Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24].CO>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[N:9]2[CH2:24][C:23]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 6 h

Procedure:
To a mixed suspension of 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (20 g) and hexamethyldisilazane (16.42 g) in toluene (60 ml) was added sulfuric acid (0.80 g) dropwise and the silylation reaction was carried out at an internal temperature of 110˜120° C. for 6 hours. After completion of silylation, the toluene was distilled off to recover a concentrate containing 7-chloro-2,4-bis(trimethylsilyloxy)quinazoline. To this concentrate were added propylene carbonate (40 ml), ethyl chloroacetate (13.72 g) and ethyl bromoacetate (3.40 g), and the reaction was carried out at an internal temperature of 125˜140° C. for 6 hours. After completion of reaction, the reaction mixture was cooled to an internal temperature of ≦70° C. and ethyl acetate (80 ml) was added. Then, methanol (60 ml) was added dropwise over 30 minuets. After completion of dropwise addition, the mixture was cooled to ≦20° C. and stirred for 1 hour. The resulting crystal crop was harvested by filtration, washed serially with methanol (40 ml) and water (100 ml) and dried to provide ethyl 2-(7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetate (28.16 g) as white crystals.
Reaction SMILES: C([O:4][CH2:5][CH3:6])(=O)C.[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[C:9]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:6][CH2:5][OH:4])[CH:8]=[CH:7][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Product: OCCCCCCCCCCCCCc1ccccc1

Procedure:
Rf value : 0.24 (ethyl acetate:hexane=1:5)
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>C1COCC1>[CH2:3]([O:9][C:11]1[C:15]([C:16]2[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1ccc(-c2nsnc2Cl)cn1
Reactant: CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOc1nsnc1-c1ccc(C)nc1
Reaction time: 2 h

Procedure:
Sodium hydride (0.72 g, 15 mmol) was dissolved in dry THF (20 ml) and 1-hexanol (1.53 g, 15 mmol) and a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)-6-methylpyridine (1.06 g, 5 mmol) in dry THF (15 ml) was added. The reaction mixture was stirred for 2 h. After addition of water the mixture was extracted with ether, and the ether phase was dried and evaporated. The residue consisted of the crude title compound, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH3:17])([CH3:16])[N:6](C(OC)=O)[CH2:7]2.[OH-].[K+]>C(O)CO.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH3:17])([CH3:16])[NH:6][CH2:7]2
Reactant: COC(=O)N1Cc2cccc(Br)c2CC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC1(C)Cc2c(Br)cccc2CN1
Temperature: 150 °C
Yield: 40.5 %

Procedure:
To a solution of Intermediate 24E (4.6 g) in ethylene glycol (50 mL) was added 50% aqueous KOH solution (23 mL) and the reaction was heated at 150° C. for 3 days. The reaction mixture was cooled, diluted with H2O, extracted with EtOAc twice. The combined organics were extracted with 1.5 N HCl solution, the aqueous layer was basified with 10% NaOH solution, extracted with EtOAc twice and the combined organics were washed with H2O, brine, dried over Na2SO4, filtered and concentrated to give Intermediate 24 (1.5 g, 39.4%) as a brown liquid. MS (ESI) m/z: 242.2 (M+H)+.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:8]([CH:12]=1)[C:9](O)=[O:10].[NH4+].O[N:26]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH:3]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:8]([CH:12]=1)[C:9]([NH2:26])=[O:10])=[O:2]
Reactant: On1nnc2ccccc21
Reactant: COC(OC)c1ccc(OCCN2CCOCC2)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(C=O)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 35 h
Yield: 73 %

Procedure:
A solution of 5-dimethoxymethyl-2-(2-morpholinoethoxy)benzoic acid (0.40 g, 1.23 mmol) obtained in Step 4 in DMF (5.00 mL) was added with 1-hydroxybenzotriazole ammonium salt (0.30 g, 1.97 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 g, 1.84 mmol), followed by stirring at room temperature for 35 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the residue was added with hydrochloric acid (3 mol/L, 3.00 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution (50 mL) and was extracted with ethyl acetate (50 mL×3). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain 5-formyl-2-(2-morpholinoethoxy)benzamide (0.25 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][C:12]1[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][C:12]2[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(c1ncccc1CNc1nc(Cl)ncc1Cl)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2,4,5-trichloropyrimidine (1.0 g, 5.45 mmol) is suspended in 20 mL DCM and the reaction mixture is cooled to 0° C. Then a solution of N-(3-aminomethyl-pyridin-2-yl)-N-methyl-methanesulphonamide (1.17 g, 5.45 mmol) and DIPEA (1.95 mL, 10.9 mmol) in 10 mL DCM is added and the mixture is stirred overnight. The reaction mixture is diluted with DCM and washed 3× with 1 N NH4Cl solution. The organic phase is dried on magnesium sulphate and evaporated down in vacuo. The crude product A-2b (HPLC-MS: tRet.=2.00 min; MS (M+H)+=362) is used in successive reactions without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)CCC1CNCCO1
Product: CCOC(=O)C1=C(CN2CCOC(CCC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 49.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.7 g, 1.4 mmol) was reacted with 3-(morpholin-2-yl)propanoic acid (0.22 g, 1.4 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.40 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[N:10]=[C:9]2[S:11][C:12]([SH:14])=[N:13][C:8]2=[CH:7][CH:6]=1.Br[CH:16]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:17]([OH:19])=[O:18]>C(N(CC)CC)C>[Cl:4][C:5]1[N:10]=[C:9]2[S:11][C:12]([S:14][CH:16]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:17]([OH:19])=[O:18])=[N:13][C:8]2=[CH:7][CH:6]=1
Reactant: Sc1nc2ccc(Cl)nc2s1
Reactant: O=C(O)C(Br)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Sc1nc2ccc(Cl)nc2s1)c1ccc(Cl)cc1
Yield: 68.2 %

Procedure:
A methylene chloride solution of 6.0 g (0.03 m) of 5-chloro-2-mercaptothiazolo[5,4-b]pyridine, 7.5 g (0.03 m) α-bromo-α-(p-chlorophenyl) acetic acid and 6.0 g (0.06 m) triethylamine is heated to gentle reflux overnight. The solution is extracted twice with a dilute hydrochloric acid solution and then once with water. After drying over anhydrous MgSO4, the solvent is removed and the residual solid is recrystallized from acetonitrile. 7.5 g (68% yield) of title compound, melting at 144°-6° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[NH:22]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[NH:22]2)[CH:7]=1
Reactant: O=c1[nH][nH]c2ccccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1[nH]c(=O)c2ccccc21)C(F)(F)F
Reaction time: 336 h
Yield: 21.5 %

Procedure:
To a solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (0.29 g) and 1,2-dihydroindazol-3-one (0.17 g) in anhydrous dimethylsulfoxide (1 mL) was added sodium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 1.0 mL). After 14 days, the reaction mixture was diluted with ethyl acetate and washed twice with water. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (eluted with 1% ethanol-methylene chloride) to give 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1,2-dihydroindazol-3-one as a white solid (91 mg), m.p. 141° C.-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24](O)=[O:25])(=[O:18])=[O:17])=[O:4].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:58]([N:60]([CH2:64][CH3:65])[CH2:61][CH2:62][NH2:63])[CH3:59].Cl>CN(C=O)C>[CH2:58]([N:60]([CH2:64][CH3:65])[CH2:61][CH2:62][NH:63][C:24]([C:20]1[S:21][CH:22]=[CH:23][C:19]=1[S:16]([NH:15][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:5]=1[C:3]([O:2][CH3:1])=[O:4])(=[O:17])=[O:18])=[O:25])[CH3:59]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccsc2C(=O)O)ccc2c1CCCC2
Reactant: CCN(CC)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1sccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 463B (100 mg, 0.253 mmol) in DMF (2.0 mL) was treated with 4-methylmorpholine (111 μL, 1.012 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (192 mg, 0.506 mmol), stirred for one hour at room temperature, treated with N,N-diethylethylenediamine (71 μL, 0.506 mmol), stirred for 3 days at room temperature, treated with 1N HCl, and extracted twice with dichloromethane. The combined extracts were dried (MgSO4), filtered, concentrated, and purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 494 (M+H)+; (ESI(−)) m/e 492 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.06 (br s, 1H), 8.82 (t, 1H), 7.82 (d, 1H), 7.26 (d, 1H), 7.10 (d, 1H), 6.92 (d, 1H), 3.77 (s, 3H), 3.24-3.14 (m, 8H), 2.68 (br s, 2H), 2.55 (br s, 2H), 1.66 (quint, 4H), 1.21 (t, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N+:14]([O-:16])=[O:15])[C:7]2[O:11][CH:10]([CH3:12])[CH2:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[NH3:17].COCCO>O>[NH2:17][C:7]1[C:6]([N+:14]([O-:16])=[O:15])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=1[CH2:9][CH:10]([OH:11])[CH3:12]
Reactant: N
Reactant: CC1Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2O1
Solvent: COCCO
Solvent: O
Product: CC(O)Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N
Temperature: 70 °C

Procedure:
0.39 Mole (88 g) of 2,3-dihydro-5,7-dinitro-2-methylbenzofuran, prepared according to J.A.C.S. 80, p. 4711-4714 (1958), is suspended in 1.1 l of 20% strength ammonia solution and 600 ml of Methyl Cellosolve. After 18 hours' heating at 70° C., the reaction mixture is cooled. The precipitate formed is drained and, after being made into a paste in water until neutral and then dried under vacuum, is recrystallized from 170 ml of dioxane. After being dried under vacuum, 0.30 mole (72 g) of the expected product is obtained; it melts at 177° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:55])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:51]([CH3:54])[CH2:52][CH3:53])[C@H:33]([O:49][CH3:50])[CH2:34][C:35](=[O:48])OC3C(F)=C(F)C(F)=C(F)C=3F)[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:57][O:58][C@@H:59]([C@@H:65]1[CH2:69][CH2:68][CH2:67][NH:66]1)[C@@H:60]([CH3:64])[C:61]([OH:63])=[O:62].C(N(C(C)C)CC)(C)C>ClCCl>[CH:5]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:55])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:51]([CH3:54])[CH2:52][CH3:53])[C@H:33]([O:49][CH3:50])[CH2:34][C:35]([N:66]3[CH2:67][CH2:68][CH2:69][C@H:65]3[C@H:59]([O:58][CH3:57])[C@H:60]([C:61]([OH:63])=[O:62])[CH3:64])=[O:48])[CH3:31])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a mixture of #104 (2.00 g, <2.58 mmol, 1 eq.) in dichloromethane (6 mL, 0.4 M) was added a solution of #103 (483 mg, 2.16 mmol, 1 eq.) in dichloromethane (2 mL) followed by diisopropylethylamine (1.35 mL, 7.73 mmol, 3 eq.). The reaction mixture was stirred for 16 hours, then adsorbed onto silica and purified by silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane) to give #105 (1.67 g, 83%) as a white foam. Fractions containing the desired product with impurities (0.571 g) were collected separately.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13]O.C1C=CC(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:29]([CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccccc1-c1cnccn1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1ccccc1-c1cnccn1
Temperature: 25 °C

Procedure:
To a stirred solution of (2-pyrazin-2-ylphenyl)methanol (1.14 g, 6.13 mmol) in anhydrous THF (12.5 mL) at 0° C. was added DPPA (1.59 ml, 7.36 mmol) and DBU (1.01 mL, 6.75 mL). The resulting cloudy yellow mixture was allowed to warm to room temperature, and after 3.5 h was warmed to 80° C. for 3 h. The mixture was then cooled to room temperature and the THF was removed in vacuo. The residue was partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed successively with a 10% aqueous solution of citric acid, saturated aqueous NaHCO3 and brine. The organic solution was dried (anhydrous Na2SO4), filtered and concentrated to a yellow-brown oil. Silica gel chromatography (40% EtOAc-hexanes) afforded the title compound as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.82 (d, J=1.6 Hz, 1 H), 8.67 (dd, J=1.6, 2.4 Hz, 1 H), 8.59 (d, J=2.4 Hz, 1 H), 7.55–7.48 (m, 4 H), 4.60 (s, 2 H). LCMS (M+H): 212.1.
Reaction SMILES: FC(F)(F)C([NH:5][CH:6]([CH2:17][C:18](=[O:32])[N:19]1[CH2:24][CH2:23][N:22]2[C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=[C:21]2[CH2:20]1)[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])=O.O.[OH-].[Li+]>CO.O>[O:32]=[C:18]([N:19]1[CH2:24][CH2:23][N:22]2[C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=[C:21]2[CH2:20]1)[CH2:17][CH:6]([NH2:5])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16]
Reactant: O=C(CC(Cc1cc(F)c(F)cc1F)NC(=O)C(F)(F)F)N1CCn2c(nnc2C(F)(F)F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 27.5 °C
Reaction time: 24 h
Yield: 38.6 %

Procedure:
In a 25 mL three neck flask (2S) N-trifluoroacetyl-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (wt.-0.250 g, % Purity by HPLC-96.5%) was dissolved in a mixture of MeOH (2.5 mL) and water (0.5 mL) at 25-30° C. To the reaction mixture lithium hydroxide monohydrate (21 mg) was added. It was stirred at 0 to 5° C. for 4 h and at 25 to 30° C. for 24 h. Distilled out solvent at reduced pressure on Buchi rotavapour. To the thick liquid water (2.5 mL) was added. It was transferred into a separating funnel. It was extracted twice with ethyl acetate. Both the extracts were combined and washed with water and brine solution. It was dried over anhydrous sodium sulfate. Distilled out solvent to obtain a 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (Wt.-78 mg, % Purity by HPLC-83.1%).
Reaction SMILES: [C@@H:1]1([OH:7])[CH2:5][CH2:4][CH2:3][C@@H:2]1[OH:6].F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]>>[F:15][C:13]1[CH:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]([CH:14]=1)[O:6][C@H:2]1[CH2:3][CH2:4][CH2:5][C@H:1]1[OH:7]
Reactant: O[C@@H]1CCC[C@@H]1O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: O=[N+]([O-])c1ccc(F)cc1O[C@H]1CCC[C@H]1O

Procedure:
Prepared analogously to III.1 from cis-1,2-cyclopentandiol (1.0 g) and 1.28 ml 2,4-difluoronitrobenzene.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.Cl.[F:20][C:21]1([F:26])[CH2:24][CH:23]([NH2:25])[CH2:22]1>ClCCl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:25][CH:23]1[CH2:24][C:21]([F:26])([F:20])[CH2:22]1)=[O:7]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: NC1CC(F)(F)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC(F)(F)C1)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
3-(Chloromethyl)benzoyl chloride (13.93 mmol, 2.63 g) was stirred in dichloromethane (50 ml) at 0° C. Triethylamine (41.8 mmol, 5.81 ml, 4.23 g) and 3,3-difluorocyclobutanamine hydrochloride (13.93 mmol, 2 g) were combined in dichloromethane and added dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was washed with water, dried over sodium sulfate and concentrated under vacuum to afford the title compound (3.33 g). MS (ESI) m/z 260.3 [M+H]+
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:9][C:4]([CH3:10])([CH2:3][CH2:2][O:1][S:12]([CH3:11])(=[O:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C)(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CCOS(C)(=O)=O
Temperature: -20 °C

Procedure:
To a solution of methyl 4-hydroxy-2,2-dimethylbutanoate (1 eq.) from the previous step in DCM (0.1 M) at −40° C. was added methanesulfonyl chloride (1.5 eq.) and triethylamine (3.0 eq.). The reaction was warmed to −20° C. over 30 min and then quenched with saturated aqueous NaHCO3 solution. The aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was used in the next step without further purification.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](Cl)=[O:11])[CH3:8].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:7]([O:9][C:10](=[O:11])[NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: NC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)NC1CCCC1
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of cyclopentylamine (5.8 mL, 59 mmol, 1.0 eq.) in CH2Cl2 (250 mL) at room temperature was added ethylchloroformate (7.3 mL, 1.3 eq.) followed by an aqueous solution of K2CO3 (37 g in 500 mL of H2O). The mixture was stirred vigorously for 1 h. The separated aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated to give cyclopentyl-carbamic acid ethyl ester (9.6 g, 88%).
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O>[CH3:25][O:1][CH:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:14][CH:15]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)c1ccc(C(O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of tert-butyl 4-(hydroxy(phenyl)methyl)benzoate (1.4 g, 4.9 mmol) was dropped to the suspension of sodium hydride (237 mg, 5.9 mmol) in N,N-dimethylformamide (20 mL) and then the mixture was stirred 0.5 hour. Then iodomethane (3.0 mL) was added to the mixture and stirred at room temperature for 2 hours. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=6:1) to give tert-butyl 4-(methoxy(phenyl)methyl)benzoate as a colorless oil (1.25 g, 86%). 1H NMR (300 MHz, CDCl3): δ 7.95 (d, J=8.1 Hz, 2H), 7.42-7.31 (m, 7H), 5.28 (s, 1H), 3.39 (s, 3H), 1.58 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][C:30]1([CH2:36][OH:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:29][C:30]1([CH2:36][OH:37])[CH2:35][CH2:34][N:33]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:32][CH2:31]1
Reactant: CC1(CO)CCNCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C)(CO)CC3)n(C)c2n1

Procedure:
Following General Procedure E of amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and (4-methylpiperidin-4-yl)methanol were reacted to give 268. LCMS: M+H+=491.3