Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:47]C1C=CC(CCCCCCCCCCCCCCCCCCO)=CC=1>C(Cl)Cl.C1C=CC=CC=1>[I:47][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCCCCCCCCCCCCCCCO
Reactant: OCCCCCCCCCCCCCCCCCCc1ccc(I)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCCCCCCCCCCI
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 90 %

Procedure:
Ethyl 17-hydroxy-heptadecanoate 79 (264 mg, 0.84 mmol), Ph3P (262 mg, 1 mmol) and imidazole (94 mg, 1.39 mmol) were dissolved in the mixture of CH2Cl2 (3 ml) and benzene (3 ml) and cooled to 0° C. Solid 12 (254 mg, 1 mmol) was added and the reaction mixture was stirred at 0° C. for 40 min. The reaction mixture was quenched by addition of MeOH (0.5 ml), diluted with EtOAc and washed with the aqueous NaHCO3—Na2S2O3 solution, dried over Na2SO4 and evaporated. Chromatography in hexane-EtOAc (97:3) afforded the product 80 (321 mg, 90%).
Reaction SMILES: C(S[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH3:15])[C:7](=[O:16])[CH2:6][N:5]=1)C.[CH:17]([NH:19][NH2:20])=O>C(O)CCC>[CH3:15][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4]2=[N:20][N:19]=[CH:17][N:5]2[CH2:6][C:7]1=[O:16]
Reactant: NNC=O
Reactant: CCSC1=NCC(=O)N(C)c2ccccc21
Solvent: CCCCO
Product: CN1C(=O)Cn2cnnc2-c2ccccc21
Reaction time: 16 h

Procedure:
A mixture of 1,3-dihydro-5-(ethylthio)-1-methyl-2H-1,4-benzodiazepin-2-one (1 eq.) and formic hydrazide (5.8 eq. Aldrich) in n-butanol (0.1 M in benzodiazepine) was stirred at reflux under N2 for 24 hours. An additional 1.67 eq. of formic hydrazide was added and refluxing continued an additional 16 hours. The yellow solution was evaporated in vacuo and the residue was purified via flash chromatography eluting with a gradient from 98:2 to 96:4 CH2Cl2/MeOH.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c1c(-c1csc(C(=O)NC3CC3)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(NC1CC1)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-cyclopropylthiophene-2-carboxamide (68.4 mg) in acetonitrile (10 mL) were added sodium iodide (53.6 mg) and chloro(trimethyl)silane (0.181 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (56.8 mg).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:32]=1[CH2:33]Br>C(O)C.O.O1CCOCC1>[F:39][C:36]1[CH:37]=[CH:38][C:31]([C:30]([F:29])([F:40])[F:41])=[C:32]([CH2:33][S:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:28])([F:27])[F:15])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: O=S(=O)(Cc1cc(F)ccc1C(F)(F)F)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
Sodium sulfite (102 g, 809 mmol) was added to sodium phosphate, dibasic (58 g, 409 mmol) and water (550 ml). 4-(trifluoromethyl)benzenesulfonyl chloride (100 g, 409 mmol) and dioxane (65 ml) were then added to the reaction mixture. The reaction was heated to reflux. After 75 min, the reaction was cooled slightly and a solution of 2-trifluoromethyl-5-fluoro-benzyl bromide (75 g, 292 mmol) in ethanol (95 ml) were added and the mixture was refluxed for 1 hr. The reaction was diluted with water (400 ml) and cooled to 0° C. for 1 hr. The reaction mixture was filtered and the solid was washed with water (2×400 ml) and then with heptane (200 ml). The residue was dried under vacuum to a constant weight and carried to the next step without further purification.
Reaction SMILES: C1(S(C=C(SC)SC)(=O)=O)C=CC=CC=1.C[C:17]1[N:18]=CN[C:21]=1[CH2:22]SCCN.[C:27]1([S:33]([CH:36]=[C:37](SC)[NH:38][CH2:39][CH2:40][S:41][CH2:42][C:43]2[NH:47][CH:46]=[N:45][C:44]=2[CH3:48])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N)C#C>>[C:27]1([S:33]([CH:36]=[C:37]([NH:18][CH2:17][C:21]#[CH:22])[NH:38][CH2:39][CH2:40][S:41][CH2:42][C:43]2[NH:47][CH:46]=[N:45][C:44]=2[CH3:48])(=[O:34])=[O:35])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=CS(=O)(=O)c1ccccc1)NCCSCc1[nH]cnc1C
Agent: C#CCN
Agent: CSC(=CS(=O)(=O)c1ccccc1)SC
Product: C#CCNC(=CS(=O)(=O)c1ccccc1)NCCSCc1[nH]cnc1C

Procedure:
Reaction of methylphenylsulfone with carbon disulphide under strongly basic conditions and treatment of the product with methyl iodide yields 1-benzenesulphonyl-2,2-bis(methylthio)ethylene. When 1-benzenesulfonyl-2,2-bis(methylthio)ethylene is reacted with 2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamine according to the procedure of Example 6, Step A, the product is 1-benzenesulfonyl-2-methylthio-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene. Reaction of this methylthio compound with propargylamine by the procedure of Example 6, Step B, yields the title compound.
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[CH2:22][O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:8])[N:6]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:2]2[O:3][CH:4]=[C:5]([C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]3[CH2:22][O:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:8])[N:6]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Cl)n2)C(COc2cccnc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)co2)cc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A solution of tert-butyl 4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (117 mg, 0.277 mmol), p-anisidine (68 mg, 0.554 mmol) and potassium carbonate (76 mg, 0.554 mmol) in THF (2 mL) was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was filtered and concentrated under reduced pressure. The material was purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient), yielding 35.5 mg (25%) of the title compound as the TFA salt. LC-MS: RT=6.76 min, [M+H]+=510.0.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:18][CH:19]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1
Reactant: CN(C)C(=O)CBr
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCC(=O)N(C)C)cc3)cc12

Procedure:
2-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)-N,N-dimethylacetamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) and following the procedure described for Example 139, but using 2-bromo-N,N-dimethylacetamide. 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.70 (s, 1H), 8.28 (d, 1H), 7.40 (s, 1H), 7.18 (t, 3H), 6.87 (d, 2H), 6.56 (br, 2H), 4.72 (s, 2H), 3.20 (t, 2H), 3.07 (s, 3H), 3.05 (t, 2H), 2.87 (s, 3H), 2.45 (s, 3H). LRMS [M+H]=415.2
Reaction SMILES: [Br:1][CH2:2][C@@:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24])([O-:15])=[O:14].C(N(CC)CC)C>C1COCC1>[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:4](=[O:5])[C@:3]([OH:8])([CH3:7])[CH2:2][Br:1])=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26])([O-:15])=[O:14]
Reactant: C[C@](O)(CBr)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: C[C@](O)(CBr)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A 50 L flask was set up with a mechanical stirrer, inlet for inert atmosphere, and cooling capacity. The flask was placed under an argon atmosphere and was charged with 2961.5 g (16.2 moles) of R-131 and 9.0 L of THF. The flask was cooled on ice to less than 5° C. Thionyl chloride (1200 mL, 16.4 moles) dissolved in 6.0 L of THF was added slowly via an addition funnel to the reaction flask. The temperature of the reaction flask was maintained less than or equal to 10° C. The addition time was 1 hour 10 minutes. The reaction mixture was allowed to agitate for an additional 2 hours 50 minutes. Then a solution of 2359.4 g of (11.4 moles) of 4-nitro-3-trifluoromethylaniline (Aldrich, 98%) and 3.83 L of triethylamine in 6.0 L THF was added over a period of 3 hours 5 minutes. The temperature of the reaction flask was maintained less than or equal to 10° C. The ice bath was removed, and the reaction mixture was allowed to stir for 30 minutes. With a heating mantle, the reaction mixture was heated to 50° C. for 15 hours and 10 minutes. After the reaction was complete as analyzed by TLC, the reaction mixture was cooled to less than 30° C. and 7.5 L of deionized water was added. The aqueous layer was removed and a second water wash (7.5 L) was performed. The organic layer was then washed three times with 10% bicarbonate (8.1 L) until the pH was greater than 7.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].BrC[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21].[C:22](=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[CH3:19][O:18][C:15]1[CH:16]=[C:17]([CH:12]=[C:13]([O:20][CH3:21])[CH:14]=1)[CH2:22][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CBr)c(OC)c1
Reactant: O=Cc1ccccc1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(COc2ccccc2C=O)cc(OC)c1

Procedure:
Salicylaldehyde (0.32 cm3, 3.00 mmol), 4-bromomethyl-1,3-dimethoxybenzene (0.63 g, 2.73 mmol), potassium carbonate (0.42 g, 3.00 mmol), and 18-crown-6-ether (0.07 g, 0.27 mmol) were stirred together at room temperature in acetone (50 cm3, 99%) under nitrogen for 18 hours. The solution was evaporated under reduced pressure, and the residue was taken up in dichloromethane (20 cm3) and water (20 cm3). The aqueous layer was extracted with dichloromethane (2×20 cm3), and the combined extracts were washed with water (2×50 cm3), dried (MgSO4), and evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane:ethyl acetate, 5:1) to give a white crystalline solid. The solid was recrystallized from heptane and ethyl acetate to give the ether, (0.58 g, 78%), as white fibrous needles, mp 68-69° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][O:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+:29]>O1CCCC1>[C:1]1([C:7]#[C:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][O:19][CH2:20][C:21]([O-:23])=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:29]
Reactant: CCOC(=O)COCc1nc2ccccn2c1C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])COCc1nc2ccccn2c1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45 %

Procedure:
0.061 g (0.182 mmol) of ethyl 2-((3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)acetate were solubilised with magnetic stirring in 3 ml of a mixture consisting of methanol and tetrahydrofurane (1/1, v/v) and then 0.173 ml (0.173 mmol) of a 1N NaOH aqueous solution were added. The mixture was stirred at r.t. for 2 d before being concentrated in vacuo. The crude residue was triturated in 3 ml of diisopropyl ether, the obtained solid was isolated by filtration and dried under a vacuum bell jar in order to obtain 0.027 g (yield=45%) of sodium 2-((3-(phenyl ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)acetate. LC-MS: m/z=307 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.62 (d, J=6.7 Hz, 1H), 7.79-7.58 (m, 3H), 7.45 (dd, J=8.8, 7.2 Hz, 4H), 7.13 (t, J=6.5 Hz, 1H), 4.74 (s, 2H), 3.70 (s, 2H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11])=O.O.[NH2:19][NH2:20]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:8]2[C:9](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:11])[NH:20][N:19]=1
Reactant: NN
Reactant: COC(=O)c1ccccc1C(=O)c1cccs1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2cccs2)c2ccccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-(thiophene-2-carbonyl)benzoate (0.445 g, 1.81 mmol) and hydrazine hydrate (0.40 mL, 7.1 mmol) in ethanol (6 mL) was stirred at 80° C. overnight, concentrated, and azeotroped with toluene to give the title compound, which was used without purification: 1H NMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.42-8.28 (m, 1H), 8.23-8.09 (m, 1H), 7.95 (dtd, J=19.0, 7.3, 1.5, 2H), 7.82-7.69 (m, 1H), 7.68-7.55 (m, 1H), 7.33-7.19 (m, 1H), 4.12 (s, OH), 1.91 (s, OH), 1.74 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:19][O:18][C:15]1[N:16]=[CH:17][C:12]([NH:11][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(N)cn1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncccc2[N+](=O)[O-])cn1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 39.2 %

Procedure:
A solution of 15 g of 2-chloro-3-nitropyridine, 11.7 g of 5-amino-2-methoxypyridine and 26.1 g of potassium carbonate in 150 mL dimethylformamide was stirred at room temperature for 4 hours and 25 minutes and further stirred at 70° C. for 3 hours and 10 minutes. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted once with ethyl acetate. The organic layer was washed 3 times with a saturated aqueous ammonium chloride solution and once with brine, and dried over sodium sulfate. The residue was purified crudely by short-column chromatography. From and the resulting black brown oil was extracted with diethyl ether to give 9.10 g of the title compound as reddish brown crystals (39% y.). (2) N2-(6-Methoxy-3-pyrdyl)-2,3-pyridinediamine
Reaction SMILES: NC1C=CC=C2C=1C(=O)[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])C(C)=N2.[CH3:22][C:23]1O[C:25](=[O:36])[C:26]2[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.NC1CCC(=O)NC1=O>>[CH3:22][C:23]1[N:5]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[C:25](=[O:36])[C:26]2[C:27](=[CH:29][CH:30]=[CH:31][C:32]=2[N+:33]([O-:35])=[O:34])[N:28]=1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Agent: NC1CCC(=O)NC1=O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In yet 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) reacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one with 3-aminopiperidine-2,6-dione or a salt thereof in a solvent to form 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; and (b) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione via transfer hydrogenation 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.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]([OH:16])=O)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[C:58]([Si:62]([CH3:73])([CH3:72])[O:63][C:64]1[CH:65]=[C:66]([CH:69]=[CH:70][CH:71]=1)[CH2:67][NH2:68])([CH3:61])([CH3:60])[CH3:59]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:16])[NH:68][CH2:67][C:66]2[CH:69]=[CH:70][CH:71]=[C:64]([O:63][Si:62]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:72])[CH3:73])[CH:65]=2)=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 20.2 %

Procedure:
To a solution of 3-Trifluoromethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (560 mg, 2.20 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.92 mL, 6.6 mmol), HBTU (1.0 g, 2.64 mmol), HOBT (360 mg, 2.64 mmol), and 3-(tert-Butyl-dimethyl-silanyloxy)-benzylamine (630 mg, 2.64 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-40% EtOAc in hexane to afford the desired product (0.21 g, 20% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:14]([CH:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4])[C:12]([O:18][CH2:19][CH3:20])=[O:17])(=[O:15])[CH3:16]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(CC(=O)c1ccc(Br)cc1)C(C)=O

Procedure:
A mixture of 2,4′-dibromoacetophenone (3.0 g, 10.8 mmol), ethyl acetoacetate (1.48 mL, 10.8 mmol) and potassium carbonate (4.5 g, 32.4 mmol) were heated in 2-butanone (50 mL) at reflux for 24 hours. Upon cooling, the mixture was filtered over diatomaceous earth and concentrated. The residue was purified by chromatography with DCM to provide the title compound as an oil. 1H NMR (CDCl3) δ ppm 1.30 (3H), 2.10 (3H), 3.19 (2H), 3.75 (1H), 4.15 (2H), 7.50 (2H), 7.81 (2H); MS (ESI) m/z 326/328.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][OH:21])=[CH:14][CH:13]=1.CCCCCCC.C(OCC)(=O)C.C(O)C#C>ClCCl>[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([C:18]#[C:19][CH:20]=[O:21])=[CH:16][CH:17]=1
Reactant: Cc1ccc(C#CCO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: C#CCO
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C#CC=O)cc1
Yield: 57.1 %

Procedure:
Pyridinium chlorochromate (22.1 g; 102.6 mmol; 2 eq) was added to a stirred solution of 3-p-tolylprop-2-yn-1-ol (7.5 g; 51.3 mmol) in dichloromethane (200 mL) at room temperature under nitrogen. The mixture was stirred for 4 h until TLC (2:1 heptane/ethyl acetate) indicated the disappearance of the starting propargyl alcohol. The mixture was then filtered through a bed of celite, and the filter cake was rinsed with dichloromethane (100 mL). The dichloromethane was concentrated using a rotary evaporator to give the desired product (4.22 g; 29.3 mmol; 57%) which was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.39 (s, 3 H) 7.20 (d, 2H) 7.50 (d, 2H) 9.41 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][N:10]([CH3:14])[CH2:11]2)=[CH:6][CH:5]=1.[CH2:21]([CH:23]1[O:25][CH2:24]1)Br.C1(O)C=CC=CC=1>O1CCCC1.O>[O:25]1[CH2:24][CH:23]1[CH2:21][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9][N:10]([CH3:14])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: BrCC1CO1
Reactant: CN1Cc2cc(O)ccc2C(c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Solvent: O
Product: CN1Cc2cc(OCC3CO3)ccc2C(c2ccccc2)C1

Procedure:
Sodium hydride (0.72g) was added to a solution of 7-hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (2.33g) in dry tetrahydrofuran (75 ml). Epibromohydrin (4.11 g) was added and the solution refluxed for 2 hr. until thin layer chromatography (alumina, chloroform-ether 1:5) showed the absence of starting phenol. Water (25ml) was added and the mixture extracted with ether. The combined ether layers were dried (MgSO4) and the solvent removed under reduced pressure. The oil was taken up in xylene (50 ml) and evaporated to dryness to give the title compound in quantitative yield. τ (CDCl3) 7.68 (3H,s), 7.55-7.0 (3H,m), 6.95-6.6 (2H,m), 6.4 (2H,s), 6.2-5.65 (3H,m), 3.5-3.1 (3H,m), 2.85 (5H,s).
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1)(C)(C)C.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH3:11][C:9]1[CH:10]=[CH:5][CH:6]=[C:7]([CH3:12])[C:8]=1[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:20]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1cccc(C)c1C(=O)c1ccccc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
81 parts of 5-tert.-butyl-m-xylene and 70 parts of benzoyl chloride are kept with 2.4 parts of ferric chloride for three hours at from 100° to 120°C. The whole is cooled to 25°C and 600 parts of benzene and 100 parts of aluminum chloride are added. 20 parts of hydrogen chloride is passed into the mixture during six hours at 70° to 80°C. The mixture is poured onto 1000 parts of ice-water. The organic phase which forms is separated and 77 parts (73.3% of theory) of 2,6-dimethylbenzophenone having a boiling point of 122° to 125°C is isolated by distillation at 0.3 mm Hg.
Reaction SMILES: N[C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[BrH:12].BrBr.N([O-])=O.[Na+]>O>[Br:12][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1N
Reactant: Br
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nccnc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a solution of methyl 3-amino-2-pyrazinecarboxylate (13.06 mmol, 2 g) in hydrobromic acid (13.06 mmol, 7.4 ml, 1.057 g) at 0° C. was added bromine (38.9 mmol, 2 mL, 6.22 g) drop wise and then a solution of sodium nitrite (33.3 mmol, 2.3 g) in water (4 mL). The reaction was stirred for 2 h at 0° C. and the reaction mixture was extracted with CH2Cl2. Organic layer was dried and evaporated to give crude methyl 3-bromopyrazine-2-carboxylate 101 (1.2 gr, 43%). (m/z)=217 and 219 (M+H)+.