Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([C:9](=C(C)C)[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:3])[CH3:2].C(Cl)Cl.C[OH:30]>O=[O+][O-].O=O>[C:1]([O:4][C@@H:5]1[N:8]([C:9](=[O:30])[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:3])[CH3:2]
Reactant: CO
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OC(C)=O
Agent: O=O
Agent: O=[O+][O-]
Solvent: ClCCl
Product: COC(=O)C(=O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OC(C)=O

Procedure:
Into a solution of 910 mg (2.5 mmol) of methyl 2-((3S,4S)-4-acetoxy-3-t-butyloxycarbonylaminoazetidin-2-on-1-yl)-3-methylbut-2-enoate in 40 ml of methanol, for 120 minutes at -10° C. in a mixture of ozone and oxygen is introduced at a rate of 0.1 mmol of ozone per minute. The obtained crystalline residue is dissolved by addition of 160 ml of methylene chloride and the solution is washed subsequently with 60 ml of a 10% aqueous sodium bisulfite solution and 60 ml of saturated sodium chloride solution. The organic layer is dried over sodium sulfate and dried in vacuo, affording 640 mg of a noncrystalline solid. Recrystallisation from cold methanol furnishes 613 mg (74%) of pure title compound of a melting point of 144° to 146° C. IR spectrum in methylene chloride: 3400, 3000, 1840, 1765, 1720, 1500, 1360, 1220, 1160 and 1040 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[C:12]1([C@@H:18]2[CH2:22][O:21][C:20](=[O:23])[NH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:19]1[C@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][O:21][C:20]1=[O:23])=[O:11]
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: O=C(O)Cc1ccccc1F
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Cc1ccccc1F)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 90 °C

Procedure:
A mixture of 107.7 g of o-fluorophenylacetic acid, 100 g of (R)-4-phenyl-2-oxazolidinone, 186 g of triethylamine, and 1.0 L of toluene is heated to an internal temperature of 80° C. (heating mantle temperature 90° C.) to afford a solution; 88.5 g of pivaloyl chloride is added over period of 30 minutes with efficient stirring while maintaining an internal temperature 80-85° C. and stirred at this temperature for 2 hours. An additional 44.1 g of pivaloyl chloride is added over a period of 15 minutes while maintaining an internal temperature 80-85° C., and the mixture is stirred at the same temperature for additional 3 hours. The mixture is cooled to an internal temperature of 40° C. over a period of 10 minutes and 300 mL of water (prewarmed to 40° C.) is added over a period of 2 minutes while maintaining an internal temperature below 40-45° C. (slightly exothermic reaction). The organic layer is separated and washed with 358 mL of 2.17 N HCl solution (prewarmed to 40° C.) and 100 mL of water (prewarmed to 40° C.) sequentially while maintaining an internal temperature 40-45° C. and concentrated to dryness under reduced pressure (58-61 mbar; bath temperature, 51-53° C.) to obtain 3-[2-(2-fluorophenyl)-1-oxoethyl]-4-(R)-phenyl-2-oxazolidinone as a semi-solid. The semi-solid is suspended in 400 mL of tert-butyl methyl ether and the mixture is heated to reflux (internal temperature of 58-61° C.) to obtain a yellow solution. The solution is cooled to 20-25° C. over a period of 20 minutes and stirred at this temperture for 4 hours. The mixture is then further cooled to 5 to 9° C. and stirred at this temperature for additional 2 hours. The solids are collected by filtration and washed with a total of 27 mL of tert-butyl methyl ether (precooled to 5-9° C.) in three equal portions of 9 mL each. The product is dried at 45-50° C. (86-99 mbar) for 12 hours to obtain optically pure of 3-[2-(2-fluorophenyl)-1-oxoethyl]-4-(R)-phenyl-2-oxazolidinone as a white solid; m.p. 110-111° C.; [α]D : -110.4 (c=1, MeOH)
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:4]([CH3:6])([CH3:5])[CH:3]1[CH2:7][OH:8].[H-].[Na+].[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[O:19]>CN(C=O)C.O.CCOC(C)=O>[Cl:12][C:13]1[C:14]([O:8][CH2:7][CH:3]2[C:4]([CH3:6])([CH3:5])[C:2]2([CH3:9])[CH3:1])=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])=[O:19]
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1(C)C(CO)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C(COc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)C1(C)C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
To a stirred solution of (2,2,3,3-tetramethylcyclopropyl)methanol (80 mg, 0.62 mmol) in dry DMF (10 mL) at 0° C. was added NaH (25 mg, 0.62 mmol). After being stirred for 30 min, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (54 mg, 0.21 mmol) was added. After being stirred at room temperature for 18 h, the mixture was diluted with water (10 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 ml×2). The combined organic layers was dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 5-chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethylcyclopropyl)-methoxy)benzamide (20 mg, 25% yield) as a white solid. LCMS (ESI) Method A: RT=5.11 min, m/z: 268 [M-109]+. 1H NMR (500 MHz, DMSO-d6): δ 7.35 (d, J=9.0 Hz 1H), 7.03 (d, J=7.0 Hz, 1H), 6.04 (brs, 1H), 3.99 (d, J=7.5 Hz, 2H), 2.80 (s, 3H), 1.06 (s, 6H), 0.99 (s, 6H), 0.65 (t, J=7.5 Hz, 1H); 13C NMR (125 MHz, MeOH-d4): δ 159.4 (d, J=3.5 Hz), 133.9 (d, J=2.1 Hz), 114.1, 104.2, 103.9, 71.4, 41.7, 32.5, 24.2, 23.7, 17.4.
Reaction SMILES: Cl.Cl.[CH2:3]1[C@H:8]2[CH2:9][NH:10][CH2:11][CH2:12][N:7]2[CH2:6][CH2:5][O:4]1.[CH3:13][C:14]([O:17][C:18]([N:20]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:21]([C:29]1[C:34]([F:35])=[C:33](Cl)[N:32]=[C:31]([Cl:37])[N:30]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOCC>[CH3:16][C:14]([O:17][C:18]([N:20]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:21]([C:29]1[C:34]([F:35])=[C:33]([N:10]2[CH2:11][CH2:12][N:7]3[C@@H:8]([CH2:3][O:4][CH2:5][CH2:6]3)[CH2:9]2)[N:32]=[C:31]([Cl:37])[N:30]=1)[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[O:19])([CH3:13])[CH3:15]
Reactant: C1CN2CCOC[C@H]2CN1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(N2CCN3CCOC[C@H]3C2)c1F
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of crude (9aR)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (1.7185 g, 7.99 mmol) in DMF (40 mL) was added tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (3.97 g, 7.98 mmol) and N,N-diisopropylethylamine (4.60 mL, 26.41 mmol). The solution was stirred overnight and then diluted with Et2O (200 mL). The mixture was washed with water (2×100 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (100 mL). The combined organic phase was washed with a fresh portion of water (50 mL), and then dried over anhydrous Na2SO4. The mixture was filtered, concentrated in vacuo, and the residue was dissolved in DCM (200 mL) and dried over anhydrous Na2SO4. The mixture was filtered, and the solution was concentrated in vacuo. The residue was purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N) to afford tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (4.34 g, 90%) as a white foam. LCMS: (M+H)+: 603.3.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]=1[C:11]([OH:13])=O.[NH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:19]=1>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]=1[C:11]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[N:19]=1)=[O:13]
Reactant: CC1=C(C(=O)O)Cc2ccccc21
Reactant: Nc1nc(Cc2ccc(-c3ccncc3)cc2)cs1
Product: CC1=C(C(=O)Nc2nc(Cc3ccc(-c4ccncc4)cc3)cs2)Cc2ccccc21

Procedure:
Using a procedure similar to the synthesis of Example 2, 3-methyl-1H-indene-2-carboxylic acid was reacted with 2-amino-4-(4-(pyridin-4-yl)benzyl)thiazole to give Example 170. MS Found: (M+H)+=424.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:16]=3)=[CH:14][C:9]=2[CH:8]=[C:7]([C:28]([O:30]C)=[O:29])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:20]=3)=[CH:14][C:9]=2[CH:8]=[C:7]([C:28]([OH:30])=[O:29])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCN1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of methyl 1-allyl-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (262 mg) in a mixture of tetrahydrofuran (19 ml) and methanol (19 ml) was added 1N sodium hydroxide solution (6.3 ml), and the mixture was stirred at room temperature overnight. Then, water and 1N hydrochloric acid were added to make acidic (pH=4) at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give the solid, which was washed with hexane to give 1-allyl-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (199 mg) as yellow crystals.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:6][CH3:7].[OH-].[K+]>C(O)C.O>[OH:4][CH2:3][CH2:2][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:11]2[CH2:10][CH2:9][C@H:8]([CH2:5][CH2:6][CH3:7])[CH2:13][CH2:12]2)=[CH:15][CH:16]=1
Reactant: OCCBr
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC[C@H]1CC[C@H](c2ccc(OCCO)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-1-ethanol (5.0 g, 0.04 mol) and 4-(trans-4-propylcyclohexyl)phenol (4.4 g, 0.02 mol) were dissolved in ethanol (300 ml) and agitated at room temperature. To this solution was gradually dropwise added a solution of KOH (10 g) in water (20 ml), over 30 minutes, followed by stirring for 40 hours, distilling off about 200 ml of ethanol under reduced pressure, adding water (500 ml) to deposit solids, separating the solids from liquid, dissolving them in toluene (100 ml), filtering off insoluble matter, washing the toluene solution twice with 2N-NaOH, then three times with water, drying over anhydrous sodium sulfate, distilling off toluene and recrystallizing the resulting crystals from n-heptane to obtain the objective 1-(2-hydroxyethoxy)-4-(trans-4-propylcyclohexyl)benzene. Yield: 1.8 g (34%). C-S: 71.5° C. S-I: 81.4° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:15][N:16](C=O)C.O>[C-]#N.[Zn+2].[C-]#N>[C:15]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:16]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
A mixture of 2.0 g (7.43 mmol) of 3-bromo-5-(trifluoromethyl)benzoic acid [US 2006/0069261-A1, compound 1.2], 995 mg (8.48 mmol) of zinc cyanide and 859 mg (0.743 mmol) of tetrakis-(triphenylphosphine)palladium(0) in 75 ml of DMF/water (99:1) was initially degassed and then, under an atmosphere of argon, heated at 120° C. for 3 h. After cooling to RT, the mixture was diluted with about 300 ml of water and extracted three times with in each case about 150 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness on a rotary evaporator. The product was isolated by preparative HPLC (Method 9). Evaporation of the product fractions and drying of the residue under high vacuum gave 421 mg (26% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Cl)=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[C:11]([CH2:12][NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][CH3:18])=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N
Reactant: CN1C(=O)C(C)(C)Nc2ccc(Br)c(CCl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccccc1NCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
A mixture of 7-bromo-8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 2, 1.82 g, 5.73 mmol), 2-methoxyaniline (728 μL, 6.46 mmol), and potassium carbonate (1.19 g, 8.61 mmol) were suspended in anhydrous N,N-dimethylformamide (30 mL) and the mixture was stirred at 80° C. overnight. After cooling down, ethyl acetate (100 mL) and diethylether (100 mL) were added. The organic layer was washed with water (200 mL, 100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.45 g) as a pale yellow amorphous product. (Yield 63%)
Reaction SMILES: [C:1]([C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)([OH:3])=[O:2].CO.[CH3:27]CN=C=NCCCN(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:2][C:1]([C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)=[O:3]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C(=O)O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6α-carboxyandrostane-3,17-dione (II-aq, Prepn. 17, 34 mg) in CH2Cl2 (1.5 mL) at 0° C., MeOH (8 μL), DMAP (1 mg) and EDAC (39.4 mg) were added. After stirring overnight at room temperature, H2O was added and the mixture was extracted with CH2Cl2 (2×). The combined organic extracts were washed with H2O, brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/EtOAc 60/40) to give the title compound II-as (25 mg, 70%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 3.59 (s, 3H), 2.53-0.75 (m, 21H), 1.02 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1/[CH:19]=[CH:20]/[CH:21]([OH:30])[CH2:22][C:23](=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].Cl>C(O)C.O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1/[CH:19]=[CH:20]/[CH:21]([OH:30])[CH2:22][CH:23]([OH:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)CC(O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Yield: 99.4 %

Procedure:
Sodium tetrahydridoborate (1.55 g, 41.1 mmole) was added with stirring to a cooled solution (5° C.) of methyl (E)-7-(2,4-dichloro-6-phenylmethoxyphenyl)-5-hydroxy-3-oxo-6-heptenoate (34.8 g, 82.3 mmole) in ethanol (200 ml) at a rate sufficient to maintain the internal temperature at 15°-20° C. The resulting solution was stirred with ice-bath cooling for 15 min. and then acidified with 6 N hydrochloric acid. The resulting mixture was diluted with water (500 ml) and extracted with ether (3×250 ml). The organic extracts were combined, washed with brine (4×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo, leaving the title compound as a yellow oil (34.8 g, 99.5%): pmr CDCl3) δ2.45 (2H, d), 3.65 (3H, s), 4.18 (H, m), 4.45 (H, m), 4.98 (2H, s), 7.28 (5H, s).
Reaction SMILES: [CH:1]1([C:7]([O:9][CH3:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1COCC1.BrCCOC[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:7]([O:9][CH2:10][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1CCCCC1
Reactant: BrCCOCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1
Yield: 88.3 %

Procedure:
Using Methyl cyclohexanecarboxylate (5.55 g), KHMDS (100 ml of a 0.5M solution in toluene), anhydrous THF (100 ml) and benzyl 2-bromoethyl ether (10.09 g) and the procedure set forth previously (Example 108, Step 1), the desired intermediate benzyl ether (6.83 g) was obtained after silica gel column chromatography (EtOAc:Hexanes: 15:85).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3/[C:12](=[CH:19]\[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])/[C:11]([F:26])([F:25])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29]1([C:35]2[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=2[C:37](O)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(=O)C)C.[ClH:50]>C(Cl)(Cl)Cl>[ClH:50].[F:25][C:11]1([F:26])[CH2:10][CH2:9][N:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:28][CH:27]=2)=[O:7])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2/[C:12]/1=[CH:19]\[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CN(C)CC/C=C1\c2ccccc2N(C(=O)c2ccc(N)cc2)CCC1(F)F
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(C)CC/C=C1\c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CCC1(F)F

Procedure:
Using 690 mg of (E)-1-(4-aminobenzoyl)-5-(3-dimethylaminopropylidene)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepine and 430 mg of o-phenylbenzoic acid, 520 mg of free base was synthesized in the same manner as described in Reference Example 8. Next, 340 mg of the free base was dissolved in chloroform, the resulting solution was mixed with 4N hydrochloric acid ethyl acetate solution, and the solvent was evaporated. Then, the resulting residue was mixed with hexane to obtain 111 mg of (E)-4'-[[4,4-difluoro-5-(3-dimethylaminopropylidene)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzanilide hydrochloride in the form of colorless amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:23]#N)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[C:11]([O:19][CH:20]([F:22])[F:21])[CH:10]=2)[CH2:5][CH2:4]1.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(O)[O-:38].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[C:11]([O:19][CH:20]([F:22])[F:21])[CH:10]=2)([CH:23]=[O:38])[CH2:5][CH2:4]1
Reactant: COC1(OC)CCC(C#N)(c2ccc(OC(F)F)c(OC(F)F)c2)CC1
Reactant: O=S([O-])O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC1(OC)CCC(C=O)(c2ccc(OC(F)F)c(OC(F)F)c2)CC1
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of 4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan-1-one dimethyl ketal (1.5 g, 3.98 mmol) in toluene (50 mL) at room temperature under an argon atmosphere was treated with a solution of diisobutylaluminum hydride (1M in toluene, 10 mL, 10 mmol). After 4 h, a solution of saturated aqueous sodium bisulfite was added and the mixture was extracted twice with ethyl acetate. The combined organic extract was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (1.5 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[H-].[Na+].Br[CH2:16][CH:17]1[CH2:19][CH2:18]1.O>CN(C=O)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[N:3]=1.[Br:1][C:2]1[N:3]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Brc1cc(-c2ccccc2)[nH]n1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc(-c2ccccc2)n(CC2CC2)n1
Product: Brc1cc(-c2ccccc2)nn1CC1CC1
Reaction time: 17 h

Procedure:
5.7 g of 3-bromo-5-phenyl-1H-pyrazole were dissolved in 50 ml of anhydrous DMF, 0.74 g of sodium hydride and 4.1 g of bromomethylcyclopropane were added and the mixture was allowed to stand for 17 h at room temperature. The reaction mixture was then treated with 1 ml of water and the volatile constituents were removed in vacuo. Chromatography on reversed phase silica gel yielded 1.4 g of 3-bromo-1-cyclopropylmethyl-5-phenyl-1H-pyrazole and 2.7 g of 5-bromo-1-cyclopropylmethyl-3-phenyl-1H-pyrazole as viscous oils.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]([OH:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)(=O)C>O>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7](/[CH:10]=[C:25](/[C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)\[C:26]([OH:28])=[O:27])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)Cc1cccs1
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCCc1ncc(/C=C(\C(=O)O)c2cccs2)n1Cc1ccccc1Cl
Temperature: 140 °C
Reaction time: 6 h

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (2 mmol), 2-thienylacetic acid (2.3 mmol), potassium carbonate (0.91 mmol), and acetic anhydride (1 mL) is heated gradually to 140° C. and held at this temperature for 6 hours. The cooled reaction is diluted with water and the solid is separated, triturated several times with ether, and the solid is crystallized to give the title compound.