Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(C(=C)CCCO)=CC=1.[CH:14]([CH:16]([CH2:28][CH2:29][CH3:30])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])=[CH2:19])=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[OH:15][CH2:14][CH:16]([CH2:28][CH2:29][CH3:30])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])=[CH2:19]
Reactant: C=C(CC(C=O)CCC)c1ccc(Cl)cc1Cl
Agent: C=C(CCCO)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C=C(CC(CO)CCC)c1ccc(Cl)cc1Cl
Yield: 90.5 %

Procedure:
By the procedure described for the preparation of 4-(4-chlorophenyl)pent-4-en-1-ol (see Example 1), 4-formyl-2-(2,4-dichlorophenyl)hept-1-ene (1.7 g) and lithium aluminium hydride (0.5 g) in dry diethyl ether (30 ml) gave 4-(hydroxymethyl)-2-(2,4-dichlorophenyl)hept-1-ene (1.55 g, 91%) as a colourless oil, 1H nmr (CDCl3): δ3.52 (2H, d J 6 Hz, CH2OH).
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=O.P(Br)(Br)[Br:15].O>C(OCC)C>[Br:15][CH2:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[F:1]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1F
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CBr)c1F
Temperature: -30 °C
Reaction time: 12 h
Yield: 67.3 %

Procedure:
A solution of 35.4 g (178.7 mmoles) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 500 ml of diethyl ether was cooled to −30° C. Thereto was added 54.0 g (199.5 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water and extraction with diethyl ether was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 31.4 g (yield: 80.8%) of 4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: CO[CH:3]([O:17]C)[C:4](=O)[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:15])/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13].[H-].[Na+].[C:21]([OH:24])(=[O:23])[CH3:22].O.[BH4-].[Na+]>CS(C)=O.C(O)C.O.C(OCC)C>[OH:17][CH2:3]/[C:4](/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:15])/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14])=[CH:3]/[CH2:4][CH2:5]/[C:6](/[CH3:7])=[CH:22]/[C:21]([OH:24])=[O:23]
Reactant: CC(=O)O
Reactant: COC(OC)C(=O)CC/C=C(\C)CCC=C(C)C
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/C(=O)O)CO
Reaction time: 2.5 h

Procedure:
A suspension of 14.1 g of (E)-4-methyl-5-carboxy-4-penten-1-yltriphenylphosphonium bromide, 8.4 g of (E)-1,1-dimethoxy-6,10-dimethyl-5,9-undecadien-2-one and 2.5 g of 63.8% sodium hydride in 30 ml of anhydrous dimethyl sulfoxide was stirred at 50°-55° C. for 2.5 hours and 40 ml of acetic acid-water (5:1) was added thereto. The resulting mixture was again stirred at 50°-55° C. for 30 minutes. After completion of the reaction, the reaction mixture was extracted four times with n-hexane and the extracts were washed with water, dried over anhydrous sodium sulfate and then the solvent was distilled off to leave 10.4 g of an yellow oily substance. The resulting oil was dissolved in 50 ml of ethanol, 1.2 g of sodium borohydride was added thereto at 5°-10° C. and the resulting mixture was stirred for 1 hour. To the reaction mixture were added ethyl ether and water and, after stirring, an aqueous layer was separated and neutralized with hydrochloric acid under ice-cooling. The so separated oily substance was extracted with ether and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to afford 3.98 g of the end product.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:2]3[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OB(O)c1ccc(OC2CCCCC2)nc1
Reactant: Cc1cnc(N)c(Cl)n1
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: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc(N)c(-c2ccc(OC3CCCCC3)nc2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (48.3 mg) was added to a suspension of 3-chloro-5-methylpyrazin-2-amine (200 mg), 6-(cyclohexyloxy)pyridin-3-ylboronic acid (339 mg) and sodium carbonate (295 mg) in DME (5 mL) and water (1 mL) and the mixture was stirred at 90° C. under nitrogen for 3 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (339 mg) as light brown gum.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=O)=[CH:32][C:31]=1[C:40]#[N:41])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.[NH3:42]>[Ni].O.CO>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([NH2:42])=[O:38])=[CH:32][C:31]=1[C:40]#[N:41])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: N
Reactant: COC(=O)c1ccc(CN(Cc2nc3ccccc3n2C(=O)OC(C)(C)C)C2CCCc3cccnc32)c(C#N)c1
Agent: [Ni]
Solvent: O
Solvent: CO
Product: N#Cc1cc(C(N)=O)ccc1CN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reaction time: 16 h
Yield: 36 %

Procedure:
To 0.5 mL of Raney Nickel in water was added a solution of 2-{[(2-cyano-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (0.55 g, 1 mmol) in methanol (25 mL). The solution was then saturated with ammonia gas for 10 minutes. The reaction vessel was then shaken vigorously under an atmosphere of hydrogen (40 psi) for 16 hours. The mixture was filtered through a celite pad and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (88:12 CH2Cl2:MeOH) to afford to give the amide (0.20 g, 36%). 1H NMR (CDCl3) δ 1.73 (m, 1H), 2.01 (m, 2H), 2.35 (m, 1H), 2.85 (m, 2H), 3.88 (t, 2H, J=15.9 Hz), 4.16 (m, 1H), 4.21 (d, 1H, J=9.6 Hz), 4.26 (d, 1H, J=7.8 Hz), 5.71 (br, 1H, NH), 6.12 (br, 1H, NH), 7.19 (m, 3H), 7.46 (d, 1H, J=7.8 Hz), 7.55 (br, 2H), 7.80 (d, 1H, J=8.1 Hz), 7.87 (d, 1H, J=8.1 Hz), 7.96 (s, 1H), 8.64 (dd, 1H, J=4.5 Hz). 13C NMR (CDCl3) δ 21.71, 24.65, 29.44, 49.92, 53.09, 61.84, 112.81, 117.49, 122.30 (4C), 122.97, 130.44 (2C), 131.98, 132.32, 133.56, 135.37, 138.05 (2C), 147.13, 147.29, 155.27, 156.87, 167.82. ES-MS m/z 437 (M+H). Anal. Calcd. for C26H24N6O.0.6CH2Cl2: C, 65.54; H, 5.21; N, 17.24. Found: C, 65.93; H, 5.51; N, 17.44.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[CH2:7](Br)[CH:8]=[CH2:9].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[CH3:1][C:2]([OH:6])([C:4]#[C:5][CH2:9][CH:8]=[CH2:7])[CH3:3]
Reactant: C=CCBr
Reactant: C#CC(C)(C)O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: C=CCC#CC(C)(C)O
Yield: 59.8 %

Procedure:
The coupling reaction was conducted in the manner described in the procedure of Example VI using the following reagents: 1.00 mL (10.3 mmoles) of 2-methyl-3-butyn-2-ol, 1.00 mL (11.6 mmoles) of allyl bromide (3-bromopropene), 2.21 g (16.0 mmoles) of anhydrous potassium carbonate, 93 mg (0.94 mmoles) of cuprous chloride, and 207 mg (0.91 mmole) of benzyltriethylammonium chloride in 3.00 mL of acetonitrile (HPLC-grade). Isolation of the product in the manner described in the procedure of Example III afforded, after removal of the volatile organic solvents at reduced pressure, 765 mg (60% yield) of the named alcohol, the identity and purity of which were ascertained by IR and proton NMR analysis.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:17][CH3:18])=[N:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH2:1]([C:8]1[C:9]([O:17][CH3:18])=[N:10][CH:11]=[C:12]([C:14]([O:16][CH3:19])=[O:15])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(C(=O)O)cc1Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cnc(OC)c(Cc2ccccc2)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 2.1 g of 3-benzyl-2-methoxypyridine-5-carboxylic acid and 2.9 g of potassium carbonate was suspended in 40 ml of N,N-dimethylformamide. 1.1 ml of methyl iodide was added-thereto at room temperature under stirring. After stirring for 40 minutes, water was added thereto and extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography using 11-14% ethyl acetate/hexane as an eluent for separation and purification, to give 2.2 g of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([NH2:26])[CH:3]=1.[OH-].[Na+].Br[CH2:30][CH2:31][O:32][CH2:33][CH2:34]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N:26]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:3]=1
Reactant: BrCCOCCBr
Reactant: Cc1c(Cn2c(C(C)C)nc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: Cc1c(Cn2c(C(C)C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Reaction time: 2.5 h

Procedure:
The product from previous reaction 4-bromo-2-isopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (4.7 g, 11.03 mmol) was stirred in 6M sodium hydroxide (100 mL, 600 mmol) solution with 1-bromo-2-(2-bromoethoxy)ethane (6.87 mL, 55.1 mmol) and tetrabutylammonium iodide (0.407 g, 1.103 mmol) at 110° C. After stirring for 2.5 hr the mixture was cooled and the aqueous was decanted and the remaining sticky solid was dissolved in EtOAc. The organic was washed with H2O and brine and dried over MgSO4 and concentrated to leave a thick dark residue containing the desired product. The desired product was purified by flash chromatography on a silica column eluting with EtOAc/Hex 15% to 40% over 20 column volumes. The fractions containing the desired compound by TLC were combined and concentrated to provide 4-(4-bromo-2-isopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (2.75 g, 4.99 mmol, 45.2% yield) as a light orange solid. MS (ES+) m/e: 495.1, 496.1 [M+H]+
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:31])[CH2:6][O:7][C:8]1[C:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[Cl:25])[CH:16]=2)=[C:12]([OH:26])[C:11]([CH:27]=[O:28])=[C:10]([CH3:29])[C:9]=1[Cl:30].C1COCC1.Cl>O.CO>[Cl:30][C:9]1[C:10]([CH3:29])=[C:11]([CH:27]=[O:28])[C:12]([OH:26])=[C:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[Cl:25])[CH:16]=2)[C:8]=1[O:7][CH2:6][C:5]([OH:31])=[O:4]
Reactant: COC(=O)COc1c(Cl)c(C)c(C=O)c(O)c1Cc1ccc2c(Cl)cccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(Cl)c(OCC(=O)O)c(Cc2ccc3c(Cl)cccc3c2)c(O)c1C=O
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Aqueous potassium hydroxide (10%, 2.7 mL) was added in to a solution of [2-chloro-6-(5-chloro-naphthalen-2-ylmethyl)-4-formyl-5-hydroxy-3-methyl-phenoxy]-acetic acid methy ester (1.14 g, 2.63 mmol), THF(15 mL) and MeOH (15 mL). The mixture was stirred for 1 hour, poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from hexane/EtOAc, gave a light yellow solid (0.65 g, 60% yield, m.p. 194°-196° C.).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCCC1CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), 2-(aminomethyl)-1N-Boc-pyrrolidine (20.9 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 25 mL/min, 220 nM, product retention=32.9 min) to provide (R/S)-tert-butyl 2-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)pyrrolidine-1-carboxylate (28 mg, 0.046 mmol, 65.6% yield): LCMS=614.3 [M+H]+. The (R/S)-tert-butyl 2-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)pyrrolidine-1-carboxylate (28 mg, 0.046 mmol) was added to TFA (1 mL, 12.98 mmol) and stirred for 30 min. The reaction mixture was concentrated to provide (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(pyrrolidin-2-ylmethyl)acetamide, TFA (24 mg, 0.037 mmol, 80% yield): LCMS=514.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=7.92 Hz), 7.54-7.79 (7 H, m), 5.21 (1 H, s), 3.66-3.81 (1 H, m), 3.48-3.62 (2 H, m), 3.16-3.30 (2 H, m), 1.91-2.18 (3 H, m), 1.70-1.82 (1 H, m); HPLC peak RT=8.3 min (Condition A).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:50]([O:54][C:55](=[O:66])[C:56]1[CH:64]=[C:63]([NH2:65])[CH:62]=[C:58]([C:59]([OH:61])=[O:60])[CH:57]=1)([CH3:53])([CH3:52])[CH3:51].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:50]([O:54][C:55](=[O:66])[C:56]1[CH:64]=[C:63]([NH:65][C:21](=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[CH:62]=[C:58]([C:59]([OH:61])=[O:60])[CH:57]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)c1cc(N)cc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)O)cc(C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of hexadecandioic acid mono t-butyl ester (100 mg, 0.29 mmol) in dry DCM (2 ml), HOAt (44 mg, 0.29 mmol) and DCC (72 mg, 32 mmol) was added. The mixture was stirred at 50° C. for 1 h. The oil bath was removed. 5-Amino-isophthalic acid mono t-butyl ester (69 mg, 0.29) and DIPEA (0.07 ml, 0.32 mmol) was added. The mixture was stirred at RT over night under nitrogen. The yellow suspension was filtered and the filtrate was concentrated. The residue was redissolved in EtOAc and extracted with 0.1N HCl (2×), brine (1×), dried (Na2SO4) and concentrated to give a white solid, which was purified twice by flash chromatography using EtOAc/Hept 1:2+5% AcOH. The title compound was obtained in 86% yield (0.140 g) as an oil containing an impurity.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=2)([CH2:7][CH2:8][CH3:9])[O:5][C:4](=[O:20])[C:3]=1[O:21]CC1C=CC=CC=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[OH:21][C:3]1[C:4](=[O:20])[O:5][C:6]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:14][CH:15]=2)([CH2:7][CH2:8][CH3:9])[C:2]=1[OH:1]
Reactant: CCCC1(c2ccc(CC(C)C)cc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CCCC1(c2ccc(CC(C)C)cc2)OC(=O)C(O)=C1O
Yield: 6.9 %

Procedure:
Hydrogenolysis of 4-hydroxy-5-(4-isobutylphenyl)-3-phenylmethoxy-5-(1-propyl)-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide 200 mg (6.9% yield) of 3,4-dihydroxy-5-(4-isobutylphenyl)-5-(1-propyl)-2(5H)-furanone as an oil, which was purified by preparative TLC using hexanes/acetone/acetic acid (70/29/1) as eluant: 1H NMR (acetone-d6) δ 7.48-7.13 (m, 4H), 2.47 (d, J=10.3 Hz, 2H), 2.10-1.66 (m, 1H), 1.29-0.85 (m, 13H). 13C NMR (acetone-d6) δ 169.20, 155.54, 141.58, 137.91, 129.24, 125.32, 118.25, 83.37, 45.02, 39.60, 30.26, 22.03, 16.84, 13.63. Anal Calcd for C17H22O4: C, 70.32; H, 7.64. Found: C, 70.01; H, 7.61.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3I)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C-:22]#[N:23].O>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>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([C:22]#[N:23])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Ic1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: [C-]#N
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Temperature: 160 °C
Yield: 78.9 %

Procedure:
A mixture of (R)-indan-1-yl-(5-iodo-quinolin-2-yl)-amine (example 6, step A) (1.44 g, 3.73 mmol), zink cyanide (482 mg, 4.1 mmol) and tetrakis-(triphenylphosphine)-palladium (431 mg, 0.37 mmol) in DMF (20 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (diethyl ether/hexane) to yield 2-((R)-indan-1-ylamino)-quinoline-5-carbonitrile as light yellow solid (840 mg, 79%). M.p. 150° C.; MS: m/e=286.2 (M+H+).
Reaction SMILES: [CH2:1]([CH2:13][CH2:14][C:15](O)=[S:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)(=O)C(Cl)=O.C1(C)C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O.CC(N(C)C)=O.C(N(CC)CC)C>[O:38]1[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][CH2:32][NH:31][C:15](=[S:16])[CH2:14][CH2:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:36][CH2:37]1
Reactant: CCCCCCCCCCCCCCC(O)=S
Reactant: NCCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCC(=S)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.1 %

Procedure:
In a 200 ml flask equipped with a stirrer, a condenser and a calcium chloride dryer tube were charged 8.23 g of 3-dodecylthiopropionic acid, 4.6 g of oxalyl chloride and 50 ml of toluene, and the mixture was stirred under room temperature for 20 hours. After completion of the reaction, excessive oxalyl chloride and toluene were removed by distillation under reduced pressure to prepare acid chloride. Whole amount of the resulting acid chloride was gradually added dropwise to 5.2 g of N-(3-aminopropyl)morpholine, 3.7 g of triethylamine and 60 ml of DMAc solution which had been previously charged in a flask, and after completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into 300 ml of distilled water and extracted with chloroform. The chloroform layer was washed with a saturated saline solution and chloroform was removed by distillation. The residue was recrystallized from methanol to obtain 6.5 g of the title compound. Melting point: 46° C.
Reaction SMILES: C(C1C=C(OC)C(OC)=CC=1C(O)=O)C.Cl.CC(O)(C1C=C(OC)C(OC)=CC=1CC)CS(CC(C1C=C(OC)C(OC)=CC=1CC)(O)C)(=O)=O.[NH:52]([CH:59]=[C:60]([CH2:63][C:64]1[CH:69]=[C:68]([O:70][CH3:71])[C:67]([O:72][CH3:73])=[CH:66][C:65]=1[CH2:74][CH3:75])[C:61]#N)C1C=CC=CC=1.[NH2:76][C:77]([NH2:79])=[NH:78]>CO>[NH2:78][C:77]1[N:79]=[C:59]([NH2:52])[C:60]([CH2:63][C:64]2[CH:69]=[C:68]([O:70][CH3:71])[C:67]([O:72][CH3:73])=[CH:66][C:65]=2[CH2:74][CH3:75])=[CH:61][N:76]=1
Reactant: CCc1cc(OC)c(OC)cc1CC(C#N)=CNc1ccccc1
Reactant: N=C(N)N
Agent: CCc1cc(OC)c(OC)cc1C(=O)O
Agent: CCc1cc(OC)c(OC)cc1C(C)(O)CS(=O)(=O)CC(C)(O)c1cc(OC)c(OC)cc1CC
Agent: Cl
Solvent: CO
Product: CCc1cc(OC)c(OC)cc1Cc1cnc(N)nc1N

Procedure:
2-Ethyl-4,5-dimethoxybenzoic acid is esterified in methanol containing hydrochloric acid. The methyl ester is converted consecutively to methyl-α-(2-ethyl-4,5-dimethoxyacetophenone) sulphone, methyl-β-hydroxy-β-(2-ethyl-4,5-dimethoxyphenyl)ethyl sulphone, and β-anilino-α -(2-ethyl-4,5-dimethoxybenzyl) acrylonitrile according to Example 107. Following the procedure of Example 121 the β-anilino-α-(2-ethyl-4,5-dimethoxybenzyl) acrylonitrile is allowed to react with guanidine to give 2,4-diamino-5-(2'-ethyl-4',5'-dimethoxybenzyl)pyrimidine, m.p. 206°-207° C. after recrystallization from 60% to ethanol.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][CH:4]([C:9]1[CH:23]=[CH:22][C:12]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][CH:16](O)[C:11]=2[CH:10]=1)[S:5]([NH2:8])(=[O:7])=[O:6].[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>ClCCl>[F:24][CH:2]([F:1])[O:3][CH:4]([C:9]1[CH:23]=[CH:22][C:12]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][CH:16]([CH2:27][CH:26]=[CH2:25])[C:11]=2[CH:10]=1)[S:5]([NH2:8])(=[O:6])=[O:7]
Reactant: C=CC[Si](C)(C)C
Reactant: NS(=O)(=O)C(OC(F)F)c1ccc2c(c1)C(O)Oc1ccccc1-2
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCC1Oc2ccccc2-c2ccc(C(OC(F)F)S(N)(=O)=O)cc21
Reaction time: 1 h

Procedure:
A solution of Example 27G (0.14 g, 0.39 mmol) in dichloromethane (10 mL) at −78° C. was treated with allyltrimethylsilane (0.13 g, 1.16 mmol) and borontrifluoride etherate (0.156 g, 1.16 mmol), stirred for 1 hour, and treated with saturated sodium bicarbonate (10 mL) to provide two laters. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-50% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)Q1MS) m/z 380 (M−H)−.