Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>[Cu]>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: COc1ccc(I)cc1
Agent: [Cu]
Product: COc1ccc(-c2ccc(C(C)=O)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
A stirred mixture of 4-iodoanisole (174.5 g.), 4'-bromo-3'-nitroacetophenone (162.5 g.) and copper powder (144 g.) was heated at 80°C. for 5 hours and the temperature was then gradually raised during 4 hours to 110°C. The stirred mixture was maintained at 110°C. for a further period of 3 days. The reaction mixture was cooled to room temperature and extracted with methylene dichloride. The extract was filtered and the filtrate evaporated under reduced pressure to remove methylene dichloride. The residue was distilled in vacuo to give the product, b.p. 200° - 210°C./0.6 mm., which solidified on cooling. This product was recrystallized from methanol to give 4-acetyl-4'-methoxy-2-nitrobiphenyl, m.p. 127° - 129°C. (novel intermediate A).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[CH3:39][N:40](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[CH:11]=[CH:12][C:7]([C:39]#[N:40])=[N:8][C:9]=4[CH3:36])[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:34])[F:35])[C:28]([F:30])([F:29])[F:31])=[CH:23][CH:24]=1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1nc(C#N)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Yield: 82 %

Procedure:
Under nitrogen atmosphere, to a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (209.5 mg, 0.352 mmol), zinc cyanide (62.0 mg, 0.528 mmol), tetrakis(triphenylphosphine)palladium(0) (40.7 mg, 0.0352 mmol) and N,N-dimethylformamide (1.5 mL) was stirred at 100° C. for 2 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (136.1 mg, 0.288 mmol, 82%).
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][C:4]([P:17]([O:23]C(C)C)(=[O:22])[O:18]C(C)C)([P:7]([O:13]C(C)C)(=[O:12])[O:8]C(C)C)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:47]>>[Cl:47][CH:2]1[CH2:6][CH2:5][C:4]([P:17]([OH:23])(=[O:22])[OH:18])([P:7]([OH:13])(=[O:12])[OH:8])[CH2:3]1
Reactant: CC(C)OP(=O)(OC(C)C)C1(P(=O)(OC(C)C)OC(C)C)CCC(O)C1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=P(O)(O)C1(P(=O)(O)O)CCC(Cl)C1
Yield: 69 %

Procedure:
Tetraisopropyl 3-hydroxycyclopentane-1,1-diphosphonate (3.00 g, 7.24 mmol) was dissolved in 50 mL dry CCl4. Triphenylphosphine (3.80 g, 14.5 mmol) was added and the mixture was refluxed for 72 h. The mixture was filtered, concentrated, and the residue chromatographed (3:2 hexane:THF) on silica gel to afford 2.15 g (69%) of the desired product as a clear, viscous oil: 1H NMR (CDCl3) chemical shift 4.97-4.68 (m, 4H, OCHMe2), 4.24 (m, 1H, J=7 Hz, CHOH), 2.65-1.87 (m, 6H, ring CH2), 1.36 (d, 24H, J=6 Hz, CH3); 31P NMR (CDCl3) 25.3, 24.9, 24.4, 24.0; ammonia Cl mass spectrum m/e 433, 435 (MH+).
Reaction SMILES: C(OC([C:6]1[S:20][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[O:21][CH3:22])=O)C.C(Cl)(Cl)Cl.[Br:27]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:8]2[C:7]([O:21][CH3:22])=[C:6]([Br:27])[S:20][C:9]=2[CH2:10][CH2:11]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1sc2c(c1OC)CCN(C(=O)OCC)CC2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCc2sc(Br)c(OC)c2CC1

Procedure:
The product of step c) (17 mg, 0.067 mmol) was dissolved in 1 mL 1:1 acetic acid:CHCl3 and treated with N-bromosuccinimide (12 mg, 0.068 mmol). After 30. minutes, the reaction solution was added dropwise to a solution of saturated sodium bicarbonate and extracted with ethyl acetate. The organic extracts were concentrated to give the subtitle compound, which was used without further purification.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:9]([NH2:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>>[CH2:9]([NH:20][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCCCCCCCCN
Reactant: C=CCCCC(=O)O
Product: C=CCCCCCCCCCNC(=O)CCCC=C

Procedure:
Following the aforementioned procedure, diene was prepared from hex-5-enoic acid and undec-10-en-1-amine. The resulting yellow solid was purified by silica gel chromatography (5:1 hexanes: ethyl acetate) to afford the desired product as a white solid. IR (neat): 3291 (br, s), 3078 (m), 2924 (s), 2853 (s), 1640 (s), 1550 (s), 1438 (s), 1369 (m), 1257 (m), 991 (s), 908 (s), 722 (m), 634 (m); 1H NMR (400 MHz, CDCl3): δ 5.86-5.73 (2H, m), 5.39 (1H, s, br), 5.05-4.91 (4H, m), 3.23 (2H, dt, J=13.2, 7.2, 6.6 Hz), 2.16 (2H, t, J=7.4 Hz), 2.12-2.00 (4H, m), 1.78-1.70 (2H, m), 1.50-1.46 (2H, m), 1.38-1.27 (12H, m); 13C NMR (100 MHz, CDCl3): δ 172.8, 139.3, 138.1, 115.4, 114.3, 39.6, 36.2, 33.9, 33.3, 29.8, 29.6, 29.5, 29.4, 29.2, 29.1, 27.1, 24.9; HRMS (ESI+) [M+H]+ calcd for C17H32N1O1: 266.2484. found: 266.2491.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[C:42]([C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[N:49]=[C:48]([NH:53][CH3:54])[N:47]=[CH:46]3)=[C:41]([CH3:55])[CH:40]=[CH:39][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]([CH3:38])[CH3:37])[CH:30]=1)=O>C1(C)C=CC=CC=1>[F:23][C:24]1[C:42]([C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[N:49]=[C:48]([NH:53][CH3:54])[N:47]=[CH:46]3)=[C:41]([CH3:55])[CH:40]=[CH:39][C:25]=1[C:26](=[S:10])[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]([CH3:38])[CH3:37])[CH:30]=1
Reactant: CNc1ncc2cc(-c3c(C)ccc(C(=O)Nc4cccc(OC(C)C)c4)c3F)ccc2n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CNc1ncc2cc(-c3c(C)ccc(C(=S)Nc4cccc(OC(C)C)c4)c3F)ccc2n1

Procedure:
A mixture of Lawesson's reagent (47 mg, 115 μmol) and 2-fluoro-N-(3-isopropoxyphenyl)-4-methyl-3-(2-(methylamino)quinazolin-6-yl)benzamide (93 mg, 209 μmol) in toluene (8 mL) was heatred at reflux for 16 h. Solvent was removed in vacuo and the residue was purified by flash chromatography (25-70% EtOAc/hexane) to give the title compound. MS (M+H)+ 461.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:8][C:9]2[C:14]([F:15])=[C:13](Cl)[N:12]=[C:11]([CH3:17])[N:10]=2)[N:6]=1.O.[NH2:19][NH2:20]>CS(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:8][C:9]2[N:10]=[C:11]([CH3:17])[N:12]=[C:13]([NH:19][NH2:20])[C:14]=2[F:15])[N:6]=1
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(NCc2csc(N)n2)n1
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(NN)c(F)c(NCc2csc(N)n2)n1
Reaction time: 8 h
Yield: 28 %

Procedure:
N-[(2-Amino-1,3-thiazol-4-yl)methyl]-6-chloro-5-fluoro-2-methyl-4-pyrimidinamine (450 mg, 1.56 mmol) was dissolved in 5 ml of DMSO and 5 ml of hydrazine monohydrate was added. The mixture was stirred overnight and was purified by RP-HPLC to provide 6-{[(2-amino-1,3-thiazol-4-yl)methyl]amino}-5-fluoro-4-hydrazino-2-methylpyrimidine (125 mg, 28%). LCMS: (M+H)+: 284.1.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:40]1[CH:45]=[CH:44][C:43]([C:46]2[S:50][S:49][C:48](=[S:51])[CH:47]=2)=[CH:42][CH:41]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][C:40]1[CH:41]=[CH:42][C:43]([C:46]2[S:50][S:49][C:48](=[S:51])[CH:47]=2)=[CH:44][CH:45]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccc(-c2cc(=S)ss2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To the solution of 1 (acetylsalicylic acid, 416 mg, 2.31 mmol) in 40 mL of dimethylformamide, hydroxybenzotriazole (343 mg, 2.54 mmol) and DCC (523 mg, 2.54 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 5-p-hydroxyphenyl-1,2-dithiole-3-thione (2; 574 mg, 2.54 mmol) was added and stirred for 1 h at 0° C. and 3 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product was loaded on a silica gel open column and eluted with ethyl ether/petroleum ether (1/1), from which 4-(5-thioxo-5H-1,2-dithiol-3-yl)phenyl 2-acetoxybenzoate (3) was obtained (354 mg, 40% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][S:14](O)(=[O:16])=[O:15]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([S:14]([Cl:13])(=[O:16])=[O:15])=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Cl
Yield: 19.9 %

Procedure:
Synthesized as described for 1 using 1-tert-butyl-3,5-dimethylbenzene (5.76 mL; 30.81 mmol), chlorosulfonic acid (2.46 mL; 36.96 mmol) and anhydrous dichloromethane (200 mL). The crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 25% v/v gradient elution over 400 mL) to give the title compound as a white solid (1.60 g).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:15][CH:16]([CH3:18])[CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[O:25][C:26]=1[CH3:27]>>[CH:16]([O:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[O:25][C:26]=1[CH3:27])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:19])([CH3:18])[CH3:17]
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)OC(C)C
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Product: Cc1ccccc1-c1nc(Cn2ccc3cc(CC(OC(C)C)C(=O)O)ccc32)c(C)o1

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-isopropoxy-propionic acid methyl ester (preparation 8) was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole to give rac-2-isopropoxy-3-[1-(5-methyl-2-o-tolyl-oxazol-4-ylmethyl)-1H-indol-5-yl]-propionic acid as off-white solid.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+]>CN(C=O)C.C(Br)C1C=CC=CC=1>[C:1]1([C:7](=[O:8])[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)C(Cc1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To deoxybenzoin (0.20 g, 1.02 mmol) in DMF (5 mL) were added at 0° C. NaH in oil (0.050 g, 1.22 mmol) and benzyl bromide (183 μL). After 1 h at room temperature, the reaction mixture was partitioned between NH4OAc and ether. After usual work up procedure the title compound was purified by flash chromatography (0.95 g).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][C:7]2[NH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)=[C:10]([Cl:12])[N:11]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[N:1]1([CH2:5][CH2:6][C:7]2[NH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[O:18])=[C:10]([Cl:12])[N:11]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(CCN2CCC2)nc1Cl
Agent: Cl
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCN2CCC2)nc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 27, except 3-(2-(2-(azetidin-1-yl)ethyl)-4-chloro-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 157.3) was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 488 (M+H)+.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[CH2:2][CH2:3][C:4]([O:6][N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24])=[O:5]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Temperature: 0 °C
Yield: 100 %

Procedure:
A mixture of Z-βAla 50 (37.42 g, 0.168 mol) and N-hydroxysuccinimide (19.34 g, 1 equiv) in methylene chloride (700 mL) was stirred at 0° C. and treated with DCC (34.69 g, 1 equiv). The reaction was allowed to warm to rt. After 16 h the DCU was removed by filtration and the filtrate was concentrated in vacuo to give a white foam (53.80 g, 100%). 1H-NMR (CDCl3) δ 2.86 (s and m, 6H), 3.60 (q, 2H), 5.12 (s, 2H), 5.41 (m, 1H), 7.37 (m, 5H). MS (DCl) 321 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:35][CH:24]3[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH:23]3[CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:22][CH:23]3[CH2:27][NH:26][CH2:25][CH:24]3[CH2:35]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1
Reactant: Cc1c2ccc(Nc3ncc(Cl)c(NC4CC5CN(C(=O)OC(C)(C)C)CC5C4)n3)cc2nn1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c2ccc(Nc3ncc(Cl)c(NC4CC5CNCC5C4)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of tert-butyl 5-((5-chloro-2-((2,3-dimethyl-2H-indazol-6-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (452.1 mg, 0.908 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (250 mL×3). The combined organic phases were washed with brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/5) to give the title compound as a beige solid (179.6 mg, 49.7%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:31][C@H:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34]>C1(C)C(C)=CC=CC=1>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][CH2:2][NH:1][C:33](=[O:34])[C@@H:32]([OH:31])[CH2:37][CH2:36][OH:35])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C1OCC[C@@H]1O
Solvent: Cc1ccccc1C
Product: O=C(NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)[C@@H](O)CCO
Temperature: 130 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
5-(2-aminoethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.6, preparation of starting materials, 0.5 g, 1.19 mmol) was heated to 130° C. in xylene (20 ml) until it had dissolved. (S)-(−)-α-hydroxy-γ-butyrolactone (0.10 ml, 1.31 mmol) was added and the mixture was stirred at 130° C. for 3 hours. More (S)-(−)-α-hydroxy-γ-butyrolactone (0.05 ml, 0.66 mmol) was added and the mixture was heated for a further 2 hours. The resultant precipitate was filtered off while the mixture was hot, washed with diethyl ether (3×10 ml) and dried to give the title compound as a solid (430 mg, 69%); NMR spectrum (DMSO-d6) 1.38-1.55 (m, 1H), 1.69-1.85 (m, 1H), 3.37-3.50 (m, 2H), 3.61-3.77 (m, 2H), 3.89-4.00 (m, 1H), 4.28-4.45 (m, 3H), 5.29 (s, 2H), 5.51 (d, 1H), 7.13 (d, 1H), 7.22 (d, 1H), 7.28-7.41 (m, 2H), 7.49-7.62 (m, 2H), 7.71 (t, 1H), 8.01 (d, 1H), 8.14-8.25 (m, 1H), 8.45 (s, 1H), 8.59 (d, 1H), 9.82 (s, 1H); Mass spectrum MH+ 523.9.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22][CH3:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22][CH3:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCCl)c2n1
Reactant: C1CCNC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCN3CCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 38 from 2-(butyloxy)-9-(6-chlorohexyl)-8-(methyloxy)-9H-purin-6-amine and pyrrolidine.
Reaction SMILES: N[C:2]1C=CC=C2[C:3]=1C(=O)N(C1CCC(=O)NC1=O)C(C)=N2.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[C:24]=1[C:25]([OH:27])=[O:26]>C(O)(=O)C>[CH3:2][C:3]1[O:26][C:25](=[O:27])[C:24]2[C:28]([N+:32]([O-:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:23]=2[N:22]=1
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Solvent: CC(=O)O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1

Procedure:
In one particular 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-amino-6-nitrobenzoic acid with an activated acetic acid in a solvent to form 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one; (b) 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 in the presence of a coupling reagent to form 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; and (c) 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; and wherein steps (a), (b), and (c) are each as described herein elsewhere.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]3[CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CC1CCNCC1
Product: CC1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 4-methylpiperidine according to conditions described in general procedure C. Mp: 145-146° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.86 (d, J=6.0 Hz, 3 H), 1.50-1.62 (m, 1 H), 3.30 (m, 8 H), 6.19-6.21 (m, 1 H), 6.99 (d, J=11.0 Hz, 1 H), 7.19 (d, J=9.0 Hz, 1 H), 7.41-7.43 (m, 1 H), 7.49 (s, 1N), 7.57-7.62 (m, 3 H), 7.85 (d, J=8.2 Hz, 1 H), 7.99 (d, J=8.5 Hz, 1 H), 8.25-8.27 (m, 1 H), 10.46 (s, 1 H).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:24])[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.P(Br)(Br)[Br:26]>ClCCl>[Br:26][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:24])[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1
Reactant: BrP(Br)Br
Reactant: O=C(C(c1ccccc1)c1ccccc1)N1CCC(CCO)CC1
Solvent: ClCCl
Product: O=C(C(c1ccccc1)c1ccccc1)N1CCC(CCBr)CC1
Yield: 26.3 %

Procedure:
1-[4-(2-Hydroxyethyl)piperidin-1-yl]-2,2-diphenylethanone (2.39 g; 8.11 mmol) was dissolved in dichloromethane (20 ml). At room temperature, phosphorous tribromide (1.6 ml; 8.92 mmol) was slowly added dropwise. The reaction mixture was heated under reflux for 4 h. Cooling was followed by washing with saturated NaHCO3 solution, 2N HCl and saturated NaCl solution, and the organic phase was separated off and dried over Na2SO4. The solvent was removed under reduced pressure. Purification of the residue through a cartridge (silica gel) resulted in 1-[4-(2-bromoethyl)-piperidin-1-yl]-2,2-diphenylethanone (0.75 g; 2.13 mmol).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].N1C=CC=CC=1>ClCCl>[C:1]([O:12][CH:11]([C:10]1[S:9][CH:8]=[N:7][C:6]=1[CH3:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ncsc1C(O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccccc1)c1scnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (0.6 ml) was added to a solution of 1-(4-methyl-5-thiazolyl) -1-phenylmethanol (800 mg) and pyridine (0.5 ml) in dichloromethane (30 ml) at 0° C. under an atmosphere of dry nitrogen. The mixture was allowed to warm room temperature and was then stirred overnight. Evaporation and purification of the residue by flash chromatography gave the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][C:5](=[O:12])[NH:4][CH:3]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:1]=[C:2]1[CH:7]([C:8]([O:10][CH2:11][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:9])[CH2:6][C:5](=[O:12])[NH:4][CH:3]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)C1CC(=O)NC(Cc2ccccc2)C1=O
Product: O=C1CC(C(=O)OCc2ccccc2)C(=O)C(Cc2ccccc2)N1

Procedure:
3,6-Dioxo-2-(phenylmethyl)-4-piperidinecarboxylic acid, methyl ester, 4 g (0.015 mole) was added to benzyl alcohol, 8.1 g (0.075 mole), and the mixture warmed to 170° for three hours. The mixture was cooled and the residue chromatographed using 200 g of silica gel and eluting with 500 ml of dichloromethane-methanol (98:2) to give (±)-3,6-dioxo-2-(phenylmethyl)-4-piperidinecarboxylic acid, phenylmethyl ester, 4.5 g; mp. 119°-120.5°.