Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].C1(C)C=CC(S(O[CH2:18][CH:19]2[CH2:23][S:22][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:20]2)(=O)=O)=CC=1>CN(C)C=O.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:18][CH:19]1[CH2:23][S:22][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:20]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)OCC2CSC(NC(=O)OC(C)(C)C)=N2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=NC(Cc2ncc[nH]2)CS1
Temperature: 70 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
0.21 g of imidazole predissolved in 10 cm3 of dimethylformamide is added to a solution of 0.085 g of sodium hydride in 20 cm3 of dimethylformamide. After the sodium hydride has disappeared, a solution of 1 g of tert-butyl N-[(4RS)-4-(p-toluenesulfonyloxymethyl)-4,5-dihydro-2-thiazolyl]carbamate in 10 cm3 of dimethylformamide is added and the mixture is then stirred at a temperature in the region of 70° C. for 3 hours. The reaction medium is diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue obtained is chromatographed on a column of alumina, eluting with ethyl acetate and a mixture of ethyl acetate/methanol (80/20 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions to give 0.25 g of tert-butyl N-[(4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolyl]carbamate in the form of a sticky yellow mass [mass spectrum: DCI m/z=283 MH+ m/z=183 (M-C5H7O2)+].
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[C:24]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1)=[O:20]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Product: COC(=O)c1ccc2c(c1)C(=Cc1cc(C(C)C)c(OC)c(C(C)C)c1)C(=O)N2

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-methoxycarbonyl-2-oxindole to give 0.25 g of 3-(3,5-Diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester as a yellow-orange solid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:14][OH:15]>>[CH3:14][O:15][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8]
Reactant: CO
Reactant: O=C1CCCCCO1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCO
Temperature: 25 °C

Procedure:
A solution of ε-caprolactone (11.4 g, 0.100 mol), MeOH (300 mL) and concentrated H2SO4 (5 mL) was refluxed overnight. The resulting mixture was cooled to room temperature and concentrated. Water was added to the residue and the pH was adjusted to 7 with solid NaHCO3. The aqueous layer was extracted with ether. The combined organic layers were washed with water, dried and concentrated to give 6-hydroxy-hexanoic acid methyl ester as a colorless oil, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:19][S:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([S:20][CH3:19])=[CH:22][CH:23]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: CSc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(SC)cc2)cc1
Yield: 90.3 %

Procedure:
Using the procedure described in Example 55, Part B, N1-(4-methoxybenzoyl)-1,2-benzenediamine (772 mg, 3.19 mmol) was reacted with 4-(methylthio)benzoic acid (772 mg, 4.59 mmol) to yield 1.13 g (91%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[N+:19]([O-])([OH:21])=[O:20]>O>[CH3:1][O:2][C:3]1[C:13]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][C:11]([N+:19]([O-:21])=[O:20])=[C:5]([CH:4]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCCOC)c(OC)c1
Solvent: O
Product: CCOC(=O)c1cc(OC)c(OCCOC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
Ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate (9.5 g, 37 mmol) was added in portions to stirred concentrated nitric acid (75 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for a fuirther 90 minutes. The mixture was diluted with water and extracted with methylene chloride, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with hexane to give ethyl 5-methoxy4-(2-methoxyethoxy)-2-nitrobenzoate (10.6 g, 95%) as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[Br:22]N1C(=O)CCC1=O>O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[C:9]([Br:22])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1[nH]c(C)c(Br)c1C
Temperature: 4 °C
Yield: 75.9 %

Procedure:
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (204 g), 177 g of potassium carbonate and 1428 mL of acetonitrile were stirred and cooled to 4° C. in an ice bath. N-Bromosuccinimide (228 g) was added in portions with vigorous stirring keeping the temperature under 17° C. The mixture was warmed to 20° C. and 2856 mL of water was slowly added. The precipitate was collected by vacuum filtration and washed three times with 400 mL of ethanol:water 1:2 each time. The solids were dried under vacuum at 60° C. to give 228 g (76% yield) of 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester as an off-white solid. 1H-NMR (dimethylsulfoxide-d6) δ 1.26 (t, 3H, CH3), 2.14, 2.17 (2×s, 2×3H, 2×CH3), 4.20 (d, 2H, CH2O), 11.75 (br s, 1H, NH). MS m/z 246, 248 [M+1].
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][CH:53]=1)[CH3:50]>CN(C=O)C>[CH2:49]([O:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=2)=[CH:56][CH:57]=1)[CH3:50]
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.012 g of product in 41% yield: LCMS (ESI) m/z 402 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[C:56]1([CH2:62][C@@H:63]([C:65]2[O:66][C:67]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[N:68][N:69]=2)[NH2:64])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37](=[O:38])[NH:64][C@H:63]([C:65]1[O:66][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[N:68][N:69]=1)[CH2:62][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C

Procedure:
First, N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was synthesized by analogy with the synthesis of intermediate 17 by reacting 20 mg (29 μmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 7) with 12.2 mg (32 μmol) (1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanamine trifluoroacetic acid salt (intermediate 14).
Reaction SMILES: [Br:1]Br.[CH2:3]([N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C)=[N:14][C:15]=2[NH2:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC([O-])=O.[Na+]>>[CH2:3]([N:10]1[C:18]([Br:1])=[N:17][C:16]2[C:11]1=[N:12][C:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:14][C:15]=2[NH2:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCCCCc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 70 °C
Yield: 8 %

Procedure:
A mixture of 4-amino-5-cyanoimidazole (1.09 g, 11 mmol) and hexaneamide (4.39 g, 38 mmol) was heated at 210° C. for 15 h under N2 atmosphere. After cooling, the residue was dissolved in a mixture of DMF (200 ml) and water (50 ml). Benzyl chloride (3 ml) and K2CO3 (3 g) was added to the mixture, and heated at 70° C. for 6 h. Solvent was evaporated under vacuum, the residue was extracted by CH2Cl2. The resulting organic layer was evaporated under vacuum. 9-benzyl-2-pentyladenine was obtained by the purification of the residue by column chromatography (CH2Cl2 :MeOH=100:1-50:1). Bromine (2 ml) was added to the mixture of 9-benzyl-2-hexyladenine and NaOAc (5 g) in ACOH (40 ml) within an ice bath, and the mixture was heated at 70° C. for 6 h. Solvent was evaporated under vacuum, the residue was extracted by EtOAc. The resulting organic layer was evaporated under vacuum, 9-benzyl-8-bromo-2-pentyladenine was obtained by the purification of the residue by column chromatography (CH2Cl2 :MeOH=100:1). A mixture of 9-benzyl-8-bromo-2-pentyladenine and conc.HCl (20 ml) was refluxed for 6 h. After cooling, aqueous NH3 was added to neutralize and crystallize the product (pH=8), and the desired compound was collected by filtration (0.25 g, Yield: 8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH3:16].[C:17](OC(=O)C)(=O)[CH3:18]>C(O)(=O)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=[C:17]2[CH3:18])=[C:10]([CH3:16])[CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Br)ccc1Nc1ccccc1N
Solvent: CC(=O)O
Product: Cc1cc(Br)ccc1-n1c(C)nc2ccccc21
Reaction time: 30 h

Procedure:
A mixture of 5.22 g (18.8 mmol) of N-(2-aminophenyl)-4-bromo-2-methyl-aniline and 7.1 ml (75.2 mmol) of acetic acid anhydride is heated to boiling for 30 hours, combined with 15 ml of glacial acetic acid and heated to boiling for another 30 hours. Then the reaction mixture is concentrated and purified by flash chromatography (silica gel; methylene chloride).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][S:16]([CH3:15])(=[O:18])=[O:17])[C@H:10]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CN(Cc2ccccc2)C[C@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To an ice-cold (0-5° C.) solution of the product from Step 2 (5.27 g, 27.3 mmol) and TEA (8.27 g, 81.9 mmol) in dichloromethane (50 mL), was added methanesulfonyl chloride (6.87 g, 60.0 mmol) over a period of 30 minutes. After stirring at RT overnight, the reaction mixture was washed with water. The organic layer was dried (sodium sulfate), filtered, and concentrated to give the crude product which was purified over a silica column (5:95 EtOAc/hexane) to obtain pure product (6.44 g, 67.6%). 1H NMR (400 MHz, CDCl3) δ 7.32-7.26 (5H, m), 5.14 (2H, m), 3.65 (2H, s), 3.15-3.08 (2H, m), 3.08 (6H, s), 2.76 (2H, dd). MS m/z 350 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(OCC)OCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:17]([CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)[CH:25]=[N:15][C:14]=4[CH:16]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Product: Clc1ccc2oc(-c3ccc4c(c3)ncn4C3CCOCC3)nc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 973.4 %

Procedure:
To a solution of 5-chloro-2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 100-2) (300 mg, 0.873 mmol) in triethyl orthoformate (5 mL) was added p-toluenesulfonic acid (10 mg), and this was stirred at 100° C. for 2 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude crystals that were washed with diethyl ether and ethyl acetate to yield the title compound (200 mg, 65% yield) as brown crystals.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:14])[CH2:5]1)=[C:2]=[O:3].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C1C=CC=CC=1>[CH2:15]([O:22][C:2]([NH:1][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:14])[CH2:5]1)=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: O=C=NC1CC(=O)c2ccccc2C1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(NC1CC(=O)c2ccccc2C1)OCc1ccccc1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A solution of 3-isocyanato-1-oxo-1,2,3,4-tetrahydronaphthalene (10 g), benzyl alcohol (7.3 g), dry pyridine (3 mL), and benzene (50 mL) was refluxed for 90 min. At the conclusion of this period, the solution was cooled to room temperature, diluted with benzene (150 mL), and then washed with 5% aqueous hydrochloric acid solution (60 mL twice). The organic layer was dried and evaporated under vacuum to yield a residue. The residue was crystallized by dissolving in benzene (35 mL) and diluting with petroleum ether (25 mL). Crystals thus obtained were recrystallized in the same manner to obtain the title compound (6.6 g, mp 79.5–81.5° C.).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]O)=[C:10]([CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]([O:19][C:20](=[O:33])[CH2:21][C:22]([OH:32])([C:25]1[CH:30]=[CH:29][NH:28][C:27](=[O:31])[CH:26]=1)[CH2:23][CH3:24])([CH3:18])([CH3:17])[CH3:16].C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:15]([O:19][C:20](=[O:33])[CH2:21][C:22]([C:25]1[CH:30]=[CH:29][N:28]([CH2:12][C:11]2[C:2]([Cl:1])=[N:3][C:4]3[C:9]([C:10]=2[CH3:14])=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:27](=[O:31])[CH:26]=1)([OH:32])[CH2:23][CH3:24])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCC(O)(CC(=O)OC(C)(C)C)c1cc[nH]c(=O)c1
Reactant: Cc1c(CO)c(Cl)nc2ccccc12
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CCC(O)(CC(=O)OC(C)(C)C)c1ccn(Cc2c(Cl)nc3ccccc3c2C)c(=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39.4 %

Procedure:
A mixture, under an argon atmosphere, of 2-chloro-4-methyl-3-quinolinemethanol (obtained according to 3.c, 2.08 g, 10 mmol), of tert-butyl3-hydroxy-3-(2-oxo-1,2-dihydro-4-pyridinyl)pentanoate (obtained according to 1.h, 2 g, 11 mmol), and tributylphosphine (2.75 ml, 11 mmol) in anhydrous tetrahydrofuran (40 ml) is treated dropwise with diethyl azodicarboxylate (2.6 ml, 15 mmol). The reaction mixture is then agitated at ambient temperature for 6 hours, then concentrated under reduced pressure. The resulting oily residue is taken up in dichloromethane (200 ml) and washed with saturated aqueous ammonium chloride then with saturated aqueous sodium chloride. The organic phase is dried over sodium sulphate then concentrated to 5 ml and acetonitrile is added in order to obtain a white precipitate which is kept at 4° C. for 16 hours. The precipitate is collected by filtration then washed with isopropyl ether in order to produce 1.8 g (39%) of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][CH2:14][C:15](OC)(OC)OC>C(O)C>[Cl:13][CH2:14][C:15]1[O:12][C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[CH:9][CH:10]=2)[N:1]=1
Reactant: COC(CCl)(OC)OC
Reactant: COC(=O)c1cccc(O)c1N
Solvent: CCO
Product: COC(=O)c1cccc2oc(CCl)nc12
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A mixture of methyl 2-amino-3-hydroxybenzoate (3.5 g, 20.70 mmol) and 2-chloro-1,1,1-trimethoxyethane (3.0 mL, 22.06 mmol) in ethanol (30 mL) was stirred under reflux for 6 h. The reaction mixture was cooled to ambient temperature and the solvent volume was reduced under reduced pressure approximately to ⅔ of initial volume. The precipitate formed was filtered, washed with ether (3×10 mL), and dried under vacuum to afford methyl 2-(chloromethyl)benzoxazole-4-carboxylate (3.1 g, 66%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.05 (dd, J=8.0, 1.0 Hz, 1H), 7.78 (dd, J=9.0, 1.0 Hz 1H), 7.47 (t, J=5.0 Hz, 1H), 4.84 (s, 2H), 4.04 (s, 3H); (APCI+) m/z 226 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:15]([CH3:17])[CH3:16])=[C:4]([Cl:11])[N:3]=1
Reactant: CC(C)I
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2,6-dichloro-9H-purine (a) (6.0 mmol) dissolved in anhydrous DMF (5.0 mL) was slowly added sodium hydride (7.8 mmol) with stirring at rt over 2 hr. 2-iodopropane was added and the mixture was stirred for 16 hr. The mixture was concentrated. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (20:1 to 3:1) to afford the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.15 (s, 1H), 4.91 (m, 1H), 1.63 (d, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.Cl[C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35]>>[CH2:37]([O:36][C:34]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])=[CH:13][N:12]=2)[CH2:32][CH2:31]1)=[O:35])[CH2:38][CH3:39]
Reactant: CCCOC(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCCOC(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and propyl chloroformate (Aldrich) to give 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid propyl ester. MS (M+H)+, 432.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-])=O)([CH3:3])[CH3:2]>[Pt].C(OCC)(=O)C>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[NH2:19])([CH3:3])[CH3:2]
Reactant: CC(C)OCCCNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)OCCCNc1c(N)cnc2cccnc12
Reaction time: 2.5 h
Yield: 95.4 %

Procedure:
N4-(3-Isopropoxypropyl)-3-nitro[1,5]naphthyridin-4-amine (4.2 g, 14.5 mmol), platinum on carbon (1.1 g of 5%), and ethyl acetate (100 mL) were placed in a hydrogenation flask. The mixture was shaken under a hydrogen pressure of 50 psi (3.5 Kg/cm2) for 2.5 hours. The reaction mixture was filtered and the catalyst was washed with ethyl acetate. The filtrate was dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 3.6 g of N4-(3-isopropoxypropyl)[1,5]naphthyridine-3,4-diamine as a bright yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.70 (dd, J=4.1, 1.6 Hz, 1H), 8.39 (s, 1H), 8.17 (dd, J=8.4, 1.6 Hz, 1H), 7.37 (dd, J=8.4, 4.1 Hz, 1H), 5.99 (broad s, 1H), 3.98 (broad s, 2H), 3.63-3.55 (m, 5H), 1.87 (pentet, J=6.2 Hz, 2H), 1.17 (d, J=6.1 Hz, 6H); MS (EI): m/e 260.1.630 (260.1637 calc'd for C14H20N4O).
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[O:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>C(O)(=O)C>[O:1]=[C:2]1[N:6]([C:16](=[O:18])[CH3:17])[N:5]=[C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[O:3]1
Reactant: O=c1[nH]nc(-c2nc3ccccc3o2)o1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)n1nc(-c2nc3ccccc3o2)oc1=O

Procedure:
5.0 g of 2-(2-oxo-3H-1,3,4-oxadiazole-5-yl)benzoxazole in 50 ml of acetic acid containing 5 ml of acetic anhydride was heated for 1 hour at 100°. The mixture was poured into water and the crystalline product filtered. Recrystallization from acetonitrile gave mp. of 231°-232°.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:32])([CH3:31])[C:4]#[C:5][C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)=[CH:13][CH:14]=3)[C@@:9]3([CH2:29][O:28][C:27]([NH2:30])=[N:26]3)[C:8]=2[CH:7]=1>CO.[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH3:32])([CH3:31])[CH2:4][CH2:5][C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)=[CH:13][CH:14]=3)[C@@:9]3([CH2:29][O:28][C:27]([NH2:30])=[N:26]3)[C:8]=2[CH:7]=1
Reactant: COC(C)(C)C#Cc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(C)(C)CCc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 25 °C

Procedure:
To a solution of (R)-2′-(3-methoxy-3-methylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (23 mg, 0.054 mmol) in MeOH (1 mL) suspension of palladium on carbon (28.7 mg, 0.027 mmol) in ethyl acetate (0.5 mL) was added and the mixture was hydrogenated (1 atm) overnight at 40° C. The mixture was cooled to room temperature, filtered through plug of Celite and concentrated to give (R)-2′-(3-methoxy-3-methylbutyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine.