Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](N)=[O:13])[CH2:5]1.[ClH:19]>O>[Cl:19][CH2:8][CH2:7][CH:6]1[CH2:5][N:4]([CH3:3])[C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[O:9]1
Reactant: CN1CCC(Oc2ccccc2C(N)=O)C1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CC(CCCl)Oc2ccccc2C1=O

Procedure:
To 54 g (1.35 mole) of sodium hydroxide in 800 ml of water was added 148 g (0.67 mole) of 2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide and the mixture brought to reflux for 18 hr. The pH was adjusted to 7 with hydrochloric acid and the solution filtered and concentrated. The residue was boiled with 400 ml of isopropanol and filtered. The filtrate was concentrated and the residue (which crystallized) was refluxed with 300 ml of thionyl chloride for 0.5 hr. and concentrated in vacuo. The residue was dissolved in 300 ml of chloroform and the solvent boiled off in vacuo. The residue was redissolved in chloroform, 150 ml of triethyl amine added and the mixture refluxed 1 hr. The solution was concentrated in vacuo and the residue partitioned between 400 ml of ethyl acetate, 400 ml of isopropyl ether and 500 ml of dilute hydrochloric acid. The organic layer was washed twice with water and once with dilute sodium hydroxide, dried with sodium sulfate and concentrated. The residue was crystallized from isopropanol-water. Yield of product was 75 g (47%), m.p. 97°-107° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)[CH2:9]1)=O)(C)(C)C.Cl.CCOC(C)=O.C(Cl)[Cl:33].CO>CCOC(C)=O>[ClH:33].[CH:20]1[C:21]2[C:16](=[C:15]([NH:14][CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:18][N:19]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cccc3cnccc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: c1cc(NC2CCCNC2)c2ccncc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a solution of 3-(isoquinolin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (80 g, 0.244 mol) in EtOAc (1000 mL) was added HCl-EtOAc (1000 mL) at room temperature. The mixture was stirred at room temperature for 2.5 hours. TLC (methylene chloride:methanol=10:1) showed the reaction was complete. The reaction mixture was filtered. The filtered cake was dried under vacuum to give the title compound (66 g, 100%) as a yellow solid.
Reaction SMILES: O1CCOCC1.Cl.[NH2:8][C:9]([NH2:11])=[NH:10].[OH-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:22]([NH:10][C:9]([NH2:11])=[NH:8])([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23]
Reactant: N=C(N)N
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N=C(N)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,4-Dioxane (20 ml) is added to a solution of guanidine hydrochloride (0.96 g, 10 mmol) and sodium hydroxide (0.8 g, 20 mmol) in water (10 ml) and the resulting mixture is cooled to 0° C. Benzyloxycarbonyl chloride (1.1 ml, 7.7 mmol) is added dropwise with vigorous stirring over a period of 10 min. After the addition is completed, the ice-bath is removed and stirring is continued for 1 h at room temperature. The mixture is concentrated in vacuo to one third of its original volume and extracted three times with ethyl acetate (20 ml each). The combined extracts are washed with brine (20 ml) and dried with anhydrous sodium sulfate. After filtering and removal of the solvent under reduced pressure N-Cbz-guanidine (1.31 g, 88%) is obtained as a white powder: mp: 120-122° C.; 1H NMR (360 MHz, DMSO-d6) δ 7.35-7.25 (m, 5H), 6.88 (br s, 4H), 4.95 (s, 2H); Electrospray-MS m/e 194 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8].[CH:9](I)([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:9]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8])([CH3:11])[CH3:10]
Reactant: CC(C)I
Reactant: NC1CCCCC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)NC1CCCCC1O
Reaction time: 20 h

Procedure:
19 Grams of 2-aminocyclohexanol, 20 g of isopropyl iodide and 15 g of potassium carbonate are added to 50 ml of dimethylformamide and the mixture is agitated at 80°-90° C. for 20 hours. After the reaction, the solution is concentrated and the residue is dissolved in chloroform, washed with water and then dried with anhydrous sodium sulfate (Na2SO4). After filtering off the desiccant, the mother liquor is concentrated and the residue is crystallized with petroleum ether. The obtained crystals are recrystallized from ethanol, resultantly obtaining 8 g of 2-isopropylaminocyclohexanol in the form of colorless crystals. m.p. 54°-55° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH2:15][OH:16])(=[O:12])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([N:24]=[CH:25][N:26]=2)[N:23]=1.[Cl-].[Na+]>CN(C)C=O.O1CCCC1>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH2:15][O:16][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[CH:25][N:26]=3)[N:23]=2)(=[O:12])=[O:11])[CH2:6][CH2:5]1
Reactant: CN1CCN(S(=O)(=O)CCCO)CC1
Reactant: Clc1ccc2ncnn2n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1CCN(S(=O)(=O)CCCOc2ccc3ncnn3n2)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 60.6 %

Procedure:
In 10 ml of dimethylformamide was suspended 0.21 g of 60% sodium hydride in oil followed by addition of 1.12 g of 3-(1-methyl-4-piperazinylsulfonyl)-1-propanol and the mixture was stirred under reduced pressure at room temperature for 75 minutes. Then, 0.773 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture was further stirred at room temperature for 1.5 hours. Following addition of 40 ml of ice water, the reaction mixture was saturated with sodium chloride. The aqueous layer was extrated with tetrahydrofuran and the extrat was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography, elution being carried out with dichloromethane-methanol (10:1). The fractions containing the desired product were pooled and concentrated to provide 1.032 g of the title compound. m.p. 140°-141° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid (3.7 g, 0.011 mol), 10% palladium on carbon (0.5 g) and ethanol (100 ml) is shaken on a Parr hydrogenator for 1.5 hours at a hydrogen pressure of 40 psi. The catalyst is filtered off and the filtrate is concentrated to yield 3-amino-4-phenoxy-5-sulfamoylbenzoic acid (IX-A).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@H:25]([O:27][CH3:28])[C@H:24]([O:29][CH3:30])[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O>O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][C@H:24]([O:29][CH3:30])[C@H:25]([O:27][CH3:28])[CH2:26]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CO[C@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1OC
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC
Reaction time: 8 h
Yield: 89.4 %

Procedure:
708 mg of N-iodosuccinimide was added little by little to a mixture of 783 mg of 2-benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)pyridine and 7.0 ml of N,N-dimethylformamide under ice-cooling, followed by stirring overnight as it was. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with sodium thiosulfate, water and brine, and the solvent was removed. Then, the residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (5:1) and then with hexane/ethyl acetate (3:1), to give 995 mg of the target compound.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a solution of benzyl alcohol (1.04 mL, 10.0 mmol) in dichloromethane (30 mL) is added rhodium (II) acetate dimer (40 mg) followed by ethyl diazoacetate (1.14 g, 10.0 mmol). The reaction mixture is stirred at RT for 20 min. The reaction mixture is rotary evaporated, and the residue is vacuum distilled at 110° C. to give 1.81 g of the product 390. 1H NMR (CDCl3) δ 7.4-7.26 (m, 5H), 4.65 (s, 2H), 4.23 (q, 2H), 4.10 (s, 2H), 1.30 (t, 3H)
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)=O.C([O-])(O)=O.[Na+]>Cl>[N+:16]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[C:12]([F:13])([F:14])[F:15])[NH2:5])([O-:18])=[O:17]
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 97 %

Procedure:
2,2-dimethyl-N-[3-nitro-4-(trifluoromethyl)phenyl]propanamide (45.0 g, 155.0 mmol) in 6N HCl (200 mL) was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and was carefully neutralized with solid NaHCO3 to pH=9. The reaction mixture was extracted with CH2Cl2 and dried over Na2SO4. The solvent was evaporated in vacuo to obtain the crude product 3-nitro-4-(trifluoromethyl)aniline (31.0 g, 97%), which was used directly for the next step.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][CH2:12][CH2:13][CH2:14]Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Br:11][CH2:12][CH2:13][CH2:14][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: BrCCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: BrCCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-iodophenol (1.0 g) in dimethylformamide (10 ml), 273 mg of sodium hydride and 0.603 ml of 1,3-dibromopropane were added under ice-cooling, and the reaction solution was stirred at room temperature for 1 hour. To the reaction solution was added 10% aqueous citric acid, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50/50)) to afford the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][C:19]([OH:21])=O)[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH:10]([CH3:26])[N:9]=1.ON1C2C=CC=CC=2N=N1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][C:19]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:21])[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH:10]([CH3:26])[N:9]=1
Reactant: Cc1nnc2n1-c1sc(CC(=O)O)cc1C(c1ccccc1Cl)=NC2C
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1sc(CC(=O)N3CCOCC3)cc1C(c1ccccc1Cl)=NC2C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.1 g of 2-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]acetic acid in 15 ml of dimethylformamide are added 0.4 g of N-hydroxybenzotriazole and 0.27 ml of morpholine and stirred at room temperature for 10 minutes. To the mixture is added 0.65 g of dicyclohexyl carbodiimide under ice-cooling and stirred for 1 hour and furthermore stirred at room temperature for 18 hours. The resulting dicyclohexylurea is filtered off and to the filtrate is added 50 ml of chloroform. The solution is washed with 5% aqueous sodium hydrogen-carbonate carbonate solution and water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from isopropyl ether. The precipitated crystals are collected by filtration and recrystallized from ethyl acetate to give 0.9 g of 2-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]acetic acid morpholide as colorless crystals, melting at 126°-129° C.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.[F:12][C:13]([F:26])([F:25])[O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[N:1]1[C:10]2[C:5](=[C:6]([NH:11][C:21]([NH:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]([F:12])([F:26])[F:25])=[CH:24][CH:23]=3)=[O:22])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Reactant: Nc1cccc2nnccc12
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)Nc1cccc2nnccc12

Procedure:
Prepared from cinnolin-5-amine [Sci Pharm. 1982, 50, 246] and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 363 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[F:17][C:18]1[C:31]([F:32])=[C:30](F)[C:29]([F:34])=[C:28]([F:35])[C:19]=1[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21]>N1C=CC=CC=1>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:30]2[C:29]([F:34])=[C:28]([F:35])[C:19]([C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21])=[C:18]([F:17])[C:31]=2[F:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCNC1
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(N2CCC(NC(C)=O)C2)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To 2.62 g (20.4 mmol) of 3-acetamidopyrrolidine dissolved in 50 mL of pyridine and cooled to 0° C. was added 2.06 g (20.4 mmol) of triethylamine and 5.24 g (18.6 mmol) of ethyl 2,3,4,5,6-pentafluorobenzoylacetate, from step 2 above. The solution was stirred at 0° C. for 1 hour, then at room temperature overnight. The solvent was removed by evaporation under vacuum and the residue was dissolved in chlorform, which was washed with 0.5N HCl and 5% potassium carbonate solution. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was further dried by adding and distilling off ethylene dichloride, chloroform and methylene, followed by further drying under vacuum. The crystalline residue was washed with hexane and dried to afford 6.8 g of the title compound as a tan solid, mp 90°-92° C. MS M/Z: 391 (M+H). IR (CDCl3): 1635, 1680, 1740 cm-1. NMR (CDCl3) d: 1.26 (m, 3H), 2.00 (m, 5H), 2.22 (m, 2H), 3.54 (m,1H), 3.77 (m, 2H), 3.85 (m, 1H), 3.98 (m, 1H), 4.22 (m, 2H), 5.75 (m, 1H). Analysis calculated for C17H18F4N2O4 : C, 52.31; H, 4.65; N, 7.18. Found: C, 52.47; H, 4.67; N, 7.33.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[C:28]([N+:34]([O-])=O)[CH:27]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][C:28]=2[NH2:34])[CH2:12]1)=[O:9])=[O:5]
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCl
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Nc1cc(Cl)ccc1CN1CC[C@@H](NC(=O)CNC(=O)c2cc(OC(F)(F)F)ccc2N)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-3-[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 4-chloro-2-nitrobenzyl chloride (0.050 mmol), peperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) was stirred overnight at 50° C. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with 50% CHCl3/CH3OH (10 mL) and CH3OH (10 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material was added ethanol (3 mL) and 10% Pd-C (15 mg), and the mixture was stirred under H2 at room temperature for 1.5 h. Filtration, concentration, and preparative TLC afforded (R)-3-[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}amino]-1-(2-amino-4-chlorobenzyl)pyrrolidine (Compound No. 1921) (2.2 mg, 6%): The purity was determined by RPLC/MS (81%); ESI/MS m/e 486.2 (M++H, C21H23ClF3N5O3).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[N:6]=[C:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]3[CH2:27][CH3:28])[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:10]=2[N:11]=1.[CH3:29][O:30][P:31]([O:34]C)[O:32][CH3:33]>>[CH3:29][O:30][P:31]([CH2:2][C:3]1[S:4][C:5]2[N:6]=[C:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]3[CH2:27][CH3:28])[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:10]=2[N:11]=1)(=[O:34])[O:32][CH3:33]
Reactant: COP(OC)OC
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)sc2n1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CP(=O)(OC)OC)sc2n1
Temperature: 120 °C
Yield: 87 %

Procedure:
A mixture of 2-bromomethyl-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (670 mg, 1.46 mmol) in trimethylphosphite (10 mL) was heated to reflux (120° C.) for 1 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-2%) then (Si—PCC, MeOH:EtOAc, 0-5%) affording the title compound as a yellow solid (620 mg, 87%)._LCMS (method H): RT 2.46 min, [M+H]+ 489.3
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.CC1N(C2CC[C:36](=[O:39])NC2=O)C(=O)C2C(=CC=CC=2[N+]([O-])=O)N=1>C(O)=O>[O:20]=[C:14]1[CH:13]([N:5]2[C:4](=[O:21])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][CH:36]=[O:39])[N:7]=[C:6]2[CH3:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O
Solvent: O=CO
Product: Cc1nc2cccc(NC=O)c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In another embodiment, provided herein is a method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof comprising the steps of (a) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione in a solvent in the presence of formic acid to form N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide; and (b) hydrolyzing N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide in a solvent to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; wherein steps (a) and (b) are each as described herein elsewhere.
Reaction SMILES: Cl.[CH:2]1([CH2:8][C@H:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:21](O)[CH3:22]>O>[NH2:10][C@H:9]([CH2:8][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[C:11]([O:13][CH2:21][CH3:22])=[O:12]
Reactant: CCO
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)[C@H](N)CC1CCCCC1
Temperature: 80 °C

Procedure:
The process is performed as in Example 2, starting with 10 g of β-cyclohexyl-(D)-alanine hydrochloride in 96 cm3 of absolute ethanol, by treating it with a stream of dry hydrogen chloride at a temperature in the region of 0° C. for 20 minutes. After heating to about 80° C. for 4 days, followed by cooling to 0° C., the mixture is again treated with a stream of hydrogen chloride for 20 minutes, followed by heating to a temperature in the region of 80° C. for 20 hours. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C., and the residue obtained is dissolved in 200 cm3 of water, made alkaline by addition of 19 g of solid potassium carbonate. After evaporation, the resulting solid is taken up in 200 cm3 of ethanol at a temperature in the region of 80° C. The insoluble material is filtered off and the filtrate is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in 130 cm3 of ethanol at room temperature. The insoluble material is filtered off and the filtrate is again evaporated under the same conditions as above. 4.8 g of ethyl (2R)-2-amino-3-cyclohexylpropionate are obtained in the form of a whitish paste. (Rf=0.80 in a 90/10 by volume mixture of ethanol/aqueous ammonia, on a Merck 60F254R silica plate).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH:4]=[CH:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].[OH-].[Na+].CCCCCC.CC(C)=[O:24]>CO>[F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([NH2:10])=[O:24])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: N#CC=CNC=CC(=O)C(F)(F)F
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Product: NC(=O)c1cnccc1C(F)(F)F
Yield: 65.6 %

Procedure:
3-[(4,4,4-Trifluoro-3-oxo-1-butenyl)amino]-2-propenenitrile (a low-polar compound IIa; 1.90 g, 10 mmol) was dissolved in methanol (15 ml), and sodium hydoxide (600 mg, 15 mmol) was added. The mixture was heated under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/acetone=1/1) to obtain 1.25 g (yield 65.6%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][SH:17])=[CH:14][CH:13]=1.[Na]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:16]([S:17][CH:16](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)[C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: C#Cc1ccc(C)cc1C
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2C)c2ccc(Cl)cc2)c2ccc(Cl)cc2)c(C)c1

Procedure:
A solution of 2,4-dimethylphenylacetylene (0.02 mol), 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-dimethylstyryl-4-chlorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.