Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].B>>[CH2:11]([N:7]1[CH2:8][CH2:9][CH:5]([CH2:3][OH:2])[CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: B
Agent: [Al+3]
Agent: [H-]
Product: OCC1CCN(Cc2ccccc2)C1

Procedure:
Reduction of 1-benzyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester 11 with a suitable reducing agent (such as lithium aluminum hydride, borane, and the like) gives N-benzyl-3-hydroxymethylpyrrolidine 12. Removal of the benzyl group under catalytic hydrogenation reaction conditions followed by reaction of 3-hydroxymethylpyrrole 13 with di-tert-butyl dicarbonate in the presence of a base (e.g., sodium hydroxide, sodium carbonate, and the like) gives N-tert-butoxycarbonyl-3-hydroxymethylpyrrolidine of Formula (Ic). Compound (Ic) is then converted to a compound of Formula (I) as shown below.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=4)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(I)cc3)cnc12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(-c4cccc(OC)c4)cc3)cnc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
A mixture of 60 mg (0.126 mmol) of 7-cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, 29 mg (0.19 mmol, 1.5 equiv) of 3-methoxyphenylboronic acid, 5 mg (0.0063 mmol, 5 mol %) of Pd catalyst, and 80 mg (0.378 mmol, 3 equiv) of potassium phosphate was placed into a carousel tube. After a vacuum and argon cycle, 1,4-dioxane (3 mL) was added, and the resulting mixture was heated at 80° C. under argon for 14 h. Since analysis by LC-MS revealed unreacted starting material still present, 29 mg (0.19 mmol, 1.5 equiv) of 3-methoxyphenylboronic acid, 10 mg (0.012 mmol, 10 mol %) of Pd catalyst, and 80 mg (0.378 mmol, 3 equiv) of potassium phosphate was added and heating was continued for 24 h. The reaction mixture was then diluted with ethyl acetate, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a brown residue (crude coupling product), which was chromatographed on silica gel (Biotage; gradient elution 2% to 5% ethyl acetate in dichloromethane) to afford 47 mg (82% yield) of desired 7-cyclohexyl-6-(3′-methoxy-biphenyl-4-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester as indicated by 1H NMR; LC-MS—calcd for C28H29N3O3 [M++H]+: 456.22, found: 456.2.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]3[C:7]=2[C:8](Cl)=[N:9][C:10]([Cl:20])=[N:11]3)[CH2:4][CH2:3][CH2:2]1.[NH3:22]>>[NH2:22][C:8]1[C:7]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[C:15]([O:16][CH3:17])[C:6]=2[O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[N:11]=[C:10]([Cl:20])[N:9]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2c(OC2CCC2)c1OC
Reactant: N
Product: COc1cc2nc(Cl)nc(N)c2c(OC2CCC2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
5-Cyclobutyloxy-2,4-dichloro-6,7-dimethoxyquinazoline (300 mg, 0.0009 mol) was suspended in a saturated ethanolic ammonia solution (10 ml) and the reaction stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, resuspended in a minimum volume of diethyl ether and the resulting solid filtered off. Drying under suction gave the subtitle compound as a white solid (189 mg, 68%). Rf 0.69 (diethyl ether). 1H-NMR (CDCl3): δ=1.56 (1H, m), 1.82 (1H, m), 2.26 (2H, m), 2.42 (2H, m), 3.85 (3H, s), 3.94 (3H, s), 4.92 (1H, m), 5.82 (1H, bs), 6.94 (1H, s), 7.72 (1H, bs).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]3[N:27]([C:28]=2[CH:29]=O)[CH:26]=[CH:25][S:24]3)=[CH:17][CH:16]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.CCCCCC>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]3[N:27]([C:28]=2/[CH:29]=[CH:2]/[C:1]([C:4]2[CH:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=2)=[O:3])[CH:26]=[CH:25][S:24]3)=[CH:19][CH:20]=1
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: O=Cc1c(-c2ccc(F)cc2)nc2sccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1c(-c2ccc(F)cc2)nc2sccn12)c1ccc2ccccc2c1
Temperature: 27 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
To a stirred solution of 2-acetyl napthalene (170 mg, 1.0 mmol) and a 6-(4-fluorophenyl) imidazo[2,1-b]thiazol-5-carbaldehyde (246 mg, 1.0 mmol) in ethanol (20 ml) 10% aqueous solution of NaOH was added (5 ml). The reaction mixture was stirred at room temperature 27° C. for 4 h and the reaction was monitored by TLC using ethyl acetate-hexane (3:7) as a solvent system. The solvent was evaporated under vacuum then the residue was dissolved in ethylacetate/water. The organic layer was washed with brine and evaporated. This was further purified by column chromatography using ethyl acetate:hexane (2:8) as a solvent system to obtain the pure product (12e) as yellow solid (298 mg, 75% yield). Mp: 216-218° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:15])[C:12]([NH2:14])=O)=[N:8][C:7]([S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])=[N:6][C:5]=2[N:26]=1.B>O1CCCC1>[NH2:14][CH2:12][C@H:11]([NH:10][C:9]1[C:4]2[S:3][C:2]([NH2:1])=[N:26][C:5]=2[N:6]=[C:7]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[N:8]=1)[CH3:15]
Reactant: C[C@@H](Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12)C(N)=O
Agent: B
Solvent: C1CCOC1
Product: C[C@H](CN)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
To a solution of the product from example 12 step a) (0.3 g) in dry tetrahydrofuran (10 ml) was added 2M borane in THF (10 ml) and the mixture heated under reflux for 6 hours. Quenched while hot with methanol (30 ml), evaporated to dryness and the residue taken up into methanol (30 ml) containing a few drops of concentrated hydrochloric acid. The mixture was then heated under reflux for a further 1 hour, evaporated to dryness to give a pale yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:11](=[O:35])[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:29])[C:23]=3[C:22]3=[N:30][O:31][C:32]([CH3:33])=[C:21]3[C:20]2=[O:34])[CH2:14]1)[CH2:9][OH:10])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH:8]([CH2:9][OH:10])[C:11]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:29])[C:23]=3[C:22]3=[N:30][O:31][C:32]([CH3:33])=[C:21]3[C:20]2=[O:34])[CH2:14]1)=[O:35]
Reactant: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)C(CO)NC(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)C(N)CO)C1)c1cccc(Cl)c21
Yield: 50 %

Procedure:
A solution of {1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-2-hydroxy-ethyl }-carbamic acid tert-butyl ester, 92.3 mg (0.18 mmol) in 8 mL of 25% TFA in CH2Cl2 was stirred rt. for three hours then concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and saturated aqueous NaHCO3. The organics were washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by radial chromatography using MeOH/chloroform as eluent and concentrated to dryness to yield 37 mg (50%) of the title compound as a white solid. MS (IS) 419.2 (M+).
Reaction SMILES: Br[C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH2:10][CH2:11][O:12][CH2:13][CH:14]=2)[S:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C1(C)C=CC=CC=1.[Cl-].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][Zn+])=[CH:31][CH:30]=1.O1CCCC1>CCOC(C)=O.[NH4+].[Cl-].C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][C:2]2[C:6]([C:7]#[N:8])=[C:5]([C:9]3[CH2:10][CH2:11][O:12][CH2:13][CH:14]=3)[S:4][C:3]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:31][CH:30]=1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: CCOC(=O)c1sc(C2=CCOCC2)c(C#N)c1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(C2=CCOCC2)c(C#N)c1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
In a sealable reaction vial, ethyl 3-bromo-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate (180.0 mg, 0.5260 mmol) and a stir pea were azeotroped with toluene 3× and dried under high vacuum overnight. To the vial was added bis(tri-t-butylphosphine)palladium(0) (26.88 mg, 0.05260 mmol). Vial was evacuated and then back-filled with argon 2×, at which time was added via syringe 4-chlorobenzylzinc chloride as a 0.50 M solution in tetrahydrofuran (3.682 mL, 1.841 mmol). The reaction was heated with stirring at 60° C. for 2 h. Reaction was cooled to room temperature and then diluted with EtOAc and sat. aq. NH4Cl. Mixture was transferred to a separatory funnel, the layers were separated, and the aqueous layer extracted 2× with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered through a pad of Celite, and concentrated in vacuo to afford a yellow oil. The residue was dissolved in DCM and loaded onto 40 g ISCO column (gradient elution: 0-25% EtOAc/hexanes) to afford ethyl 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate (92 mg, 43.6%) as a yellow solid. LC/MS: (AA) ES− 386, 388; 1H NMR (400 MHz, DMSO) δ 7.38-7.33 (m, 2H), 7.22 (m, 2H), 6.80-6.76 (m, 1H), 4.40 (s, 2H), 4.34-4.24 (m, 4H), 3.80 (dd, J=5.4, 5.4, 2H), 2.52 (dd, J=2.2, 5.0, 2H), 1.26 (dd, J=7.1, 7.1, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[N:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[C:9]([CH3:30])=[C:8]([C:31]([O:33]CC)=[CH2:32])[C:7]2=[O:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(Cl)(Cl)Cl>[C:31]([C:8]1[C:7](=[O:36])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:12]=[C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=2[C:9]=1[CH3:30])(=[O:33])[CH3:32]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCC(O)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCC(O)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.5 %

Procedure:
To a solution of 8-cyclopentyl-6-(1-ethoxy-vinyl)-2-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (255 mg, 0.52 mmol) in chloroform (2 mL) was added hydrogen chloride (2 M ethereal solution, 5.0 mL, 10.0 mmol). The reaction mixture was stirred at RT for 12 h. The solvents were evaporated and the residue was dissolved in ethanol. The ethanol was evaporated to give 6-acetyl-8-cyclopentyl-2-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (213 mg, 0.46 mmol). MS (APCI+) 463 (M+1, 100); 1H NMR δ(400 MHz, DMSO-d6) 10.90 (br, 1H), 9.07 (s, 1H), 8.19 (s, 1H), 7.91 (br, 2H), 5.91-5.89 (m, 1H), 3.77 (br, 1H), 3.62 (br, 2H), 3.07 (br, 2H), 2.58 (s, 3H), 2.40 (s, 3H), 2.30 (br, 2H), 1.98-1.86 (m, 5H), 1.65 (br, 4H); Anal. Calc'd for C25H30N6O3, 1.76 C3H8O1, 0.36 CHCl3: C, 60.20; H, 7.33; N, 13.75. Found: C, 60.48; H, 6.97; N, 13.35.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7]([CH3:18])=[C:8]([CH3:17])[C:9](=[O:16])[NH:10]2)C=C.C(Cl)(Cl)Cl.[OH-].[Na+].CN(C)[C:27]1[CH:32]=CC=C[CH:28]=1>>[CH2:32]([C:14]1[C:5]([OH:4])=[C:6]2[C:11](=[C:12]([CH3:15])[CH:13]=1)[NH:10][C:9](=[O:16])[C:8]([CH3:17])=[C:7]2[CH3:18])[CH:27]=[CH2:28]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(C)c2[nH]c(=O)c(C)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=CCc1cc(C)c2[nH]c(=O)c(C)c(C)c2c1O
Temperature: 200 °C
Reaction time: 2 h

Procedure:
5-Allyloxy-3,4,8-trimethylcarbostyril (1.02 g, 420 mmol) was dissolved in N,N-dimethylaniline (20 ml), and the mixture was stirred in a bath of 200° C. for 2 hours. The reaction mixture was condensed under reduced pressure, to which chloroform and aqueous 2N-NaOH solution were added, then extracted into the aqueous phase. The aqueous phase was neutralized with conc. HCl solution, followed by extracting with chloroform--methanol (10:1), drying, and condensing. The resultant residue was recrystallized from chloroform--methanol--ether. As a result, 989 mg of the title compound was obtained as pale yellow needles (97.0%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:10][CH2:11]C=C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:18])[CH2:10][CH2:11][CH:17]=[CH:16][CH2:15][CH2:14]1
Reactant: C=CCCC(O)(CCC=C)c1cccc(F)c1F
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: OC1(c2cccc(F)c2F)CCC=CCC1
Temperature: 40 °C

Procedure:
In a 1 L round-bottomed flask (t=g) was added 5-(2,3-difluorophenyl)nona-1,8-dien-5-ol (1.76 g, 6.98 mmol) in CH2Cl2 (600 mL) to give a colorless solution. Grubbs I (0.175 g, 0.209 mmol) was added, and the mixture was heated at 40° C. for 2 hours. TLC showed clean conversion to a more polar spot (some impurities from starting material remained). Combined with 68908-198 and concentrated to dryness and the residue was subject to purification up to 50% Et2O/hexane (twice). The major peak was pooled and concentrated to a light green oil (1.40 g, 89.2%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 1H), 7.08-7.00 (m, 2H), 5.90-5.80 (m, 2H), 2.60-2.48 (m, 2H), 2.21 (t, J=7.0 Hz, 2H), 2.10-1.98 (m, 2H), 1.90-1.75 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C.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>[CH3:11][O:10][C:8]1[C:7]([O:12][CH3:13])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH:9]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cc(Br)c(C=O)cc1OC
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(C=O)c(-c2cccnc2)cc1OC
Temperature: 140 °C

Procedure:
A mixture of 2-bromo-4,5-dimethoxybenzaldehyde (0.368 g, 1.5 mmol), pyridin-3-ylboronic acid (0.246 g, 2.0 mmol), Pd(PPh3)4 (0.173 g, 0.150 mmol), and cesium carbonate (0.977 g, 3 mmol) were suspended in dioxane (4 mL) and water (1 mL). The mixture was heated to 140° C. in a microwave for 1 h. The reaction vessel was allowed to cool to ambient temperature, diluted with ethyl acetate (˜25 mL), filtered through a bed of Celite, and conc. in vacuo to afford the aldehyde which was purified via SiO2 chromatography (40 g) using ethyl acetate/hexanes (5:1) as eluent to afford the title compound as a white solid (0.340 g, 93%); m/z 244.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1([NH2:37])[CH2:36][CH2:35]1.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:37][C:34]4([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=5)[CH2:36][CH2:35]4)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: NC1(c2ccccn2)CC1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1(c2ccccn2)CC1
Reaction time: 2 h

Procedure:
Into a solution of 0.50 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylbenzoyl chloride in 10 mL of dichloromethane, 0.20 g of 1-(2-pyridyl)cyclopropylamine was dropped while stirring and ice-cooling the solution and after the completion of the dropping, the stirring was continued at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL×2). The organic phase was cleaned with water (10 mL×1) and then was dehydrated and dried with saturated brine and over anhydrous sodium sulfate, respectively, in this order, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:1) to obtain 0.16 g of the objective substance as a yellow resin-state substance.
Reaction SMILES: [CH3:1][N:2]([S:6][C:7]([CH3:14])([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:8])[C:3](Cl)=[O:4].[C:15]1([OH:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>O1CCOCC1.O>[CH3:1][N:2]([S:6][C:7]([CH3:14])([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:8])[C:3]([O:25][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: CC(C)C(=O)C(C)(C)SN(C)C(=O)Cl
Reactant: Oc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)C(=O)C(C)(C)SN(C)C(=O)Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 64.7 %

Procedure:
To a solution of 10.0 g (0.042 m) of N-methyl-N-(2,4-dimethyl-3-oxo-2-pentanesulfenyl)carbamoyl chloride and 6.06 g (0.042 m) of 1-naphthol in 75 ml of dioxane was added 4.26 g (0.042 m) of triethylamine. After stirring at room temperature for 17 hours the reaction mixture was diluted with 500 ml of cold water and the product taken into ethyl acetate. The organic phase was washed in turn with 1.0 percent sodium hydroxide and water and then dried over magnesium sulfate. On removal of the solvent it yielded 9.4 g of a residual oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH2:28]([O:31][C:32]1[N:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=1)[CH:29]=[CH2:30].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[CH2:28]([O:31][C:32]1[N:33]=[CH:34][C:35]([NH:38][C:13](=[O:15])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:36][CH:37]=1)[CH:29]=[CH2:30]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: C=CCOc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=CCOc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 80.3 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 510 mg, 1.54 mmol) in methylene chloride (15 mL) and N,N-dimethylformamide (2 drops) was cooled to 5° C. and then treated with oxalyl chloride (0.27 mL, 3.09 mmol). After stirring for 5 min, the cooling bath was removed, and the stirring continued at 25° C. for 10 min. The solvents were concentrated in vacuo, the residue was dissolved in benzene (25 mL), and the solvent was concentrated in vacuo again. The resulting acid chloride was dissolved in methylene chloride (10 mL), cooled to 5° C. and then treated with a solution of 5-allyloxy-pyrazin-2-ylamine (238 mg, 1.57 mmol) and pyridine (0.32 mL, 3.96 mmol) in methylene chloride (15 mL). The mixture was further stirred at 25° C. for 16 h. The reaction mixture was then diluted with methylene chloride (25 mL) and washed with a saturated aqueous sodium bicarbonate solution (25 mL), a 0.5M aqueous hydrochloric acid solution (25 mL), and a saturated aqueous sodium chloride solution (25 mL). Each aqueous layer was back-extracted with another portion of methylene chloride (25 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, eluted with increasing concentrations of ethyl acetate/hexanes) afforded N-(5-allyloxy-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide as a white foam (574 mg, 80%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([NH:12][NH:13][C:14]([NH2:16])=[S:15])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].CS(O)(=O)=O>C1(C)C=CC=CC=1>[NH2:16][C:14]1[S:15][C:10]([C:9]2[CH:17]=[CH:18][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)=[N:12][N:13]=1
Reactant: CCCCOc1ccc(C(=O)NNC(N)=S)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(-c2nnc(N)s2)cc1
Temperature: 10 °C
Yield: 23.1 %

Procedure:
To a slurry of 1-(4-n-butyloxybenzoyl)thiosemicarbazide (20 g) in toluene (213.3 ml) at 40° C., was added dropwise over 30 minutes, methanesulfonic acid (6.92 ml). The mixture was stirred under refluxing for 12 hours. After cooling to 10° C., the sulfonate salt was filtered and dried. The salt was placed in water, the solution was adjusted to pH 9 with 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 2-amino-5-(4-n-butyloxyphenyl)-1,3,4-thiadiazole (4.314 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:25]([N:32]1[CH2:37][CH2:36][N:35]([NH2:38])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCOC(C)=O.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCN(C(C)C)C(C)C.C(Cl)Cl.CO>[CH2:25]([N:32]1[CH2:33][CH2:34][N:35]([NH:38][C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]2[CH:16]=[N:17][C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=3)=[N:14]2)[CH2:36][CH2:37]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NN1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NN1CCN(Cc2ccccc2)CC1
Yield: 7.3 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.220 g, 1.2 eq.), 4-benzylpiperazin-1-amine (0.10 g, 1.0 eq.) and EtOAc (15 ml). T3P (50% in EtOAc 0.99 g, 3.0 eq.) and DIPEA (0.27 mg, 4.0 eq.) were added under nitrogen atmosphere to the cold (−60° C.) solution. The progress of the reaction was followed by TLC analysis (SiO2, 15% MeOH:CH2Cl2 as mobile phase, visualization under UV light). The reaction mixture was quenched in water and extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure (25° C., 20 mmHg) to afford 0.35 g of crude solid. Purification on Combi-flash (eluting with 10% MeOH/CH2Cl2) afforded 20 mg (yield: 6%) (Z)—N-(4-benzylpiperazin-1-yl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide. 1H NMR (400 MHz, DMSO-d6) δ 9.44-9.48 (t, 3H), 9.10 (s, 1H), 8.51 (s, 2H), 7.23-7.41 (m, 6H), 6.46-6.49 (d, J=10.4 Hz, 1H), 5.83-5.86 (d, J=10.4 Hz, 1H), 3.47 (s, 2H), 2.81 (s, 4H), 2.23-2.33 (d, 2H) LCMS for C24H23F6N6O [M+H]+ 525.47. found 525.20 (RT 9.87 min, purity: 100%).