Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[C:9]=1[OH:10])[CH:5]=O.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c(C(F)(F)F)c1
Reactant: CC(=O)c1ccccc1
Product: O=C(C=Cc1cc(O)c(O)c(C(F)(F)F)c1)c1ccccc1

Procedure:
The procedure described in Example 8 was repeated using 2.06 g of 3,4-dihydroxy-5-trifluoromethylbenzaldehyde and 1.20 g of acetophenone. Yield 2.19 g (71%), m.p. 196°-210° C.
Reaction SMILES: C=C([O:4][C:5](=O)[NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:24]([CH3:25])=[N:23][C:16]3[N:17]=[C:18]([NH:21][CH3:22])[N:19]=[CH:20][C:15]=3[CH:14]=2)[C:10]([CH3:26])=[CH:9][C:8]=1[F:27])C.Cl.[F:30][C:31]([F:39])([F:38])[C:32]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33]1.CN1CCCC1>C1COCC1.CCOC(C)=O>[F:27][C:8]1[CH:9]=[C:10]([CH3:26])[C:11]([C:13]2[C:24]([CH3:25])=[N:23][C:16]3[N:17]=[C:18]([NH:21][CH3:22])[N:19]=[CH:20][C:15]=3[CH:14]=2)=[CH:12][C:7]=1[NH:6][C:5]([NH:37][CH2:36][CH2:35][C:32]1([C:31]([F:39])([F:38])[F:30])[CH2:34][CH2:33]1)=[O:4]
Reactant: NCCC1(C(F)(F)F)CC1
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)nc3nc2C)c(C)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC4(C(F)(F)F)CC4)c(F)cc3C)c(C)nc2n1
Temperature: 65 °C
Yield: 41.8 %

Procedure:
Treat a mixture of prop-1-en-2-yl(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (1.09 g, 2.86 mmol) and 2-(1-(trifluoromethyl)cyclopropyl)ethanamine hydrochloride (0.542 g, 2.86 mmol) in THF (30 mL) with 1-methylpyrrolidine (1.52 mL, 14.3 mmol) and heat at 65° C. for 4 h. Cool the mixture to RT, dilute with EtOAc, wash with brine (2×), dry over MgSO4, concentrate to dryness and purify via silica gel chromatography (MeOH/EtOAc). Treat the resulting material with acetonitrile, cool to −20° C. for 2 h, collect the solids via filtration, rinse with acetonittrile (−20° C.) and dry to afford the title compound as a pale yellow solid (570 mg, 42% yield). MS (m/z): 477.2 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=2)[CH:10]=[CH:9][N:8]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2-fluoropyridin-4-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (300 mg, 0.83 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (156 mg, 0.83 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (238 mg, 1.24 mmol) and 1-hydroxy-1H-benzotriazole (127 mg, 0.83 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (347 mg, 79%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].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.O>[CH3:10][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[C:16]1[CH:17]=[CH:18][C:13]([C:12]([F:23])([F:22])[F:11])=[CH:14][CH:15]=1
Reactant: Cc1cc(C#N)ccc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C#N)ccc1-c1ccc(C(F)(F)F)cc1
Yield: 94.6 %

Procedure:
A mixture of 4-bromo-3-methylbenzonitrile (1.00 g, 5.10 mmol), 4-(trifluoromethyl)phenylboronic acid (0.969 g, 5.10 mmol), potassium carbonate (1.76 g, 12.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.295 g, 0.255 mmol) in 1:1 dioxane:water (20 mL) was stirred at 80° C. overnight. The mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 2-methyl-4′-(trifluoromethyl)biphenyl-4-carbonitrile (1.26 g, 95%). 1H NMR (400 MHz, CDCl3, δ): 7.72 (d, 2H), 7.59 (s, 1H), 7.56 (d, 1H), 7.42 (d, 2H), 7.31 (d, 1H), 2.29 (s, 3H).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C@@H:12]2[O:14][CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl-].[NH4+]>C1COCC1.[Cu](Cl)(Cl)(Cl)Cl.[Li]>[C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C@H:12]([OH:14])[CH2:13][CH2:6][C@@H:1]([CH3:15])[CH2:2][CH3:3])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: Cl[Cu](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: CC[C@H](C)CC[C@@H](O)COS(=O)(=O)c1ccc(C)cc1
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 190.2 %

Procedure:
In a 500 ml flask as charged a 0.1 ML-1 dried THF solution containing 18 ml of lithium copper tetrachloride under a nitrogen atmosphere, followed by cooling to -50° C. The above prepared Grignard reagent was added thereto over 5 minutes, and the mixture was reacted at that temperature for 20 minutes. To the reaction mixture was added dropwise a solution of 8.07 g of (R)-glycidyl p-toluenesulfonate (produced by Aldrich Chemical Co., Inc.) in 70 ml of dried THF at the same temperature over 20 minutes through a dropping funnel, followed by further reacting for 1.5 hours. .The resulting reaction mixture was poured into a saturated ammonium chloride aqueous solution and extracted with diethyl ether. The extract was washed twice with a saturated sodium chloride aqueous solution, and the solvent was removed by distillation under reduced pressure to obtain 10.1 g (yield=95%) of a crude product. [α]D24 : -3.89° MS: 300 (M+) NMR (δ, ppm): 0.85 (6H, m), 1.3 (7H, m), 2.05 (1H, s), 2.43 (3H, s), 3.8 (1H, m), 3.97 (2H, m), 7.35 (2H, m), 7.8 (2H, m)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8][CH:9]([CH3:17])[CH2:10][CH:11](O)[CH2:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([S:8][CH:9]([CH3:17])[CH2:10][CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CC(O)CC(C)Sc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CCC(C)Sc1cccc(F)c1
Yield: 92.5 %

Procedure:
1.00 Gram of 6-(3-fluorophenylthio)-4-hydroxy-2-heptanone was dissolved in 100 ml of toluene, and 0.02 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 2.5 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 0.96 g of 6-(3-fluorophenylthio)-3-hepten-2-one. (trans : cis =5.6 : 1) (purity: 89.3%). The yield was 92.5%.
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([CH3:43])([CH3:42])[NH:6][C:7]([C:9]1[N:17]=[C:16]2[N:11]([N:12]=[C:13]([NH:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:24][CH2:23]3)[CH:14]=[CH:15]2)[N:10]=1)=[O:8])C.[OH-].[Na+].Cl>C(O)C>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:13]3[CH:14]=[CH:15][C:16]4[N:11]([N:10]=[C:9]([C:7]([NH:6][C:5]([CH3:43])([CH3:42])[C:4]([OH:44])=[O:3])=[O:8])[N:17]=4)[N:12]=3)[CH2:27][CH2:26]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(C)(C)NC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(NC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
1.71 g of N-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl]-2,2-dimethylglycine ethyl ester was dissolved in 6 ml of ethanol; 4.5 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 2 hours. Under ice cooling conditions, 1 N hydrochloric acid was added to bring the mixture to pH 5. The crystal obtained was collected by filtration, washed with water and ethyl acetate and dried to yield 1.24 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:36][CH3:37])=[CH:4][C:5]([C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[C:12]([C:32]([F:35])([F:34])[F:33])[CH:11]=2)=[N:6][C:7]=1[C:8]#[N:9].Cl.[N:39]([O-])=O.[Na+].C(OCC)(=O)C>CN1C(=O)CCC1.O>[C:8]([C:7]1[C:2]2[N:1]=[N:39][N:36]([CH3:37])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[C:12]([C:32]([F:35])([F:33])[F:34])[CH:11]=2)[N:6]=1)#[N:9]
Reactant: CNc1cc(-c2ccc(OCCC3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)nc(C#N)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)cc21
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To tert-butyl 4-(2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)piperidine-1-carboxylate (1.8 g) in NMP (20 ml) was added 1M hydrochloric acid (15 ml) and cooled to 5-10° C. with an ice bath. To above solution was then added dropwise a solution of sodium nitrite (0.335 g) in water (3 ml) during 2 minutes. The mixture was stirred further at room temperature for another 1 hour. After adding ethyl acetate (200 ml), the mixture washed with water (4×100 ml), brine (50 ml), solvent removed under reduced pressure and residue was columned on silica gel using 2:1 EtOAc:Heptane as eluant to give tert-butyl 4-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-piperidine-1-carboxylate (1.55 g) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:22])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:22])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1=O
Yield: 95.6 %

Procedure:
To acetic acid solution (15 ml) of 7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one (2.82 g, 8.99 mmol) was added aqueous 48% HBr solution (13 ml) and the mixture was heated under refluxing for 24 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The crude product thus obtained was purified with silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain 2.46 g (yield: 96%) of the title compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.[CH:11]([O:13][CH2:14][CH3:15])=[CH2:12].ClC(Cl)(Cl)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:11]([O:13][CH:14]([O:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH3:15])[CH3:12]
Reactant: C=COCC
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(C)Oc1ccc2c(c1)OCO2
Yield: 98 %

Procedure:
A stirred solution of 3,4-methylenedioxyphenol (6.0 g, 43.5 mmol), ethyl vinyl ether (3.75 g, 52.0 mmol) and a catalytic amount of trichloroacetic acid (50 mg, 0.3 mmol) in chloroform (50 ml) was stirred for two hours at room temperature. Aqueous NaOH (2N, 50 ml) was added and the resulting mixture was extracted with diethyl ether (3 times). The combined ether extracts were washed with aqueous NaOH (2N) and water, respectively, dried over Na2SO4, filtered and evaporated in vacuo to yield 5-(1-ethoxyethoxy)-1,3-benzodioxole (8.96 g, 98% yield; compound No. 1) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=[O:5].[CH3:19][CH:20]([CH2:25][CH3:26])[CH2:21][C:22](Cl)=[O:23]>N1C=CC=CC=1>[CH3:19][CH:20]([CH2:25][CH3:26])[CH2:21][C:22]([O:1][C:2]1[CH:17]=[C:16]([O:18][C:22](=[O:23])[CH2:21][CH:20]([CH3:19])[CH2:25][CH3:26])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:22](=[O:23])[CH2:21][CH:20]([CH3:19])[CH2:25][CH3:26])=[CH:8][C:7]=1[O:13][C:22](=[O:23])[CH2:21][CH:20]([CH3:19])[CH2:25][CH3:26])=[O:5])=[O:23]
Reactant: CCC(C)CC(=O)Cl
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Solvent: c1ccncc1
Product: CCC(C)CC(=O)Oc1ccc(C(=O)c2ccc(OC(=O)CC(C)CC)cc2OC(=O)CC(C)CC)c(OC(=O)CC(C)CC)c1

Procedure:
A solution of 1.2 g (0.005 mole) of 2,4,2',4'-tetrahydroxybenzophenone and 3 g (0.025 mole) of 3-methyl valeroylchloride was warmed to 50° C. for 4 hrs. in 50 mls of dry pyridine. Solvent removal via rotary evaporator left an oil. This was partitioned between H2O and CH2Cl2. The organic layer was washed with K2CO3 solution (5%) and dried over MgSO4. After filtration and solvent removal the product remained an oil; 2.5 g (78%) yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([CH3:10])=[CH:8][C:7](Cl)=[N:6][C:5]=1[O:12][CH3:13].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:16]([F:27])([F:26])[F:15])[CH:22]=2)=[N:6][C:5]=1[O:12][CH3:13]
Reactant: COC(=O)c1c(C)cc(Cl)nc1OC
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Temperature: 80 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
To a solution of 5.75 g (26.7 mmol) of 6-chloro-2-methoxy-4-methyl-nicotinic acid methyl ester in 250 ml of DMF was added 10.13 g (53.3 mmol) of 3-trifluoromethyl-phenyl-boronic acid followed by 50.0 ml of a solution of tribasic potassium phosphate (2 M in water). Finally, 1.54 g (1.3 mmol) of tetrakis-(triphenylphosphine)-palladium was added and the reaction mixture was subsequently warmed up to 80° C. After 5 hours, it was cooled down to RT, poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 1:0 to 9:1) to give 8.54 g (98%) of the title compound as light yellow oil. MS: 326.1 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[N:54]([C@@H:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH3:58])=[C:55]=[O:56]>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:20][C:21]([C@@H:23]3[CH2:32][C:31]4[CH:30]=[C:29]5[O:33][CH2:34][C@H:35]([C:37]6[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]7[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=7)=[CH:41][CH:42]=6)[O:36][C:28]5=[CH:27][C:26]=4[CH2:25][N:24]3[C:55](=[O:56])[NH:54][C@@H:57]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH3:58])=[O:22])[C:3]([OH:2])=[O:53])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: C[C@@H](NC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (20 mg) was added ((R)-1-isocyanato-ethyl)-benzene (5 equiv) and the reaction stirred at room temperature for 1 hour. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (26 mg). LCMS (m/z): 884.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[O:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:24]=[CH:25][CH:26]=2)=[CH:17]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:29][CH2:28]3)[CH:24]=[CH:25][CH:26]=2)=[CH:17]1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: c1cc(-c2ccoc2)cc(N2CCNCC2)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2cccc(-c3ccoc3)c2)CC1
Yield: 44.8 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (279 mg, 1.04 mmol), 1-[3-(3-furyl)phenyl]piperazine (215 mg, 0.942 mmol) and diisopropylethylamine (0.328 ml, 1.88 mmol) in dimethylsulfoxide (3.0 ml) was stirred at 70° C. for 3 days. Water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and ethyl acetate to give the titled compound 147 mg (44.7%) as solid product.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[CH:25]=[C:26]([CH2:28][OH:29])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>C1COCC1.C(O)C>[C:42]([CH2:41][CH2:40][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:32][CH:31]=3)[CH:25]=[C:26]([CH2:28][OH:29])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])([OH:44])=[O:43]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(CO)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2cc(CO)cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.7 %

Procedure:
To a solution of the 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-hydroxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (250 mg, 0.37 mmol) in THF (5 mL) and ethanol (5 mL) was added aqueous 1.0 N sodium hydroxide (4 mL) at room temperature. The resulting suspension was stirred for 5 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was concentrated and the residue was diluted with water (20 mL) and extracted with diethyl ether (30 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N hydrochloric acid and the precipitated white organic compound was extracted into ethyl acetate (2×30 mL). The combined ethyl acetate extracts were washed with brine solution (50 mL) and the organic layers were dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent afforded 4-[2-(2-carboxy-ethyl)-3-[6-(5-hydroxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (65 mg, 37%) as a white solid: ES(+)-HRMS m/e calcd for C33H40O9S (M+Na)+ 635.2285. found 635.2284.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[CH2:9][C:10]#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:24])C.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[CH2:9][CH:10]=[O:24]
Reactant: CC(=O)O
Reactant: CC1CC(C)(C)CC1CC#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CC(C)(C)CC1CC=O
Temperature: 25 °C

Procedure:
2-(2,4,4-Trimethylcyclopentyl)acetonitrile 4 is placed in toluene at 10° C. under an inert atmosphere. 1.2 eq. of Dibal (diisobutylaluminum hydride) are added thereto dropwise. The reaction medium is stirred at ambient temperature for a few hours and then poured onto a 20:40:40 mixture of acetic acid, water and ice. The aqueous phase is extracted once with toluene. The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product, obtained in the form of two diastereomers in proportions of 70:30, is distilled under reduced pressure.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][NH:12][C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[C:11]1=[O:21]
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O

Procedure:
The product is produced as described in example 1 from 2.4 g of NaH (80% suspension in mineral oil), 21.6 g of 1-(4-chlorophenyl)-5-phenyl-4-imidazolin-2-one, 160 cc. of DMF, 19.0 g of 8-bromocaprylic acid methyl ester and 2.4 g of NaJ.