Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([C:18](=[O:23])N(OC)C)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[C:25]([NH:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[CH3:38])([CH3:28])([CH3:27])[CH3:26]>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[C:18](=[O:23])[CH2:38][C:32]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=1[C:30](=[O:39])[NH:29][C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Cl)ccc1C(=O)NC(C)(C)C
Reactant: CON(C)C(=O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C
Product: CC(C)(C)NC(=O)c1ccc(Cl)cc1CC(=O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2,5-Difluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (2.5 g, 7.4 mmol) and N-tert-Butyl-4-chloro-2-methyl-benzamide (5.0 g, 22 mmol) followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[OH:13][CH2:14][C:15]([CH3:19])([CH2:17]O)[CH3:16].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]2[O:13][CH2:14][C:15]([CH3:19])([CH3:17])[CH2:16][O:10]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C=O)cc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COCOc1ccc(C2OCC(C)(C)CO2)cc1

Procedure:
A solution of 4-methoxymethoxybenzaldehyde, neopentyl glycol (10.3 g, 98.9 mmol), pyridinium para-toluenesulfonate (1.0 g, 3.98 mmol), and benzene (500 ml) was refluxed with azeotropic removal of water for several hours, under argon. The cooled reaction mixture was quenched with 2 ml of triethylamine, and concentrated on rotary evaporator. The product was chromatographed (silica gel, 5% ethyl acetate in hexanes), yielding about 14.83 g of the product.
Reaction SMILES: [CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]2[CH:16]=[C:15]([C:18](=O)[CH3:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]2[CH:16]=[C:15]([C:18](=[N:26][OH:27])[CH3:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc(C(C)=O)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(C(C)=NO)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
After 5.45 g of 1-(9,9-di-n-butylfluorene-2-yl)-ethanone (12) (17 mmol) was dispersed in 50 ml of ethanol and 1.42 g of hydroxylamine hydrochloride (20.4 mmol) and 1.67 g of sodium acetate (20.4 mmol) were added thereto, the reaction mixture was slowly heated and refluxed for 1 hour. The reaction mixture was cooled to room temperature, and 100 ml of distilled water was added thereto and stirred for about 30 minutes. Then, the product was extracted with 200 ml of ethylacetate and sequentially washed with saturated aqueous sodium bicarbonate solution and 100 ml of distilled water, and the recovered organic layer was dried over anhydrous magnesium sulfate, followed by distilling the solvent under reduced pressure. The obtained solid product was dried, thereby obtaining 4.97 g of 1-(9,9-di-n-butylfluorene-2-yl)-ethanone oxime (13) (87.3%) as a light yellow product.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:37](COCC[Si](C)(C)C)[CH:36]=[N:35][C:5]=2[C:6]([CH2:26][C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])=[N:7][C:8]=1[NH:9][C:10]1[CH:23]=[CH:22][C:13]([C:14]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:15])=[CH:12][C:11]=1[O:24][CH3:25])#[N:2].S(=O)(=O)(O)[OH:47]>O>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=1[CH2:26][C:6]1[C:5]2[N:35]=[CH:36][NH:37][C:4]=2[C:3]([C:1]([NH2:2])=[O:47])=[C:8]([NH:9][C:10]2[CH:23]=[CH:22][C:13]([C:14](=[O:15])[NH:16][CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])=[CH:12][C:11]=2[O:24][CH3:25])[N:7]=1
Reactant: O=S(=O)(O)O
Reactant: COc1cc(C(=O)NCCN(C)C)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2ncn(COCC[Si](C)(C)C)c2c1C#N
Solvent: O
Product: COc1cc(C(=O)NCCN(C)C)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c2c1C(N)=O

Procedure:
A solution of the product of Example 31C (60 mg, 0.1 mmol) in concentrated sulfuric acid (3 mL) and water (0.5 mL) was stirred for 10 minutes at 0° C. and at 90° C. for 1.5 hours. The mixture was quenched with crushed ice and adjusted pH 9 with sodium bicarbonate solution. The precipitate was filtered off and the filtrate was extracted with 4/1 dichloromethane/methane (5×50 mL). The organic layers were collected, concentrated and purified by preparative HPLC using a gradient of 10/90 to 80/20 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 12.2 (s, 1H), 9.59 (s, 1H), 9.38 (s, 1H), 8.58-8.62 (d, J=12 Hz, 2H), 7.88-7.92 (m, 2H), 7.59-7.62 (m, 2H), 7.39-7.47 (m, 2H), 7.06 (m, 2H), 4.75 (s, 2H), 3.89 (s, 3H), 3.58-3.60 (d, J=6 Hz, 2H), 3.25-3.27 (d, J=6 Hz, 2H), 3.88 (s, 6H). MS: 556 (M+H+).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH2:27]>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH:27][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=1
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Reactant: NCCc1ccccc1F
Product: CCCCCCCCOc1ccc(CNCCc2ccccc2F)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-(octyloxy)benzaldehyde and 2-(2-fluorophenyl)ethylamine gave the title compound as an oil. HPLC (Condition A), Rt: 4.37 min (HPLC purity: 76.0%).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:8][C:7]1=[O:19])(=O)[CH2:2][CH2:3][CH3:4].[CH2:20]([O:23][NH2:24])[CH:21]=[CH2:22]>CO>[CH2:20]([O:23][NH:24][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:8][C:7]1=[O:19])[CH2:2][CH2:3][CH3:4])[CH:21]=[CH2:22]
Reactant: CCCC(=O)C1C(=O)CC(C2CCOCC2)CC1=O
Reactant: C=CCON
Solvent: CO
Product: C=CCONC(CCC)=C1C(=O)CC(C2CCOCC2)CC1=O

Procedure:
14.0 parts by weight of 2-butyryl-5-(tetrahydropyran-4-yl)-cyclohexane-1,3-dione and 4.2 parts by weight of allyloxyamine in 100 parts by volume of methanol are stirred for 16 hours at room temperature. The solvent is distilled off under reduced pressure, the residue is dissolved in dichloromethane, the solution is then washed with 5% strength hydrochloric acid and water and dried over sodium sulfate, and the solvent is stripped off under reduced pressure to give 12.9 parts by weight of 2-(1-allyloxyamino-n-butylidene)-5-(tetrahydropyran-4-yl)cyclohexane-1,3-dione in the form of a solid (active ingredient No. 2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([NH:16]C(=O)OC(C)(C)C)[CH:13]=[CH:14][CH:15]=1)=[O:8])([O-:3])=[O:2].[ClH:27]>O1CCOCC1>[ClH:27].[NH2:16][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:24]=[CH:25][CH:26]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl {3-[(3-nitrobenzoyl)amino]phenyl}carbamate (0.60 g, 1.7 mmol) was mixed with 4 M of hydrogen chloride in 1,4-dioxane (7 mL) and stirred at rt for 2 h. After concentration, the desired white powder solid product (0.49 g, 99%) as a HCl salt was used in the next step. MF=C13H11N3O3; LCMS calculated for C13H11N3O3 (M+H)+: m/z=258.0. 1H NMR (400 MHz, CD3OD): δ 8.82 (t, J=2.0 Hz, 1H), 8.46 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 8.36 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 8.21 (t, J=2.0 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.68 (ddd, J=8.0, 4.0, 2.4, 1H), 7.54 (t, J=8.4 Hz, 1H), 7.19 (ddd, J=8.0, 2.0, 1.2 Hz, 1H).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:18]3=[C:19]4[CH:25]=[CH:24][NH:23][C:20]4=[N:21][CH:22]=[C:17]3[NH:16][N:15]=2)[CH2:9]1>N1C=CC=CC=1>[CH:1]1([S:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:18]4=[C:19]5[CH:25]=[CH:24][NH:23][C:20]5=[N:21][CH:22]=[C:17]4[NH:16][N:15]=3)[CH2:9]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: c1cc2c(ncc3[nH]nc(C4CCCNC4)c32)[nH]1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Product: O=S(=O)(C1CC1)N1CCCC(c2n[nH]c3cnc4[nH]ccc4c23)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.2 %

Procedure:
Cyclopropanesulfonyl chloride (0.076, 0.54 mmol) was added to a solution of 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.13 g, 0.54 mmol) in pyridine (5 mL), and the mixture was stirred at room temperature for about 4 h. The solvent was removed in vacuo and the residue purified by RP-HPLC (Table 2, Method q) to yield 1-(1-(cyclopropylsulfonyl)piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.019 g, 0.055 mmol, 10%) as a white solid: LC/MS (Table 2, Method n) Rt 1.75 min; m/z: 346 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][OH:10].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][O:10][C:30]1[CH:29]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:26][CH:31]=1
Reactant: Cc1cccc(Cl)c1CO
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(OCc2c(C)cccc2Cl)c1
Reaction time: 4 h

Procedure:
A solution of (2-chloro-6-methylphenyl)methanol (Step A, 3 g, 19.1 mmol) and diisopropyl azodicarboxylate (DIAD, 4.13 ml, 21 mmol) in THF (20 ml) was added drop wise to a solution of ethyl 2-(3-hydroxyphenyl)acetate (3.79 g, 21 mmol) and triphenylphosphine (5.48 g, 21 mmol) in THF (30 ml) at 0° C. under argon. The reaction mixture was stirred at the same temperature for 4 hours, diluted with ether and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 2:1) to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[CH2:25]([NH:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([N:29]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1)[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)no1
Temperature: 25 °C
Reaction time: 65 h
Yield: 77 %

Procedure:
A suspension of 1.30 g (0.0037 mol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 15 ml of dimethylformamide was treated with 2.4 g (0.01 9 moll of dibutylamine. After stirring at room temperature for 65 hrs. the orange solution obtained was freed completely from solvent. The residue was chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent. The product was recrystallized from methanol/ether and there were obtained 1.27 g (77%) of 3-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 137°-140°.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[CH2:18][C:13]3[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1ccccc1CCl
Reactant: Cc1c(N)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(Br)cccc1N1Cc2ccccc2C1
Temperature: 120 °C
Yield: 62.5 %

Procedure:
A mixture of 3-bromo-2-methylaniline (372 mg, 2.00 mmol), 1,2-bis(chloromethyl)benzene (385 mg, 2.20 mmol), and potassium carbonate (304 mg, 2.20 mmol) in water (2 mL) was heated via microwave irradiation in a sealed tube at 120° C. for 25 min. The mixture was extracted with EtOAc and the organic phase was washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 30:70 EtOAc-hexane) to provide 2-(3-bromo-2-methylphenyl)isoindoline as a light yellow oil (360 mg, 63%). Mass spectrum m/z 288, 290 (M+H)+.
Reaction SMILES: [C:1]1([N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([N:17]1[C:29]2[CH:28]=[CH:27][C:26]([CH:30]=O)=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]>C(O)C>[C:1]1([N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=[CH:30][C:26]2[CH:27]=[CH:28][C:29]3[N:17]([CH2:15][CH3:16])[C:18]4[C:23]([C:24]=3[CH:25]=2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Solvent: CCO
Product: CCn1c2ccccc2c2cc(C=NN(c3ccccc3)c3ccccc3)ccc21

Procedure:
1,1-diphenylhydrazine and N-ethylcarbazole-3-carbaldehyde were reacted in ethanol at room temperature to obtain N-ethylcarbazole-3-carbaldehyde diphenylhydrazone with melting point of 160.2°-160.5° C., and 60 parts of this hydrazone compound and 100 parts of a polyester (Vylon 200 by Toyobo Co., Ltd.) were dissolved in 450 parts of tetrahydrofuran to prepare a coating solution. Then selenium was vacuum evaporated on a 10 μm thick aluminum foil laminated on a 75 μm thick polyester film to form a charge generating layer with thickness of approximately 0.3 μm, and to this layer was applied the above-said coating solution by a film applicator and dried to form a 20 μm thick charge transporting layer. In this way, there was obtained a double-layer type electrophotographic plate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1)#[CH:2].I[C:18]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>>[C:12]([O:11][C:10]([NH:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:18]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])[CH:8]=[CH:7][CH:6]=1)=[O:16])([CH3:13])([CH3:15])[CH3:14]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1I
Product: COC(=O)c1ccc([N+](=O)[O-])cc1C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Yield: 87 %

Procedure:
This compound was prepared according to the procedure of Example B19 step C, using tert-butyl (3-ethynylphenyl)carbamate and methyl 2-iodo-4-nitrobenzoate as the starting materials in 87% yield. LCMS calculated for C21H21N2O6(M+H)+: m/z=397.1.
Reaction SMILES: [OH:1][C:2]1([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)C(=O)N[C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH-].[Na+]>C(O)(=O)C>[S:13]1[CH:14]=[CH:15][C:11]([CH:2]2[O:1][C:5](=[O:9])[NH:4][C:3]2=[O:10])=[CH:12]1
Reactant: O=C1NC(=O)C(O)(c2ccsc2)C(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(c2ccsc2)O1
Reaction time: 0.25 h
Yield: 51.4 %

Procedure:
5-Hydroxy-5-(3-thienyl)-2,4,6(1H,3H,5H)pyrimidinetrione (1.16 g., 5.1 mmoles) was dissolved in 1 N sodium hydroxide (11 ml., 11 mmoles) and allowed to stand at room temperature for 15 minutes. The solution was acidified with acetic acid, and product allowed to crystallize over 35 minutes. Filtration gave 5-(3-thienyl)oxazolidine-2,4-dione (480 mg., 51%; m.p. 133°-135° C.). An additional crop of product was obtained by extracting the mother liquor with ethyl acetate. The extract was back washed with water, and evaporated to dryness (80 mg., contaminated with starting material).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].Br[C:11]([CH3:16])([CH3:15])[C:12](Br)=[O:13]>ClC(Cl)C>[CH3:15][C:11]1([CH3:16])[C:12](=[O:13])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=2[O:8]1
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1ccc(N)c(O)c1
Solvent: CC(Cl)Cl
Product: Cc1ccc2c(c1)OC(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-amino-m-cresol (10 g, 81.2 mmol) in dichloroethane (100 mL) was treated with 11.1 mL of 2-bromoisobutyryl bromide (89.3 mmol). The reaction was allowed to stir at room temperature for 3 hours, then refluxed overnight. The reaction was cooled to room temperature and filtered through celite. The filtrate and washings were combined and excess solvent removed to yield crude product which was then triturated with hexanes to give pure product as a white solid. MS (electrospray): mass calculated for C11H13NO2, 191.09; m/z found 192.2, [M+H]+.
Reaction SMILES: C(=O)([O-])O.[Na+].[N+]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1)([O-])=O.O.C(OCC)(=O)C.[NH:24]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:25]([C:38]([OH:40])=[O:39])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH:36]=[O:37])[CH:28]=1>>[NH:24]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:25]([C:38]([O:40][CH2:13][C:12]1[CH:15]=[CH:16][CH:9]=[CH:10][CH:11]=1)=[O:39])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH:36]=[O:37])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 47.7 %

Procedure:
In 5 mg of DMP was dissolved 0.33 g of t-Boc-Trp(CHO)-OH, 0.17 g of sodium hydrogen carbonate was added. The solution was then stirred. To the mixture was added 1.08 g (5 mmol) of p-nitrobenzyl bromide, and stirring was effected at room temperature for 24 hours. Water and ethyl acetate were added to the reaction solution. The mixture was shaken, and the organic layer was recovered and the solvent was evaporated. The residue was purified with a silica gel column (manufactured by Merck Co., Kieselgel 60, 50 g, elution with hexane:ethyl acetate=6:4), to obtain 0.2 g of t-Boc-Trp(CHO)-OBzl (NO2). The peptide was dissolved in 5 ml of DMF, 0.5 ml of piperidine was added thereto, and the mixture was stirred at 0° C. for 1.5 hours. The solvent was evaporated under reduced pressure, 0.5 ml of 98% formic acid was added thereto, and the mixture was stirred at room temperature for 4 hours. About 30 ml of ether was added to obtain a precipitate. The precipitate was filtered and dried to obtain 0.16 g of H-Trp-OBzl (NO2).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:52])[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@@H:25]3[CH2:29][C@H:28]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[C@@H:27]([OH:35])[C@H:26]3[OH:36])=[C:18]([NH:37][CH2:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:53]1(C)[C:54](S(O)(=O)=O)=CC=C[CH:58]=1.[OH-].[NH4+]>CC(C)=O.COC(OC)(C)C>[CH2:1]([O:8][C:9](=[O:52])[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@H:25]3[C@H:26]4[C@H:27]([O:35][C:53]([CH3:54])([CH3:58])[O:36]4)[C@@H:28]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH2:29]3)=[C:18]([NH:37][CH2:38][CH:39]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of {(R)-1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid benzyl ester (0.63 g, 0.89 mmol) in acetone (10 ml) and 2,2-dimethyloxypropane (5 ml) is treated with toluenesulfonic acid (ca.60 mg) and then stirred at room temperature overnight. The mixture is basified using ammonium hydroxide and the solvent is removed in vacuo. The crude product is partitioned between DCM and water and the organic portion is washed with brine, dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. [MH+ 745].
Reaction SMILES: C([O:8][C:9]1[CH:32]=[CH:31][C:12]2[O:13][C@@H:14]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][C@H:20]([C:24]4[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=4)[CH2:19]3)[CH2:15][O:16][C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OCC)C>CCOC(C)=O.[Pd]>[OH:30][C:26]1[CH:25]=[C:24]([C@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([CH2:17][C@@H:14]3[O:13][C:12]4[CH:31]=[CH:32][C:9]([OH:8])=[CH:10][C:11]=4[O:16][CH2:15]3)[CH2:19]2)[CH:29]=[CH:28][CH:27]=1
Reactant: Oc1cccc([C@H]2CCCN(C[C@H]3COc4cc(OCc5ccccc5)ccc4O3)C2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Oc1cccc([C@H]2CCCN(C[C@H]3COc4cc(O)ccc4O3)C2)c1
Reaction time: 3 h

Procedure:
To a solution of 10% Pd/C (33 mg) in EtOAc (10 ml) was added 3-[(R*)-1-((S)-6-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol (66 mg, 0.125 mmol). The mixture was stirred under hydrogen for 3 h at normal pressure. The mixture was then filtered and evaporated to give an oil. After trituration with diethyl ether the title compound was obtained as a white solid (40 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C1(N)CC1.[Cl:18][C:19]1[CH:56]=[CH:55][C:22]([C:23]2[C:28]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:39]5N(CC)C6C=C[C:48](C(O)=O)=[CH:49][C:41]=6[N:40]=5)[CH:35]=4)[N:30]=3)=[CH:27][C:26]([O:53][CH3:54])=[CH:25][CH:24]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]2[C:28]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:39]5[N:40]([CH:41]6[CH2:49][CH2:48]6)[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:35]=4)[N:30]=3)=[CH:27][C:26]([O:53][CH3:54])=[CH:25][CH:24]=2)=[CH:55][CH:56]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Agent: NC1CC1
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CC4)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and cyclopropylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[CH3:20])[N:12]=[C:11]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30](Br)=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:34]([Cu])#[N:35]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[CH3:20])[N:12]=[C:11]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([C:34]#[N:35])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#C[Cu]
Reactant: CC1CCCN1c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncc(Br)cn3)CC2)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CCCN1c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncc(C#N)cn3)CC2)n1

Procedure:
Heat a mixture of 2-{4-[6-(3-chloro-4-fluorophenyl)-2-(2-methylpyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-5-bromopyrimidine (478 mg) and CuCN (270 mg) in DMF at 150° C. for 16 h in a round bottom flask that is open to the air. Let cool, dilute with EtOAc (15 mL), wash with water (3×10 mL), dry (Na2SO4), and evaporate. Purify by silica gel chromatography, eluting with 3:1 hexanes:EtOAc to provide the title compound.