Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Br:20])[CH:13]=2)[C:9]2[C:8](=[O:21])[N:7]([CH2:22][CH3:23])[C:6](=[O:24])[N:5]([CH2:25][CH2:26][O:27]C(=O)C)[C:4]=2[N:3]=1.Cl.[NH2:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[OH:38].C(=O)(O)[O-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O.CO.CN(C)C(=O)C>[CH3:23][CH2:22][N:7]1[C:6](=[O:24])[N:5]([CH2:25][CH2:26][OH:27])[C:4]2[N:3]=[C:2]([NH:32][CH:33]3[CH:34]([OH:38])[CH2:35][CH2:36][CH2:37]3)[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Br:20])[CH:13]=3)[C:9]=2[C:8]1=[O:21]
Reactant: CCn1c(=O)c2c(nc(Br)n2Cc2ccc(OC)c(Br)c2)n(CCOC(C)=O)c1=O
Reactant: N[C@@H]1CCC[C@H]1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CCn1c(=O)c2c(nc(NC3CCCC3O)n2Cc2ccc(OC)c(Br)c2)n(CCO)c1=O
Yield: 85 %

Procedure:
Compound 7A (about 1 mole) was combined with (R,R)-2-amino-1-cyclopentanol hydrochloride (Compound 8A, about 1.2 moles) and sodium bicarbonate (about 3 moles). To this reaction mixture was added N,N-dimethylacetamide (“DMA”), and the reaction mixture was agitated at about 135–140° C. for about 15–17 hours until complete consumption of the starting material was indicated. Compound 9A is an intermediate that is formed, but not isolated, from the reaction mixture. The reaction mixture was then cooled to about 45–50° C., and tetrabutylammonium hydroxide (about 0.05 moles of about a 40% solution in water) was charged therein, followed by methanol. The reaction mixture was refluxed at about 80–85° C. for about 8–9 hours until complete deprotection of the acetate group was indicated. The reaction mixture was cooled to about 40–45° C. and concentrated under vacuum. The pH of the reaction mixture was adjusted to about 5–6 with dilute acetic acid, and the reaction mixture was heated to about 55–65° C., and seeded with a small amount of Compound 13A. The reaction mixture was then cooled to about 30–35° C. over a period of about 2 hours, and water was added over a period of about 1 hour. The reaction mixture was further cooled to about 0–5° C. over a period of about 1 hour, and agitated at that temperature for about 4 hours. The Compound 13A product was isolated by filtration, washed with water and dried to provide about an 85–90% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C[O-].[Na+].CO.C([O:19][C:20](=[O:26])[C:21](OCC)=O)C.Cl>C1COCC1.C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:21]([C:20]([OH:26])=[O:19])=[CH:9][C:8](=[O:10])[C:6]=2[CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(F)ccc1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(=O)c2cc(F)ccc2o1
Temperature: 17.5 °C

Procedure:
A solution of 20 g of 5′-fluoro-2′-hydroxyacetophenone (13 mol) in 100 ml of THF was slowly added at 5-10° C. to a solution of 52 ml of 30% sodium methoxide in methanol (0.30 mol). The temperature was then allowed to reach 15° C. and 22 g of diethyloxalate (0.15 mol) were added between 15 to 25° C. to give a complete solution. The reaction progress was monitored by TLC until less than 5% of raw starting material was present. The mixture was adjusted to pH 1-2 by the addition of 20 ml of 36% HCl (0.24 mol) and 100 ml of water between 5 to 15° C. The solid residue formed was removed by filtration then the aqueous layer removed by decantation. The organic layer was then washed with 40 ml of an aqueous solution of 15% NaCl and concentrated under reduced pressure at 40-50° C. to give a yellow oil. This residual oil was dissolved in 100 ml of glacial acetic acid and 100 ml of water at reflux for 17-20 h. After cooling to 15-20° C., the suspension of the title compound was filtered to give after drying 20 g of a white or off-white solid (yield: 75%). A second crop can be obtained after concentration of the mother liquor and the residue warmed up in 50 ml glacial acetic acid and 50 ml water to reflux for 20 h to hydrolyze the ester to give an additional batch of the title compound (2-3 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.O.C(#N)C>C(OCC)C.O1CCCC1>[CH:11]1([C:2]([C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=2)([OH:3])[CH3:1])[CH2:13][CH2:12]1
Reactant: Br[Mg]C1CC1
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Cl)cc1)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.50 g (9.70 mmol) of 4-chloroacetophenone were dissolved in 8 ml of diethyl ether at 0° C., and 38.8 ml (19.41 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, addition of water and acetonitrile to the reaction solution, and filtration of the mixture through kieselguhr. The organic solvents were removed in a rotary evaporator, and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, and the solvents were removed in vacuo. The crude product was purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient). The acetonitrile was removed from the combined product phases in a rotary evaporator, and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were again washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvents were removed in vacuo. 1.37 g (72% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(NC2CCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (0.3 g, 1.33 mmol) and cyclopentanone (0.56 g, 6.6 mmol) in methanol (3 mL), acetic acid (0.159 g, 2.6 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.208 g, 3.3 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure to give the desired compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.CCN=C=NCCCN(C)C.[F:36][C:37]([F:57])([F:56])[C:38]1[O:42][C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]([F:52])([F:51])[F:50])=[N:40][C:39]=1[C:53](O)=[O:54].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+]>ClCCl>[CH3:2][O:3][C:4](=[O:24])[CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:23])[CH2:20][CH2:21][NH:22][C:53]([C:39]3[N:40]=[C:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]([F:51])([F:50])[F:52])[O:42][C:38]=3[C:37]([F:36])([F:56])[F:57])=[O:54])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCN)cc2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2C(F)(F)F)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4C(F)(F)F)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-aminopropionylamino)phenyl]cyclohexyl}acetic acid methyl ester HCl salt (300 mg, 0.846 mmol), EDCI (405.23 mg, 2.114 mmol), 5-trifluoromethyl-2-(2-trifluoromethylphenyl)oxazole-4-carboxylic acid (288.68 mg, 0.888 mmol), HOBt (171.39 mg, 1.268 mmol) and ethyldiisopropylamine (383.39 mg, 2.959 mmol) were put into dichloromethane solvent (10 mL) and stirred at room temperature for 24 hours. After the reaction, aqueous NaHCO3 was added thereto, and extracted with dichloromethane. The organic layer was washed with brine, then the product was dried with anhydrous sodium sulfate, and the solvent was removed. Column chromatography was conducted on the crude material to obtain trans-{4-[4-(3-{[5-trifluoromethyl-2-(2-trifluoromethylphenyl)oxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (461 mg, 87%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:16])[CH2:4][C:5](=O)[CH2:6][C@H:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].[OH-].[K+].O.NN>C(O)COCCO>[CH3:16][C@H:3]([CH2:4][CH2:5][CH2:6][C@H:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:2][OH:1]
Reactant: CC(C)CCC[C@@H](C)CC(=O)C[C@@H](C)CO
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CO

Procedure:
A mixture of 3.98 g. (0.0174 mole) of (2R,6R)-1-hydroxy-2,6,10-trimethylundecan-4-one, 108 ml. of diethylene glycol, 25 g. of KOH and 43.5 ml. of hydrazine hydrate was stirred and heated until distillation began. Distillation wan then continued until the internal temperature of the reaction mixture reached 195° C. then the mixture was maintained at reflux for 4 hours. After cooling, the resulting mixture was treated with ice and 3 N aqueous HCl and worked-up by ether extraction in the manner of Example 1 giving 2.9 g. of a pale yellow oil. This material was chromatographed on 180 g. of silica gel. Elution with 4:1 parts by volume hexane-ether yielded (2R,6R)-(+)-2,6,10-trimethylundecan-1-ol which was evaporatively distilled affording 2.22 l g. of a colorless oil, b.p. 90- 105° C. (bath temperature (0.2 mm Hg.); [α]25D + 9.44° (c 2.04, hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Yield: 80.7 %

Procedure:
A stirred solution of 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268 A1)(0.21 g, 0.0008 mole) in a mixture of DME (10 ml) and water (30 ml) under argon was treated with 4-boronobenzoic acid (0.14 g, 0.0008 mole), sodium carbonate (0.39 g, 0.0037 mole) and tetrakis (triphenylphosphine)palladium (0)(16 mg), then heated under reflux for 4 hours. The mixture was dried (Na2SO4) and concentrated in vacuo to leave the title compound as a white solid (0.19 g, 78%).
Reaction SMILES: Br[C:2]1[CH:22]=[N:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7]3[N:16]=[CH:15][C:14](C)=[C:13](C)[C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(#N)C.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.[Cu]I>[CH2:19]([N:6]1[C:5]2[N:21]=[CH:22][C:2]([C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:3][C:4]=2[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[CH:14][CH:15]=[N:16][C:7]1=2)[CH3:20]
Reactant: CCN1c2ncc(Br)cc2C(=O)N(C)c2c1ncc(C)c2C
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN1c2ncc(C#Cc3ccccc3)cc2C(=O)N(C)c2cccnc21
Yield: 120.9 %

Procedure:
To a solution of 8-bromo-5,11-dihydro-3,4-dimethyl-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.05 g, 0.14 mmol), phenylacetylene (0.03 g, 0.28 mmol), and triethylamine (3.5 mL) in 1.5 mL of acetonitrile was added tetrakis(triphenylphosphine)palladium(0) (10 mg) and copper(I) iodide (5 mg). The resultant mixture was heated at reflux for 2 hours. The solvent was removed at reduced pressure, and the residue was purified by preparative thin layer chromatography, eluting with ethyl acetate/hexanes. The product was recrystallized from ethyl acetate/petroleum ether to provide 60 mg of the title compound, m.p. 228°-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]=[CH:26][O:25]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:7][CH2:23][CH:24]2[CH2:29][CH2:28][CH:27]=[CH:26][O:25]2)=[CH:4][CH:3]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CSCC2CCC=CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A solution of 260 mg of 4-chlorobenzyl mercaptan in 3 ml of dimethylformamide was mixed with 72 mg of 55% sodium hydride, and the mixture was stirred at room temperature for 30 minutes. 2 ml of a dimethylformamide solution containing 400 mg of 2-tosyloxymethyl-3,4-dihydro-2H-pyran were then added, and the mixture was stirred at 80°-90° C. for 4 hours. The mixture was then treated and the product purified essentially as described in Example 34(a) to give 224 mg of 2-(4-chlorobenzylthiomethyl)-3,4-dihydro-2H-pyran, as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])[NH:5][CH:6]=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[C:2]1[CH:3]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])[NH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Br)c[nH]2)CC1
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)c[nH]2)CC1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A mixture of tert-butyl 4-(4-bromo-1H-pyrrole-2-carbonyl)piperazine-1-carboxylate (350 mg, 0.98 mmol), (2,4-dichlorophenyl) boronic acid (280 mg, 1.47 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), Na2CO3 (312 mg, 2.94 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=30:1) to afford the desired product (273 mg, 59% yield).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[BH4-].[Na+]>C1COCC1.CO>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)n1ccc2ccc(N)cc21
Reaction time: 0.25 h

Procedure:
To a stirring solution of 1-Boc-6-nitroindole (250 mg, 0.95 mmol) in THF (5 mL) and MeOH (10 mL) at 0° C., was added Ni(OAc)2.4H2O (473 mg, 1.9 mmol). After complete dissolution, NaBH4 (143 mg, 3.8 mmol) was added slowly. Upon addition of the NaBH4, the reaction mixture turned black and vigorous gas evolution was observed. After 15 min, the solvents were removed in vacuo and the residue was dissolved in a stirring mixture of ethyl acetate (100 mL), conc NH4OH (10 mL) and water (20 mL). The layers were separated and the organic phase was washed again with 33% conc NH40OH in water and then washed twice with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.C(O)C>ClCCl>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)=[O:4]
Reactant: CC(C)(O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(COC(=O)C(C)(C)O)cc1

Procedure:
2-hydroxy isobutyric acid (1.56 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-1, step a). The title compound (2.65 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.45.
Reaction SMILES: N[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[CH3:10].Cl.N([O-])=O.[Na+].O[PH2]=O>C(O)(=O)C.O>[Cl:8][C:7]1[CH:2]=[C:3]([CH3:10])[CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: Cc1cc(Br)cc(Cl)c1N
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Cl)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
Step G1. To an ice-water-cooled and stirred solution of 2-amino-5-bromo-3-chlorotoluene (12 g, 54 mmol) in a mixture of 100 mL of acetic acid, 43 mL of H2O and 11.5 mL of concentrated HCl was added dropwise a solution of NaNO2 (4.48 g, 65 mmol) in 15 mL of H2O. The reaction mixture was stirred for 30 min and was then added to an 112 mL solution of 50% H3PO2 cooled at 0° C. After being stirred for 6 h at 0° C., the reaction mixture was allowed to stand at room temperature overnight. The solid was filtered and washed with water, then dried in vacuum. 3-Chloro-5-bromo-toluene (9 g, 81%) was obtained as brown solid. Crystals. 1H NMR (CDCl3): δ 2.31 (s, 3H), 7.10 (s, 1H), 7.21 (s, 1H), 7.31 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([F:30])=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].CC(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C1(C)C=CC=CC=1>[Cl:17][C:18]1[C:19]([F:30])=[C:20]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26]
Reactant: CCOc1ccc(B(O)O)c(F)c1Cl
Reactant: CCCC1CC=C(c2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CC=C(c2ccc(-c3ccc(OCC)c(Cl)c3F)cc2)CC1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
6.0 g of the compound (16), 5.5 g of the compound (12), 5.9 g of potassium carbonate and 0.13 g of Pd(PPh3)2Cl2 were added to a reactor having 60 mL of IPA placed therein under nitrogen atmosphere. The mixture was stirred under refluxing and heating for 3 hours. After cooling the reaction mixture to 25° C., 200 mL of toluene and 200 mL of water were added thereto, and the resulting toluene solution was washed with a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water. Thereafter, the solvent was removed by distillation to obtain a residue. The resulting residue was purified by recrystallization from a mixed solvent of toluene and ethyl acetate (toluene/ethyl acetate=1/1 by volume). The resulting crystals were purified by silica gel column chromatography using toluene as eluent, and then further purified by recrystallization from a mixed solvent of heptane and ethanol (heptane/ethanol=5/1 by volume) to obtain 5.9 g of 3-chloro-4-ethoxy-2-fluoro-4′-(4-propylcyclohexa-1-enyl)biphenyl (No. 130). The resulting compound (No. 130) was colorless crystals. The yield based on the compound (13) was 45.0%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[F:22][C:5]1[CH:4]=[CH:3][C:2]([C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:21][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1F
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc(-c2cncnc2)ccc1F

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 57 using 5-bromo-2-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 59.1) and pyrimidin-5-ylboronic acid to afford the title compound as a white powder. UPLC-MS (Condition 2) tR=1.04 min, m/z=378.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.39 (d, J=8.99 Hz, 2H) 7.56 (t, J=9.19 Hz, 1H) 7.85 (d, J=8.99 Hz, 2H) 8.01-8.09 (m, 1H) 8.15 (dd, J=6.65, 2.35 Hz, 1H) 9.22 (s, 3H) 10.72 (s, 1H).
Reaction SMILES: [CH2:1]([CH:10]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[N:11]1[CH:14]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:17])[CH:13]([CH:28]=[CH2:29])[C:12]1=[O:30])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[OH-:40].[Na+].[BH4-].[Na+].Cl>O1CCCC1.C([O-])(=O)C.[Hg+2].C([O-])(=O)C.C(OCC)C.O>[CH2:31]([CH:10]([CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[N:11]1[CH:14]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:17])[CH:13]([CH:28]([OH:40])[CH3:29])[C:12]1=[O:30])[C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1
Reactant: C=CC1C(=O)N(C(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)C1CC(=O)OCc1ccc(OC)cc1
Reactant: [OH-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(COC(=O)CC2C(C(C)O)C(=O)N2C(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1
Temperature: 35 °C
Reaction time: 5 h

Procedure:
2.85 g of 1-(di-p-anisylmethyl)-3-ethenyl-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone was dissolved in 14 ml of tetrahydrofuran, and 7 ml of water and 2.0 g of mercury (II) acetate were added thereto, followed by stirring at 35° C. for 5 hours. 12 ml of a 1N aqueous solution of sodium hydroxide was added thereto at 0° C., and to the resulting mixture was then added dropwise a solution of 0.25 g of sodium borohydride in 1 ml of a 1N aqueous solution of sodium hydroxide. After stirring at the same temperature for 15 minutes, the reaction mixture was neutralized with a 2N hydrochloric acid aqueous solution. Diethyl ether was added thereto, followed by filtration using Celite. The filtrate was extracted with diethyl ether, and the extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and distilled off to remove the solvent, thereby to obtain 2.6 g of 1-(di-p-anisylmethyl)-3-(1-hydroxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].[F:25][C:26]1[CH:27]=[CH:28][C:29](C2C=CC(C)=CC=2C(O)=O)=[N:30][CH:31]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:29]1[CH:28]=[CH:27][C:26]([F:25])=[CH:31][N:30]=1)=[O:11]
Reactant: Cc1ccc(-c2ccc(F)cn2)c(C(=O)O)c1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccc(F)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-(5-fluoropyridin-2-yl)-5-methylbenzoic acid. MS (ESI) 342 (M+H).