Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH:3]=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Br.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH:3]=1)[CH:21]1[O:23][CH2:22]1
Reactant: COC(=O)Cc1ccc(O)cc1OCC(F)(F)F
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(OCC2CO2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 4-hydroxy-2-(2,2,2-trifluoroethoxy)phenylacetate (0.60 g, 2.4 mmol) from Step 4 of Example 32 in DMF (7 mL) was added epibromohydrin (0.50 g, 3.6 mmol) and Cs2CO3 (1.55 g, 4.8 mmol). The mixture was stirred at ambient temperature for 3 h. EtOAc was added (15 mL) and the solid was removed by filtration. The filtrate solvents were removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give methyl 4-(glycidyloxy)-2-(2,2,2-trifluoroethoxy)-phenylacetate as a pale yellow oil (HPLC retention time=8.3 min (method A)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:23]2[CH2:27][CH:26]([CH2:28][OH:29])[O:25][C:24]2=[O:30])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([NH:14][C:15]2[N:16]=[N:17][N:18](COC)[CH:19]=2)=[CH:12][CH:13]=1.Cl>O1CCCC1>[NH:18]1[CH:19]=[C:15]([NH:14][C:11]2[N:10]=[CH:9][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:23]4[CH2:27][CH:26]([CH2:28][OH:29])[O:25][C:24]4=[O:30])=[CH:3][C:2]=3[F:1])=[CH:13][CH:12]=2)[N:16]=[N:17]1
Reactant: COCn1cc(Nc2ccc(-c3ccc(N4CC(CO)OC4=O)cc3F)cn2)nn1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1OC(CO)CN1c1ccc(-c2ccc(Nc3c[nH]nn3)nc2)c(F)c1

Procedure:
The crude 3-(3-fluoro-4-(6-((1-(methoxymethyl)-1H-1,2,3-triazol-4-yl)amino)pyridine-3-yl)phenyl)-5-(hydroxylmethyl)oxazolidin-2-one obtained in the last step was dissolved in 20 mL tetrahydrofuran. Into the solution were added 20 mL of 6 N hydrochloric acid and 4 mL of concentrated hydrochloric acid, and reacted and refluxed for 18 h. After concentration and chromatography on a silica gel column (CH3OH:CH2Cl2=1:50), a light yellow solid was obtained. Recrystallization from methanol yielded 70 mg of 3-(4-(6-((1H-1,2,3-triazol-4-yl)amino)pyridin-3-yl)-3-fluorophenyl)-5-(hydroxylmethyl)oxazolidin-2-one, at a yield over two steps of 16.9%.
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[N:18]1([CH2:24][CH2:25][NH:26][C:27]([NH:29][C:30]2[S:31][C:32]3[CH:38]=[C:37]([SH:39])[CH:36]=[CH:35][C:33]=3[N:34]=2)=[O:28])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[BH4-].[Na+]>C(N(CC)CC)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([S:39][C:37]4[CH:36]=[CH:35][C:33]5[N:34]=[C:30]([NH:29][C:27]([NH:26][CH2:25][CH2:24][N:18]6[CH2:23][CH2:22][O:21][CH2:20][CH2:19]6)=[O:28])[S:31][C:32]=5[CH:38]=4)=[N:3][N:4]=3)[N:7]=2)=[CH:12][CH:13]=1
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(S)cc2s1
Reactant: Fc1ccc(-c2ccc3nnc(Cl)n3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCOCC1)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1

Procedure:
The 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea was prepared according to the method described in Example 1a, but using 240 mg of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine, 338 mg of 1-(2-morpholin-4-ylethyl)-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea, 0.14 cm3 of triethylamine and 38 mg of sodium borohydride. The crude obtained is chromatographed on a Merck cartridge (30 g of silica 15-40 μm), elution being carried out with dichloromethane. 117 mg of 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea are thus recovered in the form of a beige solid, the characteristics of which are as follows:
Reaction SMILES: [OH-:1].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>CO>[Na+:2].[OH:15][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3])[CH2:11][CH2:12][C:13]([O-:14])=[O:1]
Reactant: [OH-]
Reactant: CCCCCCCC1CCC(=O)O1
Agent: [Na+]
Solvent: CO
Product: CCCCCCCC(O)CCC(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 43.6 g sodium hydroxide in 150 ml of methanol heated to reflux, 200 g gamma-undecalactone were dropped in. After stirring 2 hours at reflux, the mixture was cooled to room temperature and evaporated to dryness. The resulting crystals were washed with hexane to yield 240 g white crystals.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17](O)[NH:16][C:15]1=[O:22]>N1C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([Br:2])[NH:16][C:15]1=[O:22]
Reactant: BrP(Br)Br
Reactant: O=c1cc(O)[nH]c(=O)n1-c1c(Cl)cc(Cl)cc1Cl
Solvent: c1ccncc1
Product: O=c1cc(Br)[nH]c(=O)n1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 0 °C

Procedure:
10 ml of phosphorus tribromide was added dropwise to 0.60 g of pyridine with stirring at 0° C. and, after stirring this solution at 0° C. for 15 minutes, 1.6 g of the obtained 3-(2,4,6-trichlorophenyl)-6-hydroxy-2,4(1H,3H)-pyrimidinedione was added thereto. The mixed solution was stirred at 80° C. for 3 hours, then added into ice water and extracted with 100 ml of ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and then the solvent was distilled away under reduced pressure to form a crude product. This crude product was recrystallized from a mixed solvent of hexane and isopropyl ether to obtain 0.62 g of the objective compound.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH3:27][N:28]([CH3:43])[CH2:29][CH2:30][CH2:31]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:31][CH2:30][CH2:29][N:28]([CH3:43])[CH3:27])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 200 °C
Yield: 403.1 %

Procedure:
A 5 mL microwave vial was charged with Compound 157 (290 mg, 0.79 mmol), 3-(dimethylamino)propyl-4-methylbenzenesulfonate (224 mg, 0.87 mmol), potassium carbonate (218 mg, 1.58 mmol) and 2 mL of anhydrous DMF, under nitrogen atmosphere. The reaction mixture was heated at 200° C. for 30 min. in microwave with high absorption. The reaction was quenched with addition of water, and the solid precipitate out was collected by filtration and purified through preparative HPLC to provide title compound (1438 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.33 Hz, 3 H) 1.99 (qd, J=6.61, 6.44 Hz, 2 H) 2.20 (s, 6 H) 2.26 (s, 3 H) 2.53-2.56 (m, 2 H) 3.41 (q, J=7.33 Hz, 2 H) 4.25 (t, J=6.19 Hz, 2 H) 7.05-7.09 (m, 1 H) 7.11-7.14 (m, 1 H) 7.54 (d, J=1.52 Hz, 1 H) 7.85 (t, J=7.83 Hz, 1 H) 7.98 (t, J=6.95 Hz, 2 H) 8.06-8.08 (m, 1 H) 8.27 (d, J=1.77 Hz, 1 H) 12.13 (s, 1 H); [M+H] calc'd for C25H30N3O3S, 452.2; found, 452.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:24]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
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: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1nc(C)c2cc(Sc3ccccc3)ccc2c1O
Yield: 28.2 %

Procedure:
1-Bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid methyl ester (0.2 g), tetrakis(triphenylphosphine)palladium (60 mg), trimethyl boroxine (65 mg), and potassium carbonate in 1,4-dioxane (4 ml) were heated in a microwave reactor (sealed tube) for 10 min at 140° C. After cooling reaction mixture was concentrated and partitioned between 1 N hydrochloric acid and ethyl acetate. Organic layer dried over magnesium sulfate and filtered. Filtrate concentrated and separated by silica gel chromatography (eluting with 2% ethyl acetate in methylene chloride) to give the title compound (47 mg). MS-(+)-ion M+1=326.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7](Cl)(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>O.CCOCC>[C:7]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(=O)Cl
Reactant: NCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCC(=O)NCCC(=O)O

Procedure:
β-Alanine (20 mmol) was reacted with valeryl chloride (22 mmol) in the presence of NaOH (40 mmol) in a mixture of H2O and ether using the method described in Example 5. The crude crystalline product (2.75 g, 79%) was recrystallized from a mixture of isopropyl ether (150 ml) and ethyl acetate (10 ml) to give title acid (1.51 g, 44%), m.p. 73°-76° C.
Reaction SMILES: C(Cl)Cl.CCCCCCCCCCCCCCC[C:19]1[C:24](=[O:25])[N:23]([CH3:26])[C:21](=[O:22])[C:20]=1[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[CH:28]=1.[C:37](Cl)(=[O:44])C1C=CC=CC=1.[OH-].[Na+]>O>[CH3:36][N:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([C:20]2[C:21](=[O:22])[N:23]([CH3:26])[C:24](=[O:25])[C:19]=2[O:44][CH3:37])=[CH:28]1
Reactant: CCCCCCCCCCCCCCCC1=C(c2cn(C)c3ccccc23)C(=O)N(C)C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC1=C(c2cn(C)c3ccccc23)C(=O)N(C)C1=O
Reaction time: 4 h
Yield: 15.5 %

Procedure:
Into a methylene chloride (500 ml)/a triethylamine (11 g, 1.1 mol) was dissolved IM-7 (124.6 g, 1 mol). Benzoyl chloride (140.6 g, 1 mol) was added dropwise at room temperature. After the mixture was stirred for four hours, water (100 ml) and an aqueous 5% NaOH solution (50 ml) were added, then, the mixture was separated. After a methylene chloride layer was dried with magnesium sulfate, it was concentrated, then, distillated under a reduced pressure (150 to 160° C., 6 mmHg) to obtain 42 g of IM-8.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH2:18][O:19][C:20]3[CH:35]=[CH:34][C:23]4[O:24][CH2:25][C:26]5[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=5[CH:28]([SH:29])[C:22]=4[CH:21]=3)=[N:15]2)=[CH:10][CH:9]=1.Br[CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CC(C)=O>[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH2:18][O:19][C:20]3[CH:35]=[CH:34][C:23]4[O:24][CH2:25][C:26]5[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=5[CH:28]([S:29][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:22]=4[CH:21]=3)=[N:15]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCCBr
Reactant: SC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Yield: 67.6 %

Procedure:
0.43 g of potassium carbonate was added to 1 g of 2-(7-chloroquinolin-2-yl)methoxy-11-mercapto-6,11-dihydrodibenz[b,e]oxepine and 0.56 g of ethyl 4-bromobutanoate dissolved in 25 ml of acetone and the mixture was stirred under heating for 3 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was condensed under reduced pressure. The resulting residue was applied to silica gel column chromatography to obtain 0.86 g of 2-(7-chloroquinolin-2-yl)methoxy-11-(3-ethoxycarbonylpropylthio)-6,11-dihydrodibenz[b,e]oxepine as a brown oily product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]2[CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1.CC1C=CC2C=CC3C=C[C:32](C)=[N:33]C=3C=2N=1.CN>CN(C=O)C.C1COCC1.[Cu]I>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]2[C:5]3[CH:6]=[CH:7][C:2]([NH:33][CH3:32])=[CH:3][C:4]=3[O:21][CH:9]2[CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc2ccc3ccc(C)nc3c2n1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(I)cc3OC2C1
Agent: [Cu]I
Agent: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNc1ccc2c(c1)OC1CN(C(=O)OC(C)(C)C)CCC21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Anhydrous DMF was sparged with argon gas for 1 h before being used. Tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (1 g, 2.5 mmol) sodium tert-butoxide (723 mg, 7.5 mmol), neocuproine (52 mg, 0.25 mmol) and copper (I) iodide (290 mg, 1.5 mmol) were dissolved in anhydrous DMF (20 mL). To this mixture was added a 2M solution of methylamine in THF (6 mL) and the reaction shaken at 80° C. for 16 h. The solvent was evaporated and the residue dissolved in DCM and washed with H2O (3×). The solvent was evaporated and the crude residue used as such in the next reaction step.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:10]=2)[C:5]1=[O:21].O.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:10]=2)[C:5](=[O:21])[N:4]([CH3:3])[CH:13]=1
Reactant: BrBr
Reactant: Cc1ccc(-c2ccc3c(=O)n(C)ccc3c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2ccc3c(=O)n(C)cc(Br)c3c2)cn1
Temperature: 25 °C
Reaction time: 0.28 h
Yield: 67.2 %

Procedure:
Bromine (97 mg, 0.61 mmol) in acetic acid (0.61 mL) was added dropwise to 2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-1-one (160 mg, 0.64 mmol) in acetic acid (6 mL) at 0° C. After stirring at room temperature for 17 min, water (22 mL) was added and the pH was adjusted to 7-8 with 1M NaOH. Extractive work up with ethyl acetate and purification by silica gel chromatography (PE:EA=2:1 to 3:2) gave the title compound (135 mg, 64.3%) as a yellow solid. LCMS: 329.0 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.[Cl:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH2:30].C(N1CCOCC1)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH:30][C:4](=[O:6])[C@@H:3]1[CH2:7][CH2:8][C:9](=[O:10])[N:2]1[CH3:1]
Reactant: NCc1ccc(F)cc1Cl
Reactant: CN1C(=O)CC[C@H]1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1C(=O)CC[C@H]1C(=O)NCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
1-Methyl-5-oxo-proline (0.050 g, 0.35 mmol, prepared as described below) was dissolved in anhydrous dichloromethane (˜7 ml) and to this was added 1-hydroxybenzotriazole (0.047 g, 0.42 mmol), [(2-chloro-4-fluorophenyl)methyl]amine (0.056 ml, 0.42 mmol), N-ethyl morpholine (0.166 ml, 1.04 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.067 g, 0.42 mmol). The mixture was stirred at room temperature overnight. A further aliquot of [(2-chloro-4-fluorophenyl)methyl]amine (0.100 ml, 0.8 mmol) was added to the mixture and stirring continued for a while longer but HPLC indicated that no further product was forming. The mixture was washed sequentially with 2M aqueous hydrogen chloride (5 ml) and saturated aqueous sodium hydrogen carbonate (5 ml). The organic layer was collected and evaporated to give the crude product. The crude material was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-1-methyl-5-oxo-prolinamide (0.015 g) as a white solid. LC/MS [M+H]+=285, retention time=2.04 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C@H:7]([CH2:16][OH:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(O[C:22](=O)[CH:23]([C:25]#[N:26])[CH3:24])C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[C@H:7]([CH2:16][OH:17])[N:8]([CH2:22][CH:23]([C:25]#[N:26])[CH3:24])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(C)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C#N)CN(C(=O)OC(C)(C)C)[C@@H](CO)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a 100 mL flask with a Dean-Stark condenser and an argon inlet was added N-Boc-L-serine tert-butyl ester 2 (5.00 g, 19.1 mmol), ethyl-2-cyanopropionate (3.65 g, 28.7 mmol), p-toluenesulfonic acid monohydrate (0.200 g, 1.05 mmol) and anhydrous toluene (60 mL). The reaction mixture was heated to reflux while stirring. Solvent was removed through the Dean-Stark trap and replaced with an equal amount of fresh toluene. After refluxing for 6 h, the reaction mixture was cooled to room temperature. The solution was washed once with saturated aqueous NaHCO3, twice with H2O, and twice with saturated aqueous NaCl. The organic layer was separated, dried over anhydrous MgSO4, and concentrated to a viscous yellow oil. 1H NMR (CDCl3): δ 1.43 (m, 21H, CH3—CH—NH—, 2 (CH3)3), 3.25 (s, 1H, CH3-CH—CN), 3.85 (t, 2H, CO2, —CH2—CH—), 3.85 (t, 2H, CO2—CH2—CO2Bu), 4.25 (s, 1H, NH—CH—CH2—), 5.55 (d, 1H, NH). This material can be converted to the cyanoacrylic monomer by following the general procedure set forth above for the alanine-derived monomer.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:4][CH:3]=1.CC1C=CC=C(C)N=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>C(Cl)Cl>[C:32]([N:15]1[CH2:16][CH2:17][C@H:13]([O:12][C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=3)[CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=2)[CH2:14]1)(=[O:35])[CH:33]=[CH2:34]
Reactant: O=c1[nH]nc(-c2cc3ccc(Cl)cc3c(O[C@H]3CCNC3)n2)[nH]1
Reactant: C=CC(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(Cl)cc23)C1
Temperature: 0 °C
Yield: 18.6 %

Procedure:
To a mixture of (S)-3-(7-chloro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one (180 mg, 0.489 mmol) in DCM (10 mL) was added 2,6-dimethylpyridine (157 mg, 1.467 mmol) at −20° C. followed by the dropwise addition of acryloyl chloride (88 mg, 0.978 mmol, 10 mg/mL in dry DCM). The reaction mixture was warmed to 0° C. over a 30 minute period. The reaction was quenched with MeOH (5 mL) and the mixture concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (35 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.06 (br, 1H), 11.84 (s, 1H), 8.16 (s, 1H), 8.09 (dd, J=1.8 Hz and 8.9 Hz, 1H), 8.03 (s, 1H), 7.83-7.86 (m, 1H), 6.55-6.72 (m, 1H), 6.12-6.19 (m, 2H), 5.63-5.72 (m, 1H), 4.65-4.12 (m, 4H), 2.25-2.42 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N)cc(C(F)(F)F)c1
Yield: 95 %

Procedure:
A solution of methyl 3-nitro-5-(trifluoromethyl)benzoate (Reference Example 27, 24.6 g, 98.9 mmol) in ethanol (1500 mL) was sparged in a Parr bottle with nitrogen for 10 min. After this time, 10 wt % Pd/C (5.0 g, 5.0 mmol) was added and the reaction mixture was subjected to 40 psi of hydrogen on Parr shaker at room temperature for 1 h. After this time, the reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to provide Methyl 3-amino-5-(trifluoromethyl)benzoate (20.6 g, 95%) as a light purple oil.
Reaction SMILES: [O:1]=[C:2]([CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC1C=CC=CC=1)[C:3]([OH:5])=[O:4].C(Cl)C1C=CC=CC=1>C(#N)C>[C:14]1([CH2:6][C:2](=[O:1])[C:3]([OH:5])=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C(=O)C(Cc1ccccc1)c1ccccc1
Solvent: ClCc1ccccc1
Solvent: CC#N
Product: O=C(O)C(=O)Cc1ccccc1
Yield: 66 %

Procedure:
By the same operation as in Example 61 except that 6 ml of acetonitrile was used as the solvent, 2-oxo-3,4-diphenylbutanoic acid formed in a yield of 66 % by the reaction of 0.49 g (3 mmoles) of phenylpyruvic acid with 0.5 ml of benzyl chloride, as determined by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]2[N:13]=[C:12]([NH:14]C(=O)C)[CH:11]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:9]=2)[CH:7]=1.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1cc(Nc2ccc(C)cc2)cc(NC(C)=O)n1
Agent: NN
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(C)cc2)cc(N)n1
Yield: 44.9 %

Procedure:
To a solution of N-[6-(5-chloro-2-methoxy-phenyl)-4-p-tolylamino-pyridin-2-yl]-acetamide (15 mg, 0.039) prepared according to Example 5 in ethanol (4 ml) was added hydrazine (0.01 ml). After heating under reflux for 3 hours, the mixture was concentrated under reduced pressure. The residue was treated with water (40 ml) and extracted with ethyl acetate (50 ml). The organic extract was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (6 mg, 45% yield). 1H NMR (acetone-d6) δ 2.31 (s, 3H, CH3), 3.90 (s, 3H, CH3), 5.40 (s, 2H, NH2), 6.16 (t, 1H, J=2.0 Hz, Ar), 7.04 (bs, 1H, Ar), 7.09 (t, 1H, J=8.8 Hz, Ar), 7.17 (bs, 4H, Ar), 7.32 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.72 (s, 1H, NH), 7.93 (d, 1H, J=2.8 Hz, Ar).
Reaction SMILES: C([O:3][C:4](=[O:44])[CH:5]([C:10]1[CH:11]=[C:12]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][CH:31]=[CH:30]4)=[CH:25][CH:24]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][CH:35]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][CH:31]=[CH:30]4)=[CH:25][CH:24]=3)[CH2:17]2)[CH:15]=1)[C:4]([OH:44])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(-n4cccc4)cc3)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(-n4cccc4)cc3)C2)c1
Temperature: 78 °C

Procedure:
To compound 44a, 4-Methyl-2-{5-[1-(4-pyrrol-1-yl-benzyl)-piperidin-3-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl ester (56.2, 0.09 mmol) in EtOH (5 ml) was added 2M KOH (0.5 ml, 0.93 mmol). The reaction was heated to 78° C. for 1.5 hours, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, salt exchange with 1N HCl (aqueous) gave the product as a white lyophilate, (32 mg, 56% ). 1H NMR (300 MHz, MeOD) δ ppm 0.89-0.97 (m, 6 H) 1.50 (dt, J=13.28, 6.74 Hz, 1 H) 1.67 (dt, J=13.47, 6.64 Hz, 1 H) 1.89-2.03 (m, 3 H) 2.05-2.15 (m, 2 H) 3.06-3.22 (m, 2 H) 3.52-3.63 (m, 2 H) 3.76 (t, J=7.72 Hz, 1 H) 4.39 (d, J=2.64 Hz, 2 H) 6.29-6.33 (m, 2 H) 7.23-7.26 (m, 2 H) 7.33 (s, 1 H) 7.54 (d, J=19.97 Hz, 2 H) 7.61 (s, 4 H) 7.78 (q, J=8.41 Hz, 4 H), Calcd for C35H37F3N2O2 (M+H) 574.68, Found 575.4.