Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:22][C:23]([F:26])([F:25])[F:24])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].Cl.C[N:29](C)CCCN=C=NCC.CN(C)C=O>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:22][C:23]([F:25])([F:26])[F:24])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:29])=[O:21])=[CH:15]2)(=[O:7])=[O:8]
Reactant: O=C(O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.4 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylic acid (2.50 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (1.89 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.38 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was washed with hexane to give the title compound (2.23 g, yield 89%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point >300° C.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1.C(=O)(O)[O-:12].[Na+]>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N+:5]=1[O-:12]
Reactant: O=C([O-])O
Reactant: Cc1cccc(Cl)n1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc(Cl)[n+]1[O-]
Temperature: 87.5 °C
Yield: 96.5 %

Procedure:
30% Hydrogen peroxide solution (20 mL, 0.176 mol) was added slowly into a solution of 2-chloro-6-methylpyridine (5.0 g, 39.4 mmol) in glacial acetic acid (30 mL) whilst the mixture was kept below 20° C. The reaction mixture was then heated to 85-90° C. overnight. The reaction was cooled and neutralised with cold sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (4×50 mL) and the combined organic layers washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-6-methyl-pyridine-1-oxide (5.43 g, 96.5%) as an oil.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:28][C@H:26]([OH:27])[CH2:25][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17])=[O:15])[CH2:7][C:8]1[CH:13]=[N:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCl>[NH:1]1[CH2:28][C@H:26]([OH:27])[CH2:25][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:17])=[O:15])[CH2:7][C:8]1[CH:13]=[N:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resultant Boc-Hyp-Pal-N(Me)Bzl is dissolved in 40 ml of CH2 Cl2 and mixed with 20 ml of TFA whilst cooling with ice. The mixture is stirred for 15 minutes at ambient temperature, concentrated on the rotary evaporator, the residue is taken up in ethyl acetate and extracted twice with saturated NaHCO3 solution. The aqueous phase is extracted successively with ethyl acetate and CH2Cl2. All the organic phases are united, dried with MgSO4, concentrated and the residue is chromatographed over silica gel by means of acetonitrile/water/MeOH (4:1:1). 0.39 g of H-Hyp-Pal-N(Me)Bzl is obtained as a highly viscous, colourless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:4]([O:22][CH3:23])[CH:3]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=1)[C:29](O)=[O:30]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[N:34]=[C:26]([C:25]([F:40])([F:24])[F:39])[CH:27]=2)=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCCS(C)(=O)=O
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2-methanesulfonyl-ethyl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 15 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Brown solid (42%). MS (ESI): m/z=584.09 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]([C:28]1[C:29]([C:45]#[N:46])=[N:30][N:31]([C:33]2[C:38]([Cl:39])=[CH:37][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:35][C:34]=2[Cl:44])[CH:32]=1)(=O)[CH3:26]>ClCCl>[C:45]([C:29]1[C:28]([C:25]([CH3:26])=[C:20]([Br:24])[Br:21])=[CH:32][N:31]([C:33]2[C:38]([Cl:39])=[CH:37][C:36]([C:40]([F:43])([F:41])[F:42])=[CH:35][C:34]=2[Cl:44])[N:30]=1)#[N:46]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=C(Br)Br)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N

Procedure:
A solution of triphenylphosphine (0.94 g) and carbon tetrabromide (0.6 g) in anhydrous dichloromethane (30 ml) at 0° C. was stirred for 5 minutes. 4-Acetyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.25 g) was then added and the mixture was heated under reflux for 6 hours and then evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a pale pink solid, m.p. 119-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.I[CH:18]([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:10])=[O:11])[C:5]([O:8][CH:18]([CH3:20])[CH3:19])=[N:6][CH:7]=1
Reactant: CC(C)I
Reactant: CC(C)(C)NS(=O)(=O)c1cc(Br)cnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ncc(Br)cc1S(=O)(=O)NC(C)(C)C
Temperature: 100 °C
Yield: 38.7 %

Procedure:
To a solution of 5-bromo-N-(tert-butyl)-2-hydroxypyridine-3-sulfonamide (1.50 g, 4.85 mmol) in DMF (40 mL) was added 2-iodopropane (0.825 g, 4.85 mmol) followed by K2CO3 (1.34 g, 9.70 mmol) at RT. The reaction mixture was heated to 100° C. for 14 h. The reaction mixture was allowed to cool and the volatile components were removed under reduced pressure. The residue was diluted with cold water (150 mL) and extracted into ethyl acetate (2×100 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure and the residue was purified by CombiFlash (REDISEP®, silica gel, 24 g, 50% EtOAc/petroleum ether) to give 5-bromo-N-(tert-butyl)-2-isopropoxypyridine-3-sulfonamide (0.660 g, 37.7%) as a white solid. LCMS Condition B-22: retention time 1.92 min, [M+1]=351.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.13 (s, 9H), 1.35 (d, J=6.8 Hz, 6H), 5.06 (dt, J=13.6 Hz, J=6.8 Hz, 1H), 6.96 (s, 1H), 8.00 (d, J=2.6 Hz, 1H), 8.36 (d, J=2.6 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11]([C:13]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=1[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:22][S:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][C@@H:24]([CH3:29])[C:25]([F:27])([F:28])[F:26])=[C:13]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:5]2)=[O:12])[CH:18]=1)(=[O:20])=[O:21]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(Br)cccc21)C(F)(F)F
Reactant: C1COCCN1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(N3CCOCC3)cccc21)C(F)(F)F
Yield: 57 %

Procedure:
A mixture of 0.2 mmol (4-Bromo-2,3-dihydro-indol-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (example 211), 0.4 mmol morpholine, 0.3 mmol sodium tert-butylate, 2.5 mg rac.BINAP and 2.0 mg tris-(dibenzylidenaceton)-dipalladium chloroform complex in 5 ml toluene is heated at 80° C. for 3 hours. Fresh morpholine (0.4 mmol) is added and the mixture hold at 80° overnight. The reaction mixture is concentrated. Chromatography of the residue (silica gel; ethyl acetate/heptane) yields the title compound as a slightly yellow solid. Yield=57%. MS (m/e): 499.3 [M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=O)=[N:8][NH:9]2)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)[CH:21]=[CH:20][C:18]=1[NH2:19].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([NH:19][C:18]3[CH:20]=[CH:21][C:22]([B:24]4[O:25][C:26]([CH3:31])([CH3:32])[C:27]([CH3:30])([CH3:29])[O:28]4)=[CH:23][C:17]=3[O:16][CH3:15])=[O:14])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: COc1ccc2c(C(=O)O)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To 6-methoxy-1H-indazole-3-carboxylic acid (64 mg, 0.333 mmol) in dichloromethane (10 ml) was added 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (166 mg, 0.666 mmol), O-(7-azabenzotriazol-1-yl)1,1,3,3-tetramethyluronium hexafluorophosphate (190 mg, 0.500 mmol) and N,N-diisopropylethylamine (0.174 ml, 0.999 mmol). The reaction mixture was stirred overnight at room temperature. Then the reaction mixture was concentrated in vacuo and the residue was purified by column chromatograpy (silica gel; dichloromethane/methanol 99/1) and thereafter by column chromatograpy (silica gel; heptane/ethyl acetate 2/1) to give 6-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazole-3-carboxamide (54 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@H:13]3[NH:17][CH2:16][Si:15]([CH3:19])([CH3:18])[CH2:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([NH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26]([N:17]1[C@H:13]([C:10]2[NH:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[N:9]=2)[CH2:14][Si:15]([CH3:19])([CH3:18])[CH2:16]1)=[O:27])[CH:29]([CH3:31])[CH3:30]
Reactant: C[Si]1(C)CN[C@H](c2nc(-c3ccc(Br)cc3)c[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1C[Si](C)(C)C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Yield: 66.1 %

Procedure:
A mixture of (R)-5-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine (350 mg, 0.92 mmol, Preparation 9), (S)-2-methoxycarbonylamino-3-methyl-butyric acid (170 mg, 0.97 mmol), HATU (400 mg, 1.05 mmol), and DIPEA (700 mg, 5.4 mmol), in DCM (50 mL) was stirred at RT overnight. The reaction mixture was washed with water and brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (20% EtOAc in petroleum ether) to give the title intermediate (300 mg, 66% yield) as a straw yellow solid. (m/z): [M+H]+ calcd for C21H29BrN4O3Si, 493.12 found 493.1.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8]1)=[O:6])[CH3:3].[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[C:18]([CH3:23])[CH:17]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:22][C:21]1[CH:20]=[CH:19][C:18]([CH3:23])=[CH:17][CH:16]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: Cc1ccc(O)cc1
Reactant: CC(C)NC(=O)C1OC1c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(OC(c2ccccc2)C(O)C(=O)NC(C)C)cc1

Procedure:
This compound was prepared as in Example 12 from N-(1-methylethyl)-3-phenyl-2-oxiranecarboxamide (6.16 g.), p-cresol (3.3 g.), sodium hydride (50% oil dispersion, 1.5 g.), 18-crown-6 (0.9 g.) and acetonitrile (250 ml.). The product melted at 152°--152°, and amounted to 2.4 g.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][OH:12])[CH2:2][CH:3]=[CH2:4].[CH2:13]([O:16][C:17]1([CH3:46])[CH2:22][CH2:21][N:20]([C:23]2[N:28]3[N:29]=[C:30]([CH2:32]I)[CH:31]=[C:27]3[N:26]=[C:25]([CH3:34])[C:24]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:19][CH2:18]1)[CH:14]=[CH2:15].[H-].[Na+]>CN(C=O)C>[CH2:13]([O:16][C:17]1([CH3:46])[CH2:18][CH2:19][N:20]([C:23]2[N:28]3[N:29]=[C:30]([CH2:32][O:12][CH2:11][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[CH2:1][CH2:2][CH:3]=[CH2:4])[CH:31]=[C:27]3[N:26]=[C:25]([CH3:34])[C:24]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:21][CH2:22]1)[CH:14]=[CH2:15]
Reactant: C=CCCc1ccccc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCc1ccccc1COCc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 45.2 %

Procedure:
To a mixture of (2-(but-3-en-1-yl)phenyl)methanol (35.1 mg, 0.216 mmol) in DMF (3 mL) at 0° C. was added (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (115 mg, 0.197 mmol) and NaH (7.87 mg, 0.197 mmol). It was then stirred at 0° C. for 4 h. The reaction mixture was quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to obtain (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (55 mg, 0.089 mmol, 45.2% yield) as an oil. LCMS (M+1)=619.4.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 90 °C

Procedure:
K2CO3 (66.8 g, 0.48 mol) was added to a stirred solution of ethyl 3-hydroxybenzoate (1) (40.0 g, 0.24 mol) and (chloromethyl)benzene (33.5 g, 0.26 mol) in DMF (256 mL) and the reaction mixture was heated at 90° C. for 3 h. The reaction mixture was filtered through Celite, the filtrate was diluted with water (500 mL), extracted with EtOAc (500 mL). The organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give ethyl 3-(benzyloxy)benzoate (2) as colorless liquid. Yield (61.0 g, 98%); 1H NMR (400 MHz, DMSO-d6) δ 7.56-7.53 (m, 2H), 7.47-7.44 (m, 3H), 7.39 (t, J=7.2 Hz, 2H), 7.35-7.29 (m, 2H), 5.17 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:21][CH:20]([CH3:22])[S:19](=[O:24])(=[O:23])[CH:18]([CH3:25])[CH2:17]1.CO.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:17][CH:18]([CH3:25])[S:19](=[O:23])(=[O:24])[CH:20]([CH3:22])[CH2:21]1
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CC(C)S(=O)(=O)C(C)C3)c[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CC(c2c[nH]c3c(C(=O)O)cc(Br)cc23)CC(C)S1(=O)=O
Temperature: 85 °C
Yield: 105.9 %

Procedure:
Ethyl 5-bromo-3-(2,6-dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxylate (0.189 g, 0.441 mmol), was stirred in a methanol (5 mL)/water (3 mL) solution. 6M NaOH (0.735 mL, 4.41 mol, 10 eq) was added and the reaction was heated to 85° C. for 1.5 hours. LCMS analysis indicated the reaction was completed. The methanol was concentrated and the aqueous solution was acidified with 6M HCl. The resulting white solid was filtered and dried under vacuum to give 0.187 g (92%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:42]=[CH:41][C:10]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)=[O:12])=[CH:9][CH:8]=1.[OH-].[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:42]=[CH:41][C:10]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=3)[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 53.9 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]-2-(4-trifluoromethylphenoxy)propionate (269 mg), which is the product of Example 122, was reacted with aqueous sodium hydroxide solution (1N, 0.55 ml) and the reaction mixture was treated to give the title compound (138 mg) as a white powder.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.Cl.[OH:17][NH3+:18]>CN(C)C=O>[OH:17][N:18]=[CH:1][C:3]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: [NH3+]O
Reactant: COC(=O)c1cccc2c(C=O)c[nH]c12
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c(C=NO)c[nH]c12
Yield: 97.4 %

Procedure:
5 g of methyl 3-formylindole-7-carboxylate (0.024 mol) are added to a solution of 0.03 mol of hydroxylammonium hydrochloride in dimethylformamide. The reaction mixture is heated at 125° for one hour and subjected to conventional work-up, giving 5.1 g of methyl 3-(hydroxyiminomethyl)indole-7-carboxylate.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:15]1[O:17][CH2:16]1>>[C:8]1([N:7]([CH2:16][CH:15]([OH:17])[CH2:14][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:1](=[O:6])[CH2:2][C:3]([CH3:5])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CC(=O)CC(=O)Nc1ccccc1
Product: CC(=O)CC(=O)N(CC(O)COc1ccccc1)c1ccccc1
Temperature: 170 °C

Procedure:
Acetoacetanilide was mixed with phenyl glycidyl ether in a molar ratio of 1:1.2, and a reaction was allowed to proceed by heating the mixture at 170° C. for 1 hour. Then, the remaining unreacted phenyl glycidyl ether was removed in the same manner as in Reference Example 1, thereby obtaining a reaction product, (D)-2. Reaction product (D)-2 was further subjected to infrared spectrophotometry and gel permeation chromatography in the same manner as in Reference Example 1. This reaction product (D)-2 was a mixture containing, besides the desired compound formed by the reaction of the 1:1 reactants, high molecular weiqht compounds formed through further reactions.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OC(=O)C)(=[O:20])C>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:20])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Temperature: 80 °C
Yield: 66 %

Procedure:
4-(4-(Trifluoromethyl)phenyl)pyridine-1-oxide (1.9 g, 7.9 mmol) was heated to 140° C. in acetic anhydride (80 mL) for 5 h. The mixture was concentrated and then heated at 80° C. for 1 h in a mixture of MeOH (20 mL) and aqueous 1 N NaOH (15 mL). The resulting black solution was concentrated to a volume of 15 mL, and the solid was filtered off, rinsed with CH2Cl2 and dried under vacuum to provide the title compound (1.26 g, 66%) as a brown solid: 1H NMR (300 MHz, CD3OD) δ 7.80-7.74 (br m, 5H), 6.85-6.66 (br m, 2H).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[N:6]=[C:7]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[CH3:11].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>C(O)C>[CH3:11][C:10]1[C:9](=[O:12])[N:8]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:7]2=[N:6][C:5]=1/[CH:4]=[CH:23]/[C:22]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Cc1nc2c(C)cccn2c(=O)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(/C=C/c2nc3c(C)cccn3c(=O)c2C)cc(OC)c1OC

Procedure:
To a solution of 1.3g of sodium methoxide in 75ml of absolute ethanol is added 2.0g of 2,3,9-trimethyl-4H-pyrido-[1,2-a]pyrimidin-4-one, followed by 4.0g of 3,4,5-trimethoxybenzaldehyde. The mixture is stirred and heated under reflux for 89 hours. The reaction mixture is cooled, the solid is filtered, washed with 20ml of ether and 25ml of water, dried, and recrystallized from 75ml of acetonitrile to yield the title compound, melting point 218°-219°C dec.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:7](C(=O)C)[C:6](=[O:11])[N:5]([C:12](=[O:14])[CH3:13])[C:4]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>Br.C(O)(=O)C>[C:12]([N:5]1[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:3]([CH2:2][Br:1])[NH:7][C:6]1=[O:11])(=[O:14])[CH3:13]
Reactant: CCOC(=O)c1c(CBr)n(C(C)=O)c(=O)n1C(C)=O
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CBr)[nH]c(=O)n1C(C)=O
Reaction time: 4 h

Procedure:
Crude ethyl 5-(bromomethyl)-1,3-diacetyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate is dissolved in 30% hydrobromic acid in acetic acid and the solution is allowed to stand at room temperature for 4 hours. The solid which precipitates is separated by filtration and dried in vacuo at 80° C. over potassium hydroxide to give ethyl 3-acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate melting at about 193°-194° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[CH2:21]([SH:26])[CH2:22][CH2:23][CH2:24][SH:25]>>[SH:25][CH2:24][CH2:23][CH2:22][CH2:21][S:26][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: SCCCCS
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Product: CC1(c2ccccc2)OC(CC(SCCCCS)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 1,4-butanedithiol to provide 5-[2-[(4-mercaptobutyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (CDCl3) δ1.30 (m, 1H), 1.55-1.70 (broad s with fine structure, 4H) and 1.65 and 1.68 (singlets, 3H), 2.33-2.42 (m, 2H), 2.42-2.55 (m, 2H), 3.06-3.25 (m, 2H), 4.40 (m, 1H), 5.37 and 5.39 (singlets, 1H), 7.05-7.18 (m, 2H), 7.25-7.40 (m, 6H); MS (HR-FAB) m/z 405.1029 (M+H calcd. for C21H25O2S3 405.1017).