Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C@@H:30]2[CH2:34][CH2:33][CH2:32][NH:31]2)[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[C@H:27]([CH3:28])[CH2:26][C@@H:25]([OH:29])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.C=O.[CH:37](O)=O.C([O-])(O)=O.[Na+].Cl.O1CCOCC1>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C@@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH3:37])[C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[C:20]4[C@H:27]([CH3:28])[CH2:26][C@@H:25]([OH:29])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:17][CH2:18]2)=[O:12])=[CH:6][CH:5]=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=CO
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4C)CC3)c21
Reaction time: 0.5 h

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 di-hydrochloride (0.213 g, 0.4027 mmol) was treated with 37% aqueous formaldehyde (0.1109 mL, 4.027 mmol), formic acid (0.1519 mL, 4.027 mmol) and water (400 uL). The mixture was heated to reflux for 6 hours. After cooling, the reaction was neutralized with saturated NaHCO3 and then extracted with methylene chloride. The aqueous was extracted with methylene chloride (2×). The combined organic portions were dried over Na2SO4 and concentrated in vacuo. The residue was subjected to chromatography on SiO2 and eluted with a stepped gradient from 2% MeOH/1% NH4OH/dichloromethane to 5% MeOH/1% NH4OH/dichloromethane. The free base was collected and concentrated in vacuo. The residue was concentrated from MeOH and then re-dissolved in MeOH. The solution was treated with HCl in dioxane (4M, 1 mL, 4 mmol). The solution was concentrated in vacuo, re-suspended in MeOH and re-concentrated three times. The solution was re-dissolved in MeOH (0.25 mL+0.125 mL wash) and added dropwise to a stirred flask containing Et2O (15 mL). The suspension was stirred for 30 minutes. The suspension was then filtered, washed with Et2O and dried under a blanket of nitrogen. (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)-1-methylpyrrolidin-2-yl)ethanone dihydrochloride was recovered as a solid (0.117 g, 62%). MS (ESI+) [M+H] 470.1/472.1. 1H NMR (CD3OD, 400 MHz) δ 8.57 (s, 1H), 7.47-7.41 (dd, 4H), 5.31 (t, J=8.0 Hz, 1H), 4.54 (d, J=9.1 Hz, 1H), 4.25-4.16 (m, 2H), 4.11-4.05 (m, 1H), 3.93-3.62 (m, 6H), 3.51-3.42 (m, 1H), 3.26-3.17 (m, 1H), 2.95 (s, 3H), 2.34-2.26 (m, 1H), 2.23-2.06 (m, 3H), 2.05-1.92 (m, 1H), 1.85-1.73 (m, 1H), 1.21-1.16 (d, 3H).
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.C(N(CC)CC)C.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>O>[CH:26]1([C:29]([N:9]2[CH2:10][CH:11]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([CH2:12]3)[CH2:8]2)=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc(C23CNCC2C3)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N1CC2CC2(c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To a stirred slurry of 61.2 g. of 1-phenyl-1,2-cyclopropanedicarboximide (U.S. Pat. No. 3,166,571, Ex. 8) in 2 liters of benzene is added 400 ml. of Vitride® under nitrogen. The mixture is stirred at room temperature for 2 hours, refluxed for 4 hours and then stirred at room temperature for 20 hours. A 400 ml. portion of 10 N sodium hydroxide is added cautiously with stirring. The organic layer is washed twice with dilute sodium hydroxide and then with water, dried over magnesium sulfate and evaporated to give an amber oil. This oil is dissolved in dilute hydrochloric acid, washed with ether, filtered and the filtrate made basic with sodium hydroxide. The basic filtrate is extracted with benzene, dried over magnesium sulfate, filtered and evaporated to give 1-phenyl-3-azabicyclo[3.1.0]hexane as an amber oil. To a solution of 15.9 g. of 1-phenyl-3-azabicyclo[3.1.0]hexane in 100 ml. of benzene and 20 ml. of triethylamine is added 11.0 g. of cyclopropanecarboxylic acid chloride in 20 ml. of benzene over 5 minutes. The mixture is stirred for 30 minutes and 50 ml. of water is added. The benzene layer is extracted with dilute sodium bicarbonate followed by dilute hydrochloric acid and then water, dried over magnesium sulfate and evaporated to give the product 3-cyclopropylcarbonyl-1-phenyl-3-azabicyclo[3.1.0]hexane as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])(C)C.O=O>[N+]([O-])([O-])=O.[Mn+2].[N+]([O-])([O-])=O.C(O)(=O)C>[C:5]([CH:4]=[CH:1][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([CH3:10])([CH3:6])[CH3:1]
Reactant: CC(C)(C)c1ccccc1
Agent: [Mn+2]
Agent: O=O
Agent: O=[N+]([O-])[O-]
Solvent: CC(=O)O
Product: CC(C)(C)C=Cc1ccccc1
Reaction time: 10 h

Procedure:
To an aqueous solution containing 0.5 g of manganese nitrate was added 10 ml. of silica gel particles. After being evaporated to dryness, the mixture was calcined at 450°C for 10 hours. The thus obtained silica gel was immersed in 10 ml. of pyridine solution containing dissolved therein 0.02 g of palladium propionate and 0.1 g of uranium acetate, and then evaporated to dryness to obtain a catalyst. The catalyst (10 ml.), 10 ml. of tert-butylbenzene and 1 ml. of acetic acid were enclosed in a similar bomb to that used in Example 4, and etylene and oxygen were introduced into the bomb both in terms of a pressure of 20 kg/cm2 from the upper valve. The reaction was carried out at 140°C for 10 hours with shaking. tert-Butylstyrene was yielded in a proportion of 1200 %, based on the mole of palladium in the catalyst used.
Reaction SMILES: O1CCOCC1.[CH3:7][C:8]1[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:10](=[O:17])[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1.C(OC(=O)C)(=O)C.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]=O>C(=O)(O)[O-].[Na+]>[CH3:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:9]1[C:10](=[O:17])[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:8]1[CH:7]=[CH:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=1
Reactant: Cc1ccccc1-n1c(C)nc2ccsc2c1=O
Reactant: O=Cc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: Cc1ccccc1-n1c(C=Cc2ccccn2)nc2ccsc2c1=O
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To a mixture of fused zinc chloride (2.13 g, 15.6 mmol) and dioxane (75 mL), 2-methyl-3-(2-methylphenyl)-3H-thieno[3,2-d]pyrimidin-4-one (2.0 g, 7.81 mmol, preparation 2), and acetic anhydride (2.2 mL, 23.4 mmol) was added 2-pyridine carboxaldehyde (2.2 mL, 23.4 mmol). The reaction was refluxed 1.5 hours, cooled to ambient temperature, and diluted with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic extracts were washed with water and brine, dried over sodium sulfate and concentrated to leave a dark residue. This material was flash chromatographed on silica gel (45×125 mm). Elution with 20% ethyl acetate/hexane removed an unweighed impurity. Continued elution with 40% ethyl acetate/hexane gave a sticky yellow foam. The foam was triturated with 5% ethyl acetate/hexane to yield 1.9 g (70%) of 3-(2-methyl-phenyl)-2-[2-pyrid-2-yl-vinyl]-3H-thieno[3,2-d]pyrimidin-4-one as a yellow solid.
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]([C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40])#[CH:36].[ClH:44]>C(O)(C)C.CO.C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[ClH:44].[CH2:1]([S:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:40][C:39]3[CH:41]=[CH:42][CH:43]=[C:37]([C:35]#[CH:36])[CH:38]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: C#Cc1cccc(N)c1
Reactant: CCCSc1ccc2c(=O)[nH]cnc2c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(SCCC)ccc23)c1

Procedure:
7-Propylsulfanyl-quinazolin-4-one (300 mg, 1.36 mmol), triphenylphosphine (785 mg, 2.99 mmol), 1.31 mL of carbon tetrachloride and 5 mL of chloroform were refluxed for 16 hours and the reaction mixture was concentrated in vacuo to a residue which was diluted with 5 mL of isopropyl alcohol and 3-ethynylaniline (175 mg, 1.49 mmol) and refluxed for 3 hours. The cooled reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluted with 10% methanol in chloroform. Fractions containing the pure title product, as the frree amine, were concentrated in vacuo to afford solid which was added to 3 mL of 1N HCl in methanol. This solution was evaporated in vacuo to a residue which was triturated with 4 mL of hot isopropyl alcohol cooled and filtered. The solid thus obtained was dried in vacuo at 70° C. to afford pure title product; 239 mg (55%); mp 229°-230° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[N:4][C:5]([NH:20][CH2:21][C:22](O)=[O:23])=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.CC(C[Al]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[C:3]([F:25])=[N:4][C:5]([NH:20][CH2:21][CH2:22][OH:23])=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)c(F)nc(NCC(=O)O)c2Cl)ccc1O
Agent: CC(C)C[Al]CC(C)C
Solvent: C1CCOC1
Product: CC(C)c1cc(Oc2c(Cl)c(F)nc(NCCO)c2Cl)ccc1O

Procedure:
By reduction of the methyl ester of 3,5-dichloro-2-fluoro-4-(3-isopropyl-4-hydroxyphenoxy)-6-hydroxycarbonyl-methylaminopyridine (example 2), with Dibal-H in THF.
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)([CH2:5][OH:6])[CH2:3][OH:4].C1COCC1.C([O-])([O-])=O.[Na+].[Na+].[Cl:25][CH2:26][C:27](Cl)=[O:28]>O>[Br:13][C:9]1[CH:8]=[C:7]([C:2]([NH:1][C:27](=[O:28])[CH2:26][Cl:25])([CH2:5][OH:6])[CH2:3][OH:4])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCl
Reactant: NC(CO)(CO)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCl)NC(CO)(CO)c1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a stirred suspension of 2-amino-2-(3-bromo-phenyl)-propane-1,3-diol (3.5 g, 14.22 mmol), 30 ml of THF and 30 ml of 10% aqueous Na2CO3 solution was added dropwise chloroacetyl chloride (1.472 ml, 18.5 mmol) at 0° C. over a period of 10 min. The mixture was stirred for 1 h, diluted with water and extracted with EtOAc. The organic phase was washed with 1N aqueous NaOH solution, 10% aqueous Na2CO3 solution and brine. Chromatography on silica gel (EtOAc/hexane 50-30%) gave the title compound in the form of a colourless solid. TLC (hexane/EtOAc=1:1): Rf=0.21; HPLC: RtH2=2.926 min; 1H-NMR (400 MHz, CD3OD): 7.58 (s, 1H), 7.44 (d, 1H), 7.37 (d, 1H), 7.29 (t, 1H), 4.91 (s, 2H), 4.07 (d, 2H), 4.00 (d, 2H); MS: 322, 324, 326 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14]C)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:25]([C:24]3[CH:28]=[CH:29][C:21]([CH3:20])=[CH:22][CH:23]=3)=[O:26])=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C1CCc2ccc(OC)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1CCc2cc(C(=O)c3ccc(C)cc3)c(O)cc21
Temperature: 25 °C

Procedure:
A solution of 20.6 g of 6-methoxy-indane-1-carboxylic acid methyl ester in a little methylene chloride is first slowly added dropwise, at 0° to 10° C, to a suspension of 66.8 g of finely powdered aluminum chloride in 100 ml of methylene chloride, which is being stirred under anhydrous conditions; 46.3 g of p-methylbenzoyl chloride are then added dropwise under such conditions that the reaction mixture boils gently under reflux. After completion of the addition, the mixture is heated to the boil for a further 31/2 hours. It is then allowed to cool to room temperature, poured onto 500 g of ice and extracted with twice 500 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo (finally in a high vacuum). The evaporation residue, when crystallized from cold ether-petroleum ether, gives 5-(p-toluoyl)-6-hydroxyindane-1-carboxylic acid methyl ester which after a further crystallisation from ethanol-petroluem ether, melts at 74°-76° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)C.Cl>CO.C1COCC1>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:21])=[O:5])=[CH:8][CH:9]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cn1
Temperature: 35 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A 1N sodium hydroxide solution (20 mL) is added to a mixture of 4-(6-methoxy-pyridin-3-yl)-benzoic acid ethyl ester (2.43 g, 9.44 mmol) in MeOH (20 mL) and THF (20 mL) and stirred at 35° C. for 1 hour. The reaction is cooled and 1N HCl added until the pH is˜4. The precipitate is isolated by filtration and dried in a vacuum desiccator to give a the product as a white solid (2.03 g, 8.86 mmol). 1H NMR (DMSO-d6, 300 MHz) δ8.57 (d, 1H), 8.08 (dd, 1H), 7.99 (d, 2H), 7.82 (d, 2H), 6.95 (d, 1H), 3.89 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][CH2:3]1>CO>[CH3:1][N:2]1[C@H:11]2[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[NH:5][CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)OCc2ccccc2)[C@H]2CCCC[C@H]21
Solvent: CO
Product: CN1CCN[C@H]2CCCC[C@H]21
Yield: 144.1 %

Procedure:
Phenylmethyl (4aR,8aS)-4-methyloctahydro-1(2H)-quinoxalinecarboxylate (Example 221) (2.58 g, 9.0 mmol) was dissolved in 120 mL of MeOH, degassed and placed under argon. 10% Pd/C (380 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for approximately 2 hrs. The contents were then degassed and filtered through Celite, and the Celite pad was washed with DCM and MeOH. After 19.0 mL 1N HCl was added, the resulting filtrate was concentrated in vacuo to provide the hydrochloride salt of (4aS,8aR)-1-methyldecahydroquinoxaline (2.0 g, 100%). LCMS: (M+H)+: 155.1.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:9]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([CH:27]([OH:54])[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40](=[O:49])[C@H:41]([CH:46]([CH3:48])[CH3:47])[NH:42][C:43](=[O:45])[CH3:44])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH:6]([CH3:8])[CH3:7])(=[O:3])[CH3:2]>CC(C)=O.[Cr](O)(O)(=O)=O>[C:1]([NH:4][C@H:5]([C:9]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([C:27](=[O:54])[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40](=[O:49])[C@H:41]([CH:46]([CH3:48])[CH3:47])[NH:42][C:43](=[O:45])[CH3:44])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:10])[CH:6]([CH3:7])[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H](C(=O)N[C@H](C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@@H](NC(C)=O)C(C)C)C(C)C)C(C)C)C(C)C
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Product: CC(=O)N[C@H](C(=O)N[C@H](C(=O)NC(Cc1ccccc1)C(=O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@@H](NC(C)=O)C(C)C)C(C)C)C(C)C)C(C)C
Reaction time: 1.25 h
Yield: 8.8 %

Procedure:
A solution of the resultant compound of Example 59 (0.056 mmol) in 10 ml of acetone was cooled to 0° C. and treated with 5 drops of aqueous chromic acid. After 1.25 h, the solution was quenched with 2-propanol and aqueous NaHCO3, filtered through Celite, extracted with 10% methanol in chloroform, and concentrated in vacuo. Flash chromatography using 7.5% methanol in chloroform gave 3.7 mg (9%) of the desired compound (Rf 0 39, 10% methanol in chloroform). Mass spectrum (M+H)+ =749.
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=O)NC=1)=[O:2].[H-].[Na+].CI.N1C=CC(=O)NC1=O.[CH3:23][N:24]([CH:26]=[O:27])[CH3:25]>O.CO>[CH3:23][N:24]1[CH:25]=[C:3]([CH:1]=[O:2])[C:4](=[O:10])[N:5]([CH3:6])[C:26]1=[O:27]
Reactant: O=Cc1c[nH]c(=O)[nH]c1=O
Reactant: CN(C)C=O
Agent: O=c1cc[nH]c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CO
Product: Cn1cc(C=O)c(=O)n(C)c1=O
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a slurry of 400mg of 5-formyluracil (2.8 mM) in DMF (10 mL) at room temperature was added sodium hydride (280 mg, 7 mM, 60% in oil). After stirring for 30 min., MeI (1.013 g, 7.2 mM) was added. When the turbid reaction mixture became a homogeneous yellow solution tlc revealed the absence of starting uracil. The reaction mixture was treated with MeOH and water, concentrated on the rotovap and the residue partitioned between MeOH and hexane. The MeOH fraction was concentrated and the residue partitioned between chloroform and water. The organic phase dried (MgSO4), filtered and concentrated to give 420 mg (89% yield) of 1,3-dimethyl-5-formyluracil as an off-white waxy solid. 1H-NMR (DMSO-d6), δ=9.82 (s, 1H), 8.52 (s, 1H), 3.43 (s, 3H), 3.2 (s, 3H). LC/MS; rt=0.34 mins. m/z=169, [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[CH2:11][NH:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[CH2:11][N:12]([CH3:13])[C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: CNCc1cc(Br)ccc1OCc1ccccc1
Product: CCCCCCCC(=O)N(C)Cc1cc(Br)ccc1OCc1ccccc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 6 g (19.6 mmol) of N-(2-benzyloxy-5-bromo benzyl)-N-methylamine with 3.4 ml (19.6 mmol) of octanoyl chloride, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (8/2), 8 g (95%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=O)=[CH:6][CH:5]=1>>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]2[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]([OH:13])=[N:2][N:1]=2)=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Product: Oc1nnc(-c2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 3 M ethanolic solution of hydrazine (20 ml, 60 mmol) is added to 2-(4-chlorobenzoyl)benzoic acid (5.5 g, 20 mmol), and the mixture is stirred at room temperature for 5 hours. Precipitation gives 4-(4-chlorophenyl)-1-hydroxy-phthalazine.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[CH:13](Br)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH:13]([N:2]([CH3:1])[CH2:3][CH2:4][NH:5][CH3:6])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNCCN(C)C(c1ccccc1)c1ccccc1

Procedure:
15.1 g (171 mmol) N,N′-dimethylethylenediamine, 35 g (255 mmol) potassium carbonate are placed in 250 ml DMF and 30.9 g (125 mmol) benzhydryl bromide are added dropwise at RT. The mixture is concentrated under vacuum. The residue is taken up in chloroform and washed with water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The purification occurs by chromatography on silica gel with chloroform: Yield 14.5 g (45%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>C(Cl)Cl>[CH3:14][O:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH2:2][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(OC)cc1CBr
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(OC)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of methyl 2-(bromomethyl)-4-methoxybenzoate (960 mg, 3.7 mmol) in DCM (18.5 mL) was added morpholine (0.68 mL, 7.8 mmol). The reaction mixture was stirred at room temperature overnight and poured onto iced water. The aqueous mixture was extracted with DCM (3×), and the combined organics were dried over MgSO4, filtered, and concentrated in vacuo to provide a yellow oil. The crude material was purified by flash chromatography on silica using a gradient of EtOAc in hexane (0 to 50%) as eluant. The tittle product was obtained as a clear oil (490 mg, 50%)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH:3]1[OH:12].[NH2:13][C:14]1[C:19]([C:20]([C:22]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]([F:30])[C:23]=2[F:31])=[O:21])=[CH:18][N:17]=[C:16](Cl)[N:15]=1.C(N(C(C)C)CC)(C)C>C(O)C>[NH2:13][C:14]1[C:19]([C:20]([C:22]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]([F:30])[C:23]=2[F:31])=[O:21])=[CH:18][N:17]=[C:16]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH:3]2[OH:12])[N:15]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(Cl)nc1N
Reactant: CS(=O)(=O)N1CCC(N)C(O)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2O)nc1N

Procedure:
The amine (44 mg, 0.22 mmol, Example 305) and chloropyrimidine (55 mg, 0.18 mmol, Example 289) were dissolved in ethanol (5 mL). To the stirred mixture at reflux, diisopropylethylamine (64 uL, Aldrich) was added and the mixture was refluxed for 20 hours. The solvent was removed and the residue was purified by HPLC (10-60%, acetonitrile/water) to give a white solid, 25 mg, 30%. MS (ES) MH+=458.
Reaction SMILES: [BrH:1].C([N:9]([CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:27]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[CH:26]=1)=[O:24])[CH2:10][CH2:11][NH:12][C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.C(O)C>O.[C].[Pd]>[C:39]([O:38][C:27]1[CH:26]=[C:25]([CH:23]([OH:24])[CH2:22][NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:30]=[CH:29][C:28]=1[O:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:36])[CH3:34])(=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43].[BrH:1]
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(=O)C(C)(C)C
Agent: [Pd]
Agent: Br
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)Oc1ccc(C(O)CNCCNC(=O)Cc2ccccc2)cc1OC(=O)C(C)(C)C
Reaction time: 18 h

Procedure:
A solution of 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-bis(pivaloyloxy)acetophenone hydrobromide (2.5 g.) in a mixture (50 ml.) containing 70% v/v of ethanol in water was hydrogenated for 18 hours at a pressure of 3.5 kg./cm2 at room temperature using 10% palladium-carbon (0.8 g.). The catalyst was separated by filtration and the filtrate evaporated. Trituration of the residue with ether (30 ml.) containing several drops of ethanol gave 1-[3,4-bis(pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)ethylamino]ethanol as its hydrobromide (1.7 g.) m.p. 111°-113° C. (hemi-hydrate).