Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[CH:18]1[CH2:22][CH2:21][CH2:20][CH:19]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])([O-])=O.[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CCOC(C)=O.CN(C=O)C>[CH:22]1([C:2]2[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]3[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=3[CH:12]=2)[CH2:21][CH2:20][CH:19]=[CH:18]1
Reactant: CCOC(=O)c1cc(I)cc2c1OC(C)(C)C2
Reactant: C1=CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C2C=CCC2)cc2c1OC(C)(C)C2
Temperature: 110 °C
Reaction time: 21 h
Yield: 0.1 %

Procedure:
In a 20-mL microwave-tube was added ethyl 5-iodo-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (0.692 g, 2.0 mol), cyclopentene (0.882 mL, 10.0 mol), TBAF (0.644 g, 2.0 mol), K2CO3 (0.691 g, 5.0 mol), DMF (8.0 mL), palladium (II) acetate (0.011 g, 0.05 mmol), and tri-o-tolyphosphine (0.030 g, 0.10 mmol) under N2. The mixture was sealed in the glass tube and was stirred at 110° C. overnight (21 hours). The reaction was cooled to room temperature and EtOAc (10 mL) was added. The mixture was stirred for 30 minutes, filtered through celite and rinsed with EtOAc (3×5 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-10% EtOAc in hexanes) to provide the desired ethyl 5-(cyclopent-2-en-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (873B) (0.380 g, 66.4%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:10]3)[C:6]=2[CH:21]=1.[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=5)[N:8]=[C:7]4[C:6]=3[CH:21]=2)[CH2:28][CH2:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Brc1ccc2c(c1)-c1nc(-c3cccnc3)cn1CCO2
Reactant: CC(C)(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4cccnc4)cn2CCO3)CC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of 9-bromo-2-pyridin-3-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (35 mg, 0.10 mmol), 1-tert-butylpiperidine-4-thiol (53 mg, 0.30 mmol), Pd2(dba)3 (9 mg, 10 mol %), XantPhos (12 mg, 20 mol %) and DIPEA (72 μL, 0.41 mmol) in dioxane (2 mL) was purged with argon and heated at 120° C. for 40 min, then 130° C. for 1 h and 140° C. for 1 h using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-20% 2M NH3/MeOH in EtOAc then C18, gradient 2-20% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 153 as an off-white solid (6 mg, 15%). LCMS: RT 2.42 min [M+H]+ 435.1. 1H NMR (CDCl3, 400 MHz): δ 9.03-9.02 (1H, m), 8.75-8.72 (1H, m), 8.51 (1H, dd, J=4.82, 1.67 Hz), 8.21 (1H, d, J=7.88 Hz), 7.35-7.33 (3H, m), 6.99 (1H, d, J=8.26 Hz), 4.52-4.50 (2H, m), 4.46-4.44 (2H, m), 3.03-2.98 (2H, br m), 2.20 (2H, br m), 2.06-1.94 (3H, br m), 1.66-1.62 (2H, br m), 1.06 (9H, br m)
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH3:29][C:30]1[N:35]=[N:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)[N:36]=2)[N:35]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: Cc1ccc(N)nn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (1.00 g, ˜80% purity, 1.87 mmol, 1.0 eq), 6-methylpyridazin-3-amine (CAS-Nr. 18591-82-7, 0.245 g, 2.24 mmol, 1.2 eq), N,N-diisopropylethylamine (0.33 mL, 1.87 mmol, 1.0 eq) and activated 3 Å molecular sieves in isopropanol (5.7 mL) was heated for 7 hours under reflux. On cooling, the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo. UPLC analysis of the crude product indicated a purity of >90%. The crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[CH2:9]([N:16]=[C:17]=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1.C(OCC)(=O)C>[CH2:9]([NH:16][C:17](=[O:18])[NH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(N)CC(=O)O
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)O)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a solution of 3-amino-3-methylbutanoic acid (5.86 g, 34.2 mmol) in THF was added benzyl isocyanate (5.87 ml, 47.5 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (100 ml) and brine (100 ml). Then the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was subjected to silica gel column chromatography (eluent: chloroform:methanol=95:5) to obtain the title compound (5.73 g, 67%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH3:20])[CH2:9][CH3:10]>C1C=CC=CC=1>[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:3]([CH2:2][C:1]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([CH2:8][CH2:9][CH3:10])[C:12]=2[CH3:20])=[O:7])[C:4]([OH:6])=[O:5])=[C:12]1[CH3:20])[CH2:9][CH3:10]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCn1c(C)cc2ccccc21
Solvent: c1ccccc1
Product: CCCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CCC)c3ccccc23)c2ccccc21
Temperature: 25 °C
Yield: 33.1 %

Procedure:
A stirred solution of 20.0 g (0.204 mole) of maleic anhydride and 70.0 g (0.408 mole) of 1-n-propyl-2-methylindole in 200 ml of benzene was heated at reflux for a period of approximately eighteen hours and then allowed to cool to ambient temperature. The solid which separated from the cooled solution was collected by filtration, washed with fresh chilled benzene and dried in vacuo at 60° C. to obtain 30.0 g of 2,4-bis-(1-n-propyl-2-methyl-3-indolyl)-4-oxobutanoic acid (Formula VII: R=CH3CH2CH2 ; R1 =CH3 ; Y=H) as a white solid melting over the range 210° to 215° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[N:6]=[CH:5]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:33][C:32]3[CH:31]=[CH:30][NH:29][C:28](=[O:34])[C:27]=3[CH:26]=2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CN1C(=O)CCC1.[Cu]I>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:33][C:32]3[CH:31]=[CH:30][N:29]([C:2]4[CH:3]=[C:4]5[C:8](=[CH:9][CH:10]=4)[N:7]([CH2:11][CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[N:6]=[CH:5]5)[C:28](=[O:34])[C:27]=3[CH:26]=2)=[CH:23][CH:24]=1
Reactant: O=c1[nH]ccc2oc(-c3ccc(Cl)cc3)cc12
Reactant: Brc1ccc2c(cnn2CCN2CCCC2)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: O=c1c2cc(-c3ccc(Cl)cc3)oc2ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 110 °C
Reaction time: 48 h
Yield: 1.4 %

Procedure:
A solution of 5-bromo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazole (0.349 g, 1.18 mmol) in NMP (3.3 mL) was added to 2-(4-chlorophenyl)-5H-furo[3,2-c]pyridine-4-one (0.347 g, 1.41 mmol), Cs2CO3 (0.768 g, 2.36 mmol), trans-1,2-bis(methylamino) cyclohexane (0.035 mL, 0.236 mmol) and CuI (0.269 g, 1.41 mmol) and deoxygenated with argon for 30 minutes. After stirring at 110° C. for 48 hours, the reaction mixture was cooled and diluted with CH2Cl2 (10 mL) and water (10 mL) and extracted with CH2Cl2 (4×50 mL). The organics were filtered through Celite and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% trifluoroacetic acid (TFA) and CH3CN with 0.05% TFA) yielded the title compound (7.5 mg, 13%) as a light yellow solid: ESI MS m/z 459 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@H:14]([O:15][Si](C(C)(C)C)(C)C)[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[C:29]([NH:30][C:31]([C:33]3[N:34]=[C:35]([C:46]4[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=4[F:53])[S:36][C:37]=3[NH:38]C(=O)OC(C)(C)C)=[O:32])=[CH:28][N:27]=[C:26]3[O:54][CH2:55][CH2:56][C:25]=23)[CH2:10]1)=O)(C)(C)C.[H+].[H+].F[Si-2](F)(F)(F)(F)F.O.[NH4+].[OH-]>CC#N>[NH2:38][C:37]1[S:36][C:35]([C:46]2[C:47]([F:53])=[CH:48][CH:49]=[CH:50][C:51]=2[F:52])=[N:34][C:33]=1[C:31]([NH:30][C:29]1[C:24]([N:11]2[CH2:12][C@H:13]([CH3:23])[C@@H:14]([OH:15])[C@H:9]([NH2:8])[CH2:10]2)=[C:25]2[CH2:56][CH2:55][O:54][C:26]2=[N:27][CH:28]=1)=[O:32]
Reactant: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCO3)C[C@@H](N)[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
To a solution of tert-butyl [4-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-2,3-dihydrofuro[2,3-b]pyridin-5-yl]amino}carbonyl)-2-(2,6-difluorophenyl)-1,3-thiazol-5-yl]carbamate (29.2 mg, 0.0357 mmol) in MeCN (2.0 mL) was added a 1.7 M dihydrogen hexafluorosilicate solution in water (0.5 mL, 0.8 mmol). The mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was neutralized with a 14.8 M NH4OH solution in water (300 μL, 4.44 mmol), and was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (6.0 mg, 33%). LCMS calc. for C23H25F2N6O3S (M+H)+: m/z=503.2. found 503.2.
Reaction SMILES: O1CCCC1.CC1C=CC(C(C)C)=CC=1.[F:16][C:17]([F:26])([F:25])[C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>C(N(CC)CC)C.C(O)=O>[F:16][C:17]([F:25])([F:26])[CH:18]([OH:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CC(=O)C(F)(F)F
Solvent: O=CO
Solvent: C1CCOC1
Solvent: Cc1ccc(C(C)C)cc1
Product: COC(=O)CC(O)C(F)(F)F
Temperature: 35 °C
Reaction time: 15 h

Procedure:
Into 6 mL of tetrahydrofuran were dissolved 7.5 mg of RuCl[(1R,2R)-p-TsNHCH(C6H5)CH(C6H5)NH2] (p-cymene), 5 mL of a mixture of formic acid-triethylamine (5:2 in molar ratio), 1.0 g of methyl 4,4,4-trifluoro-3-oxobutanoate, and the whole was stirred at 35° C. for 15 hours, followed by concentration under reduced pressure using an evaporator. To the resulting concentrate were added 10 mL of water and 10 mL of ethyl acetate, and then a saturated sodium carbonate aqueous solution was added thereto under stirring until the pH became 7 or higher. The ethyl acetate layer separated from the aqueous layer was concentrated to obtain optically active methyl 4,4,4-trifluoro-3-hydroxybutanoate. Upon the measurement under the above conditions, the optical purity and conversion were found to be 96.4% e.e. and 100%, respectively.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=3)[C:12](=[O:27])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+].I[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH2:52]>CN(C=O)C.C(OCC)(=O)C>[CH:3]1([NH:9][C:10]2[C:14]3([CH2:15][CH2:16][N:17]([CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH:45]=[CH2:44])[CH2:18][CH2:19]3)[N:13]([C:20]3[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=3)[C:12](=[O:27])[N:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: C=CCCCCCCCI
Reactant: O=C1N=C(NC2CCCCC2)C2(CCNCC2)N1c1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCCCCN1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(cyclohexylamino)-1-(4-iodophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one dihydrochloride (400 mg, 0.76 mmol, intermediate II.1.c.1) in DMF (6 mL) was added diisopropylethylamine (0.333 mL, 1.9 mmol) and the reaction mixture was stirred at rt for 10 min. Potassium carbonate (210 mg, 1.52 mmol) and 9-iodononene (230 mg, 0.91 mmol, prepared from 9-hydroxynonene, iodine, triphenylphosphine and imidazole) were added. The reaction mixture was stirred at 100° C., sealed, for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water. The organic layer was concentrated in vacuo and the residue was purified by reverse phase preparative HPLC (5- 95% MeCN/H2O containing 0.1% TFA, C18). The desired fractions were basified with aqueous NaHCO3, extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated in vacuo to provide the desired compound as a light brown solid. LRMS (M+1)=577.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])[CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:30])[CH:23]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(F)cc2)C1Cc1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-{3-[(trifluoromethyl)sulfonyl]benzyl}-1,3-oxazolidine-3-carboxylate (0.90 g, 1.79 mmol) in methanol (10 ml) was added a solution of 0.5N sodium hydroxide in methanol (10.8 ml, 5.40 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added water (50 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the objective substance (0.72 g, 84%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Cl.[CH2:9]([Mg]Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>[Ni](Cl)Cl.C(OCC)C>[CH2:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Clc1ccccc1Cl
Reactant: CCCCCCCCCCCC[Mg]Br
Agent: Cl[Ni]Cl
Agent: Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccccc1CCCCCCCCCCCC
Temperature: 0 °C
Yield: 84 %

Procedure:
To a 200 ml Schlenk reaction vessel were added under a nitrogen atmosphere 2.7 ml (24.0 mmol) of 1,2-dichlorobenzene, 66 mg (0.12 mmol) of nickel chloride {bis(diphenylphosphino)propane}, and 18 ml of diethyl ether. The whole was cooled to 0° C. and 65 ml (65 mmol) of a diethyl ether solution of n-dodecylmagnesium bromide (manufactured by Sigma-Aldrich, 1.0M) was added dropwise. After 11 hours of the reaction at 35° C., the reaction was stopped by adding 3N hydrochloric acid. The mixture was extracted with diethyl ether and the organic phase was washed with water and a saturated aqueous sodium hydrogen carbonate solution. The phase was dried over calcium chloride and the solvent was concentrated under reduced pressure. The residue was dried under vacuum (20 Pa) at 170° C. to obtain a liquid of 1,2-didodecylbenzene (8.36 g, yield 84%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C@H:5]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:6][CH:7]=[CH2:8])[CH3:2].CCN(C(C)C)C(C)C.[C:25]([C:27]1[CH:28]=[C:29]([C:37](Cl)=[O:38])[C:30]2[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=2[CH:36]=1)#[N:26]>C(Cl)Cl>[C:25]([C:27]1[CH:28]=[C:29]([C:37]([N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH2:6][CH:7]=[CH2:8])=[O:38])[C:30]2[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=2[CH:36]=1)#[N:26]
Reactant: N#Cc1cc2c(c(C(=O)Cl)c1)CCCC2
Reactant: C=CC[C@H](CNCC)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CN(CC)C(=O)c1cc(C#N)cc2c1CCCC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
(2S)-N-Ethyl-2-(4-fluorophenyl)pent-4-en-1-amine (0.13 g, 0.63 mmol) was dissolved in CH2Cl2 and to the solution were added DIPEA (0.18 g, 1.4 mmol) and then 3-cyano-5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride (see WO 00/34243; 0.15 g, 0.66 mmol) dissolved in CH2Cl2 (2 mL). The mixture was stirred for 2 h at room temperature and then diluted with CH2Cl2. The solution was washed with water, aqueous KHSO4 (10 mL, 1M) and brine. The solvent was removed by evaporation after the solution had been dried. The product was purified by chromatagraphy on silica gel using a gradient of methanol-CH2Cl2 (0% methanol-5% methanol). There was obtained 0.13 g (53%) of 3-cyano-N-ethyl-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide as an oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14]1.C[O:20][C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1>CCCCCC.O1CCCC1>[C:17]([CH:16]([CH:13]1[CH2:15][CH2:14]1)[C:21]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1)=[O:20])#[N:18]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: N#CCC1CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1ccc(C(=O)C(C#N)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A 2.5 molar solution of n-butyl lithium (114 mL, 285 mmol) in hexane was added to a cooled (−78° C.) solution of diisopropylamine (38.3 mL, 273 mmol) in tetrahydrofuran (300 mL). This cooled reaction mixture was then allowed to stir for 1 hour, after which time cyclopropylacetonitrile (20.8 mL, 261 mmol) was added at such a rate as to keep the temperature below −60° C. This mixture was then allowed to stir at −78° C. for 1 hour, after which time a solution of 4-cyano-benzoic acid methyl ester (40 g, 248 mmol) in tetrahydrofuran (100 mL) was added at such a rate as to keep the temperature below −60° C. This mixture was then slowly warmed to room temperature and stirred for 18 hours after which time it was quenched onto an aqueous 10% solution (weight/volume) citric acid (600 mL) and extracted with ethyl acetate (2×2500 mL). The organic extracts were washed with brine (600 mL), dried over magnesium sulphate, filtered, and evaporated under reduced pressure to give a brown oil (52.7 g, 100%). This material was used for subsequent steps without further purification. 1H NMR (400 MHz, CDCl3): δ 0.60 (m, 2H), 0.80 (m, 2H), 1.40 (m, 1H), 4.10 (d, 1H), 7.85 (d, 2H), 8.10 (d, 2H). ESCI MS m/z 243 [M−H]−
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O.Br[C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1>O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: C[C@@H](N)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Product: C[C@@H](N)c1ccc(-c2ccccc2OC(F)(F)F)cc1
Temperature: 150 °C
Yield: 82 %

Procedure:
Palladium acetate (34 mg, 0.150 mmol) was added to a mixture of 2-(trifluoromethoxy)phenylboronic acid (773 mg, 3.75 mmol) and (R)-(+)-1-(4-bromophenyl)ethylamine (300 mg, 1.50 mmol) in water (12 ml). This mixture was heated in a microwave oven at 150° C. for 10 min, then diluted with methanol (200 ml) and purified on a SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(2′-trifluoromethoxy-biphenyl-4-yl)-ethylamine (345 mg, 1.23 mmol, 81.9%) as a gum. The title compound was then prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) using 1-difluoromethyl-3-methylpyrazole-4-sulfonyl chloride and (R)-1-(2′-trifluoromethoxy-biphenyl-4-yl)-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H), 7.42-7.16 (m, 8H), 6.97 (s, 1H), 4.88 (d, 1H), 4.52 (m, 1H), 2.30 (s, 3H), 1.56 (d, 3H) ppm; MS (ESI) m/z: 476 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])[CH3:22].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])([C:24]([O:23][CH2:21][CH3:22])=[O:25])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CC2
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate 19 (50 mg) and triethylmethanetricarboxylate (0.073 ml) in toluene (1.5 ml) and tetrahydrofuran (1.5 ml), stirred at RT under an inert atmosphere of nitrogen, was added trimethylphosphine, 1M in toluene (0.344 ml). The resulting solution was cooled to −78° C. and diisopropyl azodicarboxylate (0.068 ml) was added dropwise via syringe and the reaction was stirred at −78° C. for 45 mins. The reaction mixture was removed from the cold bath and allowed to warm to RT and stirred under N2 atmosphere overnight. Reaction mixture concentrated in vacuo. The residue was taken up in DCM (20 ml) and washed with water (20 mL). The 2 phases were separated, the organic extract was dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (48 mg). LC/MS MH+ 505, Rt 3.41 min (5 minute run).