Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]12[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[CH:13]1[CH2:12][O:11][NH:10]2>C(O)(=O)C.CCOC(C)=O.[Zn]>[NH2:10][C@@:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:16][O:15][C@H:14]([C:17]([F:19])([F:18])[F:20])[C@H:13]1[CH2:12][OH:11]
Reactant: Fc1cccc(C23CO[C@H](C(F)(F)F)C2CON3)c1F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N[C@@]1(c2cccc(F)c2F)CO[C@H](C(F)(F)F)[C@H]1CO
Temperature: 0 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
(4S)-6a-(2,3-difluorophenyl)-4-(trifluoromethyl)hexahydrofuro[3,4-c]isoxazole (3.16 g) was dissolved in acetic acid (20 mL) and the reaction mixture cooled to 0° C. Zinc (5.0 g) was added, and the reaction was allowed to warm and stir at RT for 20 h. The reaction mixture was then diluted with EtOAc (50 mL) and filtered through Celite®, washing with a further 100 mL of EtOAc. The combined organic portions were evaporated, dissolved in CHCl3 (20 mL), and ammonia (28% aq., 25 mL) was added slowly. The layers were separated, and the aqueous portion was further extracted with CHCl3 (2×25 mL). The combined organic extracts were dried over anhydrous MgSO4 and evaporated to afford the title compound (3.12 g) which was used in the subsequent step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.93 (ddd, J=7.8, 5.1, 2.8 Hz, 1 H), 3.85 (dd, J=12.4, 5.1 Hz, 1 H), 4.03 (dd, J=9.1, 2.8 Hz, 1 H), 4.14 (dd, J=12.3, 2.7 Hz, 1 H), 4.35 (d, J=9.1 Hz, 1 H), 4.68 (quin, J=7.3 Hz, 1 H), 7.09-7.25 (m, 2H), 7.25-7.34 (m, 1H)
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[CH:24])[CH:18]=1>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:15][C:13]1[CH:12]=[N:11][CH:10]=[C:9]([C:24]#[C:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH:14]=1
Reactant: Brc1cncc(Br)c1
Reactant: C#Cc1cccc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Clc1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
Add triethylamine (2.38 mL, 16.88 mmol), copper (I) iodide (80.4 mg, 0.422 mmol) and bis(triphenylphosphine)palladium (II) dichloride (148 mg, 0.211 mmol) to a solution of 3,5-dibromopyridine (1 g, 4.22 mmol) and 1-chloro-3-ethynylbenzene, (prepared as described in PREPARATION 12), (574 mg, 4.22 mmol) in ethyl acetate (4.22 mL). Stir under nitrogen at 50° C. for 18 h. Concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate, to give the title compound (571 mg, 46%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(O)C.CCOCC>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([Cl:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:20]=[CH:21][CH:22]=1
Reactant: N#Cc1cnc2cnc(Cl)cc2c1Cl
Reactant: Nc1cccc(Br)c1
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1cnc2cnc(Cl)cc2c1Nc1cccc(Br)c1
Temperature: 25 °C

Procedure:
To the above 600 mg of 4,6-dichloro-[1,7]naphthyridine-3-carbonitrile in 20 mL of absolute ethanol was added 1 mL of 3-bromoaniline. After refluxing the reaction under an inert atmosphere for 4 hours, the reaction mixture was cooled to ambient temperature, diluted with ether, and the product was filtered and washed with ether. Drying in vacuo yielded 790 mg of 4-(3-bromo-phenylamino)-6chloro-[1,7]naphthyridine-3-carbonitrile as an off-white solid: mp=220-223° C.; mass spectrum (m/e): M+H 359.0, 361.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[O:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)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>[CH:11]1[C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:8]([C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=3)[CH:7]=[CH:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Brc1cccc(-c2cccc3c2oc2ccccc23)c1
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1ccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-(3-bromo-phenyl)-dibenzofuran (0.62 mmol), 4-hydroxyphenyl boronic acid (0.62 mmol), and Pd(PPh3)4, (0.05 mmol) in 2 mL of toluene and 1 mL ethanol was heated to obtain a clear solution, then Na2CO3 (1.9 mmol) in 2 mL water was added. The reaction mixture refluxed for 5 h at 80° C. The mixture was cooled to room temperature and the aqueous layer was acidified with 2N HCl. The entire reaction mixture was diluted with 25 mL ethyl acetate. The organic layer was washed with 2×30 mL portions of water, 2×30 mL portions of sat. aq. NaCl, and dried (MgSO4). After the solution was concentrated, the residue was purified by column chromatography (eluted with 5-10% EtOAc-Heptane) to afford 3′-Dibenzofuran-4-yl-biphenyl-4-ol.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:25])[CH:7]=[CH:8][C:9]=2[O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38](=[O:39])[C:37]([C:40](O)=[O:41])=[CH:36][N:35]([CH:43]([CH3:45])[CH3:44])[C:34]2=[O:46])=[CH:29][CH:28]=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:25][C:40]([C:37]3[C:38](=[O:39])[N:33]([C:30]4[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=4)[C:34](=[O:46])[N:35]([CH:43]([CH3:45])[CH3:44])[CH:36]=3)=[O:41])[CH:7]=[CH:8][C:9]=2[O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH2:2][CH2:3]1
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C3CC3)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3C3CC3)c2cc1OC

Procedure:
This compound was synthesized from 3-cyclopropyl-4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine (0.06 g, 0.20 mmol) and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.063 g, 0.21 mmol) in an analogous manner to Example 59. mp 172-174° C.; LCMS m/z=611 (M+1). 1H NMR (DMSO-d6) δ: 10.86 (s, 1H), 8.67 (s, 1H), 8.44 (d, 1H, J=5.24 Hz), 7.65 (dd, 1H, J=2.52 Hz, J=7.65 Hz), 7.58 (s, 1H), 7.31-7.48 (m, 6H), 7.16 (d, 1H, J=8.73 Hz), 6.34 (d, 1H, J=5.20 Hz), 4.70-4.85 (m, 1H), 3.94 (s, 6H), 1.78-1.88 (m, 1H), 0.73-0.82 (m, 2H), 0.62-0.69 (m, 2H).
Reaction SMILES: ClB.CSC.[CH3:6][SiH:7]([CH2:9][CH2:10][Si:11]([CH3:21])([CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH3:8].[OH:22]O>C1COCC1>[CH3:6][SiH:7]([CH2:9][CH2:10][Si:11]([CH3:21])([CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:22])[CH3:8]
Reactant: C=CCCCCCC[Si](C)(C)CC[SiH](C)C
Reactant: OO
Agent: BCl
Solvent: C1CCOC1
Solvent: CSC
Product: C[SiH](C)CC[Si](C)(C)CCCCCCCCO
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Monochloroborane-methyl sulfide (1.10 ml, 1.16 g, 10.5 mmol) was added dropwise to a stirred, cooled (0° C.) solution of compound 9 (2.56 g, 10.0 mmol) in THF (30 ml). The reaction mixture was stirred at 0° C. for 24 h, and a solution of hydrogen peroxide (10 ml, 30% in water) added dropwise and the reaction mixture stirred at 0° C. for 4 h, washed with water and the organic layer extracted into hexane/ethyl acetate (3×30 ml, 1:1). The combined extracts were washed with brine, dried (MgS04) and the solvent removed in vacuo to yield colorless oil. The crude product was purified by column chromatography [silica gel eluted with hexane/ethyl acetate (4:1)] to yield a colorless oil.
Reaction SMILES: Cl[C:2]([C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[Cl:19][C:20]1[C:21]([CH2:30][CH2:31][NH2:32])=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1.C(N(CC)CC)C>O1CCCC1>[Cl:17][C:12]1[C:11](/[C:2](/[NH:32][CH2:31][CH2:30][C:21]2[C:20]([Cl:19])=[CH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:23][N:22]=2)=[C:3](\[C:9]#[N:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: NCCc1ncc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)C(C#N)=C(Cl)c1cccnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)/C(C#N)=C(\NCCc1ncc(C(F)(F)F)cc1Cl)c1cccnc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of ethyl 3-chloro-3-(2-chloropyridin-3-yl)-2-cyanoacrylate (0.1 g, 0.369 mmol, 1 eq.) in 5 ml of tetrahydrofuran were added 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine hydrochloride (0.106 g, 0.40 mmol, 1.1 eq.) and triethylamine (TEA) (0.112 g, 1.10 mmol, 3 eq.) at room temperature. After being stirred for 8 h at 80° C., the mixture was evaporated. The residue was diluted with AcOEt and the precipitate was filtered off. The filtrate was evaporated and the residual oil was subjected to column chromatography to give ethyl (2Z)-3-(2-chloropyridin-3-yl)-3-({2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethyl}amino)-2-cyanoacrylate (0.170 g, 99% yield).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[CH:4]=[O:5]
Reactant: CON(C)C(=O)C1Cc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: O=CC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred ice-cold solution of the above amide (400 mg, 1.9 mmol) in ether (20 mL), was added lithium aluminium hydride (1 M in THF, 4 mL). After stirring the ice-cold mixture for 1 h, excess reducing agent was quenched by the careful addition of 1N sulfuric acid (10 mL). The reaction mixture was stirred for 5min, the ether layer was decanted and the remaining solid was washed with ether (100 mL). The combined ether extract was washed with water, dried over anhydrous sodium.sulfate, and evaporated to give indane 2-carboxaldehyde as a light brownish oil which was used without further purification in the next step.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[CH2:11][CH2:10][C@@H:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C@H:8]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[CH2:7]1)[CH2:3][CH2:4][CH3:5].[Br:30]Br.[OH-].[Na+]>C(Cl)Cl>[ClH:1].[Br:30][C:26]1[CH:25]=[C:24]2[O:27][CH2:28][O:29][C:23]2=[CH:22][C:21]=1[O:20][CH2:19][C@H:8]1[C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:10][CH2:11][N:6]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7]1
Reactant: CCCCN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc3c(c2)OCO3)C1
Reactant: BrBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2cc3c(cc2Br)OCO3)C1

Procedure:
(-)-trans-1-butyl-4-(4-fluorophenyI)-3-(3,4-methylenedioxyphenoxymethyl)-piperidine hydrochloride (1 g) was dissolved in CH2Cl2 (50 ml). Bromine (0.124 ml) was added dropwise at R.T. After stirring for 2 h aqueous NaOH was added, and the CH2Cl2 layer was isolated, dried over Na2SO4, filtered and evaporated to dryness. The residue was dissolved in acetone, excess conc. HCl was added and the above mentioned bromo compound was precipitated by addition of ether. M.p. 116° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:21][O:22][C:23]1[N:24]=[CH:25][C:26]([C@H:29]([NH:31][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=4[C:14]#[N:15])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:30])=[CH:27][N:28]=1
Reactant: COc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ncc([C@@H](C)Nc2ncnc3c2CN(c2ccc(C)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (430 mg, 1.51 mmol) and (R)-1-(2-methoxypyrimidin-5-yl)ethanamine (238 mg, 1.56 mmol) (prepared similarly according to the method for Intermediate 16) in acetonitrile (6 mL) and N,N-diisopropylethylamine (2 mL, 9 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9](C)[C:10](=O)C(F)(F)F)#[N:2]>C(=O)(O)[O-].[Na+].O.C(O)C>[CH3:10][NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CN(C(=O)C(F)(F)F)c1ccccc1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNc1ccccc1C#N
Yield: 189.2 %

Procedure:
N-(2-Cyanophenyl)-2,2,2-trifluoro-N-methylacetamide (3 g, 0.01 mol) was dissolved in a sodium bicarbonate/water/ethanol mixture, refluxed for 5 h and evaporated. Water was added and the mixture extracted with ethyl acetate, dried over sodium sulphate and evaporated to give the product (2.5 g). MS (+EI) 132 (M+), 1H NMR (CDCl3) 7.45 (2H, t), 6.69 (1H, d), 6.62 (1H, t), 6.19 (1H, s), 2.76 (3H, d).
Reaction SMILES: CO.[NH2:3][C:4]1[C:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:11]=2)=[CH:8][CH:7]=[C:6]([NH2:23])[N:5]=1.[OH-].[Na+].[Cl:26][C:27]1[CH:32]=[N:31][CH:30]=[C:29](Cl)[N:28]=1>CN(C)C=O>[Cl:26][C:27]1[N:28]=[C:29]([O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][C:12]3[CH:11]=[C:10]([C:9]4[C:4]([NH2:3])=[N:5][C:6]([NH2:23])=[CH:7][CH:8]=4)[O:14][N:13]=3)=[CH:17][CH:18]=2)[CH:30]=[N:31][CH:32]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4cncc(Cl)n4)cc3)no2)c(N)n1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a methanol (1.5 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (50 mg, 0.18 mmol) described in Manufacturing Example 18-1-1 was added a 2 N sodium hydroxide solution (89 μL), which was concentrated under a reduced pressure. 2,6-Dichloropyrazine (28 mg, 0.19 mmol) and N,N-dimethylformamide (0.75 mL) were added to the residue, which was stirred for 10 minutes at 100° C. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1, then ethyl acetate) to obtain the title compound (47 mg, 67%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=2[CH:17]=1.B([O-])([O-])O[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.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>[F:27][C:26]([F:29])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=3[CH:17]=2)=[CH:21][CH:22]=1
Reactant: [O-]B([O-])Oc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2OCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: CCOC(=O)C1=Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2OCC1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
Under argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (500 mg), 4-trifluoromethylphenyl borate (351.5 mg) and potassium carbonate (0.47 g) in toluene-ethanol-water (20-2-2 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenylphosphinepalladium (0.06 g), and the mixture was refluxed for 20 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:10) to give ethyl 7-(4-trifluoromethylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (489 mg) as colorless crystals.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][OH:9].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH:8]=[O:9]
Reactant: OCC1CC2CCC1C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC1CC2CCC1C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
A stirred suspension of 2-norbornylmethanol (0.5 ml; 5.8 mmol) and PCC on Al2O3* in CH2Cl2 (25 ml) was stirred at 2–3° C. for 1 h and then allowed to slowly warm up to rt. The reaction mixture was filtered and the solid material washed with CH2Cl2 (2×25 ml). The combined organic fractions were adsorbed onto silica and chromatographed to give 300 mg (42%) product as an oil. *[see Cheng Y.-S, Liu W.-L. and Chen S.-H., Synthesis, (1980) 223.]
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][N:6]=2)=[O:29])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(CO)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared in example 53(B)(a), 110 mg, 0.26 mmol) in diethyl ether (500 μL) was cooled to 0° C. and then slowly treated with lithium aluminum hydride (15 mg, 0.38 mmol). The reaction mixture was stirred at 0° C. for 30 min then allowed to warm to 25° C. After 1 h at 25° C., thin layer chromatography still indicated the presence of the starting material. An additional amount of lithium aluminum hydride (10 mg, 0.26 mmol) was added to the reaction mixture, and the reaction mixture was allowed to stir at 25° C. for 1 h. The reaction mixture was then slowly quenched by the dropwise addition of water (10 mL). The resulting mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, ⅓ hexanes/ethyl acetate) afforded the 3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide (60 mg, 57%) as a yellow foam: mp 74-77° C.; EI-HRMS m/e calcd for C21H26N2O4S (M+) 402.1613, found 402.1617.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][CH:30]=[C:31]([CH2:33][CH2:34]O)[N:32]=2)=[CH:24][CH:23]=1)([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([CH:19]([CH3:20])[CH3:21])=[CH:23][CH:24]=3)[S:29][CH:30]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: CC(C)c1ccc(-c2nc(CCO)cs2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2csc(-c3ccc(C(C)C)cc3)n2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-[2-(4-isopropyl-phenyl)-thiazol-4-yl]-ethanol in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-isopropyl-phenyl)-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid ethyl ester as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:39]([O:41][CH2:42][CH3:43])=[CH2:40])CCC.CCOC(C)=O>O1CCOCC1.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:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:8]=3)[N:3]=[C:2]([C:39]([O:41][CH2:42][CH3:43])=[CH2:40])[CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)cc(-c3cccc(Cl)c3)c2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=C(OCC)c1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 117.4 %

Procedure:
A mixture of (±)-2-chloro-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (0.0061 mol), described in International Patent Specification WO 00/39082, tributyl (1-ethoxyethenyl)-stannane (0.0091 mol) and Pd(PPh3)4 (0.0007 mol) in dioxane(30 ml) was stirred at 80° C. for 24 hours, cooled and poured out into ice water. EtOAc was added and the mixture was filtered over celite. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 3.8 g of (±)-4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-(1-ethoxyethenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH:14]=O)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[Br-].[CH2:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:20]1(/[CH:19]=[CH:14]/[C:12]2[NH:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=3)[CH:13]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cc(-c2ccc(C(F)(F)F)cc2)n[nH]1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(/C=C/c3ccccc3)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.1 %

Procedure:
3-[4-(Trifluoromethyl)phenyl]-1H-pyrazole-5-carbaldehyde (1.20 g, 5.00 mmol) was dissolved in N,N-dimethylformamide (10 mL), benzyltriphenylphosphonium bromide (3.25 g, 7.50 mmol) and potassium carbonate (2.76 g, 20.0 mmol) were added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:2) to give the title compound (630 mg, yield 40%) as colorless crystals. MS: m/z 315 (MH+), 1H NMR (CDCl3) δ: 6.79 (1H, s), 6.99 (1H, d, J=16.5 Hz), 7.10 (1H, d, J=16.5 Hz), 7.28-7.39 (3H, m), 7.41-7.47 (2H, m), 7.64 (2H, d, J=8.5 Hz), 7.87 (2H, d, J=8.0 Hz), 10.90 (1H, s).