Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C=O.[P:10]([OH:13])([OH:12])[OH:11].[C:14](OC(=O)C)(=O)C>C(O)(=O)C>[P:10]([CH2:14][N:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])([OH:13])([OH:12])=[O:11]
Reactant: O=C1CNC(=O)N1
Reactant: OP(O)O
Reactant: CC(=O)OC(C)=O
Agent: C=O
Solvent: CC(=O)O
Product: O=C1CN(CP(=O)(O)O)C(=O)N1
Yield: 110.3 %

Procedure:
A 500 ml round-bottom flask was equipped with a thermometer, condenser, magnetic stirrer, and heating mantle. Into the flask was charged, under nitrogen, 10.0 g (0.100 mole) of hydantoin, 3.2 g (0.10 mole) of paraformaldehyde (purity: ca 95%), and 60 ml of anhydrous acetic acid. The resulting mixture was heated at reflux for 0.75 hour and then cooled. To the resulting clear solution was added 8.5 g (0.100 mole) of 97% phosphorous acid and 30.6 g (0.300 mole) of acetic anhydride. The reaction mixture was heated to reflux over 1.2 hours and held at reflux for another 0.1 hour. (A white solid precipitated early in the heating period and then redissolved toward the end.) The reaction mixture was cooled somewhat, and 150 ml of water was added to it. The resulting solution was heated at reflux for 2.0 hours, cooled, and vacuum stripped at 70° C. to give 21.4 g of crude 1-(phosphonomethyl)hydantoin as an oil. Quantitative analysis by hplc showed the yield of 1-(phosphonomethyl) hydantoin to be 46%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1C=O.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[C:24](=[O:27])([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1([CH:3]=[CH:6][CH:7]=[C:8]([N:14]2[CH2:15][CH2:16][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:13]2)[CH2:9]1)[CH:24]=[O:27]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C2=CC=CC(F)(C=O)C2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A stirred solution of 2,6-difluorobenzaldehyde 5 (10.0 g, 70 mmol) in N,N-dimethylformamide is treated with tert-butyl piperazine-1-carboxylate (14.4 g, 77.0 mmol) and potassium carbonate (11.7 g, 85.0 mmol), stirred at 80° C. for 16 h, cooled to ambient temperature, diluted with water and extracted with methylene chloride. The extracts are combined, washed sequentially with water and brine, dried over sodium sulfate, and concentrated in vacuo to afford a crude oil. This oil is purified by column chromatography (silica gel, 15:85 ethyl acetate/hexanes) to afford the title compound as a yellow solid, 15.5 g (71% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26].O>C(OCC)(=O)C>[C:25]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:27])[CH3:26]
Reactant: CCOC(=O)Cn1c(C)cc2c(N)cccc21
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)cc2c(NC(C)=O)cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The (4-amino-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester prepared above (8.59 g) was dissolved in ethyl acetate (175 ml) then triethylamine (5.2 ml, 37 mmol) added followed by acetyl chloride (2.6 ml, 37 mmol). An exotherm to 35° C. was observed and a thick suspension resulted. After stirring for 4 hours during which the mixture was allowed to cool back to ambient temperature, water (85 ml) was added and the ethyl acetate removed by evaporation under vacuum. The solid was collected by filtration, washed with water (25 ml) followed by 50% v/v aqueous acetonitrile (50 ml) then dried in a vacuum oven at 50° C. overnight to provide (4-acetylamino-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester, as an off-white solid, 7.26 g (77% from (4-nitro-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[CH:1]1([CH2:7][NH:8][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCCC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: c1cnc2[nH]cc(-c3ccnc(NCC4CCCCC4)n3)c2c1
Yield: 50.7 %

Procedure:
Using the procedure of example 1, C-cyclohexyl-methylamine (92 mg) was reacted with compound 1f (100 mg) to provide compound 16 (42 mg, 51%). 1H NMR (400 MHz, CD3OD) δ 8.96 (d, J=7.8 Hz, 1H), 8.28 (d, J=4.8 Hz, 1H), 8.20 (s, 1H), 8.12 (d, J=5.6 Hz, 1H), 7.25 (dd, J=7.8 Hz, 4.8 Hz, 1H), 7.02 (d, J=5.6 Hz, 1H), 3.37 (d, J=4.8 Hz, 2H), 1.94-1.90 (m, 5H), 1.34-1.04 (m, 6H). MS (ESI) m/z: 308 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:17]/[C:13]2[N:12]([CH3:11])[CH:16]=[CH:15][CH:14]=2)/[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: Cn1cccc1C=O
Solvent: O
Product: Cn1cccc1/C=C(\C#N)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A suspension of 4-chlorophenylacetonitrile (500 mg, 3.30 mmol) and 1-methyl-1H-pyrrole-2-carbaldehyde (370 mg, 3.39 mmol, 1.03 equiv.) in water (5 ml) was treated with 40% aqueous Triton B (1.4 ml, 3.3 mmol). Precipitate began forming almost immediately. After stirring for 2 h, the precipitate was filtered off, washed with water, and dried to afford a yellow solid (682 mg). This is Compound 6 in Table 8.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.Cl.P(OCC)(OCC)OCC>C(OCC)(=O)C.CN(C)C=O>[CH3:19][Si:18]([CH3:20])([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:8]2)[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)/C=C/c1c(O)cccc1[N+](=O)[O-]
Agent: CCOP(OCC)OCC
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(O[Si](C)(C)C(C)(C)C)cccc2[nH]1
Temperature: 170 °C
Yield: 63.7 %

Procedure:
To a round-bottomed flask at rt was charged with ethyl (2E)-3-(2-hydroxy-6-nitrophenyl)prop-2-enoate (Example 206, 260 mg, 1.10 mmol), N,N-dimethylformamide (2 mL), t-butyldimethylsilyl chloride (198 mg, 1.32 mmol), and imidazole (150 mg, 2.20 mmol). The resulting mixture was left stirring at rt for 2 hours before hydrochloric acid was added and the mixture was extracted with diethyl ether (2×20 mL). The combined organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The concentrated residue was used without further purification. It was mixed with triethyl phosphite (920 mg, 5.50 mmol) and heated to 170° C. for 3 hours before it was cooled to rt and diluted with ethyl acetate. The mixture was washed with water, brine and dried over anhydrous sodium sulfate. The concentrated residue was purified with silica gel flash chromatography by using hexane/ethyl acetate (3/1) as the eluant to give ethyl 4-(1,1,2,2-tetramethyl-1-silapropoxy)indole-2-carboxylate as a white solid (224 mg, 64%): Rf0.57 (3/1 hexane/ethyl acetate); %): MS (MH+) calcd for C17H26NO3Si 320.2, found 320.2; 1H NMR (DMSO-d6) δ 11.87 (br s, 1H), 6.99-7.15 (m, 3H), 6.47 (dd, J=7.3, 0.6 Hz, 1H), 4.33 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H), 1.01 (s, 9H), 0.22 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24](Br)[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:37][CH2:38]OC.O.B1(C=C)OB(C=C)OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH:37]=[CH2:38])[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCOc1nc(Br)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: COCCOC
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.8 %

Procedure:
Compound B (4.0 g), tetrakis(triphenyl-phosphine)palladium(0) (203 mg, 176 μmol) and 1,2-dimethoxyethane (100 Ml, 1 mol) were combined and stirred under nitrogen at room temperature for 20 minutes. Water (20.6 mL, 1.1 mol), 2,4,6-trivinylcyclotriboroxane pyridine complex (1.1 g, 44.4 mmol) and potassium carbonate (1.3 g, 9.3 mmol) were then added and the mixture was heated at 90° C. for 6-12 hours. The product was purified by flash chromatography in hexanes/EtOAc 0-75%) to yield compound C (3.2 g).
Reaction SMILES: [C:1]1([C:7]([O:9][C@@H:10]2[CH2:20][O:19][C@@H:12]3[C@@H:13]([OH:18])[C@@H:14]([O:17][C@H:11]23)[O:15][CH3:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21]I>CN(C=O)C.C(OCC)(=O)C.[Ag-]=O>[CH3:21][O:18][C@@H:13]1[C@H:12]2[O:19][CH2:20][C@@H:10]([O:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[C@H:11]2[O:17][C@H:14]1[O:15][CH3:16]
Reactant: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OC(=O)c2ccccc2)[C@H]1O
Reactant: CI
Agent: O=[Ag-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OC(=O)c2ccccc2)[C@H]1OC
Temperature: 60 °C
Yield: 76 %

Procedure:
A mixture of methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-D-glucofuranoside (1.03 g, 3.7 mmol), silver (I) oxide (0.85 g, 3.7 mmol) and methyl iodide (0.34 mL, 5.5 mmol) in DMF (2 mL) was heated at 60° C. for 1 hour. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (50 mL), filtered over celite, adsorbed on silica gel (10 g) and purified by flash chromatography (silica gel, 5-30% ethyl acetate-hexane) to give methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-D-glucofuranoside as a colorless oil, 0.82 g, 76% yield. 1H NMR (400 MHz; CDCl3): 8.11-8.09 (d, 2H), 7.60-7.56 (m, 1H), 7.46-7.44 (m, 2H), 5.24-5.20 (m, 1H), 5.18-5.09 (tr, 1H), 4.99 (s, 1H), 4.61-4.60 (d, 1H), 4.21-4.17 (tr, 1H), 4.08-4.03 (tr, 1H), 3.81 (s, 1H), 3.40 (s, 3H), 3.57 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5]OCC(O)=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][C:38]1[O:39][CH:40]=[CH:41][CH:42]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:31]([O:30][CH:29]([O:33][CH2:34][CH3:35])[C@@H:28]([N:16]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[C@@H:13]([NH:12][C:29](=[O:30])[CH2:28][N:16]([CH3:14])[NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH2:37][C:38]1[O:39][CH:40]=[CH:41][CH:42]=1)[CH3:36])[CH3:32]
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccco1
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](Cc1ccco1)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC
Yield: 55 %

Procedure:
According to the procedure described in the synthesis method of Compound II-130, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 32 mg (0.18 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-3-(furan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-28) 64 mg (0.15 mmol) to obtain the title compound 24 mg (27%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.[N:35]1[N:36]=[CH:37][N:38]([CH2:40][CH2:41]O)[CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:41][CH2:40][N:38]4[CH:37]=[N:36][N:35]=[CH:39]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: OCCn1cnnc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCn1cnnc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Diethyl azodicarboxylate (220 μl, 1.4 mmol) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (150 mg, 0.47 mmol), (prepared as described for the starting material in Example 24), 2-(1,2,4-triazol-4-yl)ethanol (64 mg, 0.56 mmol) and triphenylphosphine (369 mg, 1.4 mmol) in methylene chloride (5 ml) and the mixture stirred for 30 minutes at ambient temperature. Further 2-(1,2,4-triazol-4-yl)ethanol (16 mg, 0.14 mmol), triphenylphosphine (37 mg, 0.14 mmol) and diethyl azodicarboxylate (22 μl, 0.14 mmol) was added and the mixture stirred for 1 hour at ambient temperature. The precipitated solid was collected by filtration, washed with methylene chloride and methanol and dried under vacuum. The solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (1.5 ml of a 2.2M solution) was added. The volatiles were removed by evaporation, the solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1,2,4-triazol-4-yl)ethoxy)quinazoline hydrochloride (93 mg, 40%). 1H NMR Spectrum: (DMSOd6; CF3COOD) 4.02(s, 3H); 4.66(t, 2H); 4.85(t, 2H); 7.41(s, 1H); 7.46(dd, 1H); 7.62(t, 1H); 7.69(dd, 1H); 8.11(s, 1H); 8.89(s, 1H); 9.55 (s, 2H) MS-ESI: 415 [MH]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2=[O:20])=[CH:4][CH:3]=1>C(OCC)(=O)C.CCCCCC>[OH:20][CH2:9][CH:8]([C:12]1[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=1[OH:10])[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)c(C(CO)c2ccc(Br)cc2)c(O)c1C
Yield: 93 %

Procedure:
Using 3-(4-bromophenyl)-4,6,7-trimethyl-1-benzofuran-2 (3H)-one obtained in Reference Example 229, the title compound was synthesized in the same manner as in Reference Example 8. Yield 93%. Melting point: 114-115° C. (ethyl acetate-hexane).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[C:23]([C:27]1[CH:33]=[CH:32][C:30](N)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[N+](C1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1[N+]([O-])=O)([O-])=O>COCCO>[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH:1][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=4)[C:9](=[O:22])[C:8]=3[CH:7]=[CH:6][CH:5]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Solvent: COCCO
Product: CC(C)(C)c1ccc(Nc2cccc3c2C(=O)c2ccc([N+](=O)[O-])cc2C3=O)cc1

Procedure:
The product employed in a) can be obtained as follows: 15 g of 1,6-dinitro-anthraquinone and 30 ml of p-tert.-butyl-aniline are stirred at 125° C until no further dinitroanthraquinone is detectable (approx. 6 hours being required). The warm mixture is diluted with 30 ml of ethylene glycol monomethyl ether, stirred until cold and filtered, and the residue is successively washed with ethylene glycol monomethyl ether and water. 13.9 g of 1-(p-tert.-butyl-anilino)-6-nitro-anthraquinone are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:31][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[F:27]
Reactant: NCc1ccccc1F
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccccc3F)c2CC1)C(F)(F)F

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-fluorobenzyl amine. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 and 4:1) to give 7-chloro-6-(2-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid. MS (ES+) m/z: 401 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:6][N:5]=[C:4]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(OC)cc2)c(N)n1
Reactant: CC(=O)N1CCC(N)CC1
Product: COc1ccc(C(=O)c2cnc(NC3CCN(C(C)=O)CC3)nc2N)cc1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(4-methoxy-phenyl)-methanone (Example 358) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(4-methoxyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 370.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[C:30]([Cl:31])=[C:29]([CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:25]3[C:30]([Cl:31])=[C:29]([CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(Cl)c(C)sc3n2)cc1
Reactant: NCCc1ccc2c(c1)OCO2
Product: COC(=O)c1ccc(-c2nc(NCCc3ccc4c(c3)OCO4)c3c(Cl)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above in wherein 3,4-methylenedioxyphenethylamine is reacted with 4-(4-chloro-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:33][CH2:34][CH2:35][CH3:36])[N:14]([CH2:15][CH2:16][NH:17][C:18]([CH:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:19])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+]>Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:33][CH2:34][CH2:35][CH3:36])[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:19])[CH:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)C(CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)C(N)CC(C)C

Procedure:
1,1-Dimethylethyl N-[1-({[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]amino}carbonyl)-3-methylbutyl]carbamate (0.35 g, 0.7 mmol) was combined with 1 N hydrochloric acid (40 mL) and heated on a steam bath for 30 minutes. The reaction mixture was allowed to cool and then it was made basic with 10% sodium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 0.15 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-amino-4-methylpentamide as a white solid, m.p. 60–65° C. Analysis: Calculated for C21H31N7O: % C, 63.27; % H, 7.86; % N, 24.66; Found: % C, 62.27; % H, 7.67; % N, 24.77. HRMS (EI) calcd for C21H31N7O (M+) 397.2590 found 397.2582.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([NH:14][C:15]1[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]2[O:22][C:21]([CH2:24][OH:25])([CH3:23])[CH2:20][C:19]=2[C:26]=1[CH3:27])(=[O:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([NH:14][C:15]1[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]2[O:22][C:21]([CH:24]=[O:25])([CH3:23])[CH2:20][C:19]=2[C:26]=1[CH3:27])(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CO)O2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(C=O)O2
Yield: 42.8 %

Procedure:
A solution of oxalyl chloride (0.45 ml, 4.7 mmol) in dichloromethane (10 ml) was cooled to -78° C. and dimethyl sulfoxide (1 ml) was added dropwise with stirring. After stirring at the same temperature for 2 hours, a solution of 5-acetylamino-2-hydroxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (1.1 g, 4.2 mmol) in dichloromethane (5 ml) was added dropwise and the mixture was stirred for additional 30 minutes. Triethylamine (3.5 ml) was added and the mixture was stirred for 10 minutes. The reaction mixture was washed with 1N hydrochloric acid and aqueous saturated sodium bicarbonate solution. The reaction mixture was dried and then concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate) to obtain the desired compound (0.47 g, yield: 43.1%) as oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].CI.[C:17](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:17])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(C(C)=O)ccc1OC
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of 66.1 g (0.341 mole) of methyl 5-acetyl-2-hydroxybenzoate, 7.26 g (0.511 mole) of methyl iodide and 47.0 g (0.341 mole) of potassium carbonate in 400 ml of sieve-dried dimethylformamide is stirred at room temperature for 65 hours. The mixture is poured on 1.5 liters of N hydrochloric acid, extracted 6 times with ethyl ether, washed extract with water, NaHCO3 solution and cold 1 N NaOH, dried over Na2SO4, and evaporated solvent. Methyl 5-acetyl-2-methoxybenzoate, 51.3 g (72%) m.p. 95°-96° C., is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:26][C@H:27]([C:31]([O:33][CH3:34])=[O:32])[CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH3:34][O:33][C:31](=[O:32])[C@H:27]([CH:28]([CH3:30])[CH3:29])[NH:26][C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1)=[O:18]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)C(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
4′-Nitro-1,1′-biphenyl-4-carboxylic acid (0.60 g, 2.4 mmol) was dissolved in methylene chloride (25 mL), and then oxalyl chloride (0.32 mL, 3.7 mmol) was added, followed by one drop of N,N-dimethylformamide. The resulting mixture was heated at 50° C. for 1 h, concentrated under reduced pressure, and further dried under vacuum for 30 min. The residue was dissolved in methylene chloride (20 mL) and added dropwise to an ice-cold mixture of methyl L-valinate hydrochloride (0.54 mg, 3.2 mmol), methylene chloride (25 mL), and triethylamine (1.74 mL, 12.3 mmol). The resulting solution was stirred on ice for 1 h and then at rt overnight. The mixture was diluted with methylene chloride and washed with 1N aqueous HCl solution and brine. The organic layer was separated and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage® system, 2:1 hexanes/EtOAc) to afford methyl-N-[(4′-nitro-1,1′-biphenyl-4-yl)carbonyl]-L-valinate (0.70 g, 80%). 1H NMR (400 MHz, CD3OD) δ 1.06 (dd, 6H), 2.38 (m, 1H), 3.77 (s, 3H), 4.52 (d, 1H), 7.82 (d, 2H), 7.91 (d, 2H), 7.97 (d, 2H), 8.33 (d, 2H); LC-MS m/z 357.1 (MH+), retention time 3.07 minutes.