobenzene, which was reduced via hydrogenation to give the title compound (purple solid, 3 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.68 (d, J=8.8 Hz, 2H), 6.64 (d, J=8.8 Hz, 2H), 3.56 (t, J=5.0 Hz, 4H), 2.96 (t, J=5.0 Hz, 4H), 1.46 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])=[O:7])C[CH2:2]1.C(Cl)(=O)C(C)(C)C.C(O)(=O)CCC=C.CN1CCOCC1.C([Li])CCC.CCCCCC.CC([C@H]1COC(=O)N1)C.[NH4+].[Cl-]>C1COCC1.O>[CH3:15][CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6](=[O:7])[CH2:5][CH2:4][CH:1]=[CH2:2])[CH3:14]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCC1CC1
Agent: C=CCCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)[C@H]1COC(=O)N1
Solvent: CN1CCOCC1
Solvent: CCCCCC
Solvent: O
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(3-Cyclopropyl-1-oxopropyl)4(S)-(1-methyl-ethyl)-2-oxazolidinone: A solution of mixed anhydride was prepared by adding under a N2 atmosphere pivaloyl chloride (14.8 mL, 120 mmol) over a period of 5 min to a cooled solution (0° ) of 4-pentenoic acid (12.3 mL, 120 mmol) and N-methylmorpholine (15.4 mL, 140 mmol). The mixture was stirred at 0° or 30 min. Meanwhile, a second solution was prepared by adding dropwise under a N2 atmosphere a 1.4M solution of butyllithium in hexane (71 mL, 100 mmol) to a stirred cooled solution (-78° ) of (S)-4-(1-methylethyl)-2-oxazolidinone [12.9 g, 100 mmol, described by L. N. Pridgen et al., J. Org. Chem., 54, 3231 (1989)] in dry THF (300 mL) over a period of 45 min. (Note: The agitation was done by an overhead stirrer.) After stirring for 15 min at -78° , the latter solution was added by cannulation to the stirred solution of the mixed anhydride at -78° over a period of 20 min. The mixture was stirred for an additional 30 min at the same temperature. A saturated aqueous solution of NH4Cl (50 mL) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with H2O (300 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3×). The combined organic phases were dried (Na2SO4) and evaporated to dryness under reduced pressure to give an oily residue [i.e. 4(S)-(1-methylethyl)-3-(1-oxo-4-pentenyl)-2-oxazolidinone].
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:39])([CH2:36][CH2:37][CH3:38])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][N:16]2[C:21]([O:22][CH2:23][CH2:24][CH:25]([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:20][C:19]([CH3:34])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:39])([CH2:36][CH2:37][CH3:38])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][N:16]2[C:21]([O:22][CH2:23][CH2:24][CH:25]([C:30]([F:33])([F:32])[F:31])[C:26]([F:27])([F:28])[F:29])=[CH:20][C:19]([CH3:34])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.8 %

Procedure:
A solution of 30 mg (0.051 mmol) of rac-{1-[({2,5-dimethyl-7-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]pyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 142A) in 2 ml of dichloromethane was admixed with trifluoroacetic acid (0.117 ml). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated off under reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was removed and concentrated under reduced pressure, and the residue was purified by preparative HPLC chromatography (Method 21), which gave 1.68 mg (7% yield) of the target compound.
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH3:41])[C@@H:3]([C:16]([N:18]1[CH2:26][C@H:25]([O:27][C:28]2[C:37](Cl)=[N:36][C:35]3[C:30](=[CH:31][C:32]([O:39][CH3:40])=[CH:33][CH:34]=3)[N:29]=2)[CH2:24][C@H:19]1[C:20]([O:22][CH3:23])=[O:21])=[O:17])[NH:4][C:5]([O:7][C@@H:8]1[CH2:10][C@H:9]1[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])=[O:6].[B-](F)(F)(F)[CH:44]=[CH2:45].[K+].C(N(CC)CC)C>CCO.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][C:2]([CH3:42])([CH3:41])[C@@H:3]([C:16]([N:18]1[CH2:26][C@H:25]([O:27][C:28]2[C:37]([CH:44]=[CH2:45])=[N:36][C:35]3[C:30](=[CH:31][C:32]([O:39][CH3:40])=[CH:33][CH:34]=3)[N:29]=2)[CH2:24][C@H:19]1[C:20]([O:22][CH3:23])=[O:21])=[O:17])[NH:4][C:5]([O:7][C@@H:8]1[CH2:10][C@H:9]1[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])=[O:6]
Reactant: C=C[B-](F)(F)F
Reactant: C=CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)N1C[C@H](Oc2nc3cc(OC)ccc3nc2Cl)C[C@H]1C(=O)OC)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: C=CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)N1C[C@H](Oc2nc3cc(OC)ccc3nc2C=C)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution (0.1 M) of methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valyl-(4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate in EtOH was treated with potassium trifluoro(vinyl)borate (1.5 eq) and triethylamine (1.5 eq). The resulting mixture was degassed, then PdCl2(dppf)-CH2Cl2 adduct (0.1 eq) was added. The mixture was heated under reflux for 1 h, then cooled to room temperature and diluted with H2O and EtOAc. The organic phase was separated, washed with H2O and brine then dried. Removal of the volatiles afforded a residue that was purified by flash chromatography (20-30% EtOAc/petroleum ether) to give the title compound as a yellow foam that was used directly in the subsequent step. MS (ES+) m/z 595 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:12]=1[CH3:13])[C:7]([O:9]CC)=O.[Li+].CC([N-]C(C)C)C.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].CC(O)=O>C1COCC1>[Br:1][C:2]1[C:12]2[CH2:13][CH2:24][CH:23]([C:22]([O:26][CH3:27])=[O:25])[C:7](=[O:9])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: CCOC(=O)c1cncc(Br)c1C
Reactant: C=CC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CCc2c(Br)cncc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
Ethyl 5-bromo-4-methylnicotinate (7.04 g, 28.8 mmol) in THF (28.8 mL) was added over a period of 20 min to a solution of LDA (31.7 mmol) [generated from N,N-diisopropylamine (4.52 ml, 31.7 mmol) and n-butyllithium (19.8 mL, 31.7 mmol, 1.6M in hexane) in 144 mL THF] at −78° C. The resulting dark red solution was stirred for 20 min, then methyl acrylate (6.21 g, 72.1 mmol) in THF (28.8 mL) was added over 15 min. The reaction was stirred an additional 1.5 h, then aq. 10% AcOH was added (resulting pH=4-5) and the reaction was allowed to warm to room temperature. After evaporation, the residue was poured on aq. sat. NaHCO3 and extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4) and concentrated to afford the title compound (7.80 g, 95% in 70% purity with 30% starting material) as brown solid. MS: 284.0 (M+H+, 1Br).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH:20]1[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C4CC=CCC4)cc3c2c1C
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3ccc(C4CCCCC4)cc3c2c1C
Yield: 54.5 %

Procedure:
100 mg (0.3 mmol) of 6-(1-cyclohexen-4-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester is hydrogenated in 20 ml of ethanol with 0.1 g of Raney nickel at room temperature for 2 hours under 10 bar. After separating from the catalyst, the product is evaporated and reprecipitated from a small amount of ethanol/hexane, thus obtaining 55 mg (54.7% of theory) of 6-cyclohexyl-4-methyl-3-β-carboline carboxylic acid ethyl ester, mp 191°-193° C.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]2[N:10]([C:14]3[CH:19]=[C:18]([S:20]([C:23]([CH3:31])([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:24])(=[O:22])=[O:21])[C:17]([O:32][CH3:33])=[CH:16][C:15]=3[Cl:34])[C:11](=[O:13])[NH:12][C:7]2=[C:6]([CH3:35])[CH:5]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:44]([O:46][C:47]([O:49][CH:50](Cl)[CH3:51])=[O:48])[CH3:45]>CN(C)C=O.C(OCC)(=O)C>[Cl:34][C:15]1[CH:16]=[C:17]([O:32][CH3:33])[C:18]([S:20]([C:23]([CH3:24])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:31])(=[O:22])=[O:21])=[CH:19][C:14]=1[N:10]1[C:8]2=[N:9][C:4]([C:1]([O:3][CH:44]([O:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH3:45])=[O:2])=[CH:5][C:6]([CH3:35])=[C:7]2[NH:12][C:11]1=[O:13]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(C)cc(C(=O)O)nc32)cc1S(=O)(=O)C(C)(C)c1ccccc1
Reactant: CCOC(=O)OC(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)OC(C)OC(=O)c1cc(C)c2[nH]c(=O)n(-c3cc(S(=O)(=O)C(C)(C)c4ccccc4)c(OC)cc3Cl)c2n1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 5-carboxy-3-[2-chloro-4-methoxy-5-(1-methyl-1-phenyl-ethylsulfonyl)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (49 mg), potassium carbonate (17 mg) and potassium iodide (8 mg) in N,N-dimethylformamide (1 mL) was added 1-ethoxycarbonyloxyethyl chloride (0.015 mL), and the mixture was stirred at 60° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/2) to give the title compound (29 mg).
Reaction SMILES: C([O:3][C:4](=[S:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])C.O.[OH-].[K+].Cl>C1COCC1>[CH2:11]([CH:5]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:4]([OH:3])=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=S)C(Cc1ccccc1)CC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CC(Cc1ccccc1)C(O)=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 g of 2-benzyl-3-tert.-butylthio-propionic acid ethyl ester is dissolved in 5 ml of THF, and 3.2 ml of water and 0.9 ml of 2N potassium hydroxide solution are added thereto. The mixture is stirred overnight at room temperature, neutralised with 0.9 ml of 2N hydrochloric acid and concentrated by evaporation. The residue is purified by flash chromatography on 30 g of silica gel 60 (eluant H). Yellow oil, 1H-NMR (DMSO-d6): 1.23 ppm (s, 9H); 2.55-2.9 (m, 5H); 7.15-7.3 (m, 5H); 12.4 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[F:27].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:20][C:21]2[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=2[F:27])=[O:19])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc(O)ccc1F
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)c1cc(NC(=O)Nc2cc(O)ccc2F)no1
Temperature: 50 °C
Yield: 68.2 %

Procedure:
To a stirred suspension of phenyl 5-tert-butylisoxazol-3-ylcarbamate (prepared as described in Example 270A) (260 mg, 1 mmol) and 3-amino-4-fluorophenol (127 mg, 1 mmol) in acetonitrile (15 mL) at rt, was added DBU (0.3 mL, 2 mmol). The mixture was heated at 50° C. for 1 h. The reaction mixture was cooled to rt, concentrated under reduced pressure, and the residue purified via silica gel column chromatography to afford 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (200 mg, 68%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (m, 2H), 8.41 (m, 1H), 7.68 (m, 1H), 6.56-6.65 (m, 2H), 6.45 (s, 1H), 1.29 (s, 9H); LC-MS (ESI) m/z 294 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[NH2:16][CH2:17][CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.CO>>[CH3:27][N:19]([CH2:18][CH2:17][N:16]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[C:3]=2[N+:13]([O-:15])=[O:14])[C:8]1=[O:12])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Cc1ccc2c(=O)occc2c1[N+](=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc2c(=O)n(CCN(C)C(=O)OC(C)(C)C)ccc2c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A microwave vial was charged with 6-methyl-5-nitro-1H-isochromen-1-one (270 mg, 0.0012 mol), tert-butyl 2-aminoethylmethylcarbamate (400 mg, 0.002 mol), triethylamine (0.6 mL, 0.005 mol) and methanol (5 mL, 0.1 mol) and the reaction was heated at 100° C. for 1.5 hours. The solvents were removed under reduced pressure and the residue was purified by flash chromatography to afford the desired product as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:19])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCC1Cc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)CC(CNC(=O)OC(C)(C)C)C2
Yield: 87.7 %

Procedure:
Dissolved in 20 ml of acetone were 1.85 g (6.20 mmol) of 2-(t-butoxycarbonylaminomethyl)-5-hydroxyindane, and 1.52 g (11.0 mmol) of potassium carbonate and 1.10 g (6.60 mmol) of ethyl bromoacetate were added to the solution. The mixture was refluxed for 3.5 hours. After cooling, solids were separated by filtration, and the filtrate was concentrated. The resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain 1.90 g of a colorless crystal. Yield; 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH2:9].C(N(CC)CC)C.Cl[O-].[Na+].[OH:20][N:21]=[CH:22][C:23]1[N:24]=[C:25]([CH:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:46])[CH2:35][N:36]3[C:40]([CH3:41])=[CH:39][C:38]([C:42]([F:45])([F:44])[F:43])=[N:37]3)[CH2:30][CH2:29]2)[S:26][CH:27]=1.CC1N(CC(N2CCC(C3SC=C(C4C=C(C5C=CC=CC=5)ON=4)N=3)CC2)=O)N=C(C(F)(F)F)C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:20][N:21]=[C:22]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([C:34](=[O:46])[CH2:35][N:36]4[C:40]([CH3:41])=[CH:39][C:38]([C:42]([F:45])([F:43])[F:44])=[N:37]4)[CH2:32][CH2:33]3)[S:26][CH:27]=2)[CH2:9]1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C=Cc1ccccc1Cl
Agent: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(-c3cc(-c4ccccc4)on3)cs2)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4Cl)C3)cs2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-2-ethenylbenzene (0.035 g, 0.25 mmol), triethylamine (2.5 mg, 0.025 mmol) and Clorox® aqueous sodium hypochlorite solution (1 mL, 16.1 mmol) in dichloromethane (5 mL) was added 4-[4-[(hydroxyimino)methyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 2, Step C) (0.10 g, 0.25 mmol) in dichloromethane (5 mL) dropwise over 1 h at 0° C. The reaction mixture was allowed to stir for 1 h, then filtered through Celite® diatomaceous filter aid, and concentrated under reduced pressure to give an oil, which was purified by column chromatography on silica gel using 50% ethyl acetate in hexane as eluant to give 73 mg of the title compound as a white foam, melting at 115-122° C. (crystallized from methyl acetate/petroleum ether).