Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:24])[CH2:22][CH2:21]3)=[O:19])=[C:13]([F:33])[C:12]=2[F:34])[CH:7]=[CH:6][N:5]=1)=O.O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.[OH-].[Na+].C[N:60](C)C=O>N1C=CC=CC=1>[NH2:60][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:24])[CH2:21][CH2:22]3)=[O:19])=[C:13]([F:33])[C:12]=2[F:34])[CH:7]=[CH:6][N:5]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2F)ccn1
Reactant: CN(C)C=O
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2F)ccn1
Reaction time: 0.17 h
Yield: 61 %

Procedure:
N-(4-{[2-(Aminocarbonyl)pyridin-4-yl]oxy}-2,3-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (295 mg) was dissolved in N,N-dimethylformamide (4 ml). Water (0.0563 ml), [bis(trifluoroacetoxy)iodo]benzene (536 mg) and pyridine (0.303 ml) were added thereto at room temperature in this order, followed by stirring for 25 hr and 10 min. The reaction was stopped by adding a 1N aqueous solution of sodium hydroxide (9 ml), and the reaction mixture was partitioned between ethyl acetate (30 ml) and water (10 ml). The organic layer was washed with water (30 ml) in twice, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:3), and fractions containing the target compound were concentrated under reduced pressure. The residue was dried under reduced pressure to provide the titled compound as a pale yellow solid (168.4 mg, 61%).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[N:28]1([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.COCC(O)C>>[N:28]1([C:34]2[CH:35]=[C:36]([NH:40][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)[CH:37]=[CH:38][CH:39]=2)[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Reactant: Nc1cccc(N2CCOCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: c1cncc(-c2ccc3cnc(Nc4cccc(N5CCOCC5)c4)nn23)c1
Yield: 40.7 %

Procedure:
2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004839 mol), N,N-Diisopropylethylamine (0.126 mL, 0.000726 mol) and 3-Morpholin-4-yl-phenylamine (0.172 g, 0.000968 mol) were dissolved in 1-Methoxy-2-propanol (1.0 mL, 0.010 mol) and the reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 73.26 mg of (3-Morpholin-4-yl-phenyl)-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a lyophilized powder. (M+H)=373.7. 1H NMR (400 MHz, DMSO, d6) δ 9.45 (s, 2H), 9.07 (s, 1H), 8.81 (d, 1H, J=8.00 Hz), 8.70 (d, 1H, J=3.76 Hz), 7.78 (m, 1H), 7.35 (d, 1H, J=4.76 Hz), 7.30 (s, 1H), 7.18 (m, 2H), 7.02 (d, 1H, J=4.80 Hz), 6.62 (m, 1H), 3.69 (m, 4H), 3.02 (m, 4H).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH:28][CH3:29])(=[O:27])=[O:26].C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[NH:28][CH3:29])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CNS(=O)(=O)c1ccc(F)cc1CN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)c1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 50 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
(Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.90 g) in methanol (10 ml) was added a solution of 2-(aminomethyl)-4-fluoro-N-methylbenzenesulfonamide hydrochloride obtained in Step 1 (1.17 g) and triethylamine (1.6 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, the mixture was partitioned with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (1 ml) was added. The mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.74 g).
Reaction SMILES: [NH2:1][OH:2].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:28][C:29]#[N:30])[C:18]3[S:22][N:21]=[C:20]([N:23]4[CH:27]=[CH:26][N:25]=[CH:24]4)[N:19]=3)=[CH:11][C:6]=2[O:5][CH2:4]1>O.CO>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][N:17]([C:18]3[S:22][N:21]=[C:20]([N:23]4[CH:27]=[CH:26][N:25]=[CH:24]4)[N:19]=3)[CH2:28][C:29]([NH:1][OH:2])=[NH:30])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: NO
Reactant: N#CCN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Solvent: CO
Solvent: O
Product: N=C(CN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1)NO
Temperature: 25 °C
Reaction time: 30 h
Yield: 22 %

Procedure:
Hydroxylamine (1.0 mL of a 50 wt % in H2O, 15 mmol) was added all at once a solution of [{3-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetonitrile (30 mg, 75 μmol) in MeOH (1.0 mL) at r.t. The reaction mixture stirred at r.t. for 30 h prior to concentrating to a white solid. The residue was purified using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 7.0 mg (22%) of 2-[{3-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-N-hydroxy-acetamidine as a white solid. [M+H]+ 430.91; 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 7.07 (s, 1H), 6.82 (s, 1H), 6.76-6.70 (m, 2H), 5.89 (s, 2H), 4.19 (s, 2H), 3.65 (s, 2H), 3.58 (m, 2H), 2.63 (t, 2H), 1.94 (tt, 2H).
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[N:3][C:2]=1[NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14].[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(Cl)Cl>O>[Si:20]([O:14][CH2:13][C@@H:12]([NH:11][C:2]1[N:3]=[CH:4][C:5]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:1]=1)[CH3:15])([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CO)Nc1ncc2c(n1)CNCC2
Solvent: O
Solvent: ClCCl
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1ncc2c(n1)CNCC2
Yield: 66.2 %

Procedure:
A solution of (S)-2-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-ylamino)propan-1-ol (138, 0.215 g, 1.03 mmol), TBDMS-Cl (0.171 g, 1.14 mmol) and TEA (0.216 ml, 1.55 mmol) and DCM (5 mL) were stirred for 18 h, poured into water and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by SiO2 chromatography eluting with DCM/MeOH (500:50) to afford 0.220 g (66.1%) of (S)—N-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (152).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.I([O-])(=O)(=O)=[O:24].[Na+].I([O-])(=O)=O.[Na+]>CO.O>[Br:1][C:2]1[C:3]([S:18]([CH2:19][C:20]([OH:22])=[O:21])=[O:24])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: O=C(O)CSc1cc2onc(-c3ccccc3F)c2cc1Br
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Agent: [O-][I+2]([O-])[O-]
Solvent: CO
Solvent: O
Product: O=C(O)CS(=O)c1cc2onc(-c3ccccc3F)c2cc1Br
Yield: 86 %

Procedure:
2.8 g (7.33 mmol) of [[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio]acetic acid was combined with 30 ml (2 eq.) of 0.5M sodium periodate solution in 300 ml of 4:1 methanol/water. The mixture was refluxed for 18 hours during which the insoluble sodium iodate precipitated. The reaction mixture was then poured into excess 3N HCl and extracted several times with ethyl acetate. The ethyl acetate extracts were combined, washed with water and a saturated salt solution, dried over magnesium sulfate, filtered and evaporated to yield a white solid. The solid was triturated with hexanes and dried under vacuum to yield 2.51 g (86%) of [[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]sulfinyl]acetic acid, m.p. 173°-174° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.[CH3:14][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1)[CH2:22][C:23](O)=[O:24])=[O:19])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:16][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1)[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:24])=[O:19])[CH3:14]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(F)c(F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2cc(C(F)(F)F)nc2C1)Cc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine (64.3 mg, 0.34 mmol, from Step B) and (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (105.9 mg, 0.34 mmol) in dichloromethane (5 mL) was added HOBT (54.5 mg, 0.42 mmol) at 0° C. The reaction was stirred at 0° C. for 10 min, then EDC (96.6 mg, 0.50 mmol) was added. After removal of the ice-bath, the reaction was allowed to stir at ambient temperature for 14 h. The mixture was concentrated and purified by HPLC (Gilson; YMC-Pack Pro C18 column, 100×20 mm I.D.; solvent gradient from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.1% trifluoroacetic acid) to give 115 mg of the title compound as a foamy solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[C@@H:14]([CH3:25])[CH2:13]2)(=[O:11])=[O:10])=[C:5]([CH3:26])[CH:4]=1)#[N:2].Cl.O1CCOCC1>C(Cl)Cl>[CH3:26][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[S:9]([N:12]1[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:25])[CH2:13]1)(=[O:11])=[O:10])[C:1]#[N:2]
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN[C@@H](C)C1
Reaction time: 2 h
Yield: 98.5 %

Procedure:
1,1-Dimethylethyl (2S)-4-[(4-cyano-2-methylphenyl)sulfonyl]-2-methyl-1-piperazinecarboxylate (may be prepared as described in Intermediate 12; 5.52 g, 14.54 mmol) was dissolved in DCM (80 ml) and then 4M hydrochloric acid in dioxane (36.3 mL, 145 mmol) was added at room temperature and the reaction mixture was stirred for two hours. The solvent was removed under vacuum to give the title compound (4.0 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[C:4]#[N:5].O.NN>C(O)C.[Ni]>[NH2:5][CH2:4][C:3]1[C:2]([OH:1])=[N:9][C:8]([CH3:10])=[CH:7][C:6]=1[O:11][CH3:12]
Reactant: COc1cc(C)nc(O)c1C#N
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C)nc(O)c1CN
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
2-Hydroxy-4-methoxy-6-methylnicotinonitrile (70 mg, 0.43 mmol) was dissolved in ethanol (10 mL) and warmed to 60° C. before it was treated with raney nickel (0.5 mL slurry in water) followed by addition of hydrazine monohydrate (2 mL). The resultant mixture was allowed to stir at 60° C. for 2 hours. The cooled reaction mixture was filtered through celite and rinsed with methanol. The filtrate was concentrated in vacuo to provide crude product which was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (40 mg, 56%) as a white solid. LRMS (M+H+) m/z: calcd 168.09. found 168. HPLC purity (214 nm): 73%. 1H NMR (300 MHz, d6-DMSO): δ 6.04 (s, 1H), 3.77 (s, 3H), 3.42 (s, 2H), 2.15 (s, 3H).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:5]=1[C:6]([O:8][CH3:9])=[O:7].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1>>[CH3:14][C:10]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:13]=[CH:12][CH:11]=1)[CH2:3][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=1
Reactant: COC(=O)c1c(C)cccc1CCBr
Reactant: CCOC(=O)Cc1ccc(O)cc1
Product: CCOC(=O)Cc1ccc(OCc2cccc(C)c2C(=O)OC)cc1

Procedure:
Reaction of methyl 2-bromoethyl-6-methylbenzoate with ethyl p-hydroxyphenylacetate as described in Example 1b provides ethyl 4-(3-methyl-2-methoxycarbonylbenzyloxy)phenylacetate as an oil.
Reaction SMILES: [CH2:1]([NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(#N)C.[CH2:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17]>O>[CH2:1]([NH:10][CH2:14][CH:15]([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCN
Reactant: C=C(C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CCCCCCCCCNCC(C(F)(F)F)C(F)(F)F

Procedure:
To a mixture of nonylamine (7.5 g) and acetonitrile (10 mL) was added HFIB in several portions over a period of about 0.5 h until a gentle reflux of HFIB was observed which did not dissipate. A dry-ice condenser was used to obtain the gentle reflux of HFIB at 25° C. for 15 h. The reaction mixture was poured into water (150 mL) and the bottom layer separated, and washed with water to provide N-nonyl N-(2-trifluoromethyl-3,3,3-trifluoropropyl)amine (13.5 g): 1H NMR (CDCl3) 0.88 (t, J=7 Hz, 3H), 1.28 (m, 12H), 1.47 (quintet, J=7 Hz, 2H), 2.62 (t, J=7 Hz, 2H), 3.09 (m, 3H) ppm; 19F NMR (CDCl3) −67.0 (d, J=8 Hz) ppm; MS (m/e) 307 (M+, 2.5%), 292 (0.2%), 278 (0.3%), 264 (0.5%), 250 (0.8%), 236 (0.5%), 208 (2.6%),194 (100%),156 (5.9%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)cc1C(F)(F)F

Procedure:
A suspension of 2-trifluoromethyl-4-fluorobenzoic acid (16.85 g, 81 mmol) in dichloromethane (150 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (8.5 mL, 97.4 mmol). After the gas evolution subsided, the reaction mixture was refluxed for an additional 10 minutes, and then evaporated to dryness in vacuo. The crude acid chloride was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc(NC(=O)C(NS(=O)(=O)c2ccc(Cl)cc2)C(C)C)cc1
Yield: 38.8 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methylbutanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (665 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.9 ml) and 1-methyl-2-chloropyridinium iodide (1.05 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-methylbutanamide (542 mg).
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11]([O:14]C)=[N:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccc(C2(O)CCCCC2)cn1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1ccc(C2(O)CCCCC2)cn1Cc1ccccc1
Yield: 109.9 %

Procedure:
A mixture of 5-(1-hydroxycyclohexyl)-2-methoxy pyridine (26.3 g), benzyl bromide (21.7 g) and potassium carbonate (35 g) was heated in 500 mL of refluxing acetonitrile for 17 hours. The mixture was cooled and filtered, and the solids were washed with methanol. The filtrate was concentrated to give 39.5 g of an oil. HPLC on silica gel (elution with ethyl acetate) afforded 20.8 g of solid.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22].S(=O)(=O)(O)O>CN(C)C=O.CCOCC>[Si:6]([O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: OC[C@@H]1CCC[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC[C@H]1CO
Temperature: 24 °C
Reaction time: 22 h
Yield: 39.9 %

Procedure:
17.1 g of imidazole and 18.9 g of tert-butyldimethylsilyl chloride are added to a solution of 16 g of trans-1,2-dihydroxymethyl-cyclopentane in 146 ml of dimethylformamide at 0° C. and stirred for 22 hours at 24° C. It is diluted with 1.6 l of ether, shaken twice with 80 ml of 10% sulfuric acid each, washed neutral with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate (9+1), 12 g of trans-1-(tert-butyldimethylsilyloxymethyl)-2-hydroxymethyl-cyclopentane is obtained as colorless liquid.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C@@H:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:5]#[N:6].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:1][C@H:2]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C@@H:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[C:5]#[N:6])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCC[C@@H](O)C[C@H](C#N)c1ccc(OC)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCC[C@H](C[C@H](C#N)c1ccc(OC)cc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
To a solution of 559 mg (2.0 mmol) of (2S,4R)-4-hydroxy-2-(4-methoxyphenyl)decanenitrile in 5 ml of pyridine were added, with cooling with ice, a solution of 774 mg (4.1 mmol) of p-toluenesulfonyl chloride (TsCl) in 3 ml of pyridine and 24 mg (0.2 mmol) of 4-(N,N-dimethylamino)pyridine (DMAP). This mixture was stirred at room temperature for 3 days. The pH of the reaction mixture was adjusted to 7 with diluted hydrochloric acid, and this reaction mixture was subjected to extraction with ether (150 ml). The resulting ether solution was washed with diluted hydrochloric acid and saturated sodium chloride aqueous solution, and then concentrated. The residue was separated and purified by column chromatography (Kieselgel 60, hexane/ethyl acetate=4/1), thereby obtaining 550 mg (yield 63%) of (2S,4R)-4-p-toluenesulfonyloxy-2-(4-methoxyphenyl)-decanenitrile.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH2:17])(=[O:5])=[O:4].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>N1C=CC=CC=1.ClCCl>[F:19][C:2]([F:18])([F:1])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH:17][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])(=[O:4])=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(=O)OCc2ccccc2)c1
Temperature: 20 °C
Reaction time: 4.5 h

Procedure:
To a solution of 2-amino-4-methoxycarbonylphenyl trifluoromethanesulfonate (2.6 g) in a mixture of pyridine (5.6 ml) and dichloromethane (20 ml) was added benzyl chloroformate (2.08 ml) at 0° C., and the mixture was stirred at 20° C. for 4.5 hours. The mixture was diluted with dichloromethane and washed successively with diluted hydrochloric acid, aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane to give 2-benzyloxycarbonylamino-4-methoxycarbonylphenyl trifluoromethanesulfonate (2.61 g) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.ClCCl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:19]#[N:20])[CH:15]=[C:16]([CH2:18][Br:21])[CH:17]=2)[O:9][N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cc(CBr)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-methylphenyl)-1,2,4-oxadiazole (0.5 g, 1.91 mmol), N-bromosuccinimide (0.339 g, 1.91 mmol), and benzoyl peroxide (0.0010 g, 0.04 mmol) in carbon tetrachloride (25 mL) was heated at 80° C. for 18 hours. After this time the reaction mixture was cooled and diluted with dichloromethane. The organic solution was washed with water and brine to afford 0.595 g (91%) of 3-(2-pyridyl)-5-(3-bromomethyl-5-cyanophenyl)-1,2,4-oxadiazole.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:42]=1[F:43])#[N:36]>>[C:35]([C:37]1[CH:38]=[C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)[CH:40]=[CH:41][C:42]=1[F:43])#[N:36]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: N#Cc1cc(B(O)O)ccc1F
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(F)c(C#N)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3-cyano-4-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.87 (dd, J=6.48, 2.81 Hz, 6H), 1.47 (dt, J=13.39, 6.63 Hz, 1H), 1.65 (ddd, J=13.63, 7.09, 6.91 Hz, 1H), 1.92-2.00 (m, 1H), 3.71-3.77 (m, 1H), 7.54 (td, J=7.70, 1.47 Hz, 1H), 7.59-7.61 (m, 1H), 7.65-7.72 (m, 3H), 7.77-7.81 (m, 2H), 7.86-7.89 (m, 1H), 7.96 (ddd, J=8.80, 5.14, 2.45 Hz, 1H), 8.02 (dd, J=5.99, 2.32 Hz, 1H); Calcd for C26H21F4NO2 (M+H) 456.44, Found 456.