Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[CH3:29][C:30]1([CH3:38])[CH2:35][CH:34]([CH3:36])[CH2:33][CH:32](O)[CH2:31]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([O:19][CH:32]1[CH2:33][CH:34]([CH3:36])[CH2:35][C:30]([CH3:38])([CH3:29])[CH2:31]1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC(O)CC(C)(C)C1
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CC1CC(OC(=O)[C@@H]2CCC(=O)N2C(=O)OCc2ccccc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
34.2 g (0.13 mol) of N-benzyloxycarbonyl-L-pyroglutamic acid (prepared according to Berichte 97, 2434 [1964] or Annalen 649, 183 [1961]) are added to 150 ml of dimethylformamide, followed by 2 g of dimethylaminopyridine and then 18.48 g (0.13 mol) of 3,3,5-trimethylcyclohexanol (mixture of 90% trans isomer and 10% cis isomer) diluted in 50 ml of dimethylformamide. 26.8 g (0.13 mol) of dicyclohexylcarbodiimide are then run in over a period of about 15 minutes, the reaction medium being kept at +5° C. The mixture is then stirred at room temperature for 24 hours, after which the solvent is evaporated off, the residue is taken up with dilute hydrochloric acid and extraction is carried out with chloroform.
Reaction SMILES: Cl[S:2]([C:5]1[N:14]=[C:8]2[N:9]=[C:10]([CH3:13])[CH:11]=[CH:12][N:7]2[N:6]=1)(=[O:4])=[O:3].C[Si](C)(C)[NH:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25].CS(C)=O.Cl>CC#N>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[NH:17][S:2]([C:5]1[N:14]=[C:8]2[N:9]=[C:10]([CH3:13])[CH:11]=[CH:12][N:7]2[N:6]=1)(=[O:4])=[O:3]
Reactant: Cc1ccn2nc(S(=O)(=O)Cl)nc2n1
Reactant: C[Si](C)(C)Nc1c(F)cccc1F
Agent: Cl
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1ccn2nc(S(=O)(=O)Nc3c(F)cccc3F)nc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A solution consisting of 91.4 mg of about 77 percent pure 2-chlorosulfonyl-5-methyl-1,2,4-triazolo-[1,5-a]pyrimidine (0.30 mmole), 0.5 ml of CH3CN, 0.5 ml of N-trimethylsilyl-2,6-difluoroaniline, and 10 μl (0.141 mmole) of dimethyl sulfoxide was stirred at room temperature for 4 hours. The solution was treated with 2 ml of 1.0N HCl and the resultant mixture filtered. The precipitate was dried in vacuo, washed with CH2Cl2 and again dried to afford 68.7 mg (0.211 mmole, 70.0 percent yield) of N-(2,6-difluorophenyl)-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide product as a white powder, m.p. 250°-251° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]1[O:11][C:5]2([CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:8][CH2:9]1
Reactant: OCCO
Reactant: O=C1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: OC1CCC2(CC1)OCCO2

Procedure:
A reaction mixture consisting of 10 g. (0.085 mole) 4-hydroxycyclohexanone, 4.75 ml. ethylene glycol, 0.20 g. p-toluenesulfonic acid, and 100 ml. benzene is heated at the reflux temperature in a reaction vessel fitted with a Dean and Stark trap for 2 hours. After the reaction mixture has cooled, it is washed first with water and then with brine. The benzene is then removed by evaporation under reduced pressure giving the intermediate 4-hydroxycyclohexanone ethylene monoketal as a viscous oil weighing 14.12 g.. The 4-hydroxycyclohexanone ethylene monoketal is dissolved in 100 ml. methylene chloride and added with stirring to a suspension consisting of 55.0 g. chromium trioxide (pre-dried for 24 hours under reduced pressure over phosphorous pentoxide), one liter dry methylene chloride, and 52.8 g. 3,5-dimethylpyrazole. After continued stirring for ten (10) minutes, this dark reaction mixture is poured onto a two-liter column of silica gel. When the reaction mixture has been completely adsorbed, the chromatogram is developed with a 1:1 mixture of ethyl acetate and technical hexane (Skellysolve B -- a mixture of isomeric hexanes having a boiling range between 60° and 70° C.). The appropriate fractions as determined by TLC are collected and combined, after which the solvents are removed by evaporation under reduced pressure. The crystals thus obtained are recrystallized from technical hexane, and there is thus obtained 10.82 g. (91% yield) of the desired cyclohexane -- 1,4-dione, ethylene monoketal having a melting point at 68° to 69° C. [The literature value is 71.5° to 72.5° C.]
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])=[N+:2]=[N-:3].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[C:13]#[CH:14]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[CH:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N:1]1[CH:14]=[C:13]([C:12]([O:16][CH2:17][CH3:18])=[O:15])[N:3]=[N:2]1)=[O:7].[CH:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N:1]1[C:13]([C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:14][N:3]=[N:2]1)=[O:7]
Reactant: [N-]=[N+]=Nc1ccccc1C=O
Reactant: C#CC(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccccc2C=O)nn1
Product: CCOC(=O)c1cnnn1-c1ccccc1C=O
Temperature: 100 °C
Reaction time: 12 h
Yield: 66 %
Yield: 17 %

Procedure:
To a solution of 2-azidobenzaldehyde (100 mg, 0.68 mmol) in 1.0 mL of dry N,N-dimethylformamide was added ethyl propiolate (0.14 mL, 1.4 mmol) at room temperature. After being stirred at 100° C. for 12 h, ethyl propiolate (0.14 mL, 1.4 mmol) was added again with additional stirring for 12 h. After cooling, the reaction mixture was diluted with a 5:1 solution (12 mL) of ethyl acetate and hexane. The solution was washed with water twice, brine, and dried over Na2SO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=90/10 to 75/25) to obtain ethyl 1-(2-formylphenyl)-1H-1,2,3-triazol-4-carboxylate as a crystal (111 mg, 66%) and ethyl 1-(2-formylphenyl)-1H-1,2,3-triazol-5-carboxylate as a oil (28 mg, 17%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@H:15]([C:16](=[O:29])[NH:17][C@@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[CH2:19][OH:20])[CH2:14][C@@H:13]2[C@H:11]1[CH2:12]2)=[O:9])([CH3:6])([CH3:5])[CH3:4].IC.[C:32]([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[C:3]([O:7][C:8]([N:10]1[C@H:15]([C:16](=[O:29])[NH:17][C@@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[CH2:19][O:20][CH3:32])[CH2:14][C@@H:13]2[C@H:11]1[CH2:12]2)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: ClCCl
Product: COC[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C)c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in mineral oil, 25.7 mg, 0.64 mmol) in THF (3 mL) cooled at 0° C. under Argon was added (1R,3S,5R)-3-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (270 mg, 0.64 mmol). The reaction mixture was stirred at 0° C. for 30 min and iodomethane (0.06 mL, 0.97 mmol) was added. After 1 h the reaction mixture was poured into saturated NaHCO3 aqueous solution. CH2Cl2 was added, the layers were separated and the aqueous one back-extracted with CH2Cl2 (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 20:80) the desired compound as a colorless oil. TLC, Rf (EtOAc)=0.65; MS (UPLC/MS): 413.4/415.4 [M+H]+, 457.4/459.4 [M+HCOO]−; tR (HPLC conditions a): 3.67 min.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([Cl:12])=[CH:7][C:6]=1[NH:13][CH:14]1[CH2:16][CH2:15]1)C.[Li+].[OH-].CO>C1COCC1>[Cl:12][C:8]1[C:9]([F:11])=[CH:10][C:5]([C:4]([OH:17])=[O:3])=[C:6]([NH:13][CH:14]2[CH2:15][CH2:16]2)[CH:7]=1
Reactant: CCOC(=O)c1cc(F)c(Cl)cc1NC1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(F)c(Cl)cc1NC1CC1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A solution of 4-chloro-2-cyclopropylamino-5-fluoro-benzoic acid ethyl ester (Example B-3, 4.10 g, 15.9 mmol) in THF (100 mL) was reacted with an aqueous solution of 1.0 N LiOH (45 mL, 45 mmol) and methanol (40 mL) and allowed to stir overnight. The mixture was then concentrated to one-third volume and acidified with 1.0 N HCl. The mixture was extracted with ethyl acetate, the organic layers combined, dried with sodium sulfate, and concentrated to provide 3.0 g of the title compound as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:29])([F:28])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][C:25]([OH:27])=O)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)=[CH:11][CH:10]=1.[CH3:30][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>O.CN(C)C=O>[CH3:30][N:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25](=[O:27])[CH2:24][N:23]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[C:12]1[CH:13]=[CH:14][C:9]([C:8]([F:29])([F:28])[F:7])=[CH:10][CH:11]=1
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Reactant: CNc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21)c1ccccc1
Yield: 26.1 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (1.91 g, 0.015 mole) was added dropwise (slowly) to a stirred and chilled (5°-10° C.) solution of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3acetic acid (4,5 g, 0.014 mole) and anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 4 hours, cooled, and added dropwise to a stirred and chilled (5°-10° C.) solution of N-methylaniline (1.60 g, 0.015 mole), triethylamine (1.52 g, 0.015 mole), and anhydrous dimethylformamide (50 ml). The reaction mixture was stirred at room temperature overnight and then poured into water (300 ml). The mixture was extracted with methylene chloride (3×50 ml). The combined organic extracts were washed with potassium bicarbonate solution (2×30 ml), water (30 ml), dried over sodium sulfate and concentrated in vacuo. Recrystallization twice from isopropyl ether-petroleum ether gave 1.5 g (24%) of off-white needles, mp 158°-159° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:21][C:15]2[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30]1([CH2:33][N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[CH2:32][O:31]1.C[O-].[Na+]>C(O)(C)(C)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:21][C:15]2[N:16]=[CH:17][N:18]([CH2:32][C:30]([C:24]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=3[F:22])([OH:31])[CH2:33][N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)[C:19](=[O:20])[C:14]=2[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Reactant: O=c1[nH]cnc2sc(CCCOCc3ccccc3)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=c1c2cc(CCCOCc3ccccc3)sc2ncn1CC(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 14 %

Procedure:
6-(3-Benzyloxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A02) (3.0 g, 0.01 mole), 1[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole of the Formula (5) (2.82 g, 0.012 mole) and sodium methoxide (0.65 g, 0.012 mole), were taken in two neck round bottom flask under inert atmosphere, dry t-butanol (70 ml) was added to the above reaction mixture and the mixture was stirred under reflux for 12 hours. t-Butanol was removed on rotavapor, water (50 ml) was added to the reaction mixture, the compound from the reaction mixture was extracted with ethyl acetate (3×50 ml), dried, concentrated and purified by column chromatography to obtain the pure 6-(3-benzyloxypropyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-ylpropyl]-thieno[2,3-d]pyrimidin-4(3H)-one (1-A02) (0.8 gm, 14%). 1HNMR (CDCl3, 200 MHz):: 1.91-2.06 (m, 2H), 2.95 (t, J=6 Hz, 2H), 3.51 (t, J=6 Hz, 2H), 4.21 (d, J=14 Hz, 1H), 4.49 (s, 2H), 4.52 (d, J=14 Hz, 1H), 4.72 (d, J=14 Hz, 1H), 4.79 (d, J=14 Hz, 1H), 6.22 (s, 1H), 6.72-6.88 (m, 2H), 7.08 (s, 1H), 7.31 (bs, 5H), 7.49-7.62 (m, 1H), 7.83 (s, 1H), 7.91 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]12([CH2:38][NH:39][C:40]([C:42]3[C:43]([CH3:57])=[N:44][N:45]([C:47]4[N:52]=[C:51]([C:53](O)=[O:54])[C:50]([CH3:56])=[CH:49][N:48]=4)[CH:46]=3)=[O:41])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:28]12([CH2:38][NH:39][C:40]([C:42]3[C:43]([CH3:57])=[N:44][N:45]([C:47]4[N:52]=[C:51]([C:53]([N:58]5[CH2:63][CH2:62][O:61][CH2:60][CH2:59]5)=[O:54])[C:50]([CH3:56])=[CH:49][N:48]=4)[CH:46]=3)=[O:41])[CH2:29][CH:30]3[CH2:31][CH:32]([CH2:33][CH:34]([CH2:36]3)[CH2:35]1)[CH2:37]2
Reactant: C1COCCN1
Reactant: Cc1cnc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C)n2)nc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C)n2)nc1C(=O)N1CCOCC1
Reaction time: 8 h

Procedure:
BOP (88 mg, 8 mmol) is added to a solution of 2-{4-[(adamantan-1-ylmethyl)-carbamoyl]-3-methyl-pyrazol-1-yl}-5-methyl-pyrimidine-4-carboxylic acid (41 mg, 0.1 mmol), morpholine (13 mg, 0.15 mmol) and DIEA (39 mg, 0.3 mmol) in DCM (3 mL). The solution is stirred overnight, evaporated and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer is washed with brine, dried and evaporated. Purification by PTLC, eluting with a mixture of 5% MeOH and 1% TEA in DCM, affords the title compound. 1H NMR (CDCl3): 8.80 (s, 1H), 8.65 (s, 1H), 5.93 (s, 1H), 3.81 (s, 4H), 3.63-3.66 (m, 1H), 3.46 (s, 1H), 3.29 (t, 1H), 3.10-3.15 (m, 2H), 2.85-2.90 (m, 1H), 2.58 (s, 3H), 2.31 (s, 3H), 1.99 (s, 3H), 1.53-1.73 (m, 12H). MS (M+1)=479.37; RT=1.30 min. *IC50.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)O1.Br[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[O:33]1[CH2:34][CH2:35][N:30]([C:26]2[CH:25]=[C:24]([C:9]3[CH:10]=[C:11]4[C:16](=[N:17][CH:18]=3)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]4)[CH:29]=[N:28][CH:27]=2)[CH2:31][CH2:32]1
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C
Reactant: Brc1cncc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)N1CCCc2cc(-c3cncc(N4CCOCC4)c3)cnc21
Temperature: 90 °C

Procedure:
In a sealed tube which contains the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (generated according to the procedure for Step 3 of Example 16 in 5 ml 1,4-dioxane, 0.78 mmol) is added 4-(5-bromo-pyridin-3-yl)-morpholine (228 mg, 0.94 mmol), Na2CO3 (166 mg, 1.56 mmol) and water (1.0 ml). The mixture is bubbled with Argon for 5 min. Then PdCl2(DPPF) DCM complex (64 mg, 0.078 mmol) is added. The mixture is then bubbled with Argon for 5 min. The cap is sealed and the mixture is heated at 90° C. in oil bath for 1 h. The reaction mixture is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtrate is partitioned between water and DCM. The aqueous phase is extracted with DCM. The combined DCM phases are concentrated. The crude is purified by flash silica gel column (MeOH/DCM 0 to 4% gradient, then 4%). The fractions which contain the desired product are combined, concentrated and further purified by C-18 prep HPLC (MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 45% gradient over 10 min run). The desired fractions are combined and basified by 1N Na2CO3 to pH=10, and are extracted by DCM. The DCM phases are combined and concentrated under vacuum to obtain 60 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:34])[N:20]([CH2:22][CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH3:26])[N:21]=[C:8]2[N:7]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[C:6]=1[CH3:45])=[O:4].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:34])[N:20]([CH2:22][CH2:23][CH2:24][N:25]([S:54]([CH3:53])(=[O:56])=[O:55])[CH3:26])[N:21]=[C:8]2[N:7]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[C:6]=1[CH3:45])=[O:4]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCN(C)C(=O)OC(C)(C)C)c(=O)n2C1c1ccc(C#N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCN(C)S(C)(=O)=O)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of Intermediate 18 (0.12 g, 0.19 mmol) in DCM (2.5 mL) and TFA (0.25 mL) was added. The resulting mixture was stirred at RT for 1 hour and then evaporated in vacuo. The resulting residue was taken up in DCM (4 mL), and then triethylamine (105 μL, 0.75 mmol) added, followed by methanesulfonyl chloride (28 μL, 0.36 mmol). The reaction mixture was stirred at RT for 30 mins and then partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM as eluent to yield the title compound as a white solid (106 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)[C:22]#[N:23])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]>C1COCC1.CCO.[Pd]>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH2:20][CH:21]([C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)[C:22]#[N:23])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(-c2cccc(C=C(C#N)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1cc(-c2cccc(CC(C#N)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Reaction time: 72 h

Procedure:
A solution of the nitrile from Step 2 (400 mg, 0.88 mmol) in THF/EtOH (1:1, 10 mL) containing Pd/C (10%, 40 mg) was stirred under H2 (1 atm) for 3 days. Filtration on celite, evaporation, stirring vigorously in ether for 1 h then filtration afforded the 3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(4-methanesulfonyl-phenyl)-propionitrile compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12]([S:15][CH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](Cl)=[O:19])(=[O:14])[CH3:13]>C(=O)([O-])O.[Na+].O.O1CCCC1>[C:12]([S:15][CH2:16][CH:17]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:18]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[O:19])(=[O:14])[CH3:13]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cc(C(=O)O)ccc1C
Yield: 52.4 %

Procedure:
3-Amino-4-methylbenzoic acid (1.5 g) is dissolved in a solution of sodium hydrogen carbonate (1.68 g) in water (25 ml), and to the mixture is added dropwise a solution of 2-acetylthiomethyl-3-phenylpropionyl chloride (2.86 g) in tetrahydrofuran (8 ml) with vigorously stirring, and the mixture is stirred at room temperature for 3 hours. Tetrahydrofuran is distilled off at a low temperature under reduced pressure, and the residue is washed with diethyl ether and acidified with hydrochloric acid, and the resulting oily substance is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The oily residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure, and the precipitated crystals are separated by filtration to give the title compound (1.93 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[C:9]([C:27]([O:29][CH3:30])=[O:28])([CH2:10][N:11]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)=[O:15])[N:12]=3)[CH2:8][CH2:7][C:6]=2[CH:31]=1.C(Cl)Cl.Cl[S:36][N:37]([CH3:47])[C:38](=[O:46])[O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[C:9]([C:27]([O:29][CH3:30])=[O:28])([CH2:10][N:11]([C:14]([N:16]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=4)[S:36][N:37]([CH3:47])[C:38]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:46])=[O:15])[N:12]=3)[CH2:8][CH2:7][C:6]=2[CH:31]=1
Reactant: CCCCCCOC(=O)N(C)SCl
Reactant: COC(=O)C12CCc3cc(Cl)ccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCOC(=O)N(C)SN(C(=O)N1CC2(C(=O)OC)CCc3cc(Cl)ccc3C2=N1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of the title compound of Step E above (2.2 g, 0.005 mol) in25 ml methylene chloride cooled to 0° C. was added triethylamine (1.0 g) and hexyl (chlorosulfenyl)(methyl)carbamate, (prepared in a mannersimilar to Example 1, Step D), (2.5 g 75% pure) dropwise at 0° C. The mixture was stirred at room temperature for additional one hour. The reaction mixture was concentrated under high vacuum and subjected to silica gel column chromatography using hexane-ether (1:1) as an eluent. The title compound (2.5 g) was obtained, melting point 128°-129° C. in high purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=[O:11].CO.[Si](C=[N+]=[N-])(C)(C)[CH3:16].CCOCC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([O:12][CH3:16])=[O:11]
Reactant: O=C(O)Cc1c(F)cccc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-Difluorophenylacetic acid (2.61 g, 15.16 mmol) was taken up in THF (52 mL)/MeOH (13 mL). TMS-Diazomethane, 2 M in Et2O (8.5 mL, 17.00 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue purified by MPLC (2-20% EtOAc-hexanes) to give methyl 2,6-difluorophenylacetate as a colourless oil.