Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([CH3:25])([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+:27]>C(O)C.O>[Cl:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([CH3:25])([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:3]([O-:5])=[O:4].[Na+:27]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC(C)(C)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(COc1ccc(CC(Cl)C(=O)[O-])cc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
In 15 ml of ethanol is dissolved 3.6 g of ethyl 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)phenyl]propionate, and under cooling with ice and stirring, a solution of 0.35 sodium hydroxide in 3.5 ml water is added. The mixture is kept under the same condition for 30 minutes, after which the solution is concentrated to dryness. The residue is dissolved in 10 ml of water, the solution is washed three times with ether, and then the solution is concentrated to dryness. The procedure yields 2.6 g of sodium 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)-phenyl]propionate, as white amorphous substance.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:27]([O:28]C(=O)C)[C@H:26]([O:32]C(=O)C)[C@@H:25]([CH2:36][O:37]C(=O)C)[O:24][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C@@H:6]1[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:32])[C@H:27]([OH:28])[C@H:5]1[OH:4]
Reactant: CCc1ccc(Cc2ccc(N)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(Cc2ccc(N)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 90.4 %

Procedure:
To a solution of 5-amino-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.19 g) in methanol (3.5 mL) was added sodium methoxide (28% methanol solution; 0.064 mL), and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was concentrated under reduced pressure, and to the residue was added water. Precipitated crystals were collected by filtration, washed with water and dried to give 5-amino-2-(4-ethylbenzyl)-phenyl β-D-glucopyranoside (0.12 g).
Reaction SMILES: C(OC([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH2:21][N:22]([C@H:30]([CH3:40])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=[O:39])[CH:33]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=O)(C)(C)C.N>CO>[Si:42]([O:41][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][N:22]([C@H:30]([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=[O:39])[CH:33]=1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:44])[CH3:43]
Reactant: C[C@H](Cc1cccc(C=O)c1)N(C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OC(=O)OC(C)(C)C)c2[nH]c(=O)ccc12)C(=O)OC(C)(C)C
Agent: N
Solvent: CO
Product: C[C@H](Cc1cccc(C=O)c1)N(C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (R)-2-(8-(tert-butoxycarbonyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilyloxy)ethyl((R)-1-(3-formylphenyl)propan-2-yl)carbamate (Example 276, step h) (0.521 g) was suspended in methanol (20 mL) and treated with ‘880’ aqueous ammonia (2.5 mL) to give a suspension that was stirred at room temperature for 3 hours. The mixture was concentrated by blowing with a stream of nitrogen, and the residue was partitioned between ethyl acetate, water and brine, and the phases separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried MgSO4) and concentrated in vacuo to afford the subtitled compound. Yield 0.476 g. Material used immediately in the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:27]=[CH:26][C:6]2[CH:7]([C:17]3[C:18]([S:24][CH3:25])=[N:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].F[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([N:35]([CH3:51])[CH2:36][C:37]([NH:39][C:40]2[S:41][CH:42]=[C:43]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:44]=2)=[O:38])[N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH2:1]([C:3]1[CH:27]=[CH:26][C:6]2[CH:7]([C:17]3[C:18]([S:24][CH3:25])=[N:19][C:20](=[O:23])[N:21]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:35]([CH3:51])[CH2:36][C:37]([NH:39][C:40]5[S:41][CH:42]=[C:43]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:44]=5)=[O:38])[N:30]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)nc1SC
Reactant: CCOC(=O)Cc1csc(NC(=O)CN(C)c2nccc(F)n2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1csc(NC(=O)CN(C)c2nccc(-n3cc(C4c5ccc(C)cc5C=Cc5cc(CC)ccc54)c(SC)nc3=O)n2)n1

Procedure:
The product of step (iv) (0.37 g), and the product of step (ii) (0.35 g) was stirred with cesium carbonate (0.32 g) in dry 1-methyl-2-pyrrolidinone (15 ml) at 65-70° C. for 20 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer collected, dried (MgSO4), and solvent evaporated under reduced pressure. Yield 0.61 g.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:14][C:15]3[N:16]=[C:17]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[C:20]=3[N:21]=2)=[CH:8][C:7]=1[CH3:34].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:17]2[N:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[C:20]3[N:21]=[C:13]([C:9]4[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[C:7]([CH3:34])[CH:8]=4)[O:14][C:15]=3[N:16]=2)=[CH:28][CH:29]=1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCCCBr)c(C)c3)nc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCCCN4CCOCC4)c(C)c3)nc12
Temperature: 60 °C
Yield: 58.9 %

Procedure:
A mixture of 230 mg of 2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidine, 74 mg of morpholine and 233 mg of potassium carbonate in 5 ml of dimethylformamide was heated to 60° C. for 3 h. After cooling to room temperature, the solids were removed by filtration. The solvent was distilled off in vacuo and the residue was purified by preparative HPLC to yield 137 mg of the title compound in the form of the 5-(4-chloro-benzyl)-2-[3,5-dimethyl-4-(3-morpholin-4-yl-propoxy)-phenyl]-7-propoxy-oxazolo[5,4-d]pyrimidine trifluoroacetic acid salt.
Reaction SMILES: [O:1]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[C:22]([CH2:23][OH:24])=[C:21]([O:29][CH3:30])[CH:20]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=C1.[C:36]([Si:40](Cl)([CH3:42])[CH3:41])([CH3:39])([CH3:38])[CH3:37].O>CN(C)C=O>[O:24]([CH2:23][C:22]1[C:21]([O:29][CH3:30])=[CH:20][C:19]([O:1][Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:26][C:25]=1[O:27][CH3:28])[Si:40]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:42])[CH3:41]
Reactant: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of the crude 4-t-butyldiphenylsiloxy-2,6-dimethoxybenzyl alcohol (4.01 g) obtained by the above-described procedure in anhydrous dimethylformamide (30 mL) were added imidazole (1.29 g, 18.98 mmol) and t-butylchlorodimethylsilane (1.79 g, 11.86 mmol). After stirring at 50° C. for 4 hours, water was added and the resulting mixture was extracted with ethyl acetate-hexane (1:2). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude 4-(t-butyldimethylsiloxy)methyl-1-t-butyldiphenylsiloxy-3,5-dimethoxybenzene was obtained as a colorless amorphous powder (5.33 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:10][C:11]1[N:12]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([N:23](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[C:14]=2[N:42]=1)[CH3:9].[OH-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([NH:10][C:11]1[N:12]([CH2:43][CH:44]([CH3:45])[CH3:46])[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:23])[C:14]=2[N:42]=1)[CH3:9]
Reactant: CCNc1nc2c(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc3ccccc3c2n1CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1nc2c(N)nc3ccccc3c2n1CC(C)C
Temperature: 50 °C
Yield: 19.5 %

Procedure:
Trifluoroacetic acid (20 mL) was added to N2-ethyl-N4,N4-bis(4-methoxybenzyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine (2.0 g, 3.8 mmol), and the reaction was heated at 50° C. for four hours and allowed to cool to ambient temperature. Aqueous sodium hydroxide (6 M) was added to adjust the solution to pH 9, and then dichloromethane and saturated aqueous sodium bicarbonate were added. The organic layer was separated and washed twice with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered through a layer of CELITE filter agent, and concentrated under reduced pressure. The residue was purified twice by automated flash chromatography (silica cartridge, eluting with 12% methanol in dichloromethane followed by silica cartridge, eluting with 3-12% methanol in dichloromethane). The resulting product was recrystallized from acetonitrile containing a few drops of methanol, combined with material from another run, and recrystallized again using the same solvents to provide 210 mg of N2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine as beige needles, mp 188-190° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([CH3:17])([CH3:16])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]([N:27]=[C:28]=[O:29])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:20][C:19]([NH:27][C:28]([N:7]1[C:8]([CH3:16])([CH3:17])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6]1)=[O:29])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:18]
Reactant: CC(C)(N=C=O)c1ccccc1
Reactant: CCCCC1=NNC(C)(C)C1c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC1=NN(C(=O)NC(C)(C)c2ccccc2)C(C)(C)C1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
Crude 3-(n-Butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole (Intermediate IV-1) (1.03 gram, 4.48 mmol maximally) was dissolved in toluene (10 ml) and treated with 1-methyl-1-phenyl-ethylisocyanate (Intermediate VII-2) (0.72 g, 4.48 mmol) and 2 drops of triethylamine and the resulting solution was stirred at room temperature for 16 hours. The solution was concentrated and purified using Sepacore equipment: (petroleum ether/diethyl ether=85/15 (v/v)) to give N-(1-methyl-1-phenyl-ethyl)-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole-1-carbox-amide as a colorless oil (0.97 gram, 55% yield). Rf (petroleum ether/diethyl ether=4/1 (v/v))˜0.3. 1H-NMR (400 MHz, CDCl3) δ 0.88 (t, J=7, 3H), 1.08 (s, 3H), 1.26-1.39 (m, 2H), 1.44 (s, 3H), 1.45-1.56 (m, 2H), 1.70 (s, 3H), 1.76 (s, 3H), 2.09-2.18 (m, 1H), 2.25-2.35 (m, 1H), 3.70 (s, 1H), 6.59 (br s, 1H), 7.03 (br d, J˜8 Hz, 2H), 7.20 (br t, J˜8 Hz, 1H), 7.26-7.36 (m, 5H), 7.44 (br d, J˜8 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[S:11].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:27]2[C:28]3[CH2:34][CH2:33][NH:32][CH2:31][C:29]=3[S:30][C:26]=2[N:25]2[C:35]([CH3:38])=[N:36][N:37]=[C:24]2[CH2:23][N:22]=1>ClCCCl>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:27]2[C:28]3[CH2:34][CH2:33][N:32]([C:10](=[S:11])[NH:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:12])([F:1])[F:13])[CH2:31][C:29]=3[S:30][C:26]=2[N:25]2[C:35]([CH3:38])=[N:36][N:37]=[C:24]2[CH2:23][N:22]=1
Reactant: Cc1nnc2n1-c1sc3c(c1C(c1ccccc1Cl)=NC2)CCNC3
Reactant: FC(F)(F)c1ccccc1N=C=S
Solvent: ClCCCl
Product: Cc1nnc2n1-c1sc3c(c1C(c1ccccc1Cl)=NC2)CCN(C(=S)Nc1ccccc1C(F)(F)F)C3
Reaction time: 4 h

Procedure:
A mixture containing 2-trifluoromethylphenyl isothiocyanate (0.82 g, 0.004 mol) and 6-(2-chlorophenyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4′,3′;4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (1 g, 0.0027 mol) in 30 ml of 1,2-dichloroethane is agitated for 4 hours and at a temperature close to 20° C. Half the solvent is evaporated off with the rotary evaporator then 10 ml of ether is added. Agitation is carried out for 20 minutes at a temperature close to 20° C. followed by filtering on frit then washing with 20 ml of ether, with 20 ml of isopropyl ether and with 20 ml of isopentane. After drying under vacuum a cream coloured solid is obtained (1.21 g, 78%). Melting point: 190–192° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([CH2:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1.O>[CH2:1]([N:8]1[CH2:9][C@@H:10]([OH:11])[C@H:12]([NH:22][CH2:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: NCCc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1NCCc1ccccc1

Procedure:
19.4 g (0.1 mol) of 90% strength 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hexane are heated under reflux with 14.5 g (0.12 mol) of benzylmethylamine in 100 ml of dioxane and 200 ml of water overnight. The mixture is extracted with CHCl3, the extracts are dried with K2CO3 and concentrated and the residue is subjected to incipient distillation up to 160° C. (oil bath temperature).
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.[CH3:29][C:30]([CH3:36])([CH2:34][OH:35])[C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][C:30]([CH3:36])([CH3:29])[C:31]([N:26]1[CH2:25][CH:24]=[C:23]([C:21]2[NH:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]5[N:6]=[CH:5][S:4][C:8]=5[CH:9]=4)[C:15]=3[CH:22]=2)[CH2:28][CH2:27]1)=[O:32]
Reactant: CC(C)(CO)C(=O)O
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CO)C(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine trihydrochloride (50.0 mg, 0.11 mmol) in DMF (3 mL) was added 2,2-dimethyl-3-hydroxypropionic acid (150 mg, 1.3 mmol), TBTU (42.0 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.50 mmol). The reaction mixture stirred at rt for 16 h. The mixture was concentrated in vacuo and purified via MDP, which afforded the title compound as yellow solid. MS (ES+): m/z: 448.96 (100) [MH+]. HPLC: tr=2.35 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, DMSO-d6): δ=1.20 (s, 6H), 3.19 (s, 1H), 3.46 (s, 2H), 3.79-3.81 (m, 2H), 4.21 (s, 2H), 4.59 (bs, 1H), 6.43 (s, 1H), 6.84 (d, J=1.6 Hz, 1H), 7.87 (dd, J=1.6, 8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.34 (s, 1H), 8.91 (d, J=2.0 Hz, 1H), 9.23 (s, 1H), 9.62 (s, 1H), 12.03 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:15])[C:5]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24]>>[CH3:1][C:2]1[N:16]([CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[C:4](=[O:15])[C:5]2[C:6](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[N:7]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
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-amino-6-nitrobenzoic acid with 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. In one aspect of the embodiment, the molar ratio of the activated acetic acid versus 2-amino-6-nitrobenzoic acid is ranging from about 1 to about 10, from about 1 to about 5, from about 1.5 to about 5, or from about 1.5 to about 2.5; and wherein steps (a), (b), and (c) are each as described herein elsewhere.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34](Cl)=[C:29]3[CH:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34]([O:12][C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[N:4][CH:3]=[N:2]5)=[CH:11][CH:10]=4)=[C:29]3[CH:28]=[N:27]2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Oc1ccc(-n2cncn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(-n5cncn5)cc4)ncnc32)CC1
Temperature: 180 °C
Yield: 40.8 %

Procedure:
A mixture of 4-(1,2,4)-triazol-1-yl-phenol (Lancaster; 14 mg, 0.09 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 29.5 mg, 0.09 mmol) and potassium carbonate (14.4 mg, 0.10 mmol) in anhydrous DMF (1 mL) was heated in a microwave at 180° C. for 10 min. The mixture was cooled and filtered. The solid was washed with dichloromethane. The filtrate was concentrated and purified using a 4 g silica gel column, eluting with 0-5% methanol/dichloromethane to give 4-[4-(4-[1,2,4]triazol-1-yl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (17 mg, 42%).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:30])[C:27](Cl)=[O:28])=[CH:22][CH:21]=1>O1CCCC1>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]([CH3:30])[C:27]([N:3]2[C@H:2]([CH3:1])[C@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][C:4]2=[O:13])=[O:28])=[CH:24][CH:25]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CC(C(=O)Cl)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(4R,5S)-(+)-4-Methyl-5-phenyl-2-oxazolidinone (0.348 g, 1.96 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. n-Butyllithium (1.6M in hexanes; 1.64 mL, 2.62 mmol) was added, and the reaction was stirred for 1 hour at −78° C. 2-(4-Bromo-phenyl)-propionyl chloride (0.540 g, 2.18 mmol) in tetrahydrofuran (10 mL) was added, and the reaction was stirred for 30 minutes. The mixture was concentrated, and the residue was partitioned between EtOAc and water. The organic layer was separated, dried, and concentrated, and the crude material was purified by silica gel chromatography (0-25% EtOAc in hexanes) to give two diastereomers as separated products. Diastereomer A was the first product to come off the column, while Diastereomer B was the second product to come off the column.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:44])([F:32])[F:45])=[CH:39][CH:38]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C(F)(F)F)cc3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79 μmol), (4-trifluoromethyl-phenyl)-acetic acid (21.8 mg, 106 μmol) and DIPEA (48.94 μL, 277 μmol) in THF (3 mL), T3P (166 μL, 277 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as a white solid. (91%, 45 mg).
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[C:20]([F:23])[CH:19]=[C:18]([C:24]([NH:26][CH:27]4[CH2:29][CH2:28]4)=[O:25])[CH:17]=3)=[CH:12][CH:11]=2)=[N:7][N:6]=1)=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][CH2:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:21]([CH3:22])=[C:20]([F:23])[CH:19]=[C:18]([C:24]([NH:26][CH:27]4[CH2:29][CH2:28]4)=[O:25])[CH:17]=3)=[CH:14][CH:15]=2)=[N:7][N:6]=1
Reactant: [H][H]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN=[N+]=[N-])o2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1

Procedure:
4′-[5-(Azidomethyl)-1,3,4oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 35) (208 mg) and palladium on carbon (10% w/w, 21 mg) in ethanol (10 ml) were hydrogenated under 1 Atm. of hydrogen for 24 hours at room temperature. The reaction was filtered through celite and the filtrate reduced to dryness under vacuum. The residue was applied to a bond-elut (silica, 10 g) and eluted with an ethyl acetate/cyclohexane gradient (50-100% ethyl acetate) and then with methanol in ethyl acetate (0-50%). The solvent was evaporated from the product fractions under vacuum to give 4′-[5-(aminomethyl)-1,3,4oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide.