Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[N:13]=[C:12](Cl)[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=2)[N:5]=1>C1COCC1>[Cl:3][C:4]1[NH:13][C:12](=[O:1])[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Clc1ccc2c(Cl)nc(Cl)nc2c1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(Cl)nc2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A 1.0 M aqueous solution of sodium hydroxide (19 mL, 19 mmol) was added to a mixture of 2,4,7-trichloroquinazoline (2.0 g, 8.5 mmol) and THF (30 mL) that had been cooled to 0° C. The reaction mixture was allowed to warm to rt and was stirred vigorously for 2 h. The mixture was concentrated to remove the THF, and the remaining aqueous phase was cooled to 0° C. and acidified by addition of 1.0 M aqueous HCl (25 mL). The resulting mixture was allowed to stand at 0° C. for 20 min, the solid was collected by filtration and dried to provide the titled compound (1.7 g, 92%). The MS and NMR data are in agreement with those that have been previously described: Journal of Medicinal Chemistry, 2007, 50, 2297-2300.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[CH2:19]([N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[C:20]#[CH:21].[CH2:30]1CCN2C(=NCCC2)CC1>CC(N(C)C)=O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:24]([S:25]([CH2:26][CH2:27][N:22]([CH3:30])[C:19]1[N:3]2[C:2]([CH:7]=[N:6][C:5]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:4]=32)=[CH:21][CH:20]=1)(=[O:29])=[O:28])[CH3:23]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Reactant: C1CCC2=NCCCN2CC1
Reactant: C#CCN1CCS(=O)(=O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(=O)N(C)C
Product: CCS(=O)(=O)CCN(C)c1ccc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 80 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
A flask was charged with 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (295 mg, 0.9 mmol), 4-propargyl-thiomorpholine-1,1-dioxide (commercial, 156 mg, 0.9 mmol), copper iodide (17 mg, 0.09 mmol), dichlorobis-(triphenylphosphine)palladium (II) (13 mg, 0.018 mmol) and DBU (0.4 mL, 2.7 mmol) in dry dimethyl acetamide (3 mL). The mixture was vacuum degassed and heated to 80° C. under argon. After 1.5 hours the material was warmed to 120° C. and stirred for 12 hours. The mixture was cooled to ambient and quenched via the addition of water (45 ml) and ethyl acetate (45 ml). The material was shaken in a reparatory funnel, and the ethyl acetate phase was collected. The aqueous phases were back extracted with ethyl acetate (2×40 ml), the organics combined, dried (MgSO4), filtered and stripped. The remainder was purified by preparative TLC using 45% ethyl acetate in hexanes as eluant to provide 232 mg of (2-ethanesulfonyl-ethyl)-methyl-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-3,4,8a-triaza-as-indacen-8-yl]-amine as a dark brown oil. MS (M+H)+=421.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH3:12][C:13]([CH3:15])=O.C([BH3-])#N.[Na+].CC(O)=O>CCO>[CH:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11])([CH3:15])[CH3:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Nc1ccc([N+](=O)[O-])cc1O

Procedure:
A solution of 2-amino-5-nitrophenol (2.00 g, 13.0 mmol) in absolute EtOH (52 mL) and acetone (14.3 mL, 195 mmol, 15 equiv.) is treated with sodium cyanoborohydride (408 mg, 6.49 mmol), the pH is adjusted to 4.5-5.0 with glacial AcOH, and the mixture is stirred at ambient temperature for 4 days, during which time additional acetone (2×14.3 mL), sodium cyanoborohydride (3×408 mg) and glacial AcOH is added. The reaction mixture is then readjusted to pH 6, concentrated under reduced pressure, diluted with water (50 mL) and CH2Cl2 (75 mL), and the layers are separated. The organic phase is washed with saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M 90 g silica gel cartridge with EtOAc/heptane (20/80). Pooling and concentration of those fractions with an Rf=0.59 by TLC (EtOAc/hexanes, 50/50) gives the title compound, mp 108-110° C.; MS (ESI+) for C9H12N2O3 m/z 197 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[CH3:13][N:14](/[CH:16]=[C:3]1\[C:2](=[O:10])[NH:1][C:9]2[C:4]\1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: O=C1Cc2ccccc2N1
Solvent: ClC(Cl)Cl
Product: CN(C)/C=C1\C(=O)Nc2ccccc21
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1,3-dihydro-2H-indol-2-one 25.0 g, 189 mmol) in CHCl3 (150 mL) was added N,N-dimethylformamide dimethyl acetal (29.2 mL, 209 mmol) and the reaction was heated at 70° C. under an atmosphere of argon. After 4.5 h, the reaction was cooled to RT and was concentrated. The resulting solid was triturated with ether and filtered to give (3Z)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one as a yellow solid (iii-a, 33.0 g, 93%). NH4OAc QC conditions. DAD Retention Time=1.19 min. M+H=189.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[NH2:19][C:20]1[N:24]([CH3:25])[NH:23][C:22](=[O:26])[CH:21]=1>>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:21]3[C:22](=[O:26])[NH:23][N:24]([CH3:25])[C:20]=3[NH:19][C:4]3[CH2:5][CH2:6][O:1][C:2](=[O:8])[C:3]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=C1CCOC(=O)C1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Cn1[nH]c(=O)cc1N
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)OCC1)C2c1ccc(F)c(Br)c1
Yield: 68.5 %

Procedure:
Dihydro-2H-pyran-2,4(3H)-dione(0.11 g, 1 mmol), 3-bromo-4-fluoro-benzaldehyde (0.2 g, 1 mmol) and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.12 g, 1 mmol) were processed as described in Example 26C to provide 0.27 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.55 (m, 1H), 2.8 (m, 1H), 3.5 (s, 3H), 4.22 (m, 2H), 4.86 (s, 1H), 7.2 (m, 2H), 7.41 (dd, 1H), 9.49 (s, 1H), 9.92 (s, 1H); MS (ESI−) m/z 392 (M−H)−; Anal. Calcd for C16H13N3BrFO3.C2H6O: C, 49.11; H, 4.35; N, 9.54. Found: C, 48.87; H, 4.24; N, 9.40.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]([O:11][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
To a solution of 1-benzyl-3-tritylglycerol (17.5 g, 0.41 mol) in anhydrous dichloromethane (200 mL) at 0° C. was added triethylamine (8 mL, 0.58 mol) followed by methanesulfonyl chloride (4.1 mL, 0.54 mol). The reaction was stirred at 0° C. for 1 hour, then at room temperature for 2 hours. The reaction mixture was washed with 1N hydrochloric acid (30 mL), dried (Na2SO4), filtered and concentrated. Crystallisation using diisopropyl ether gave the title compound (15.2 g, 72%) as a solid. m/z not found, r.t.=4.41 mins. NMR (400 MHz; CDCl3) δ7.43-7.41 (6H, m), 7.38-7.23 (14H, m), 4.90-4.83 (1H, m), 4.52 (2H, m), 3.75-3.63 (2H, m), 3.41-3.33 (2H, m), 3.02 (3H, s).
Reaction SMILES: C1(COC(=O)[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:14]=[C:13]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:12]=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:15]1[CH:14]=[C:13]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:12]=[C:11]([NH2:10])[CH:16]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OCc2ccccc2)cc(OCCCCC(=O)OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(OCCCCC(=O)OC)c1
Yield: 97.2 %

Procedure:
A mixture of 8.9 g of 3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenylcarbamic acid phenylmethyl ester and 1.5 g of 10% palladium on carbon in 250 ml of THF was stirred in a hydrogen atmosphere at room temperature for 2.5 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with hexane and filtered to give 6.8 g (97% yield, mp 57°-59°) of 5-[3-amino-5(octadecyloxy)phenoxy]pentanoic acid methyl ester.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:27])[C:16](C)([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)[CH2:17][CH3:18].Br[CH2:29][CH2:30][CH2:31][Br:32]>C1COCC1.CCCCCC>[CH3:13][O:14][C:15](=[O:27])[C:16]([C:19]1[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=1)([CH:17]([CH3:18])[CH3:1])[CH2:29][CH2:30][CH2:31][Br:32]
Reactant: CC(C)NC(C)C
Reactant: CCC(C)(C(=O)OC)c1ccc(Br)cc1
Reactant: BrCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C(CCCBr)(c1ccc(Br)cc1)C(C)C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (5.04 ml, 1.5 eq) in anhydrous THF at −78° C. and n-butyllithium in hexane were mixed and dissolved into 2.5 M of solution (10.55 ml, 1.1 eq). The 2-(4-bromophenyl)-methylbutyric acid methyl ester (6.5 g, 1 eq) in the Step 2 was added into the solution and stirred. After 30 minutes, 1,3-dibromopropane (7.31 ml, 3 eq) was dissolved in anhydrous THF. The mixture was dropped into the solution and stirred at room temperature overnight. When the reaction was completed, the compound was extracted with diethylether and water, washed with 1N HCl and saturated NaHCO3. The organic layer was dried with anhydrous magnesium sulfate and the solvent was removed at low pressures. Subsequently, the target compound 5-bromo-2-(4-bromophenyl)-2-isopropylpentanoic methyl ester was obtained by separation and purification of the mixture using a column chromatography (ethyl acetate:n-hexane=1:100) (5.98 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][NH:5][C:4]([Br:10])([CH3:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(F)cn1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC1(Br)C=C(Cl)C(F)=CN1
Temperature: 75 °C
Yield: 69 %

Procedure:
4-Chloro-5-fluoro-2-picoline (2.9 g, 20 mmol), the product of Example 66, was dissolved in 50 mL of 1,2-dichloroethane in a dry flask. The resultant solution was heated, with stirring, to 75° C. and 4.09 (23 mmol) of N-bromosuccinimide was added, followed by 100 mG (0.7 mmol) of 2,2-azobisisobutyronitrile (AIBN), a free radical initiator. After the reaction mixture was stirred at 75° C. for 24 hours, it was diluted with 450 mL of methylene chloride and washed with 3×400 mL of water. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried in vacuo to give 3.5 g (69% yield) of the title compound as an amber oil; 1H NMR (CDCl3) d 4.50 (s, 2H), 7.54 (d, 1H), 8.44 (s, 1H).
Reaction SMILES: [CH2:1]=[O:2].[C:3]1(=[O:9])[NH:7][C:6](=[O:8])[CH:5]=[CH:4]1>C(=O)([O-])[O-].[K+].[K+].O>[OH:2][CH2:1][N:7]1[C:6](=[O:8])[CH:5]=[CH:4][C:3]1=[O:9]
Reactant: O=C1C=CC(=O)N1
Reactant: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1C=CC(=O)N1CO
Temperature: 25 °C

Procedure:
A mixture of 125 grams of water, 26 ml. of 37% aqueous formaldehyde solution, 25 grams of maleimide, and 0.1 gram of anhydrous potassium carbonate was heated at its reflux temperature for 90 minutes, cooled to ambient temperature, and filtered. After removal of the water by heating under vacuum, there was obtained 32 grams of N-hydroxymethylmaleimide.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:17][CH2:16][CH2:15][CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCCCCBr
Reactant: OCCCCc1ccccc1
Product: BrCCCCOCCCCc1ccccc1

Procedure:
(2.44 g), T.l.c. [K] Rf 0.68, from 1,4-dibromobutane (8.6 g) and benzenebutanol (2 g).
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:21][CH:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:19]2)=[C:14]([F:30])[CH:13]=1)([O:3]CC1C=CC=CC=1)=[O:2].[C:31](OC[C@@H]1OC1)(=[O:35])[CH2:32][CH2:33]C>O1CCCC1>[Si:23]([O:22][CH:20]1[CH2:19][N:18]([C:15]2[CH:16]=[CH:17][C:12]([N:11]3[CH2:33][C@H:32]([CH2:31][OH:35])[O:3][C:1]3=[O:2])=[CH:13][C:14]=2[F:30])[CH2:21]1)([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:25])[CH3:24]
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(NC(=O)OCc3ccccc3)cc2F)C1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
A solution of N-(carbobenzyloxy)-4-[3-[(tert-butyldimethylsilyl)oxy]-1-azetidinyl]-3-fluoroaniline (6.30 g, 14.7 mmol) in dry tetrahydrofuran (100 mL) under a nitrogen atmosphere was cooled to -78° C. and treated with n-butylithium (9.16 mL of a 1.6M solution in hexanes, 14.7 mmol). When the addition was complete, the reaction mixture was stirred at -78° C. for 15 min and then treated with (R)-glycidyl butyrate (2.21 mL, 14.7 mmol). After completion of the addition, the cooling bath was removed and the reaction mixture allowed to stir at ambient temperature for 1.5 h. After this time, saturated aqueous ammonium chloride (20 mL) was added. After 3 min, saturated aqueous sodium bicarbonate (10 mL) was added to the reaction mixture and the organic solvent removed by rotary evaporation under reduced pressure. Dichloromethane (100 mL) was added and the mixture washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography over silica gel (200 g), eluting with a gradient of 1-3% methanol/chloroform, afforded, after concentration of appropriate fractions, 4.39 g (75%) of the title compound as an off-white solid with mp 183°-186° C. and MS(EI) 396 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[NH2:14]N.O>C(O)C>[ClH:1].[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([NH:8][C:9](=[O:10])[NH:11][NH2:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: Cc1c(Cl)cccc1NC(N)=O
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)cccc1NC(=O)NN
Product: Cl

Procedure:
A mixture of 3-chloro-2-methylphenylurea (5.0 g, 27.0 mmol), hydrazine hydrate (4.0 g, 80.0 mmol), 4 ml of water and 30 ml of ethanol is heated to reflux for 12 hours. The reaction mixture is then cooled and poured onto ice. A white precipitate forms, which is collected by filtration, washed with water and dried. The resulting solid is dissolved in hot ethanol and conc. HCl is added. The mixture is cooled and the resulting white solid precipitate is collected by filtration, washed with ethanol, and dried under vacuum to give 4-(3-chloro-2-methylphenyl)semicarbazide hydrochloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.N1CCCCC1>C(O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:13][CH:14]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1
Yield: 70.4 %

Procedure:
2.0 g of oxindole was dissolved in 40 ml of ethanol, and 2.0 g of p-anisaldehyde was added thereto at room temperature. Subsequently, 1.5 ml of piperidine was added, and the mixture was refluxed with heat for 13 hours. After completion of reaction, the reaction mixture was cooled. Crystals that precipitated were collected by filtration. The resultant crude product was washed with methanol, to thereby obtain 2.6 g (yield 71%) of the title compound in the form of yellow crystals. The melting point and elementary analysis data are shown in Table 13, and NMR and MS spectrum data are shown in Table 14.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[NH:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:15]([C:24](O)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C@@H:15]([NH:14][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:24](=[O:25])[N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:9][CH2:10]2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: c1ccc(CN2CCNCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(Cc2ccccn2)CC1

Procedure:
N-{(1R)-1-[(4-Chlorophenyl)methyl]-2-oxo-2-[4-(2-pyridylmethyl)piperazinyl]ethyl}(tert-butoxy)carboxamide was prepared according to the procedure for Preparation XIX using (2-pyridylmethyl)piperazine (650 mg. 3.7 mmol) (Array), Boc-p-Cl-D-Phe-OH (1.1 g, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (2.2 g, 7.2 mmol), HOAT (560 mg, 4.10 mmol) and DMF (15 mL) (730 mg). MS (ESI, pos. ion) m/z: 459 (M+H), (ESI, neg. ion) m/z: 457 (M−H). Calc'd for C24H31ClN4O3: 458.98.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([O:8][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[CH2:4][CH2:3]1
Reactant: Clc1cnccn1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC(Oc2cnccn2)(c2ccccc2)CC1
Yield: 11.1 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (7.65 g, 40 mM), in DMSO (100 ml) was treated with 50% sodium hydride dispersion (2.0 g, 40 mM) and the mixture warmed to 80° until a clear solution was obtained. After cooling to room temperature a solution of 2-chloropyrazine (5.6 g, 40 mM) in DMSO (10 ml) was added. After 48 hours the reaction mixture was poured on to water (400 ml), extracted with ether (3×250 ml), the organic phase dried and the solvents removed under reduced pressure. Recrystallisation of the residue from cyclohexane gave recovered 1-methyl-4-phenyl-4-piperidinol (2 g). Chromatography of the mother liquors on Grade III silica using 3% methanol in chloroform as eluant, evaporation of the appropriate fractions and recrystallisation from pentane gave the title compound (1.2 g) m.p. 115°-6° C.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C1C=CC=CC=1>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][N:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:36](=[O:37])[C:35]1[CH:39]=[CH:40][CH:41]=[C:33]([C:32]([F:31])([F:42])[F:43])[CH:34]=1)[CH3:15]
Reactant: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(C(=O)c1cccc(C(F)(F)F)c1)c1ccccc1-c1ccccc1
Yield: 84.4 %

Procedure:
Analogously to Example 47b, 11.8 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 5.4 g of ethyldiisopropylamine are reacted in 70 ml of benzene with 8.7 g of m-trifluoromethylbenzoyl chloride. The reaction product is recrystallized from a mixture of isopropyl alcohol and water (1:1) to obtain 16.0 g (84.4% of theory) of ethyl-4-[m-trifluoromethyl-N-(biphenyl-2-yl)benzamido]-butyrate, MP 65° to 67°.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]2[N:11]=[CH:10][C:9](=[O:13])[N:8]([C@@H:14]3[O:28][C@H:27]([CH2:29][O:30]C(=O)C4C=CC(Cl)=CC=4)[C@@H:16]([O:17]C(=O)C4C=CC(Cl)=CC=4)[CH2:15]3)[C:7]=2[N:6]=[C:5]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:4]=1.CC(O)=O>CO>[NH2:2][C:3]1[C:12]2[N:11]=[CH:10][C:9](=[O:13])[N:8]([C@@H:14]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:16]([OH:17])[CH2:15]3)[C:7]=2[N:6]=[C:5]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:4]=1
Reactant: Nc1nc(-c2ccccc2)nc2c1ncc(=O)n2[C@H]1C[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O1
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(-c2ccccc2)nc2c1ncc(=O)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of 10 mg of sodium in 50 mL of anhydrous methanol was added 0.632 g (1 mmol) of 4-amino-2-phenyl-8-[2-deoxy-3,5-di-O-(4-chlorophenyl)-βD-ribofuranosyl]pteridine-7-one (4). The solution was stirred at room temperature for 1 hour. The solution was then neutralized by the addition of AcOH and then evaporated. The residue was re, crystallized from methanol/H2O to give 5 as 0.323 g (91% yield) of colorless crystals (m.p. 169°-172° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23](O)=[O:24])[N:21]=1)=[CH:5]2.[CH3:26][NH:27][CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:27]([CH3:28])[CH3:26])=[O:24])[N:21]=1)=[CH:5]2
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: CNC
Product: CN(C)C(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Yield: 49 %

Procedure:
The compound (50 mg, 0.13 mmol) prepared in Example 27 and dimethylamine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (26 mg, Yield 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26](O)=[O:27])[CH:18]=[CH:19][CH:20]=1)=[O:14])[CH3:11].P(Cl)(Cl)(Cl)=O.O(Cl)Cl>N1C=CC=CC=1.O>[CH2:10]([O:12][C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26](=[O:27])[NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:16]=1)[CH3:11]
Reactant: CCOC(=O)c1cccc(N2CCC[C@@H]2C(=O)O)c1
Reactant: N#Cc1ccc(N)cc1
Agent: ClOCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cccc(N2CCC[C@@H]2C(=O)Nc2ccc(C#N)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Cool a solution of 4-aminobenzonitrile (0.05 g, 0.42 mmol) in pyridine (2 mL) to 0° C., and add (R)-1-(3-ethoxycarbonyl-phenyl)-pyrrolidine-2-carboxylic acid (0.10 g, 0.38 mmol), followed by phosphorous oxychloride (0.04 mL, 0.43 mmol). Stir the mixture at 0° C. for 2 h followed by addition of a second portion of phosphrous oxychloride (0.04 mL, 0.43 mmol). Stir the mixture at 0° C. for an additional 1 hour. Dilute the mixture with water and extract with EtOAc. Wash the combined organic phase with a saturated aqueous solution of sodium bicarbonate followed by a saturated aqueous solution of ammonium chloride and then brine. Dry the mixture over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.052 g of 3-[(R)-2-(4-cyano-phenylcarbamoyl)-pyrrolidin-1-yl]-benzoic acid ethyl ester as a solid.