Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH:8]([OH:13])[C:9]([O:11]C)=[O:10])[CH2:4][CH2:3]1>O>[O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH:8]([OH:13])[C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1
Reactant: COC(=O)C(O)CC1CCC(=O)N1
Solvent: O
Product: O=C1CCC(CC(O)C(=O)O)N1

Procedure:
5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid, methyl ester (1.87 g), and Amberlite (IR--120 H+) (1.9 g) in 20 ml of water is warned at 60° C. for 36 hours, filtered, and the solvent removed under reduced pressure. The resulting solid is washed with ethyl acetate and filtered to yield 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid. NMR (DMSOD6) and 7.89 (d, J=11 Hz, 1HO, 5.35 (bs, 1H), 3.99 (m, 1HO, 3.44 (m, 1/2H), 3.30 (m, 1/2H), 2.48-1.21 (m, 6H). IR (cm-1) 3370, 3280, 2940, 1694, 1355, 1213, 1120.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[Cl:19][C:20]1[C:21]([OH:31])=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:19][C:20]1[C:21]([OH:31])=[C:22]([S:27]([NH:17][CH2:16][C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])([OH:18])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)(=[O:29])=[O:28])[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Product: O=S(=O)(NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)c1cc(Cl)cc(Cl)c1O

Procedure:
Following the procedure described in the preceeding examples but using 2-(2,4-dichlorophenyl)-3-amino-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 3,5-dichloro-2-hydroxybenzenesulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1.[Zn]>[CH2:18]([C:12](=[CH:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: O=CC=Cc1ccccc1
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCCCC(=CC=Cc1ccccc1)C(=O)OCC
Temperature: 25 °C
Yield: 38.7 %

Procedure:
In a 500 ml three necked flask was placed 7.0 g Zn dust and 0.7 g Cu powder in 150 ml dry toluene. To this suspension was added a solution of 13.2 g (0.1 mol) cinnamaldehyde and 22.3 g (0.1 mol) ethyl 2-bromohexanoate in 100 ml toluene. The reaction was refluxed overnight under nitrogen, cooled to room temperature and washed two times with 140 ml of 20% acetic acid and two times with 150 ml water. The organic phase was dried over magnesium sulfate and the solvent removed by rotary evaporation. Distillation of the crude product (24.9 g) resulted in isolation of 10.0 g ethyl 2-butyl-5-phenyl-pentadienoate. BP: 135-138 @ 0.1 mm Hg UV (CH2C12): λmax 315, ε=33,280, K=129.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[C:9]([N+:15]([O-])=O)[C:10]([C:13]#[N:14])=[N:11][CH:12]=1.C[OH:19]>>[NH2:15][C:9]1[C:10]([C:13]([NH2:14])=[O:19])=[N:11][CH:12]=[C:7]([Br:6])[CH:8]=1
Reactant: CO
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Product: NC(=O)c1ncc(Br)cc1N
Temperature: 40 °C

Procedure:
Tin chloride (90 g, 400 mmol) was added to a solution of 5-bromo-3-nitropicolinonitrile (17 g, 74 mmol) in methanol (800 mL) and the reaction was heated to 40° C. for 4.75 h. The solvent was removed in vacuo and toluene added and removed in vacuo. The crude was suspended in EtOAc and the mixture basified to pH 8 with saturated NaHCO3 (aq). The organic layer was separated and the aqueous slurry extracted with CHCl3 (×3). The combined organics were filtered through Celite, dried (MgSO4) and concentrated in vacuo to give crude 3-amino-5-bromopyridine-2-carboxamide which was used directly without further purification.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([SH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>CO.C(#N)C=C>[CH2:5]([S:12][CH2:3][CH2:2][C:1]#[N:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CC#N
Reactant: SCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CCCSCc1ccccc1
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
Acrylonitrile (21.4 g) was added dropwise to a solution of benzyl mercaptan (49.6 g) and triethylamine (4 ml) in methanol (400 ml). This addition lead to an exothermic reaction and the temperature of the reaction mixture was allowed to rise from room temperature to 35° C. After 10 minutes the reaction was almost complete as shown by TLC, there being a trace of unreacted thiol still present. Additional acrylonitrile (0.5 g) was then added to consume the last of the thiol. After a further 10 minutes the solution was evaporated to give the title compound 69.0 g as a pale yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([OH:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20](S(C)(=O)=O)[N:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([O:15][C:20]2[N:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:18]([O:17][CH3:16])[N:19]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)c1nc(NC(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(NC(C)=O)ccc1Oc1nc(OC)cc(OC)n1
Yield: 70 %

Procedure:
0.78 g (3.7 mmol) of the obtained methyl 6-acetylamino-3-hydroxypicolinate, 0.81 g (3.7 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.51 g (3.7 mmol) of potassium carbonate were added to 50 ml of DMF, and the mixture was reacted at 80° C. for two hours. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried and concentrated. The oily product thereby obtained was purified by column chromatography to obtain methyl 6-acetylamino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][CH:25]([C:40]2[N:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][N:49]([C:52](=[O:54])[CH3:53])[CH2:48][CH2:47]3)=[CH:42][N:41]=2)[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[CH2:8][C@H:7]1[CH2:55][CH3:56])=[O:5])[CH3:2].O.C(OCC)(=O)C.[CH3:64][N:65](C)C=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.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([C:64]#[N:65])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][CH:25]([C:40]2[N:45]=[CH:44][C:43]([N:46]3[CH2:47][CH2:48][N:49]([C:52](=[O:54])[CH3:53])[CH2:50][CH2:51]3)=[CH:42][N:41]=2)[C:26]2[CH:27]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=2)[CH2:8][C@H:7]1[CH2:55][CH3:56])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C(C)=O)CC3)cn2)C[C@H]1CC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)N1c2ccc(C#N)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C(C)=O)CC3)cn2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 6 h

Procedure:
(2R,4S)-4-{[5-(4-Acetylpiperazin-1-yl)pyrimidin-2-yl]-[3,5-bis-(trifluoromethyl)benzyl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg), a catalytic amount of tetrakis(triphenylphosphine)palladium, zinc cyanide (37 mg) are dissolved in N,N-dimethylformamide (2 ml), and the mixture is stirred at 100° C. for 6 hours under nitrogen flow. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate. The mixture is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=3:7→0:1) to give (2R,4S)-4-{[5-(4-acetylpiperazin-1-yl)pyrimidin-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (149 mg). MS (m/z): 705 [M+H]+.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[F:5][C:6]([F:15])([F:14])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl>[N:13]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([F:5])([F:14])[F:15])=[CH:8][CH:9]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc(N=C=S)cc1

Procedure:
Thiophosgene (5 mL) was added portion wise to a stirred solution of 4-trifluoromethyl-phenylamine (10 grams) and pyridine (12.5 mL) in dichloromethane (2 Liters) at 0° C. The reaction was maintained at the same temperature for 30 minutes. The reaction mixture was then diluted with dichloromethane and washed several times with a saturated solution of copper sulfate, followed by water, drying over sodium sulfate and evaporating to give the crude product which was further purified by passing through a column of silica gel, to yield the pure product (11 grams).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:27](O)=[O:28])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:27]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:28])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as in Example 5, morpholine (275 μl) was condensed with Boc-3-(2-naphthyl)-L-alanine (900 mg, manufactured by Bachem Fein Chemikalien AG, Switzerland) to give N-[Boc-3-(2-naphthyl)-L-alanyl]morpholine (1.10 g) as a white powder (yield quantitative). After Boc group elimination with trifluoroacetic acid, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate as obtained in Reference Example 8 (312 mg) to yield the title compound (compound 81; 695 mg) as a white powder (yield 84%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17]C[C:15]2=[O:20])[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([NH2:34])[CH:31]=[N:32][CH:33]=2)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:34][C:30]1[CH:31]=[N:32][CH:33]=[C:28]([N:25]3[CH2:26][CH2:27][O:22][CH2:23][CH2:24]3)[CH:29]=1)=[C:3]([CH3:21])[C:4]([N:14]1[CH2:19][CH2:18][CH2:17][C:15]1=[O:20])=[N:5]2
Reactant: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Br
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)piperidin-2-one (75.0 mg, 0.21 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(5,7-difluoro-3-methyl-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-2-pyrrolidinone. 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (1H, d, J=2.5 Hz), 7.86 (1H, d, J=2.3 Hz), 7.46 (1H, ddd, J=9.6, 2.5, 1.4 Hz), 7.24 (1H, d, J=14.1 Hz), 6.99 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.54 (1H, t, J=2.4 Hz), 4.22-4.33 (1H, m), 3.82 (4H, t, J=4.8 Hz), 3.48-3.58 (1H, m), 3.13-3.28 (4H, m), 2.50-2.58 (2H, m), 2.07-2.14 (1H, m), 1.95-2.04 (3H, m), 1.94 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)(Cl)Cl>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C:33]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[CH3:23])=[O:34]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(C)c3)c2cc1OC

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methyl-aniline (50 mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl isocyanate (23 μl) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to quantitatively give the title compound.
Reaction SMILES: O.NN.P(Cl)(Cl)(Cl)(Cl)Cl.Br.F[C:12]1C=CC(OC)=CC=1C#N.[F:22][C:23]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>CO>[F:22][C:23]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:24]=1[C:25]([O:27][CH3:12])=[O:26]
Reactant: O=C(O)c1cc(O)ccc1F
Reactant: COc1ccc(F)c(C#N)c1
Agent: Br
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(O)ccc1F

Procedure:
In the presence of hydrazine hydrate/glacial acetic acid, phthalic anhydride (3a) with substituent R was transformed into R-substituted phthalhydrazide (3b), which subsequently generated substituted dichlorophthalazine compounds (3c) under the action of phosphorus pentachloride. In another aspect, under the action of hydrobromic acid, 2-fluoro-5-methoxybenzonitrile (3d) was converted to 2-fluoro-5-hydroxybenzoic acid (3e), which was esterificated with methanol to give methyl 2-fluoro-5-hydroxybenzoate (3f). Under the action of sodium hydride, the prepared dichlorophthalazine compounds with substituent R (3c) was reacted with methyl 2-fluoro-5-hydroxybenzoate (3f) to give methyl 5-((4-chloronaphthyridine-1-yl)oxy)-2-fluorobenzoate with substituent R (3g), 3g was transformed into methyl 2-fluoro-5-((4-oxo-3,4-dihydro-phthalazin-1-yl)oxy)benzoate (3h) in the presence of AcOH/NaOAc under the reflux condition, 3h was then hydrolyzed under alkali condition into substituent-contained 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (3i), which finally condensated with R′ substituted nitrogen heterocycles, e.g. piperazine, piperidine, 4-hydroxypiperidine, tetrahydropyridine and 1,4-diazacycloheptane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), triethylamine and 1-hydroxy-7-azabenzotriazole (HOAt) to generate target compounds, wherein the definition of R and R′ is as described above.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[O:11][C:10]([CH3:13])([CH3:12])[O:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[CH2:17]([SiH](CC)CC)[CH3:18].OS(O)(=O)=O>C(Cl)Cl.CCO.Cl[Ti](Cl)(Cl)Cl>[CH2:17]([O:9][C:8](=[O:14])[CH:7]([O:11][CH:10]([CH3:13])[CH3:12])[CH2:6][C:5]1[CH:15]=[CH:16][C:2]([OH:1])=[CH:3][CH:4]=1)[CH3:18]
Reactant: CC[SiH](CC)CC
Reactant: CC1(C)OC(=O)C(Cc2ccc(O)cc2)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(O)cc1)OC(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
A 0° C. solution of 5-(4-hydroxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one (0.20 g, 0.900 mmol) and triethylsilane (1.05 g, 9.0 mmol) in dry CH2Cl2 (10 mL) was treated dropwise with a 1 molar solution of TiCl4 in CH2Cl2 (0.90 mL, 0.900 mmol) under N2. The resultant red slurry was stirred at 0° C. for 15 minutes and then warmed to room temperature for 45 minutes. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 0.320 g of crude acid that was carried on as is. The oil was dissolved in EtOH (25 mL) and treated with conc. H2SO4 (1 mL) and then stirred at room temperature for 17 h under N2. The solvent was removed in vacuo and the oil extracted with EtOAc and water. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 5:1 hexanes:acetone to give 0.158 g (70%) 3-(4-hydroxy-phenyl)-2-isopropoxy-propionic acid ethyl ester. Rf=0.48 (1:1 hexanes:acetone). 1H NMR (500 MHz, CDCl3) δ 7.10 (d, 2H, J=8.80 Hz), 6.73 (d, 2H, J=8.31 Hz), 4.79 (bs, 1H) 4.20-4.12 (m, 2H), 3.99 (dd, 1H, J=8.31 Hz, J=4.89 Hz), 3.49 (hp, 1H, J=5.87 Hz), 2.95-2.83 (m, 2H), 1.23 (t, 3H, J=6.85 Hz), 1.14 (d, 3H, J=6.36 Hz), 0.97 (d, 3H, J=6.36 Hz); MS (ES−) Calc'd for C14H19O4 (M−1) 251. Found m/z 251 (100%). 97.6% ee by chiral HPLC assay (Chiralcel OJ, 4.6×250 mm, 90/10 heptane/IPA eluent, 1 mL/min, 266 nm).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:35])[C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3](OCC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:35])[C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:1])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3cc(Cl)ccc3OC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(-c2ccc(OC(C)(C)CO)cc2)cc1

Procedure:
3.5 gm (7 millimols) of ethyl 2-methyl-2-{4-[2-(2-methoxy-5-chloro-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate were reduced in 30 ml of absolute ether with 0.27 gm (7 millimols) of lithium aluminum hydride. After careful addition of 8 ml of water, the mixture was filtered, the filter cake was washed first with ether and then with chloroform, the ether phase and the chloroform phase were combined with the filrate and dried over sodium sulfate. After distilling off the solvents, the residual oil was crystallized from a small quantity of ether. Yield: 1.2 gm (38% of theory); m.p. 115° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.F[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)NC(C)c1cc2ccc(CCc3ccc(Oc4ccccn4)cc3)cc2o1
Yield: 34.7 %

Procedure:
N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (40.0 mg, 0.123 mmol) obtained in Example 165, 2-fluoropyridine (0.0369 mL, 0.371 mmol) and potassium carbonate (51.3 mg, 0.371 mmol) were stirred in DMSO (0.5 mL) at 100° C. for 2 days. The reaction mixture was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 2:3), and the solvent was evaporated. The residue was triturated with a small amount of diisopropyl ether to give the title compound (17.1 mg, yield 35%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]=[C:17]=S)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:20][C:21]1[C:22]([NH2:45])=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([CH:39]=1)[C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]1)=[O:27].CC(C)N=C=NC(C)C>>[F:1][C:2]1[C:15]([NH:16][C:17]2[NH:20][C:21]3[C:22]([N:45]=2)=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([C:26](=[O:27])[NH:28][C@H:29]2[CH2:30][CH2:31][C@H:32]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:34]2)[CH:39]=3)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1F
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCC(F)F)nc1N
Agent: CC(C)N=C=NC(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3nc(OCC(F)F)c(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)cc3[nH]2)c1F

Procedure:
The title compound is prepared from N-(2-fluoro-4-chloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (55 mg, 0.18 mmol) and 5,6 diamino-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (70 mg, 0.18 mmol) with DIC in analogy to examples 8a/8b.
Reaction SMILES: N[C:2]1[C:28]([CH3:29])=[CH:27][C:5]2[C:6]([CH2:9][CH2:10][C:11]3[S:12][C:13]4[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:14]=4[C:15]=3[CH:16]([CH3:18])[CH3:17])=[N:7][O:8][C:4]=2[CH:3]=1.N([O-])=[O:31].[Na+]>OS(O)(=O)=O.O>[CH:16]([C:15]1[C:14]2[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:22][C:13]=2[S:12][C:11]=1[CH2:10][CH2:9][C:6]1[C:5]2[CH:27]=[C:28]([CH3:29])[C:2]([OH:31])=[CH:3][C:4]=2[O:8][N:7]=1)([CH3:17])[CH3:18]
Reactant: O=N[O-]
Reactant: Cc1cc2c(CCc3sc4cc(C(F)(F)F)ccc4c3C(C)C)noc2cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc2c(CCc3sc4cc(C(F)(F)F)ccc4c3C(C)C)noc2cc1O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 19.9 %

Procedure:
The above-mentioned 6-amino-3-[2-[3-isopropyl-6-(trifluoromethyl)benzothiophen-2-yl]ethyl]-5-methylbenzisoxazole (100 mg, 0.239 mmol) was suspended in 25% H2SO4 (2.0 mL). A solution of sodium nitrite (25 mg, 0.36 mmol) in water (1.0 mL) was added to the suspension under cooling with ice. After the mixture was stirred for 30 min under the same conditions, and added dropwise to 75% H2SO4 (1.5 mL) that heated to 120° C. The mixture was heated for 1 h at 120° C., cooled to room temperature, diluted with ice-cold water, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After the solvent was removed, the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 5:1) to give the titled compound (20 mg) as yellow crystal (20 mg, yield 20%).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]=1[OH:26])(=[O:8])[O:5]CC)C.Cl>C(O)C>[CH2:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:15]2[CH:14]=[CH:13][C:12]([OH:26])=[C:11]([CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[CH:16]=2)=[CH:23][CH:22]=1)[CH3:25]
Reactant: CCOP(=O)(CCc1cc(Cc2ccc(CC)cc2)ccc1O)OCC
Agent: Cl
Solvent: CCO
Product: CCc1ccc(Cc2ccc(O)c(CCP(=O)(O)O)c2)cc1
Yield: 94 %

Procedure:
To a solution of 2-[5-(4-Ethylbenzyl)-2-hydroxyphenyl]ethylphosphonic acid diethylester (0.50 g) in ethanol (5.0 mL) was added 6N—HCl (5.0 mL), and the reaction mixture was refluxed for 24 hr. Evaporation and crystallization from ethyl acetate-n-hexane gave the title compound (0.40 g) as a colorless crystal.