Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])[C:9]=1[CH3:26].CCN(CC)CC.[C:34]1([CH3:62])[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH2:44][O:45][C:46](=[O:61])[CH2:47][O:48][C:49]2[CH:54]=[C:53]([CH3:55])[C:52]([S:56](Cl)(=[O:58])=[O:57])=[C:51]([CH3:60])[CH:50]=2)(=[O:42])=[O:41])=[CH:36][CH:35]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:34]1([CH3:62])[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH2:44][O:45][C:46](=[O:61])[CH2:47][O:48][C:49]2[CH:50]=[C:51]([CH3:60])[C:52]([S:56]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:10]3[C:9]([CH3:26])=[C:8]([O:7][CH2:6][CH2:5][CH2:4][O:3][CH3:2])[CH:13]=[CH:12][N:11]=3)=[O:16])(=[O:57])=[O:58])=[C:53]([CH3:55])[CH:54]=2)(=[O:41])=[O:42])=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)Cl)c(C)c2)cc1
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2c(C)cc(OCC(=O)OCCS(=O)(=O)c3ccc(C)cc3)cc2C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To a heterogeneous solution of 2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-1H-benzimidazole sodium salt (RABEPRAZOLE sodium salt, 1.0 g, 2.62 mmol) and 5 mL of Et3N in 20 mL of CH2Cl2 was added the chlorosulfonyl ester (Intermediate 13, 1.57 g, 3.41 mmol, 1.3 eq). About 1 g of solid NaHCO3 was added after the chlorosulfonyl ester has dissolved completely in the reaction mixture. The mixture was stirred at room temperature for 3 h. Thereafter the solvent was removed by evaporation and the residual oil was purified by column chromatography (silica gel, CH2Cl2 to 1% MeOH in CH2Cl2) to give 1.7 g (77%) of 3,5-dimethyl-4-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 58) as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:12]=2[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]([NH:32][C:33](=[O:36])[CH2:34]I)([CH3:31])([CH3:30])[CH3:29].[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(OCC)(=O)C>[C:28]([NH:32][C:33](=[O:36])[CH2:34][N:14]1[C:15](=[O:16])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][CH:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:12]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:13]1=2)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)NC(=O)CI
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CC2c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)NC(C)(C)C)C(=O)C(NC(=O)OC(C)(C)C)CC2c1ccccc1
Reaction time: 5 h
Yield: 100 %

Procedure:
3-[Tert.-butoxycarbonylamino]-8-methyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-benzo[b]azepine (1.4 g, 3.8 mmol), N-t-butyl iodoacetamide (1.1 g, 4.56 mmol) and tetrabutylammonium bromide (85 mg, 0.26 mmol) were dissolved in dry tetrahydrofuran (25 ml) under nitrogen. Powder potassium hydroxide (0.3 g, 4.5 mmol) was added in one portion and the reaction was stirred for 5 hours. The reaction was diluted with ethyl acetate (25 ml) and washed with water (2×50 ml) and brine. After drying over magnesium sulfate, the solvent was evaporated in vacuo to provide the desired product as a foam; 2 g, >100% yield. This contained some excess iodoacetamide, but was suitable for use in the next reaction. IR (KBr) 1720, 1680, 1659, 1614 cm-1. 1H NMR (CDCl3) δ 7.28-7.07 (m, 6), 7.00 (d, 2), 6.05 (s, 1), 5.49 (d, 1), 4.34 (m, 1), 4.08 (d, 1), 3.62 (d, 1), 2.95 (dt, 1), 2.63 (t, 1), 2.60 (d, 1), 2.33 (s, 3), 1.41 (s, 9), 1.32 (s, 9).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH2:12][CH:13]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:13]/[CH2:12][C:11]([CH3:15])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CC=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC(C)(C)c1ccccc1
Yield: 83.5 %

Procedure:
Step C In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.3 g, 10 mmol) was reacted with 3-methyl-3-phenyl-butyraldehyde (1.8 g, 11 mmol) in CH2Cl2 at room temperature for 18 h to give [[3-methyl-3-phenyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.3 g, 93%).
Reaction SMILES: C([Mg]Cl)(C)C.[Br-].[F:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][CH:9]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17].[NH4+].[Cl-]>C1COCC1.[Cu]I.C(OCC)(=O)C>[F:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[CH2:19][C@H:18]([OH:20])[CH2:16][Cl:17]
Reactant: ClC[C@@H]1CO1
Reactant: Fc1ccc(F)c(F)c1
Agent: [Cu]I
Agent: CC(C)[Mg]Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O[C@H](CCl)Cc1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2N i-PrMgCl (26 ml) suspended in THF was added dripwise to the 2,4,5-trifluorobenzene bromide (9.55 g) dissolved in THF (30 ml) at −15° C. for 60 min. CuI (0.72 g) was added thereto at −15° C., and heated to −10° C. (S)-epichlorohydrin (4.1 ml) dissolved in THF (40 ml) was added slowly to the resulting mixture, and stirred at 0° C. for 1 hour. Satuated NH4Cl (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed with 50 ml of satuated saline, dried over MgSO4, and filtered to remove MgSO4. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH2:8][C:9](=[CH:12]N(C)C)[C:10](=O)[C:4]=2[CH:3]=1.[N+]([O-])(O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:33][C:34]([NH2:36])=[NH:35])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH2:8][C:9]3[CH:12]=[N:36][C:34]([NH:33][C:27]4[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=4)=[N:35][C:10]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(NC(=N)N)cc1OC
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Cl)cc2C1=O
Solvent: O=[N+]([O-])O
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(Cl)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for method I, 7-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-d) and N-(3,4-dimethoxyphenyl)guanidine nitrate were converted to I-24 (67%): HRMS Calcd. for C20H17ClN4O3: 397.1067, Found 397.1059.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C@@H:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18]([NH:25][C@H:26]([C:31](O)=[O:32])[C@H:27]([CH2:29][CH3:30])[CH3:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:18]([NH:25][C@@H:26]([C@@H:27]([CH3:28])[CH2:29][CH3:30])[C:31]([NH:17][C@H:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:32])([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C1(c2ccc(Cl)cc2)CCC1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
By similar method as example 2, resolved (S)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (II-S) (250 mg) was condensed with Boc-L-isoleucine (210 mg) to give the title compound (2S, 3S)-2-(Boc-amino)-N-{(S)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-3-methylvaleramide.
Reaction SMILES: [C:1]([C:3](=[C:8]1[CH2:12][CH2:11][S:10][CH2:9]1)[C:4]([O:6][CH3:7])=[O:5])#[N:2].S(Cl)(Cl)(=O)=O.N1C=CC=CC=1>C(Cl)Cl>[C:1]([CH:3]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)C(C#N)=C1CCSC1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(C#N)c1ccsc1
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
A solution of 5.00 g (27.3 mmol) of methyl 2-cyano-2-(3-tetrahydrothienylidene)acetate in 100 ml of methylene chloride was cooled to +5° under nitrogen and 3.70 g (27.3 mmol) of sulfuryl chloride in 5 ml of methylene chloride was added all at once. After 15 min. at +5° the solution was purged with a vigorous stream of nitrogen for 5 min. Pyridine (4.0 g, 50 mmol, 1.83 eq.) was added and the solution was brought to room temperature with a water bath. After 30 min. the reaction was quenched with 30 ml of 1 M H2SO4 and 70 ml of water. The mixture was stirred to 15 min. and the organic phase was separated. The aqueous phase was extracted with 30 ml of methylene chloride and the combined organic layers were dried by passing them through a cone of anhydrous calcium sulfate. Solvent was removed to yield an orange oil homogeneous by tlc and glc (SE-30, SP2300). Bulb to bulb distillation (about 120°/0.5 torr) yielded 4.67 g (94.5%) of methyl 2-cyano-2(3-thienyl)acetate as an analytically pure pale yellow oil, bp 108°-110°/0.5 torr, (lit. 107°-9°/0.95 torr). IR (film) 4.42 (w), 5.73 (s), 6.98 (m), 8.00 (s), 9.86 (m), 12.95 (s); NMR (CDCl3) 7.6-7.4 (m, 2H), 7.3-7.1 (d×d, J=2, 5 Hz, 1H), 5.00 (s, 1H), 3.90 (s, 3H), UV max=234 nm. 13C NMR (CDCl3) 165.0, 129.1, 127.5, 126.6, 124.7, 115.5, 53.9, 38.9.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:45])[C:36]2[CH:41]=[CH:40][C:39]([CH:42]=[O:43])=[CH:38][C:37]=2[F:44])=[C:30](I)[CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[CH2:21]([C:28]1[CH:33]=[CH:32][C:31]2[N:34]=[C:35]([C:36]3[CH:41]=[CH:40][C:39]([CH:42]=[O:43])=[CH:38][C:37]=3[F:44])[O:45][C:30]=2[CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(Cc3ccccc3)cc2I)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2nc3ccc(Cc4ccccc4)cc3o2)c(F)c1
Temperature: 90 °C

Procedure:
1,10-Phenanthroline (0.016 g, 0.087 mmol), cuprous iodide (0.008 g, 0.044 mmol), cesium carbonate (0.21 g, 0.65 mmol), and N-(4-benzyl-2-iodophenyl)-2-fluoro-4-formylbenzamide (0.200 g, 0.44 mmol) were combined under argon. Dioxane (2 mL) was added and the reaction was sealed and heated to 90° C. for 24 h. The reaction was cooled and partitioned between EtOAc and water. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by ISCO, 40 g, 0-30% EtOAc/hexanes to give 4-(6-benzylbenzo[d]oxazol-2-yl)-3-fluorobenzaldehyde as a white solid. MS (ESI) m/z: Calculated: 331.1; Observed: 332.1 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.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+:9]([C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1)([O-:11])=[O:10]
Reactant: OB(O)c1ccccc1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
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: Nc1ncc(-c2ccccc2)cc1[N+](=O)[O-]
Yield: 46.4 %

Procedure:
A mixture of 5-bromo-3-nitropyridine-2-amine (10 g), phenylboronic acid (8.39 g), tetrakis(triphenylphosphine)palladium(0) (5.3 g), 2N aqueous sodium carbonate solution (100 ml) and dimethoxyethane (500 ml) was heated under reflux under an argon atmosphere for 5 hr. The insoluble material was removed by filtration, and the filtrate was concentrated, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The obtained crude crystals were washed with diethyl ether to give the title compound (4.58 g, yield 46%) as yellow crystals. purity 80%. M+H: 216.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[C:13]1([CH:19]([C:22](=O)[C:23]([F:26])([F:25])[F:24])[C:20]#[N:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:21][C:20]1[N:2]([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=2)[N:3]=[C:22]([C:23]([F:24])([F:25])[F:26])[C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC(C(=O)C(F)(F)F)c1ccccc1
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Product: Nc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 2-(4-hydrazinophenyl)ethanol hydrochloride and 2-phenyl-2-(trifluoroacetyl)acetonitrile: MS (ESI) m/z 348 [M+H]+, 346 [M−H]−, 1H-NMR (CDCl3) δ 7.58 (2H, J=8.4 Hz), 7.46-7.36 (7H, m), 3.94-3.88 (2H, m), 2.94 (2H, t, J=6.4 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=3)[CH:32]=2)[O:27]1)[CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2C(C)=CC=C2C)=[CH:16][CH:17]=1)[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NO.[OH-].[K+]>C(O)C>[NH2:18][C:15]1[N:14]=[CH:13][C:12]([C@@H:10]([OH:11])[CH2:9][N:8]([CH2:25][C@H:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:36]4[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=4)[CH:32]=3)[O:27]2)[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN(C[C@H](O)c2ccc(-n4c(C)ccc4C)nc2)C(=O)OC(C)(C)C)O3)cc1
Agent: NO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN(C[C@H](O)c2ccc(N)nc2)C(=O)OC(C)(C)C)O3)cc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 57.7 %

Procedure:
To a solution of methyl 4-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}benzoate (Example 375, 162 mg, 0.26 mmol) in ethanol (4 mL) was added hydroxylamine monohydrate (182 mg, 2.65 mmol) and 2 N aq. potassium hydroxide (0.66 mL, 1.32 mmol). The mixture was stirred at room temperature for 70 hours and then concentrated in vacuo. Flash chromatography of the residue using 10% methanol/ethyl acetate afforded 80 mg (43%) of the desired product containing trace impurities. This material was taken on without further purification. Mass spectroscopy gave m/z=534.3 [M+H]+ (calc'd exact mass for C30H35N3O6=533.3).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[O:38]([C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47](O)=[O:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:47](=[O:48])[C:46]3[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=3[O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Oc2ccccc2)cc1

Procedure:
The title compound was prepared from 5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Example 59, Step C) and 2-phenoxybenzoic acid (2.5 equivalents), CDI (2.5 equiv), and DBU (2.5 equiv) according to the procedure of Example 51. Flash chromatography of the crude product on silica gel (gradient elution with 0.5-1% MeOH in CH2Cl2) gave a 55% yield of the desired material as a stiff foam, homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 738 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH3:4].[C:14](Cl)(=[O:18])[C:15]([Cl:17])=[O:16]>C(OCC)C>[CH3:1][O:2][CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14](=[O:18])[C:15]([Cl:17])=[O:16])=[CH:6]1)[CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(C)n1ccc2ccccc21
Solvent: CCOCC
Product: COC(C)n1cc(C(=O)C(=O)Cl)c2ccccc21
Temperature: 0 °C
Reaction time: 5 h
Yield: 31.1 %

Procedure:
To a solution of 1-(1-methoxyethyl)indole (4 gm, 23 mmol) (prepared as in step a) above) in anhydrous diethyl ether at 0° C. was added oxalyl chloride (4.2 mL, 48 mmol) over 5 minutes. The resulting slurry was stirred at 0° C. for 5 hours, and filtered to afford 1.9 gm of [1-(1-methoxy-ethyl)-1H-indol-3-yl]-oxo-acetyl chloride. (Yield 31%). The material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3-(trifluoromethyl)phenol.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].[CH3:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][C:36](O)=[O:37].CCCCCC>C(CC(C)(C)C)(C)C>[C:36]([O:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5])(=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=[CH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: CC(C)CC(C)(C)C
Solvent: CCCCCC
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 24 h

Procedure:
There were dissolved, in 1 g of isooctane, 100 mg of farnesol and 750 mg of ethyl ester of eicosapentaenoic acid, followed by the addition of lipase in an amount of 1% relative to the total amount of the resulting solution and then stirring the mixture at 60° C. for 24 hours. After confirming whether the reaction system reached its equilibrium state or not by the GC technique, the reaction solution was diluted by the addition of hexane to the solution in an amount of 10 times the volume thereof, followed by the removal of the lipase from the reaction solution through filtration and then the removal of the hexane through distillation to thus give a crude reaction product. The crude product was purified by silica gel column chromatography to give 107 mg of farnesyl eicosapentaenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH:30]([CH3:32])[CH3:31])[CH3:29])=[CH:23][CH:22]=1.CO>[NH4+].[OH-]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][N:28]([CH:30]([CH3:32])[CH3:31])[CH3:29])=[CH:25][CH:26]=1
Reactant: CC(C)N(C)Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(C)Cc1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Dissolve 7-chloro-6-{4-[(N-methyl-iso-propylamino)-methyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (350 mg, 0.75 mmol) in concentrated NH4OH. (10 mL) and MeOH (10 mL). Stir the reaction mixture overnight. Concentrate the mixture in vacuo. Purify by chromatography on silica gel (45 g) eluting with a gradient of 100% DCM to 1:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain 7-chloro-6-{4-[(N-methyl-iso-propylamino)-methyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (260 mg, 93%). MS (APCI+) m/z: 372 (M+11)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16]S(C)(=O)=O)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:21])([F:31])[F:32])[CH:25]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Product: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(OC(F)(F)F)c2)C1
Yield: 101.5 %

Procedure:
The title compound (D107) (112 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 5-chloro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D63) (100 mg, 0.311 mmol) and 3-(trifluoromethoxy)phenol (0.036 ml, 0.284 mmol).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[Sn](CCCC)(CCCC)CCCC.[ClH:20].[CH2:21]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH:37][C:38]3[C:47]4[C:42](=[CH:43][CH:44]=[C:45](I)[CH:46]=4)[N:41]=[CH:40][N:39]=3)=[CH:34][CH:35]=2)[CH:30]=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl>O1CCOCC1.CCOC(C)=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[ClH:20].[CH2:21]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH:37][C:38]3[C:47]4[C:42](=[CH:43][CH:44]=[C:45]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=5)[CH:46]=4)[N:41]=[CH:40][N:39]=3)=[CH:34][CH:35]=2)[CH:30]=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: Ic1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cccc1-c1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Yield: 28.6 %

Procedure:
A stirred solution of 1-methyl-2-(tri-n-butylstannyl)pyrrole (prepared as described in H. M. R. Hoffmann et al. Synthesis, 1996, 164) (1.07 g, 2.89 mmol), (1-benzylindazol-5-yl)-(6-iodoquinazolin-4-yl)-amine hydrochloride (1.0 g, 1.95 mmol), triethylamine (0.4 ml, 0.29 g, 2.87 mmol) and 1,4-bis(diphenylphosphino)-butane palladium (II) chloride (0.9 g, catalytic) in dioxane (10 ml) was heated to reflux under a nitrogen atmosphere for 18 hours. The mixture was concentrated in vacuo and purified by silica gel chromatography, eluting with 2:1 i-hexane/EtOAc. Concentration of the appropriate fractions gave a yellow solid which was dissolved in EtOAc and treated with a solution of HCl in dioxane. The precipitate was collected by filtration, washed with EtOAc and dried at 60C in vacuo to give the product as a green-yellow solid (0.26 g, 0.557 mmol, 29%); δH [2H6]DMSO 11.95 (1H,s), 8.86-8.96 (2H,m), 8.18-8.27 (2H,m), 8.07 (1H,s), 7.99 (1H,d),7.83 (1H,d), 7.65 (1H,dd), 7.22-7.40 (5H,m), 7.01 (1H,t), 6.49 (1H,dd), 6.19 (1H,t), 5.71 (2H,s), 3.82 (3H,s); m/z (M+1+) 4.31.