Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=1[C:10]([OH:12])=O)[CH3:2].[NH2:21][CH2:22][C:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([S:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=1[C:10]([NH:21][CH2:22][C:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:12])[CH3:2]
Reactant: CCSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: NCC1(O)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCSc1cccc(Oc2ncc(F)cc2C(=O)NCC2(O)CCCCC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.7 %

Procedure:
2-(3-Ethylsulfanyl-phenoxy)-5-fluoro-nicotinic acid (150 mg, 0.51 mmol) was added to a solution of 1-aminomethyl-cyclohexanol (93 mg, 0.56 mmol) and triethylamine (0.21 ml, 1.5 mmol) in dimethylformamide (3 ml) under nitrogen at room temperature. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (108 mg, 0.56 mmol) followed by 1-hydroxybenzotriazole (76 mg, 0.56 mmol) were then added and the reaction was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure, partitioned between ethyl acetate (20 ml) and water (20 ml) and the organic phase was removed, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 98:2, by volume) to give 2-(3-ethylsulfanyl-phenoxy)-5-fluoro-N-(1-hydroxy-cyclohexylmethyl)-nicotinamide (86 mg) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:33][CH:34]=3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1ccc(CCNC(=O)c2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2sc(C(=O)NCCc3ccc(OCC(=O)O)cc3)cc2C1
Yield: 90.8 %

Procedure:
To the solution of the compound prepared in (a) (250 mg) in ethanol was added 1N sodium hydroxide (2.6 ml), and the mixture was stirred under ice-cooling for 3 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added. The mixture was acidified with 1N hydrochloric acid. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 214 mg of 4-[2-[[(5-t-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]amino]ethyl]phenoxyacetic acid (yield, 91%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[CH2:9]([Li])CCC.IC>O1CCCC1>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:9])[CH3:2]
Reactant: [Li]CCCC
Reactant: CCc1ccccn1
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)c1ccccn1
Temperature: -45 °C
Reaction time: 1.5 h

Procedure:
2-Isopropylpyridine was prepared by the method of P. Rocca, et. al. (Tetrahedron Vol. 54, pp. 8771-8782 (1998). A solution of 2-ethylpyridine (1000 g, 9.332 moles) in anhydrous Tetrahydrofuran (6000 mL) was cooled to −35° C. by a dry ice/acetone bath. n-Butyllithium (3970 mL of 2.5 Molar, 9.925 moles) was added at a fast drop wise rate over a period of 1.5 hours, while maintaining the internal temperature at −20° C. to −25° C. Stirring was continued for an additional 1.5 hours at −20° C., then the reaction was cooled to −45° C. Iodomethane (642 mL, 1458 g, 10.272 moles) was added at a moderate drop wise rate over a period of 1.5 hours, while maintaining the reaction temperature between −40° C. and −45° C. After the addition was complete, the mixture was allowed to stir for an additional 2 hours at −40° C., then was quenched by the fast drop wise addition of water (4000 mL) added over a period of 30 minutes. The reaction mixture was cooled to 0° C. and treated with concentrated Hydrochloric acid (1150 mL) added over a period of 15 minutes. The mixture was allowed to stir for an additional hour while warming to 15° C., then was transferred to a separatory funnel with diethyl ether (2000 mL), and the layers separated. The aqueous phase was further washed with diethyl ether (3×1000 mL), then made basic (pH=9) by treatment with solid potassium carbonate. The aqueous mixture was extracted with diethyl ether (4×1000 mL). The combined extracts were washed with saturated brine (1000 mL) then dried (anhydrous magnesium sulfate). Filtration, followed by removal of the solvent under reduced pressure at room temperature, gave the crude product as a reddish-orange liquid (˜2000 mL). This crude product was distilled (twice) at atmospheric pressure through a three inch, glass vigreaux column, collecting the desired 2-isopropylpyridine (b.p. 158-163° C.) as a light yellow liquid (926 g, 82% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.53 (d, J=4.22 Hz, 1H) 7.59 (td, J=7.59, 1.69 Hz, 1H) 7.16 (d, J=8.01 Hz, 1H) 7.08 (ddd, J=7.38, 4.85, 0.84 Hz, 1H) 2.94-3.25 (m, J=6.91, 6.91, 6.91, 6.91, 6.91, 6.74 Hz, 1H) 1.31 (d, J=6.74 Hz, 6H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[S:8][C:7]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1>C(O)(=O)C>[Br:1][CH:10]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:9]([C:7]1[S:8][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:17]
Reactant: O=C(Cc1ccncc1)c1ccc(Cl)s1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(c1ccc(Cl)s1)C(Br)c1ccncc1
Reaction time: 1.5 h

Procedure:
At room temperature, 26.9 g (167 mmol) of bromine are added dropwise to a solution of 40.0 g (167 mmol) of 1-(5-chloro-2-thienyl)-2-(pyridin-4-yl)ethanone in 200 ml of acetic acid, and the mixture is stirred for 90 min. The resulting precipitate is filtered off, washed with MTBE and dried. This gives 64.5 g (96%) of the desired product; log P (pH2.7): 2.18 with MS (ESI): 315.9 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([CH3:30])=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[C:7]([CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[O:28][CH3:29])=[CH:6]1.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH:3]=[C:2]([CH3:30])[CH3:1])[CH:6]=[C:7]2[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29]
Reactant: COC(=O)c1ccc(Cc2cn(CC=C(C)C)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(Cc2cn(CC=C(C)C)c3ccc(N)cc23)c(OC)c1
Yield: 68.7 %

Procedure:
A slurry of methyl 4-[1-(3-methylbut-2-enyl)-5-nitroindol-3-ylmethyl]-3-methoxybenzoate (0.22 g.) and stannous chloride dihydrate (1.6 g.) in absolute ethanol (8 ml.) was heated and stirred under reflux under an atmosphere of nitrogen for 24 hours. The cooled mixture was poured into saturated sodium bicarbonate solution (30 ml.). The mixture obtained was extracted with dichloromethane (2×30 ml.). The combined extracts were washed with saturated brine (25 ml.), dried and evaporated to give methyl 4-[5-amino-1-(3-methylbut-2-enyl)indol-3-ylmethyl]-3-methoxybenzoate (F) (0.14 g.; 69%) an oil; NMR: 1.68(s,3H, =C--CH3), 1.76(s,3H, =C--CH3), 3.82(s,3H, CO.OCH3), 3.89 (s,2H, CH2.Ar), 3.91(s,3H, OCH3), 4.57(d,2H, CH2N), 5.27(t,1H, CH2CH), 6.48(m,2H), 6.91 (s,1H), 7.04(d,1H), 7.08(d,1H), 7.46(m,2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][O:12][CH3:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][O:12][CH3:13])[N:7]([CH2:15][C:16]3[CH:35]=[CH:34][C:19]4/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: COCc1nc2c(Cl)cccc2[nH]1
Product: COCc1nc2c(Cl)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 90.3 %

Procedure:
[step 3] Using 4-chloro-2-(methoxymethyl)-1H-benzo[d]imidazole (50 mg, 0.25 mmol) obtained in step 2 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (96 mg, 0.27 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (107 mg, 89%) was obtained.
Reaction SMILES: [CH2:1]([CH:4]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH:29]1[N:38]=[C:39]=[O:40])[CH2:35]2>C(Cl)Cl>[CH:30]12[CH2:36][CH:34]3[CH2:33][CH:32]([CH2:37][CH:28]([CH2:35]3)[CH:29]1[NH:38][C:39]([N:9]1[CH2:10][CH2:11][C:6]3([C:12]4[C:17](=[CH:16][CH:15]=[CH:14][C:13]=4[Cl:18])[CH:4]([CH2:1][CH:2]=[CH2:3])[O:5]3)[CH2:7][CH2:8]1)=[O:40])[CH2:31]2
Reactant: C=CCC1OC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC1OC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Cl)cccc21
Reaction time: 19 h
Yield: 69.3 %

Procedure:
To a stirred solution of 3-allyl-7-chloro-3H-spiro[isobenzofuran-1,4′-piperidine] (0.0190 g), and DIEA (0.5 mL) in CH2Cl2 (2 mL) was added 2-adamantyl isocyanate (0.0138 g, 0.0778 mmol) at rt. After 19 h, the solvents were removed in vacuo and the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 4 min, flow rate 25 mL/min) to afford N-(2-adamantyl)-3-allyl-7-chloro-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxamide (0.0220 g, 97%). LC-MS Method 1 tR=2.33 min, m/z 443, 441 (MH+); 1H NMR (400 MHz, CDCl3) δ=7.24-7.20 (m, 2H), 7.09-7.05 (m, 1H), 5.87-5.77 (m, 1H), 5.25 (t, J=5.7 Hz, 1H), 5.15-5.08 (m, 2H), 3.98 (br s, 1H), 3.94-3.88 (m, 2H), 136-3.28 (m, 2H), 2.66-2.38 (m, 4H), 1.95-1.25 (m, 16H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1>>[CH3:20][C:18]1[CH:17]=[C:16]([CH3:21])[N:15]=[C:14]([NH:13][C:10](=[O:11])[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:19]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: Cc1cc(C)nc(N)c1
Product: COc1ccc(CC(=O)Nc2cc(C)cc(C)n2)cc1

Procedure:
was prepared from 4-methoxyphenylacetyl chloride and 2-amino-4,6-dimethylpyridine following Method B. 1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.73 (s, 1H), 7.24 (d, 2H, J=8.34 Hz), 6.91 (d, 2H, J=8.59 Hz), 6.70(s, 1H), 3.81 (s, 3H), 3.66 (s, 2H), 2.35 (s, 3H), 2.29 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 271, found 271.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:21][C:22]1([F:30])[CH2:26][NH:25][C@H:24]([C:27]([NH2:29])=[O:28])[CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:22]([F:30])([F:21])[CH2:23][C@H:24]3[C:27]([NH2:29])=[O:28])=[O:14])[CH:9]=[CH:8][C:7]=2[C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2(O)CCC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(C2(O)CCC2)c(OCC2CC2)n1
Yield: 26.6 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carboxylic acid (CAN 1415899-53-4, 15 mg, 57 μmol) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1, 10.6 mg, 57 μmol) to give the title compound (6 mg, 21%) as light yellow oil, LC-MS (UV peak area, ESI) 100%, 396.1740 [MH+].
Reaction SMILES: [CH2:1]([N:8]([C:12]1[C:17]2[N:18]=[C:19](Cl)[N:20]=[C:21]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)[C:16]=2[N:15]=[CH:14][N:13]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([N:8]([CH2:9][CH2:10][OH:11])[C:12]1[C:17]2[N:18]=[C:19]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:20]=[C:21]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)[C:16]=2[N:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(N(CCO)Cc4ccccc4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(N(CCO)Cc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 8-[N-benzyl-N-(2-hydroxyethyl)-amino]-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 153°-155° C.) and piperazine.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH3:12])[CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1.C1C(=O)N([Br:20])C(=O)C1>CN(C=O)C>[Br:20][C:7]1[C:5]2[CH2:6][C@@H:2]([CH3:1])[O:3][C:4]=2[C:10]([NH2:11])=[CH:9][C:8]=1[CH3:12]
Reactant: Cc1cc(N)c2c(c1)C[C@@H](C)O2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1cc(N)c2c(c1Br)C[C@@H](C)O2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of (R)-2,5-dimethyl-2,3-dihydrobenzofuran-7-amine (3f) (1.3 g, 7.9 mmol) in DMF (16 mL) was added NBS (1.42 g, 7.9 mmol) at 0° C. It was stirred for 15 min at 0° C. The mixture was extracted with EtOAc (150 mL), washed with NaHSO3 (50 mL), water and brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1) to give the title compound (3g) as a solid. MS-ESI (m/z): 242 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]=O)=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:11]=1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18].[BH4-].[Na+]>CO>[OH:1][C:2]1[C:3]([CH2:12][NH:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH2:17][OH:18])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:11]=1
Reactant: Nc1ccccc1CO
Reactant: O=Cc1cc2c(cc1O)CCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccccc1NCc1cc2c(cc1O)CCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydrobenzopyran-7-carboxaldehyde (400 mg, 2.27 mmol) and o-aminobenzylalcohol 282 mg, 2.25 mmol) in methanol (30 mL) was brought to a gentle boil and the volume slowly concentrated to 10 mL. An additional portion of methanol (20 mL) was added and the above process repeated two times. The mixture was cooled (ice bath) and a few drops of water added to aid in the crystallization of the Schiff's base. This material (440 mg) was collected by filtration, redissolved in methanol (30 mL) and sodium borohydride (60 mg, 1.59 mmol) was added in portions. The color was discharged immediately and the mixture allowed to stir at room temperature for 10 minutes. The reaction mixture as concentrated to half its original volume then poured into water (35 mL). After acidification (pH=5) with 2N HCl the mixture was filtered, and the filtrate basified with 7% NaHCO3. The product, which precipitated, was collected by filtration and vacuum dried to afford 6-hydroxy-7-(2-hydroxymethylphenyl)aminomethyl-3,4-dihydrobenzopyran (300 mg, 46.8%), m.p. 141-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3[N:15]([CH2:25][CH2:26]C(C)(C)C)[CH:16]=[N:17][C:18]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:7]([C:11]([NH2:13])=O)[NH:8]2)=[CH:4][CH:3]=1.C(O[C:38]([C:40](F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3[N:15]([CH2:25][C:26]4[CH:40]=[CH:38][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:16]=[N:17][C:18]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:7]([C:11]#[N:13])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)CCn1cnc(-c2ccccc2)c1-c1c(C(N)=O)[nH]c2cc(Cl)ccc12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1[nH]c2cc(Cl)ccc2c1-c1c(-c2ccccc2)ncn1Cc1ccc(Cl)cc1

Procedure:
A mixture of Example 138 (150 mg, 0.33 mmol) and TFAA (1.5 mL) in DCM (1.5 mL) is heated to reflux. After completion the reaction mixture is quenched by saturated aqueous NaHCO3. DCM is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a colorless powder; ES-MS: M+H=444.9: AtRet=4.44.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][CH2:16][CH2:17][OH:18])=[O:14])=[CH:8][CH:7]=1.[CH3:20][O:21][C:22](=[O:34])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([O:15][CH2:16][CH2:17][O:18][C:32](=[O:33])[NH:31][C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:22]([O:21][CH3:20])=[O:34])=[CH:30][CH:29]=2)=[O:14])=[CH:10][CH:11]=1
Reactant: COC(=O)COc1ccc(NC(=O)OCCO)cc1
Reactant: COC(=O)COc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(NC(=O)OCCOC(=O)Nc2ccc(OCC(=O)OC)cc2)cc1
Temperature: 50 °C

Procedure:
To [4-(2-Hydroxyethoxycarbonylamino)-phenoxy]-acetic acid methyl ester 5 (1 g, 3.72 mmol) in toluene (10 ml) was added (4-Isocyanatophenoxy)-acetic acid methyl ester 4 (0.8 gram, 3.8 mmol) at room temperature and heated to 50° C. for 20 hours. Toluene was distilled off and water (10 ml) was added. Crude 6 was extracted into chloroform, dried over sodium sulphate, distilled and purified by column chromatography on silica gel using chloroform as eluant to g pure 6 (1 gram, 56.5%) as a white fluffy powder.
Reaction SMILES: CON(C)[C:4](=[O:28])[C@H:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:30][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[CH2:13]([O:12][C:10]([NH:9][CH2:8][CH2:7][CH2:6][C@@H:5]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C:4](=[O:28])[CH3:30])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CON(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -30 °C
Yield: 75 %

Procedure:
N-Methoxy-N-methyl-(R)-5-(Benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)-pentanamide (305) (10 g, 24 mmol) was dissolved in THF (250 mL) and the solution was cooled to −30° C. in a dry-ice acetone bath. MeMgBr (3M in Et2O, 123 mL, 369 mmol) was added drop-wise over 30 minutes. The bath temperature was slowly allowed to increase to 0° C. and then was maintained at 0° C. until TLC showed no further reaction progress (˜80-90% complete). Saturated NH4Cl (aq) was then slowly added to the reaction mixture at 0° C. and the THF was removed under reduced pressure. The resulting aqueous solution was then extracted with EtOAc and the extracts were washed with water and then brine. The residue was then purified by column chromatography (EtOAc/hexanes) to give (R)-6-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)-2-hexanone (306), (6.5 g, 18 mmol, 75% yield).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[N:35]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH:9]=1.O.C(=O)(O)[O-].[Na+]>Cl.C(OCC)(=O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:6][N:7]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[N:35]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:9]=1
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(NCCC(=O)OC(C)(C)C)ncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(NCCC(=O)O)ncn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103 %

Procedure:
Tert-butyl 3-(6-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-4-ylamino)-propionate (60 mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (0.5 ml) and the mixture is stirred at room temperature for 1.5 hours. To the reaction solution are added ethyl acetate and water, and followed by a further addition of a saturated aqueous sodium bicarbonate solution to make the pH of aqueous layer to be about 4, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and the mixture is concentrated under reduced pressure to give 3-(6-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-4-ylamino)-propionic acid (57 mg). MS (m/z): 666 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=3)[CH:5]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)NC2CC2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned-compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and cyclopropylamine in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][C:32]1[C:37]([C:38]#[N:39])=[CH:36][CH:35]=[C:34]([NH:40][CH2:41][CH2:42][NH2:43])[N:33]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:31][C:32]1[C:37]([C:38]#[N:39])=[CH:36][CH:35]=[C:34]([NH:40][CH2:41][CH2:42][NH:43][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:33]=1
Reactant: N#Cc1ccc(NCCN)nc1N
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 30 mg (0.14 mmol) of 2-amino-6-[(2-aminoethyl)amino]pyridine-3-carbonitrile dihydrochloride (Example 9A) and 0.125 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 45 mg (68% of theory) of the product as a solid.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][C:7](=[O:9])[O:6][C:5](=[O:10])[CH2:4]2)[CH2:2]1.Cl.[CH3:12][NH:13][O:14][CH3:15].N1C=CC=CC=1>ClCCl>[CH3:15][O:14][N:13]([CH3:12])[C:7]([CH2:8][C:3]1([CH2:4][C:5]([OH:6])=[O:10])[CH2:2][CH2:1]1)=[O:9]
Reactant: CNOC
Reactant: O=C1CC2(CC2)CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)CC1(CC(=O)O)CC1
Temperature: 25 °C

Procedure:
To a mixture of 5 g 6-oxa-spiro[2.5]octane-5,7-dione (36 mmole), 3.8 g of N,O-dimethylhydroxylamine hydrochloride (39 mmole, 1.1 eq) and 75 ml of dichloromethane are added 7 ml of pyridine (78 mmole, 2.2 eq) at 0-5° C. The solution is warmed to room temperature, stirred over night and washed with 50 ml of brine. The aqueous phase is extracted with 3×30 ml of dichloromethane and the combined organic phases are dried over magnesium sulfate and evaporated to dryness. The resulting crude product is directly used in the next step ([1-(2-oxo-propyl)-cyclopropyl]-acetic acid).