Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[CH2:39][NH2:40])=[CH:34][CH:33]=1>>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:40][CH2:39][CH:38]([C:35]2[CH:34]=[CH:33][C:32]([CH3:31])=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1ccc(C(CN)c2ccc(C)cc2)cc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(C)cc4)c4ccc(C)cc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The compound was prepared from (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (Preparation 45) and 2,2-bis(4-methylphenyl)ethanamine (J. Med. Chem., 1969, 12(1), 9) using a similar method to that of Preparation 64.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:6]=1.[H-].[Na+].Cl[C:18]([O:20][CH2:21][CH2:22]Cl)=[O:19].O>O1CCCC1>[O:19]=[C:18]1[N:1]([C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=3)[N:6]=2)[CH2:22][CH2:21][O:20]1
Reactant: N#Cc1ccc(-c2csc(N)n2)cc1
Reactant: O=C(Cl)OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2csc(N3CCOC3=O)n2)cc1
Reaction time: 1 h
Yield: 10 %

Procedure:
4-(2-Amino-thiazol-4-yl)-benzonitrile (1.5 g, 7.4 mmol), prepared in the previous step, in dry tetrahydrofuran (10 mL) was added dropwise to a suspension of sodium hydride (0.6 g, ˜15 mmol, 60% in oil) in dry tetrahydrofuran (10 mL) at room temperature. After 1 h, 2-chloroethyl chloroformate (0.83 mL, 8 mmol) was added dropwise and the mixture heated under reflux. After 16 h, the mixture was cooled, poured carefully into water, which was extracted with ethyl acetate. The organic layer was separated, dried (anhydrous Na2SO4), evaporated and the residue purified by silica gel column chromatography (ethyl acetate:hexane, 3:7) to afford the crude product. Recrystallization from ethanol gave the title compound (0.2 g, 10%), MS (ES) m/z 272 [M+H]+. HPLC 99.5% @ 210-370 nm, 99.3% @ 240 nm; RT=8.3 min, the Xterra® RP18 column, 3.5μ, 4.6×150 mm column 1.2 mL/min, 85/15-5/95 (Phos Buff. pH=2.1/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=O)[C:6]=2[CH:5]=[CH:4]1.[CH3:14][C:15]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[O:31])[CH3:30])([CH3:17])[CH3:16]>C(O)C.O>[CH3:17][C:15]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[O:31])[CH:30]=[CH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][NH:3]2)([CH3:14])[CH3:16]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(=O)c1ccccc1OCCCNC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NCCCOc1ccccc1C(=O)C=Cc1cccc2[nH]ccc12
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
3 ml of 50% sodium hydroxide solution and then 1.484 g of indole-4-carboxaldehyde were added to a solution of 2.55 g of 1-[2-{3-(1,1-dimethylethylamino)-propoxy}-phenyl]-ethanone in 35 ml of ethanol and the mixture was stirred under an inert atmosphere for 20 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over a deshydrant, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 2.804 g of 1-[2-{3-(1,1-dimethylethylamino)-propoxy}-phenyl]-3-[1H-indol-4-yl]-2-propen-1-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:41]=[CH:42][CH:43]=2)[C:22]([C:24]2[C:34](C3C=CC=CC=3)=CC=C[C:25]=2[NH:26]C(=C)C#N)=[O:23])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)C.O>[NH2:26][C:25]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:34][C:24]=1[C:22](=[O:23])[C:21]1[CH:41]=[CH:42][CH:43]=[C:19]([O:18][CH2:17][CH2:16][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:20]=1
Reactant: NNc1ccc(F)cc1
Reactant: C=C(C#N)Nc1cccc(-c2ccccc2)c1C(=O)c1cccc(OCCN2CCOCC2)c1
Solvent: O
Solvent: CCO
Product: Nc1c(C(=O)c2cccc(OCCN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4-fluorophenylhydrazine (1.0 g, 6.8 mmol) and 2-[3-(2-morpholin-4-ylethoxy)-benzoyl]-3-phenylamlinoacrylonitrile (2.0 g, 5.3 mmol) in ethanol (30 ml) was heated at reflux under a nitrogen atmosphere. After 6 h, the reaction mixture was cooled to room temperature and diluted with water. The product was extracted into ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (elution gradient: CH2Cl2-3%MeOH/CH2Cl2) gave 5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole which was converted to the hydrochloride salt (0.7 g, mpt. 191.6-192.5° C.).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:50][O:51][C:52](=[O:65])[CH2:53][CH2:54][NH:55][C:56](=[O:64])[C:57]1[CH:62]=[CH:61][C:60](O)=[CH:59][CH:58]=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:50][O:51][C:52](=[O:65])[CH2:53][CH2:54][NH:55][C:56](=[O:64])[C:57]1[CH:62]=[CH:61][C:60]([O:16][CH2:15][C:12]2[CH:13]=[N:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:59][CH:58]=1
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCNC(=O)c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (120 mg, 0.47 mmol) in THF (2 mL) and toluene (4 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 179.5 mg, 0.71 mmol) at 0° C., followed by the addition of tributylphosphine (0.18 mL, 0.71 mmol) and 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (127 mg, 0.57 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 3-{4-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-benzoylamino}-propionic acid methyl ester. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 3-{4-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-benzoylamino}-propionic acid (33 mg). MS (ES): 443.2 [M+H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:27])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[NH:23])[CH2:16][CH2:17][C:12]=3[C:11]([C:28]([F:31])([F:30])[F:29])=[N:10]2)=[CH:5][CH:4]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:26][N:24]([CH3:25])[C:22](=[N:23][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:21][CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:28]([F:31])([F:29])[F:30])=[N:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[C:14]1=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC(=N)N(C)C)CC3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC(=NS(C)(=O)=O)N(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
5-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-N,N-dimethyl-pentanamidine (0.050 g, 0.114 mmol) was dissolved in methylene chloride (10 mL). Methanesulfonyl chloride (0.1 mL, excess) and triethylamine (0.3, excess) were added to the reaction. The reaction was stirred at rt overnight, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes as the eluent followed by a methanol flush. Further purification by reverse phase HPLC and freeze-drying afforded the title compound (0.120 g, 74%): 1H NMR (CHCl3) δ 7.44 (d, j=8.7 Hz, 2H), 6.95 (d, j=8.8 Hz, 2H), 3.84 (s, 3H), 3.69 (t, j=7.0 Hz, 2H), 3.52 (t, j=6.3 Hz, 2H), 3.03 (s, 3H), 3.00(s, 3H), 2.99 (s, 3H), 3.14–2.98 (m, 2H), 2.89 (t, j=7.7 Hz, 2H), 1.75–1.62 (m, 2H) ppm; Mass Spec 516.3(M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])O[C:7](=[O:12])[C:6]=2[CH:13]=1.Cl.[NH2:15][CH:16](C)[C:17](OC)=O>N1C=CC=CC=1>[CH3:17][CH:16]1[NH:15][C:7](=[O:12])[C:6]2[CH:13]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[NH:10][C:9]1=[O:11]
Reactant: COC(=O)C(C)N
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)C(=O)NC(C)C(=O)N2
Temperature: -10 °C
Yield: 50.5 %

Procedure:
A mixture of 17.7 parts of 6-methyl-4H-3,1-benzoxazine-2,4(1H)-dione, 15.0 parts of methyl 2-aminopropanoate monohydrochloride and 62.7 parts of pyridine was refluxed for 6 hours under argon. The reaction mixture was cooled at −10° C. for 1 hour. The precipitate was filtered off, rinsed with water, triturated in ethanol and rinsed with ethanol and 1,1′-oxybisethane, yielding 10.32 parts (50.5%) of 3,4-dihydro-3,7-dimethyl-1H-1,4-benzodiazepine-2,5-dione (interm. 43).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[N:3]=1.[F:23][C:24]([F:30])([F:29])[CH2:25][N:26]=[C:27]=[S:28]>C(#N)C>[F:23][C:24]([F:30])([F:29])[CH2:25][NH:26][C:27](=[S:28])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:13](=[O:22])[C:14]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]3[C:16]2=[O:17])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1ccnc(CCCCN2C(=O)c3ccccc3C2=O)n1
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 69.8 %

Procedure:
A mixture of 4-amino-2-(4-phthalimidobutyl)pyrimidine (1 g.), 2,2,2-trifluoroethylisothiocyanate (1 g.) and acetonitrile was stirred at 70° for 18 hours. The mixture was diluted with acetonitrile (10 ml.), cooled in ice and then filtered to give 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobutyl)pyrimidine (1.03 g.), m.p. 204°-205°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH:10]([C:14]([O:27][CH2:28][CH2:29][NH:30]C(OCC2C=CC=CC=2)=O)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])[N:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH:10]([C:14]([O:27][CH2:28][CH2:29][NH2:30])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])[N:3]=1
Reactant: [H][H]
Reactant: Cc1cc(C)nc(OC(C(=O)O)C(OCCNC(=O)OCc2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)nc(OC(C(=O)O)C(OCCN)(c2ccccc2)c2ccccc2)n1

Procedure:
A solution of 13.1 g (24.2 mmol) of 2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-benzyloxycarbonylaminoethoxy)-3,3-diphenylpropionic acid in 200 ml of methanol was hydrogenated with hydrogen overnight, under atmospheric pressure and at room temperature, using 800 mg of palladium on activated carbon (10%). The reaction mixture was diluted with methanol to dissolve precipitated product, filtered and concentrated. Yield: 9.6 g of a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:19]=O)=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]=2[C:7]1=[O:21])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCCC1>C(O)C>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:19]=[C:28]3[C:27]4[C:31](=[CH:32][CH:33]=[C:25]([F:24])[CH:26]=4)[NH:30][C:29]3=[O:34])=[C:14]([C:15]([F:16])([F:18])[F:17])[C:8]=2[C:7]1=[O:21])[CH3:23]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C(F)(F)F)c2C1=O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C(F)(F)F)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A stirred solution of 5-(2-diethylamino-ethyl)-3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (40 mg, 0.121 mmol), 5-fluoro-1,3-dihydro-indol-2-one (18 mg, 0.12 mmol) in 0.4 ml of ethanol was added dropwise with anhydrous piperidine (0.1 ml). The mixture was stirred at room temperature overnight. The resulting solid was filtered under reduced pressure, washed with anhydrous ethanol (1 ml×3), purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-trifluoromethyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (46 mg, 83.6%) as a yellow solid
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=1)C.[NH3:20]>C1COCC1>[NH2:20][C:11]1[N:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:19])[CH:14]=[CH:13][N:12]=1
Reactant: CCOC(=O)CCCCc1ccnc(S(C)(=O)=O)n1
Reactant: N
Solvent: C1CCOC1
Product: Nc1nccc(CCCCC(=O)O)n1
Reaction time: 4 h

Procedure:
A solution of 26-4 (0.19 g, 0.67 mmol) in THF (5 mL) was cooled to 0° and saturated with NH3 gas. The mixture was stirred at 0° for 4 h, then evaporated and the residue partitioned between EtOAc and sat. NaHCO3. The organic layer was dried filtered and concentrated to give the amino ester 26-5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:15]=[C:16]([CH:24]=[CH:25][C:26]=3[Cl:27])[CH2:17][NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:27][C:26]1[CH:25]=[CH:24][C:16]([CH2:17][NH:18][C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])=[CH:15][C:14]=1[C:10]1[NH:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:33]([CH:30]3[CH2:32][CH2:31]3)=[O:34])=[C:3]([O:28][CH3:29])[CH:4]=2)[N:9]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1NC(=O)C1CC1
Yield: 25.9 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using N-(3-(1-(4-amino-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)cyclopropanecarboxamide (Intermediate-37, 0.050 g, 0.120 mmol), cyclopropylcarbonyl chloride (0.018 g, 0.180 mmol), DIPEA (2.0 mL) and THF (5 mL) to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (s, 4H), 0.77 (s, 4H), 1.60 (m, 1H), 2.08 (m, 1H), 3.88 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.45 (m, 2H), 7.62 (s, 2H), 7.96 (d, J=8.4 Hz, 1H), 8.69 (m, 1H), 9.49 (s, 1H), 12.54 (s, 1H); MS (m/z): 482.10 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>>[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][CH2:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH2:5][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([CH3:13])=[CH:11][CH:10]=2)=[CH:11][CH:10]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cc1ccc(CCl)cc1
Product: Cc1ccc(CCC(=O)CC(=O)CCc2ccc(C)cc2)cc1

Procedure:
Using 2,4-pentandione (195.2 g, 1.95 moles) and 4-methylbenzylchloride (635.4 g), the reaction was carried out in the same manner as described in Example 17, (1), and the residue (568 g) was recrystallized from ethanol to afford the title compound as a white needles which was an ca 1:9 mixture of Keto/Enol as seen by the methylene singlet at δ3.50 ppm and the methine singlet at δ5.43 ppm in the 1HNMR spectrum; yield: 155 g; mp 74.8°-75.7° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25])[C:12]=2[N:13]=[CH:14][N:15]=1.O>C(Cl)Cl>[Cl:9][C:10]1[C:11]2[C:18]([Cl:1])=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CC(=O)OCCOCn1ccc2c(Cl)ncnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCOCn1cc(Cl)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 192 h

Procedure:
N-Chlorosuccinimide was added to a solution of 4-chloro-7-(2-acetoxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (3) (0.35 g) in dry methylene chloride (15 mL). The reaction mixture was stirred at room temperature for 8 days. At that time, TLC established a complete disappearance of starting material. Water (50 mL) was added to the mixture and the product was extracted with CHCL3 (3×30 mL). The chloroform extracts were combined and washed with water, then dried over anhydrous Na2SO4. The solvent was removed at 40 degrees C in vacuo and the resulting thick syrup was subjected to column chromatography. Elution of the silica gel column (15×2 cm) with benzene: chloroform (1:1), yielded a colorless oil (single spot on TLC) after evaporation of all the UV absorbing fractions at a reduced temperature and pressure, which was crystallized from ethyl alcohol to afford colorless needles of the acetylated intermediate, (7a, 0.23 g) (59.95%). 4,5-Dichloro-7-(2-acetoxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (7a, 0.31 g) was then dissolved in dry methanol (15 mL) and to this solution was added methanol which had previously been saturated with ammonia at 0 degrees C. (25 mL). The reaction mixture was stirred in a pressure bottle at room temperature for 20 hours. The solvent was evaporated at 30 degrees C. in vacuo and the semi-solid mass was subjected to column chromatography. Elution of the product from a silica gel column (15×2 cm) with 2% MeOH in CHCl3 yielded a colorless compound, after evaporation of all the appropriate UV absorbing fractions. This solid was recrystallized from MeOH to furnish 0.11 g of 7. (40.74%), mp 142-143 degrees C.
Reaction SMILES: O.C[O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][CH2:30]2)[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)=[CH:7][CH:6]=1.FC(C1C=C(C=C(C(F)(F)F)C=1)COCC(C1C=CC(C(OC)=O)=CC=1)[N:51]1CCN(CC(O)=O)CC1)(F)F.N>CO>[F:28][C:25]([F:26])([F:27])[C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=1)[CH2:14][O:13][CH2:12][CH:11]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][CH2:30]1)[C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:3])[NH2:51])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)N2CCN(CC(=O)O)CC2)cc1
Agent: N
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)N2CCN(CC(=O)O)CC2)cc1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
In a small autoclave, 1.5 g (2.73 mmoles) of 4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-carboxymethyl-piperazin-1-yl)-ethyl]-benzoic acid methyl ester (compound 318) were dissolved in methanol. The solution was saturated with NH3 and heated at 100° C. for three days. Methanol was then evaporated and the crude product was purified by chromatography (eluent: CH2Cl2/MeOH/NH3: 80/20/0.5 v/v/v) to give 880 mg of {4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-carbamoyl-phenyl)-ethyl]-piperazin-1-yl}-acetic acid (compound 321) as a grey solid. 4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-carbamoylmethyl-piperazin-1-yl)-ethyl]-benzamide (compound 322) was isolated as a side product (150 mg).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]=2[CH:16]=1)(=[O:5])=[O:4].[Br:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.S(=O)(=O)(O)O>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([Br:17])[C:9]2[O:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:16]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)C(C)(C)CO2
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)c1cc(Br)c2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
To a solution of 3,3-dimethyl-2,3-dihydro-benzofuran-5-sulfonic acid methylamide (215 mg, 0.89 mmol) in trifluoroacetic acid (5 mL) and sulfuric acid (1 mL) was added portionwise N-bromosuccinimide (317 mg, 1.78 mmol). The mixture was stirred at room temperature overnight, poured into a solution of ice-water and rinsed with dichloromethane. The layers were separated. The aqueous layer was extracted twice with dichloromethane and the organic combined extract was washed with water, an aqueous solution of sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (30% ethyl acetate in hexane) to afford 91 mg of 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-sulfonic acid methylamide. 32% yield. 1H-NMR (300 MHz, CDCl3): 1.40 (s, 6H), 2.68 (d, J=5.3 Hz, 3H), 4.21 (m, 1H), 4.45 (s, 2H), 7.52 (d, J=1.8 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:3]([N:10]([CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(CNCCCSc2ccncc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N(CCCSc1ccncc1)Cc1ccccc1
Yield: 50.2 %

Procedure:
To a solution of 400 mg (1.21 mmol) of 4-[3-(N-benzylamino)propylthio] pyridine dihydrochloride and 0.55 ml (4.00 mmol) of triethylamine in 5 ml of methylene chloride, 0.17 ml (1.45 mmol) of benzoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 0.22 g of the desired compound (yield: 50.4%, yellow oil).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8](O)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:20]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([Cl:20])[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cccc(C(O)c2cccc(Br)n2)c1
Solvent: ClCCl
Product: N#Cc1cccc(C(Cl)c2cccc(Br)n2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-[(6-bromopyridin-2-yl)(hydroxy)methyl]benzonitrile (4.88 g, 16.88 mmol) in CH2Cl2 (60 mL) @ 0° C. under N2 was added SOCl2 (2.01 mL, 16.88 mmol). The mixture was warmed to rt and stirred for 48 hr. The mixture was cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate and extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (25-50% CH2Cl2 in Hexanes) to give 3-[(6-bromopyridin-2-yl)(chloro)methyl]benzonitrile. LRMS m/z (M+H) Calcd.: 307.0, found: 307.0.