Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of 1H-Imidazole-4-carboxylic acid methyl ester (1.0 g, 7.93 mmol) in N,N-dimethylformamide at 25° C. was treated with triethylamine (2.2 mL, 15.86 mmol) and triphenylmethylchloride (2.43 g, 8.72 mmol). The reaction was stirred at 25° C. for 8 h and then concentrated in vacuo. The residue was diluted with ethyl acetate and then washed with water, a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50:50 ethyl acetate/petroleum ether) afforded 1-trityl-1H-imidazole-4-carboxylic acid methyl ester (2.88 g, 98.6%) as a white foam: 1H NMR (DMSO-d6, 300 MHz) δ7.56 (s, 1H), 7.47 (m, 10H), 7.09 (m, 6H), 3.69 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:11][N:12]([CH3:21])[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[C:37]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:11][N:12]([CH3:21])[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:7]1)(=[O:39])[CH3:38]
Reactant: CN(CC(CCN1CCC(N)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of N-[4-(4-aminopiperidino)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide (1.5 g) in dichloromethane (35 mL) was added triethylamine (0.60 mL) and acetic anhydride (0.41 mL), and the resulting solution was allowed to stir for 30 minutes. The mixture was diluted with dichloromethane and was washed (0.3N sodium hydroxide, water), dried, and evaporated. The material was dissolved in toluene and the resulting solution was evaporated to give the title compound (1.63 g) as a white solid; MS: m/z=476(M+1). Analysis for C25H31Cl2N3O2 ·0.2 C6H5CH3 : Calculated: C, 64.07; H, 6.63; N, 8.49; Found: C, 64.04; H, 6.59; N, 8.32.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)([OH:18])N.Cl([O-])=O.[Na+]>C1COCC1.O>[C:1]1([C:7]2([CH2:13][C:14]([OH:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)O
Reactant: O=CCC1(c2ccccc2)CCCCO1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1(c2ccccc2)CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-phenyltetrahydro-2H-pyran-2-yl)acetaldehyde (100 mg, 0.490 mmol) and sulfamic acid (57.0 mg, 0.587 mmol) in THF (1.5 mL) was added a solution of sodium chlorite (53.1 mg, 0.587 mmol) in water (1.5 mL) dropwise, and the mixture was stirred at room temperature for 3 hrs. Then the product was extracted with EtOAc (3×) and the combined extracts were washed with brine, dried over Na2SO4, and evaporated to give 2-(2-phenyltetrahydro-2H-pyran-2-yl)acetic acid as oil. LC/MS: m/e 221.14 (M+H)+.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:20]([F:21])=[CH:19][N:18]=[C:17]([Cl:22])[N:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:23]I>CN(C=O)C>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:23])[C:15]1[C:20]([F:21])=[CH:19][N:18]=[C:17]([Cl:22])[N:16]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1nc(Cl)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCO[Si](C)(C)C(C)(C)C)c1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
Sodium hydride (0.4 g, 16.76 mmol) was added to a solution of N-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-chloro-5-fluoro-4-pyrimidinamine (Example 81, 2.68 g, 8.38 mmol) in DMF (41.90 mL). The resulting mixture was stirred at rt for 30 minutes. Methyl iodide (2.09 mL, 33.51 mmol) was added. The mixture was stirred at rt for additional 18 h, then quenched with water, and extracted with ether. The combined ether extracts were washed with water (25 mL), brine (40 mL), dried over magnesium sulfate, filtered, and concentrated. The title compound (2.76 g, 99%) was obtained after column chromatography (67% hexanes in EtOAc). 1H NMR (300 MHz, CD2Cl2) δ 7.78 (d, 1H), 3.64-3.59 (m, 4H), 3.24 (d, 3H), 1.82-1.73 (m, 2H), 0.84 (s, 9H), 0.001 (s, 6H).
Reaction SMILES: [C:1]1([CH:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Br:25][C:26]([CH2:28]Br)=[CH2:27]>C1COCC1>[C:1]1([C:7]2([CH2:28][C:26]([Br:25])=[CH2:27])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(Br)CBr
Reactant: c1ccc(C2c3ccccc3-c3ccccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(Br)CC1(c2ccccc2)c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 9-phenylfluorene in anhydrous THF is cooled to -78° C. under a nitrogen atmosphere. A solution of nBuLi in hexanes (1 eq) is added dropwise via syringe. After stirring at -78° C. for 10 min a solution of 2,3-dibromopropene (1.2eq) in THF is added dropwise via syringe. The solution is stirred at -78° C. for 1 h and then allowed to warm to room temperature. The reaction mixture is quenched by the addition of sat. aq NH4Cl. The resulting mixture is extracted with ether. The organic layer is washed with H2O and then brine, dried (Na2SO4), and concentrated in vacuo. The concentrate is purified by flash chromatography on silica gel eluting with hexanes-ethyl acetate to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: O=Cc1ccccc1Br
Reactant: NCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: OCCCNCc1ccccc1Br

Procedure:
To a stirring solution of 2-bromobenzaldehyde in dichloroethane (0.4 M) at RT under nitrogen was added 3-aminopropanol (1.5 eq), sodium triacetoxyborohydride (2 eq), and acetic acid (4 eq). After 5 hr the reaction was carefully quenched with 2M sodium carbonate and extracted with methylene chloride. The organic phase was extracted with 1N hydrochloric acid. The aqueous phase was neutralized with 1N sodium hydroxide and extracted with methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. EI-MS m/z 245 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11](O)=[O:12])=[C:9]([CH3:14])[N:8]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:6]=2[N:7]=1.ON1C2C=CC=CC=2N=N1.Cl.C(C(N=C=NCCCN(C)C)C)C.C(N(CC)CC)C.[NH2:54][CH2:55][C:56]1[C:57]([OH:64])=[N:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:54][CH2:55][C:56]3[C:57]([OH:64])=[N:58][C:59]([CH3:63])=[CH:60][C:61]=3[CH3:62])=[O:12])=[C:9]([CH3:14])[N:8]([C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1c(C(=O)O)c2cnc(Cl)nc2n1[C@H](C)c1ccccc1
Agent: CCC(C)N=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a solution of (R)-2-chloro-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (100 mg, 0.32 mmol) in dichloromethane (10 mL) was added with 1-hydroxybenzotriazole (65 mg, 0.48 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)ethyl-carbodiimide hydrochloride (92 mg, 0.48 mmol) and triethylamine (97 mg, 0.96 mmol). After stirred for 30 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (49 mg, 0.32 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. The solution was concentrated, diluted with water (20 mL), extracted with ethyl acetate (20 mL). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (100 mg, 70%). LRMS (M+H+) m/z: calcd 449.16. found 449.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([CH3:19])=[CH:13][C:10]=1[CH:11]=O>CCO.Cl>[CH3:18][O:17][C:15]1[C:14]([CH3:19])=[CH:13][C:10]([CH:11]=[C:3]2[C:4](=[O:7])[C:5](=[CH:11][C:10]3[CH:13]=[C:14]([CH3:19])[C:15]([O:17][CH3:18])=[CH:16][C:9]=3[CH3:8])[CH2:6][O:1][CH2:2]2)=[C:9]([CH3:8])[CH:16]=1
Reactant: O=C1CCOCC1
Reactant: COc1cc(C)c(C=O)cc1C
Agent: Cl
Solvent: CCO
Product: COc1cc(C)c(C=C2COCC(=Cc3cc(C)c(OC)cc3C)C2=O)cc1C
Reaction time: 24 h
Yield: 38.9 %

Procedure:
A solution of 7.0 g (0.07 mole) of tetrahydro-4H-pyran-4-one and 25.2 g (0.15 mole) of 2,5-dimethyl-p-anisaldehyde in 75 ml of EtOH and 10 ml of concentrated HCl is stirred and heated at reflux for 3 hours. The resulting mixture is kept at room temperature for 24 hours, yielding 10.7 g (39%) of yellow solid, m.p. 182°-184°.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1.[CH3:15][NH2:16]>C(O)C>[CH3:14][C:4]1[N:3]=[C:2]([NH:16][CH3:15])[N:10]=[C:9]2[C:5]=1[NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2
Reactant: CCCc1nc2nc(Cl)nc(C)c2[nH]1
Reactant: CN
Solvent: CCO
Product: CCCc1nc2nc(NC)nc(C)c2[nH]1
Temperature: 110 °C

Procedure:
To a solution of 2-Chloro-6-methyl-8-propylpurine (from Step 1 of Example 32) (0.1 g, 0.47 mmol) in ethanol (2 ml) was added condensed methylamine (1 ml) at -20° C. The mixture was then placed in a steel-bomb and heated at 110° C. for 7 hours. The reaction was cooled and the mixture was concentrated in vacuo. The residue was partitioned between CHCl3 and water, and the organic layer was separated and dried over MgSO4. The crude product obtained after removal of the solvent was purified by flash-chromatography on silica-gel using 5% MeOH in CHCl3 giving the titled compound as an amorphous solid (0.115 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[O:9]([CH2:16][CH:17]([OH:23])[CH2:18][NH:19][CH2:20][CH2:21][NH2:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[O:9]([CH2:16][CH:17]([OH:23])[CH2:18][NH:19][CH2:20][CH2:21][NH:22][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NCCNCC(O)COc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: OC(CNCCNc1ccc(Cl)nn1)COc1ccccc1

Procedure:
A mixture of 3.0 g. 3,6-dichloropyridazine, 4.2 g. 1-phenoxy-3-(2-aminoethylamino)-propan-2-ol, 3.5 ml. N-ethyldiisopropylamine and 30 ml. toluene is stirred for 24 hours at 100° C. The reaction mixture is then evaporated and the residue is digested simultaneously with 100 ml. water and 100 ml. methylene chloride, followed by suction filtration and recrystallization from isopropyl alcohol, with treatment with fullers' earth. There are obtained 1.4 g. (21% of theory) of the desired product in the form of colorless crystals; m.p. 147°-149° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[S:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:11][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1csc(CN2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1csc(CN2CCNCC2)n1
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Tert-butyl 4-((4-(tert-butylcarbamoyl)thiazol-2-yl)methyl)piperazine-1-carboxylate (2.1 g, 5.49 mmol) was dissolved in dichloromethane (20 mL). 2,2,2-Trifluoracetic acid (20 mL) was added and the reaction mixture was stirred for 2 hours. The reaction was concentrated under reduced pressure and purified by SCX column chromatography to give the title compound (1.28 g). MS (ESI) m/z 283.4 [M+H]+
Reaction SMILES: [OH:1][C@@H:2]([CH2:22][OH:23])[C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C=O)C>[Si:29]([O:23][CH2:22][C@H:2]([OH:1])[C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
tert-Butyl (1R,2R)-2,3-dihydroxy-1-(4-(trifluoromethyl)phenyl)-propylcarbamate (11 g, 32.8 mol) in 100 mL DMF was cooled in an ice-water bath. 1H-imidazole (8.2 mL, 72 mol) was added in one portion, and the mixture was stirred for 10 minutes under nitrogen. tert-Butyldimethylsilylchloride (5.43 g, 36.0 mmol) in 20 mL DMF was then added via syringe. The reaction was monitored by TLC. After 16 hours, DMF was evaporated under high vacuum. Distilled water (150 mL) was added, and the resulting mixture was extracted into diethyl ether (2×200 mL). The ether layer was washed with saturated aqueous ammonia chloride and dried over sodium sulfate. After removing the solvent, the product was obtained as a white solid (14.0 g, yield=95%). 1H NMR (400 MHz, CD3OD) δ ppm 0.08-0.12 (m, 6 H) 0.97 (s, 9 H) 1.43 (s, 9 H) 3.50 (s, 1H) 3.63 (s, 1H) 3.85 (s, 1H) 4.81 (s, 1H) 7.53-7.58 (m, 2H) 7.60-7.66 (m, 2H).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[SH:10].[F:11][C:12]([F:18])=[C:13]([F:17])[CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:12]([F:18])=[C:13]([F:17])[CH2:14][CH2:15][S:10][C:2]1[S:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2
Reactant: Sc1nc2ncccc2s1
Reactant: FC(F)=C(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)=C(F)CCSc1nc2ncccc2s1
Temperature: 60 °C
Reaction time: 24 h
Yield: 87.1 %

Procedure:
A solution of thiazolo[4,5-b]pyridine-2-thiol (6.2 g, 0.037 mol) in N,N-dimethylformamide under nitrogen is treated with 1,1,2-trifluoro-4-bromobutene (8.3 g, 0.046 mol) and potassium carbonate (1.5 g), heated to and stirred at 60° C. for 24 hours, cooled, and poured into water. The resultant aqueous mixture is extracted with diethyl ether. The organic extract is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and a 9:1 hexanes/ethyl acetate solution gives the title product as a colorless oil (8.9 g, 64% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[ClH:25].Cl.FC1C=C(NC(NC(=O)CC2C=CC=CC=2F)=S)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.[CH3:64][O:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[CH2:72][C:73]([N:75]=[C:76]=[S:77])=[O:74]>>[ClH:25].[ClH:25].[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:76]([NH:75][C:73](=[O:74])[CH2:72][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=2[O:65][CH3:64])=[S:77])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: COc1ccccc1CC(=O)N=C=S
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: Cl
Agent: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4F)cc3F)c2s1
Product: COc1ccccc1CC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1

Procedure:
Starting from the compound 219, following the procedure described above for the synthesis of 303a (example 232) but replacing 2-(2-fluorophenyl)acetyl isothiocyanate with 2-(2-methoxyphenyl)acetyl isothiocyanate, title compound 303b was obtained in 44% as an off-white solid. 1H NMR (d-DMSO) δ (ppm): 12.55 (s, 1H), 11.73(s, 1H), 8.62(m, 1H), 8.09(m, 1H), 7.65(s, 1H), 7.57(m, 1H), 7.43(s, 1H), 7.27-7.20(m, 1H), 6.98(d, 1H, J=8.2 Hz), 6.90(dt, 1H, J1=1.0 Hz, J2=7.4 Hz), 6.79(m, 1H), 4.02(s, 3H), 3.81(s, 2H), 3.77(s, 3H). MS (m/z): 548.3(M+H) (found).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]4[C@H:25]([CH3:26])[CH2:24][C@@H:23]([OH:27])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OC[CH2:49][C:50]([F:53])([F:52])[F:51])(=O)=O>CC(C)=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[CH2:49][C:50]([F:53])([F:52])[F:51])[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:18]4[C@H:25]([CH3:26])[CH2:24][C@@H:23]([OH:27])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:4][CH:3]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4)CC3)c21
Reactant: O=S(=O)(OCCC(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4CC(F)(F)F)CC3)c21

Procedure:
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone (28 mg, 0.53 mmol; see Example 3) was slurried in acetone (0.4 mL) and treated with diisopropylethylamine (0.032 mL, 0.18 mmol), 4-dimethylaminopyridine (“DMAP”; 0.0006 g, 0.005 mmol) and 3,3,3-trifluoropropyl trifluoromethanesulfonate (0.016 g, 0.066 mmol). The reaction mixture was heated to reflux for 9 hours. Additional 3,3,3-trifluoropropyl trifluoromethanesulfonate (0.016 g, 0.066 mmol) was added and the mixture was heated at reflux for 16 hours. The reaction was concentrated using N2 (g) and chromatographed on SiO2 eluting with 2% MeOH/methylene chloride. After chromatography, the product was dissolved in ethyl acetate and washed 3 times with saturated NH4Cl, once with saturated NaHCO3, once with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The residue was concentrated from dioxane, treated with 4M HCl in dioxane (2 mL) and concentrated in vacuo. The salt was redissolved in MeOH and re-concentrated three times. The salt was dissolved in a minimal amount of MeOH and added dropwise to Et2O. The salt was filtered and washed with Et2O then dried under vacuum (12.8 mg, 39%). MS (ESI+) [M+H] 538.2/540.1. 1H NMR (CD3OD, 400 MHz) δ □8.58 (s, 1H), 7.47-7.36 (m, 4H), 5.31 (t, 1H), 4.48-3.96 (m, 3H), 3.91-3.44 (m, 7H), 2.35-2.27 (m, 1H), 2.23-2.13 (m, 1H), 2.05-1.88 (m, 2H), 1.84-1.71 (m, 1H), 1.68-1.56 (m, 1H), 1.19 (d, 3H).
Reaction SMILES: C[O-].[Na+].[C:4]([O:11]C)(=O)[CH2:5][C:6](OC)=[O:7].[NH2:13][C:14]1[N:18]=[C:17]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:16][N:15]=1>CO.C(O)C>[CH2:20]([S:19][C:17]1[N:18]=[C:14]2[N:13]=[C:4]([OH:11])[CH:5]=[C:6]([OH:7])[N:15]2[N:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Oc1cc(O)n2nc(SCc3ccccc3)nc2n1
Temperature: 25 °C
Yield: 127.8 %

Procedure:
A solution of 125 g (0.58 mol) of a 25% solution of sodium methoxide in methanol dissolved in 100 ml of absolute ethanol was treated with 66.3 ml (0.29 mol) of dimethyl malonate followed by 60.0 g (0.20 mol) of 3-amino-5-benzylthio-1,2,4-triazole. The resulting solution was heated at reflux for 5 days. On cooling to room temperature the solid which had separated was collected by filtration, washed with cold ethanol and dissolved in 1000 ml of water. The resulting yellow solution was acidified with concentrated HCl to precipitate a solid. The solid was collected by filtration and dried to yield 70.1 g (82%) of the desired product as a white solid, m.p. 199°-210° C. (decomposition). IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:29]=[O:30]>O1CCCC1>[C:16]1([C@H:14]([N:10]2[CH2:11][CH2:12][O:13][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:29]=[O:30])=[CH:3][CH:4]=3)[CH2:9]2)[CH3:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C=O)cc2)C1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 101.9 %

Procedure:
To a solution of (2S)-2-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholine (intermediate 13, 63.3 g, 183 mmol) in tetrahydrofuran (450 ml) was added n-butyllithium (1.57 M in hexane solution, 175 ml, 275 mmol) at −78° C. and the mixture was stirred for 20 minutes. N,N-dimethylformamide (28.3 ml 365 mmol) was added and the mixture was stirred for 2 hours at −78° C. and then allowed to be warmed to −10° C. The reaction was quenched with aqueous ammonium chloride, and the resulting solution was partitioned between water and ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford crude 4-((2S)-4((1R)-1-phenylethyl) morpholin-2-yl)benzaldehyde (intermediate 14, 55.1 g). This compound was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)C1C=CC=CC=1.[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[K]>C1(C)C=CC=CC=1>[CH2:17]([O:24][C:25]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [K]
Solvent: Cc1ccccc1
Solvent: O=Cc1ccccc1
Product: NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 91 %

Procedure:
22.2 g(0.2 mol) of 4-aminomethyl-piperidine was dissolved in 250 ml of toluene and then 21.2 g(0.2 mol) of benzaldehyde was added thereto. The mixture was refluxed for 3 hours with Dean-stack and cooled down to 0° C., and then 34.2 g(0.2 mol) of benzylchloroformate was added thereto while stirring. After the mixture was stirred for 3 hours, 1N aqueous potassium hydrosulfate solution(220 ml) was added thereto at room temperature. The mixture was extracted three times with 200 ml of diethylether, and then the aqueous layer was basified with sodium hydroxide. The aqueous solution was saturated with sodium chloride and extracted three times with 100 ml of dichloromethane. The organic solution was dried over magnesium sulfate and distilled under reduced pressure to obtain 38 g(Yield 91%, Molecular weight 248) of the title compound