Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]3[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=3)=[CH:34][CH:33]=2)=[O:30])[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:56])C=1.CSC.O>ClCCl>[CH2:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]3[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=3)=[O:56])=[CH:34][CH:33]=2)=[O:30])[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)cc2)CCN3CC(C)C)cc1
Solvent: O
Solvent: CSC
Solvent: ClCCl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution of 1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (600 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (272 mg) in dichloromethane (15 ml) at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (433 mg) (Compound 390) as yellow amorphous.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH:14]([CH3:16])[CH3:15].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[O:13][CH:14]([CH3:16])[CH3:15])[CH2:20][CH2:19]1
Reactant: COC(=O)c1ccc(CBr)c(OC(C)C)c1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2CCC(O)CC2)c(OC(C)C)c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 82.7 %

Procedure:
A mixture of methyl 4-(bromomethyl)-3-isopropoxybenzoate (2.0 g, 6.96 mmol), 4-hydroxypiperidine (1.06 g, 10.4 mmol), potassium carbonate (1.44 g, 10.4 mmol) and N,N-dimethylformamide (20 mL) was stirred at 70° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/2) to give the title compound (1.77 g, yield 83%) as a pale-yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>ClCCl.N1C=CC=CC=1>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([Br:21])[CH:23]=2)=[O:13])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc(Br)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cccc(Br)c1
Yield: 55.8 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3-bromoaniline (1.98 g, 11.6 mmol) in 16 mL of pyridine. The crude product was recrystallized from ethyl acetate-hexanes to yield 1.99 g of the title compound, mp 194-196° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17](O)[CH3:18].CC(C)=[O:22].OS(O)(=O)=O.O=[Cr](=O)=O>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][CH2:11][C:16]([C:15]1[CH:14]=[CH:13][CH:12]=[CH:17][CH:18]=1)=[O:22]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(C)O)c1Cl
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: Cc1ccc(Cl)c(NCC(=O)c2ccccc2)c1Cl

Procedure:
The desired compound was prepared by oxidation of 1-{2-[(2,6-dichloro-3-methylphenyl)amino]phenyl}ethanol, prepared as in step 1, with Jones reagent.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[N:10]2)=[CH:5][CH:4]=1.ClC1C(CC(OCC)=O)=CC2C(=CC(OC)=CC=2)N=1.ClC1C(CC(OCC)=O)=CC2C(=CC=CC=2OC)N=1>CCOC(C)=O.CCO.[Pd]>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cc1cnc2cc(OC)ccc2c1
Agent: [Pd]
Agent: CCOC(=O)Cc1cc2c(OC)cccc2nc1Cl
Agent: CCOC(=O)Cc1cc2ccc(OC)cc2nc1Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cnc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35 %

Procedure:
Ethyl 2-(7-methoxyquinolin-3-yl)acetate. To a solution of a crude mixture of ethyl 2-(2-chloro-7-methoxyquinolin-3-yl)acetate and ethyl 2-(2-chloro-5-methoxyquinolin-3-yl)acetate in EtOAc (200 mL) and EtOH (200 mL) was added 10% Pd/C (50 mg, 0.47 mmol). The reaction mixture was placed under an atmosphere of hydrogen and stirred at ambient temperature for 3 days. The crude reaction mixture was filtered through silica and concentrated to afford a brown oil. Purification by FCC (SiO2, 0-5%, MeOH/DCM) yielded the title compound as a light brown solid (6.0 g, 35% over 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 7.20 (dd, J=9.0, 2.3 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 3.76 (s, 2H), 1.26 (t, J=6.8 Hz, 3H). [M+H]=246.2.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=1[I:16].CC(C)([O-])C.[K+]>O1CCCC1>[CH:3]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:6]=1[I:16])=[CH2:2]
Reactant: FC(F)(F)Oc1ccc(OCCCl)c(I)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=COc1ccc(OC(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.7 %

Procedure:
To 1-(2-chloroethoxy)-2-iodo-4-(trifluoromethoxy)benzene (Description 10; 12.1 g, 33 mmol) in tetrahydrofuran (50 mL) at −5° C. was slowly added potassium tert-butoxide (3.7 g, 33 mmol). After addition was complete, the solution was allowed to stir to room temperature for 20 hours, and was then quenched with water (100 mL). The mixture was extracted with 50% diethyl ether/hexane (2×100 mL) and the extracts dried (MgSO4). Concentration gave an oil which was purified by silica chromatography to give the title compound as an oil (7.62 g, 23 mmol).
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]([OH:21])[CH2:19][N:20]=2)=[CH:11][CH:10]=1)[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCCl>[CH3:1][N:2]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][CH:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]([O:21][C:35](=[O:36])[NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:19][N:20]=2)=[CH:13][CH:14]=1)[C:3](=[O:8])[C:4]([F:5])([F:7])[F:6]
Reactant: O=C=Nc1ccccc1
Reactant: CN(C(=O)C(F)(F)F)c1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Solvent: ClCCCl
Product: CN(C(=O)C(F)(F)F)c1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Yield: 38 %

Procedure:
A mixture of (5RS, 6SR)-2-[4-(N-methyltrifluoroacetamido)phenyl]-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.54 g) and phenyl isocyanate (0.6 g) in 1,2-dichloroethane (25 cc) is heated to reflux for 18 hours. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization of the residue thereby obtained in isopropyl ether, (5RS, 6SR)-2-[4-(N-methyltrifluoroacetamido)phenyl]-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.77 g), m.p. 160° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:13]([O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:13]([O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1nc2c(N)cccn2c1C
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)OC(C)(C)C)c1CNc1cccn2c(C)c(C)nc12

Procedure:
Starting from 8-amino-2,3-dimethylimidazo[1,2-a]pyridine (4.8 g), 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (9.2 g), sodium iodide (5.5 g) and sodium carbonate (8.0 g) in acetone (250 ml) analogously using the process of Example B1 gives, after chromatography on silica gel (eluent toluene/dioxane 20:1) and recrystallization from diisopropyl ether, 7.1 g (62%) of the title compound of m.p. 149-152° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[O:14]([CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(OC[C@@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a solution of (S)-(+)-N-Boc-2-phenoxymethylpyrrolidine (0.81 g, 2.9 mmol) in 5 mL of CH2Cl2 at 0° C. was added 5 mL of TFA dropwise over 1 hour. The solution was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was slowly poured into 30 mL of 10% NaOH and extracted thrice with 20 mL of CH2Cl2. The organic layer was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a light yellow oil (0.41 g, 79%). ES (+) MS m/e=178 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7]([O:9]CC)=O.Cl.[CH3:17][C:18]#[N:19]>>[CH3:17][C:18]1[NH:19][C:7](=[O:9])[C:6]2[C:5]3[CH2:12][CH2:13][CH2:14][CH2:15][C:4]=3[S:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: CC#N
Agent: Cl
Product: Cc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Yield: 62 %

Procedure:
To a 25 ml flask was added 4 (225 mg, 1 mmol) and 10 ml CH3CN. HCl gas was passed through the solution for 3 h, before the solvent was evaporated under reduced pressure. The residue was dissolved in 10 mL distilled water and treated with ammonia water solution to generate a white precipitate. The precipitate was collected by filtration to afford 143 mg (62%) of 5 as a white solid: 1H NMR (DMSO-d6) δ 1.75 (m, 4H), 2.48 (s, 3H), 2.69 (m, 2H), 2.83 (m, 2H), 12.16 (s, 1H). Anal. (C11H12N2OS) m/z (ESI) 220.067811 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:7](=[O:21])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[CH2:30]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2](/[CH:30]=[CH:29]/[C:28]([O:32][CH2:33][CH3:34])=[O:31])=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]2=[O:21])=[CH:14][CH:15]=1
Reactant: C=CC(=O)OCC
Reactant: COc1ccc(Cn2c(=O)ccc3cc(Br)ccc32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(ccc(=O)n2Cc2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.9 %

Procedure:
To a stirred solution of 6-bromo-1-(4-methoxybenzyl)quinolin-2(1H)-one (1 g, 2.9 mmol) in DMF (10 mL) were added potassium carbonate (1.19 g, 8.69 mmol), n-tert butyl ammonium chloride (0.66 g, 2.9 mmol), ethyl acrylate (1.16 g, 11.6 mmol) and palladium acetate (0.65 g, 2.9 mmol). The reaction mixture was stirred at room temperature for 20 min, then heated to 120° C. overnight. The reaction mixture was concentrated. To this, was added water and extracted with ethyl acetate, and the combined organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give (E)-ethyl 3-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-yl)acrylate as a white solid (0.8 g, 80%).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].Cl.[CH:8]1([C:11]2[C:12]([N:31]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH2:43][B:44]4[O:48]C(C)(C)C(C)(C)[O:45]4)[CH:37]=3)[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:16]([C:26]([NH:28][CH3:29])=[O:27])[C:15]=3[CH:30]=2)[CH2:10][CH2:9]1>C1COCC1.CCOC(C)=O>[CH:8]1([C:11]2[C:12]([N:31]([C:36]3[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=3)[CH2:42][CH2:43][B:44]([OH:48])[OH:45])[S:32]([CH3:35])(=[O:33])=[O:34])=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[C:16]([C:26](=[O:27])[NH:28][CH3:29])[C:15]=3[CH:30]=2)[CH2:10][CH2:9]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(CCB4OC(C)(C)C(C)(C)O4)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(CCB(O)O)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
Sodium periodate (380 mg, 1.78 mmol) and 1N aqueous HCl (1.5 mL, 1.5 mmol) were added to a cold (0° C.) solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)phenyl)methylsulfonamido)benzofuran-3-carboxamide (75 mg, 0.119 mmol) in THF (3 mL). The mixture was stirred at 0° C. for 10 min then warmed to room temperature. After one hour, the reaction mixture was diluted with EtOAc and the organic layer was separated and washed with 5% aqueous sodium thiosulfate and brine and dried over sodium sulfate. The solvent was evaporated and the residue was subjected to reverse phase HPLC (C18, acetonitrile:water with 0.1% formic acid) to give the title compound (22 mg, 34%) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 8.42-8.53 (m, 1H) 8.06-8.13 (m, 1H) 7.92-8.02 (m, 2H) 7.55 (s, 2H) 7.34-7.46 (m, 3H) 7.24-7.30 (m, 2H) 7.14-7.18 (m, 1H) 7.04-7.11 (m, 1H) 2.83 (d, J=4.68 Hz, 3H) 2.58-2.67 (m, 2H) 2.48-2.55 (m, 3H) 2.15-2.31 (m, 1H) 0.94-1.11 (m, 1H) 0.75-0.94 (m, 4H) 0.47 (m, 1H). LCMS (m/z, ES+)=551 (M+H+).
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH3:4].[OH:6][N:7]=[C:8]([C:14](=[O:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:6][N:7]=[C:8]([C:14](=[O:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCI
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCON=C(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
n-Butyl iodide (46.9 g.) was added dropwise to a stirred suspension of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), potassium carbonate (52.7 g.) and acetone (200 ml.) under ice-cooling over 5 minutes, and stirred at room temperature for 4 hours. The resultant solution was filtered, and washed with acetone. The filtrate and washing solution were combined together and concentrated in vacuo. After adding water (300 ml.) to the residue, the solution was extracted with methylene chloride three times. The solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-n-butoxyimino-3-oxobutyrate (syn isomer, 48.8 g.), oil.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][C:18]=3[CH3:27])=[CH:13][C:8]=2[C:7](=[O:28])[N:6]([CH3:29])[C:5]2[CH:30]=[CH:31][CH:32]=[N:33][C:4]1=2)[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=3[CH3:27])=[CH:13][C:8]=2[C:7](=[O:28])[N:6]([CH3:29])[C:5]2[CH:30]=[CH:31][CH:32]=[N:33][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncc(CCOc3ccc(C(=O)OC)cc3C)cc2C(=O)N(C)c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN1c2ncc(CCOc3ccc(C(=O)O)cc3C)cc2C(=O)N(C)c2cccnc21
Yield: 84.1 %

Procedure:
A solution of methyl 4-[2-(11-ethyl-6,11-dihydro-5-methyl-6-oxo-5H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-8-yl)ethoxy]-3-methylbenzoate (471 mg, 1.05 mmol) and aqueous 1 N NaOH solution (5.0 mL, 5.0 mmol) in MeOH (10 mL) and THF (5 mL) was heated to 50° C. for 5 h. Aqueous 1 N HCl solution (6 mL) was added to the cooled reaction mixture. The resulting suspension was filtered and the solid was washed with water and dried to give the title compound (382 mg, 83% yield) as a white solid.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(#N)C>[CH2:31]([N:3]1[N:2]=[N:1][C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CCOC(=O)Cc1nnn[nH]1
Reactant: CCCCCCCCCCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCCn1nnc(CC(=O)OCC)n1
Temperature: 24 °C
Yield: 49.5 %

Procedure:
The tetrazoleacetic acid, ethyl ester (50 g, 0.26 tool) obtained in (a) was suspended in acetonitrile (600 mL) and triethylamine (52.4 g, 0.52 tool)was added in one portion. The solution was heated at reflux for 5 minutes, cooled to 24° C., and then treated dropwise with 1-bromododecane (64.5 g, 0.26 mol). The solution was refluxed overnight, cooled, and the solvent concentrated in vacuo. The residue was triturated with ethyl acetate (300 mL), filtered, and the filtrate was washed with aqueous HCl (1M), brine, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo leaving a viscous liquid. The 2-isomer was separated from the crude mixture using silica gel chromatography (elution with 25% EtOAc/75% hexane), isolating 2-dodecyltetrazoleacetic acid, ethyl ester (41.8 g, 49%) as a pale yellow liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH:28]([O:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:17]([CH2:16][N:7]1[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5])=[CH:18][CH:19]=[CH:20]2)([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CC(C)Oc1ccc2c(CBr)cccc2c1
Product: CC(C)Oc1ccc2c(Cn3c(C(=O)O)cc4ccccc43)cccc2c1

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-6-isopropoxy-naphthalene and the product obtained was hydrolyzed to give 1-(6-isopropoxy-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid as a white solid. MS: 358.0 ([M−H]−).
Reaction SMILES: [Na+].[C:2]12([CH2:12][CH:13]([OH:24])[CH2:14][O:15][CH2:16][C:17]([F:23])([F:22])[S:18]([O-:21])(=[O:20])=[O:19])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.FC(F)(F)S([O-])(=O)=O.[C:33]1([SH+:39]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)(C)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([SH+:39]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([F:22])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:2]12([CH2:12][CH:13]([OH:24])[CH2:14][O:15][CH2:16][C:17]([F:22])([F:23])[S:18]([O-:21])(=[O:20])=[O:19])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: C[SH+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)COCC(O)CC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Product: F[SH+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
As shown in the following reaction scheme (4-2), the 2-(3-adamantan-1-yl-2-hydroxypropoxy)-1,1-difluoroethanesulfonic acid sodium salt produced in Step 1 was allowed to react with diphenyl methylphenyl sulfonium trifluoromethane sulfonate in the same manner as in Step 2 of Synthesis Example 1. Thus, 2-(3-adamantan-1-yl-2-hydroxypropoxy)-1,1-difluoroethanesulfonic acid diphenyl fluorophenyl sulfonium salt was obtained. Its structure was confirmed by 1H-NMR.
Reaction SMILES: [CH:1]([C:4]([CH2:11][C:12](=[O:36])[NH:13][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])([CH2:8][CH:9]=[CH2:10])[C:5]([O-])=[O:6])([CH3:3])[CH3:2].C[O-].[Na+]>CO.CCOC(C)=O>[CH2:8]([C:4]1([CH:1]([CH3:3])[CH3:2])[CH2:11][C:12](=[O:36])[N:13]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[CH:17][C:16]=2[O:25][Si:26]([CH:30]([CH3:31])[CH3:32])([CH:27]([CH3:29])[CH3:28])[CH:33]([CH3:34])[CH3:35])[C:5]1=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCC(CC(=O)NCc1cc(C(F)(F)F)ccc1O[Si](C(C)C)(C(C)C)C(C)C)(C(=O)[O-])C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCC1(C(C)C)CC(=O)N(Cc2cc(C(F)(F)F)ccc2O[Si](C(C)C)(C(C)C)C(C)C)C1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 40.9 %

Procedure:
A 100 mL round bottom flask charged with 2-isopropyl-2-(2-oxo-2-(5-(trifluoromethyl)-2-(trii sopropylsilyloxy)benzylamino)-ethyl)pent-4-enoate (1.40 g, 2.57 mmol) in MeOH (26 mL) was cooled to 0° C. The solution was treated dropwise with sodium methoxide (25% solution in MeOH, 0.048 mL, 0.206 mmol) via syringe over 3 min, and the resulting mixture was stirred for 12 h. At this time mixture was diluted with EtOAc (100 mL) washed with brine (2×20 mL). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified using a 12 g silica gel cartridge and 20:1 Hex/EtOAc to 3:1 Hex/EtOAc to elute 3-allyl-3-isopropyl-1-(5-(trifluoromethyl)-2-(triisopropylsilyloxy)benzyl)pyrrolidine-2,5-dione (538 mg, 1.05 mmol, 41% yield) as a clear oil. LC/MS [M+H]+=512.12, HPLC tR=2.55 min [Waters Sunfire C18 4.6×50 mm column, 3 min gradient from 10/90/0.1 MeOH/H2O/TFA to 90/10/0.1 MeOH/H2O/TFA at 4 mL/min flow rate]. 1H-NMR (400 MHz, CDCl3) δ=7.38 (d, J=8.0 Hz, 1H), 7.14 (s, 1H), 6.88 (d, J=8.0 Hz, 1H), 5.67 (m, 1H), 5.19 (m, 2H), 4.75 (s, 2H), 2.56 (m, 2H), 2.35 (m, 1H), 2.17 (m, 2H), 1.16 (m, 2H), 0.98 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]=[CH2:10])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[ClH:19]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][Cl:19])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CC(O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: Cl
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(/C=C/CCl)cc1Oc1ccccc1
Reaction time: 2 h

Procedure:
1-(4-Fluoro-3-phenoxyphenyl)prop-2-en-1-ol (38 g) was dissolved in tetrahydrofuran (400 cm3) and concentrated hydrochloric acid (180 cm3) was added with vigorous stirring. Stirring was continued for a further 2 hours, after which time, analysis of a withdrawn sample by gas liquid chromatography showed no starting material remaining. The mixture was diluted with water and the products extracted into ethyl acetate. The combined organic layers were washed with water (4 times), then dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave E-3-(4-fluoro-3-phenoxyphenyl)-1-chloroprop-2-ene (44 g) as a viscous oil, 98% pure by gas liquid chromatographic analysis.