Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 26.9 %

Procedure:
Using the general method of Example 149, 1-(4-aminobutyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.5 mmol) was reacted with phenyl isocyanate (0.26 mL, 2.5 mmol) to provide 299 mg of N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as an off white solid, m.p. 159.0–160.4° C. Analysis: Calculated for C26H32N6O2.1.0 H2O: % C, 67.51; % H, 7.41; % N, 18.17; Found: % C, 67.73; % H, 7.33; % N, 17.97.
Reaction SMILES: C(O[C:4](=[O:30])[CH:5]([C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)C.[CH3:31][O:32][C:33]([C:35]1[CH:39]=[C:38]([NH2:40])[NH:37][N:36]=1)=[O:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH3:31][O:32][C:33]([C:35]1[CH:39]=[C:38]2[NH:40][C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:17][CH:16]=3)=[C:5]([CH2:6][CH2:7][CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:4](=[O:30])[N:37]2[N:36]=1)=[O:34]
Reactant: CCOC(=O)C(CCC1CCCCC1)C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1cc(N)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(CCC3CCCCC3)c(=O)n2n1
Temperature: 120 °C
Yield: 10 %

Procedure:
A mixture of 71 mg (0.171 mmol) of 2-(4-benzyloxy-benzoyl)-4-cyclohexyl-butyric acid ethyl ester, 24 mg (0.171 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester, 7 mg (20 mol %) of p-toluenesulfonic acid monohydrate (PTSA), and 3 mL of chlorobenzene was heated at 120° C. overnight. The reaction mixture was then concentrated to a residue which was purified via reverse-phase chromatography (Gilson) to afford (after lyophilization) desired 5-(4-benzyloxy-phenyl)-6-(2-cyclohexyl-ethyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as a solid as indicated by LC-MS—calcd for C29H31N3O4 [M++H]+: 486.23, found: 486.2. This material was then converted to 5-(4-benzyloxy-phenyl)-6-(2-cyclohexyl-ethyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (559) via the well known. LiOH saponification protocol (10% yield over 2 steps); LC-MS—calcd for C28H29N3O4 [M++H]+: 472.22, found: 472.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].[Mg].II.[CH3:14][C:15]([CH3:35])([CH3:34])[CH2:16][C:17]([NH:19][C:20]1[C:21]([CH3:33])=[C:22]([CH3:32])[C:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25](=[O:30])[C:24]=2[CH:31]=1)=[O:18]>C1COCC1>[OH:30][C:25]1([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH:8]([CH3:10])[CH3:9])[CH:2]=2)[C:24]2[CH:31]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][C:15]([CH3:35])([CH3:34])[CH3:14])[C:21]([CH3:33])=[C:22]([CH3:32])[C:23]=2[O:27][C:26]1([CH3:28])[CH3:29]
Reactant: CC(C)c1ccccc1Br
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2=O
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccc(C(C)C)c1
Yield: 16.2 %

Procedure:
A solution of 1-bromo-2-isopropylbenzene (1.20 g, 6.03 mmol) in THF (5 mL) was added dropwise under an argon atmosphere to a mixture of magnesium (147 mg, 6.03 mmol) and a catalytic amount of iodine, and the mixture was stirred at 70° C. for 30 minutes. To the reaction solution was added dropwise a solution of 3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide (350 mg, 1.15 mmol) obtained in Reference Example 65 in THF (3 mL), and the mixture was refluxed with heating for 12 hours. The reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 79 mg (yield: 16%) of N-(3-hydroxy-3-(3-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide. To a solution of the compound (79 mg, 0.19 mmol) in trifluoroacetic acid (1 mL) was added with ice-cooling triethylsilane (44 mg, 0.38 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to water and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 1 N sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 39 mg (yield: 51%) of the title compound. Yield: 51%. Melting point: 188-189° C. (ethyl acetate-hexane).
Reaction SMILES: S([O-])([O-])=O.[Na+:5].[Na+].C(=O)([O-])O.[Na+].O.[C:13]([CH:18]([CH2:56][O:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]([CH2:67][CH3:68])([CH3:66])[CH3:65])=[CH:60][CH:59]=1)[CH2:19][NH:20][C:21]([C:23]1[CH:24]=[C:25]([S:52](Cl)(=[O:54])=[O:53])[CH:26]=[C:27]([C:29](=[O:51])[NH:30][CH2:31][CH:32]([C:46]([CH2:49][CH3:50])([CH3:48])[CH3:47])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([CH2:44][CH3:45])([CH3:43])[CH3:42])=[CH:37][CH:36]=2)[CH:28]=1)=[O:22])([CH2:16][CH3:17])([CH3:15])[CH3:14]>C(#N)C>[C:13]([CH:18]([CH2:56][O:57][C:58]1[CH:59]=[CH:60][C:61]([C:64]([CH2:67][CH3:68])([CH3:65])[CH3:66])=[CH:62][CH:63]=1)[CH2:19][NH:20][C:21]([C:23]1[CH:24]=[C:25]([S:52]([O-:54])=[O:53])[CH:26]=[C:27]([C:29](=[O:51])[NH:30][CH2:31][CH:32]([C:46]([CH2:49][CH3:50])([CH3:47])[CH3:48])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([CH2:44][CH3:45])([CH3:43])[CH3:42])=[CH:37][CH:36]=2)[CH:28]=1)=[O:22])([CH2:16][CH3:17])([CH3:14])[CH3:15].[Na+:5]
Reactant: CCC(C)(C)c1ccc(OCC(CNC(=O)c2cc(C(=O)NCC(COc3ccc(C(C)(C)CC)cc3)C(C)(C)CC)cc(S(=O)(=O)Cl)c2)C(C)(C)CC)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(C)(C)c1ccc(OCC(CNC(=O)c2cc(C(=O)NCC(COc3ccc(C(C)(C)CC)cc3)C(C)(C)CC)cc(S(=O)[O-])c2)C(C)(C)CC)cc1
Temperature: 30 °C
Yield: 82.8 %

Procedure:
To 2 g (0.016 mol) of sodium sulfite and 2.4 g (0.029 mol) of sodium hydrogen carbonate were added 100 ml of water and 20 ml of acetonitrile and the mixture was stirred at 30° C. To the mixture was added dropwise a solution of 10.5 g (0.013 mol) of 3,5-di-(2,4-di-tert-amylphenoxypropylcarbamoyl)benzenesulfonyl chloride obtained in the aforesaid step dissolved in 100 ml of acetonitrile. After stirring the resultant mixture for one hour, the reaction mixture was poured onto ice water and extracted with 150 ml of ethyl acetate. The ethyl acetate layer was washed thrice with cold water and dried over Glauber's salt. After filtrating away the Glauber's salt, the residue was concentrated to dryness to provide 8.6 g (yield of 82.8%) of a solid product.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C@@H:21]([CH3:35])[C@@H:22]([CH3:34])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[CH:16][C:15]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[N+:44]([C:47]1[NH:48][CH:49]=[CH:50][N:51]=1)([O-:46])=[O:45]>>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([CH2:23][C@H:22]([CH3:34])[C@H:21]([CH3:35])[CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:48]3[CH:49]=[CH:50][N:51]=[C:47]3[N+:44]([O-:46])=[O:45])=[C:15]([O:36][CH3:37])[CH:16]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH3:31]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCOCCOCCOCCBr)c(OC)c2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCOCCOCCOCCn3ccnc3[N+](=O)[O-])c(OC)c2)cc1OC
Yield: 83.3 %

Procedure:
The Standard Procedure 2 was followed by use of 9b (36.6 mg, 0.0627 mmol, 1.0 equiv), potassium carbonate (18.0 mg, 0.130 mmol, 2.1 equiv), and 2-nitroimidazole (6b, 14.4 mg, 0.126 mmol, 2.0 equiv). After workup and purification with column chromatography (80% EtOAc in hexanes as eluant), 10d (32.1 mg, 0.0522 mmol) was obtained in 83% yield as a yellow gummy oil: 1H NMR (CDCl3, 400 MHz) δ 0.81 (d, J=6.4 Hz, 3H, CH3), 0.82 (d, J=6.4 Hz, 3H, CH3), 1.73 (m, 2H, 2×CH), 2.25-2.31 (m, 2H, 2×ArCH), 2.73-2.75 (m, 2H, 2×ArCH), 3.57-3.86 (m, 21H, 3×OCH3+6×OCH2), 4.12 (t, J=5.0 Hz, 2H, CH2N), 4.56 (t, J=4.8 Hz, 2H, CH2O), 6.62-6.68 (m, 4H, 4×ArH), 6.75-6.79 (m, 2H, 2×ArH), 7.08 (s, 1H, nitroimidazole C5-H), 7.23 (s, 1H, nitroimidazole C4-H); 13C NMR (CDCl3, 100 MHz) δ 16.08, 16.14, 38.71, 38.80, 39.06, 39.16, 49.77, 55.73, 55.76, 55.83, 68.56, 69.28, 69.67, 70.43 70.54, 70.65, 110.96, 112.20, 112.77, 113.64, 120.85, 120.95, 127.31, 127.91, 134.37, 135.23, 144.62, 146.12, 146.96, 148.61, 149.23; IR (neat) 2925 (s), 2868 (s), 1655 (w), 1590 (w), 1515 (s), 1488 (w), 1459 (m), 1362 (s), 1260 (s), 1030 (s) cm−1; HRMS (FAB) m/z calcd for C32H46N3O9 (M+H)+: 616.3234. found: 616.3234.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH:20]([CH3:24])[N:19]1[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][CH:20]1[N:19]([C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:30]=2)[CH:18]([CH3:17])[CH2:23][N:22]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:21]1
Reactant: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Reactant: CC1CNCC(C)N1c1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC1(c2ccc(CN3CC(C)N(c4ncccn4)C(C)C3)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 647.6 %

Procedure:
N-[1-(4-Chloromethylphenyl)cyclopropyl]acetamide (22.3 mg) and 2-(2,6-dimethylpiperazin-1-yl)pyrimidine hydrochloride (265 mg) were dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (415 mg) was added and the mixture was stirred at 80° C. for 8 hr. Water (20 mL) was added and the mixture was stirred, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 2 L, elution solvent: hexane/ethyl acetate) to give the title compound (245 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13](=[O:15])[CH3:14])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:10])=[O:11]
Reactant: Nc1ccc(N)c(S(=O)(=O)O)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(N)c(S(=O)(=O)O)c1

Procedure:
That is, 2,5-diaminobenzenesulfonic acid is acetylated with acetic anhydride to obtain 2-amino-5-acetylaminobenzenesulfonic acid, which is then diazotized in an ordinary manner and coupled with 2,5-xylidine to thereby obtain the compound [E] shown below.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[CH2:6]([NH:7][C:14]1[CH:15]=[CH:16][C:11]([C:10]#[N:17])=[CH:12][CH:13]=1)[C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: NCc1ccccc1
Solvent: CC#N
Product: N#Cc1ccc(NCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
4-Fluorobenzonitrile (6.0 g, 49.5 mmol) was dissolved in acetonitrile (60 ml), and benzylamine (10.6 g, 98.9 mmol) was added thereto, followed by stirring at 100° C. for 3 days. To complete the reaction, benzylamine (21.2 g, 198 mmol) was further added thereto, followed by stirring at 100° C. for 1 day. The solvent was removed under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. After the organic layer was dried (over anhydrous magnesium sulfate), the drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The resulting oily substances were purified by silica gel column chromatography (the substances were eluted with an increasing concentration of chloroform from chloroform/hexane=1/2 to chloroform/hexane=1/1) to give the title compound (7.42 g, 72%) as oily substances.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([CH:20]=[CH:21][C:22]([O:24]C)=O)[N:12]=2)[CH:8]=[N:9][CH:10]=1)=[O:4].CC(O)=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]3[NH:17][C:22](=[O:24])[CH2:21][CH2:20][C:13]=3[N:12]=2)[CH:8]=[N:9][CH:10]=1
Reactant: COC(=O)C=Cc1nc(-c2cncc(C(=O)OC)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cncc(-c2ccc3c(n2)CCC(=O)N3)c1
Temperature: 50 °C
Reaction time: 13 h
Yield: 65.4 %

Procedure:
6-(2-Methoxycarbonyl-vinyl)-5-nitro-[2,3′]bipyridinyl-5′-carboxylic acid methyl ester (926 mg, 2.7 mmol), 10% Pd/C (300 mg) and AcOH (1.3 mL) were suspended in methanol (300 mL) and the reaction mixture was stirred at 50° C. under 50 psi H2 pressure for 13 hours. After filtration, the reaction mixture was concentrated in vacuo to give a crude product of 5-(6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridin-2-yl)-nicotinic acid methyl ester (500 mg, 65.4%) as a light yellow solid. MS: 284.1 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:13]2[C:14]3[C:6](=[C:7]([C:15]([OH:17])=O)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][NH:3]1.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:15]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:2](=[O:1])[NH:3][CH2:4][CH2:5][C:6]=2[C:14]=34)=[O:17])=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1[nH]c2cccc3c2c1CCNC3=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1[nH]c2cccc3c2c1CCNC3=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid (100 mg, 0.43 mmol), 4-fluoroaniline (48 mg, 0.43 mmol), and diisoprophylethylamine (168 mg, 1.30 mmol) were dissolved in 5 mL dry DMF. HATU (173 mg, 0.46 mmol) was added and the resulting mixture stirred at room temperature under argon for 3 d. The reaction mixture was partitioned between water and 25% iPrOH/CHCl3. The layers were separated, and the aqueous layer extracted thrice with 25% iPrOH/CHCl3. The combined organic layers were dried (MgSO4) and concentrated in vacuo leaving an off-white solid which was recrystallized from chloroform/methanol to yield 6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid (4-fluoro-phenyl)-amide, 70 mg (50%) as a pale yellow solid: m.p. 330-332° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 3.28 (m, 2H), 3.42 (m, 2H), 7.22 (m, 2H), 7.35 (app t, J=7.8 Hz, 1H), 7.65 (dd, J=7.8, 0.6 Hz, 1H), 7.77 (m, 3H), 8.16 (br t, 1H), 10.08 (br s, 1H), 11.81 (br s, 1H). MS (electrospray, MH+) 324. Anal. (C18H14FN3O2.0.4 H2O) C, H, N.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[O:15]
Reactant: C=CC(=O)OC
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COC(=O)C=Cc1c(C)cccc1[N+](=O)[O-]
Temperature: 95 °C
Yield: 0.5 %

Procedure:
2-Bromo-3-nitrotoluene (0.5 g, 23 mmol), methyl acrylate (0.39 g, 46 mmol,), palladium acetate (29 mg, 1.3 mmol), triphenylphosphine (0.06 g, 0.23 mmol,) and TEA (0.4 mL) were combined in a sealed tube and heated to 95° C. for 24 h. The residue was dissolved in MeOH, the solvent was removed and the crude product was purified by column chromatography (EtOAc:hexane=7.5:92.5) to give 0.024 g (48% yield) of the title compound as a yellow oil:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].CO[C:11]([CH3:13])=[CH2:12]>CC(C)=O.S(=O)(=O)(O)O>[CH3:4][C:3]1([CH2:7][OH:8])[CH2:5][O:6][C:11]([CH3:13])([CH3:12])[O:1][CH2:2]1
Reactant: CC(CO)(CO)CO
Reactant: C=C(C)OC
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1(CO)COC(C)(C)OC1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
1,1,1-Tris(hydroxymethyl)ethane (120.2 g) and 2-methoxypropene (75.0 g) were suspended in acetone (300 ml). After adding one drop of conc. sulfuric acid at 0° C., the mixture was stirred for 1 hour and then at room temperature for additional 2 hours. After distilling off the acetone, a fraction obtained under reduced pressure (1.7 mmHg) at 70° C. was collected to give (1,4,4-trimethyl-3,5-dioxanyl)methan-1-ol (155.2 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(C(C)C)CC)(C)C.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>O1CCCC1>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Fluoro-4-trifluoromethyl-2-nitrobenzene (5.1 g) was dissolved in tetrahydrofuran (100 mL) and diisopropylethylamine (5.5 ml) and 4-amino-1-tert-butoxycarbonylpiperidine (5.37 g) were added. The mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate and the extract solution was dried and concentrated under reduced pressure to give 1-tert-butoxycarbonyl-4-(4-trifluoromethyl-2-nitrophenyl)aminopiperidine.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][CH:5]=1.[CH2:11](Br)[CH3:12]>C1(C)C=CC=CC=1>[CH2:11]([NH:3][C:4]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][CH:5]=1)[CH3:12]
Reactant: CCBr
Reactant: Cc1cccc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCNc1cccc(C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 3000 ml dry toluene were added 185 g of 60% sodium hydride. A solution of 500 g of 6-amino-2-picoline and 500 ml of toluene were dropwise added at 60° C. over about 2 hours to the resulting dispersion. Ethyl bromide of 554 g were dropwise added at 70° C. over about 2 hours to the resulting mixture and stirred for additional one hour. The reation mixture was added to 3000 ml of ice water. The organic phase was extracted and the extract was washed two times with water, concentrated and dried. Thus, 632 g of 6-ethylamino-2-picoline were obtained.
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=1.[C:24]([O:28][C:29]([NH:31][C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:30])[NH:31][CH:32]1[CH2:36][CH2:35][N:34]([C:2]2[N:10]([CH2:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])[C:9]3[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=3[N:3]=2)[CH2:33]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2C#N)n(C)c1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: Cn1c(=O)c2c(nc(N3CCC(NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2C#N)n(C)c1=O

Procedure:
2-(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile (1 A) (100 mg, 0.30 mmol) was reacted with (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (282 mg, 1.52 mmol), and purified as described in example 7, step A, to afford compound (8A) as white crystals.
Reaction SMILES: [C:1]([CH2:3][N:4]([CH2:11][CH2:12][OH:13])[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])#[N:2].[C:14](OCCN(C#N)CC(C)C(OC)=O)(=[O:16])[CH3:15]>>[C:14]([O:13][CH2:12][CH2:11][N:4]([CH2:3][C:1]#[N:2])[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:16])[CH3:15]
Reactant: COC(=O)C(C)CN(C#N)CCOC(C)=O
Reactant: COC(=O)CCN(CC#N)CCO
Product: COC(=O)CCN(CC#N)CCOC(C)=O

Procedure:
By following the same procedure as Synthesis Example 3 except that methyl N-cyanomethyl-N-(2-hydroxyethyl)-3-aminopropionate was used instead of N,N-bis(2-hydroxyethyl)-3-aminopropiononitrile, methyl N-(2-acetoxyethyl)-N-cyano-methyl-3-aminopropionate was synthesized.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26]>ClCCl.CN(C1C=CN=CC=1)C>[C:7]([O:9][CH2:10][C:11](=[O:13])[NH:32][CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:33])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)/C=C/C(=O)OCC(=O)O
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)/C=C/C(=O)OCC(=O)NCC(=O)OC(C)(C)C
Yield: 20 %

Procedure:
Following general procedure B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetic acid (23) (0.50 g, 2.65 mmol) was activated with oxalyl chloride (0.30 mL, 0.40 g, 3.18 mmol) in dichloromethane (DCM) at ca. 0° C. and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). A DCM solution of the freshly prepared crude acid chloride was reacted ca. 0° C. (ice bath) with glycine tert-butyl ester (H-GlyOtBu) (0.53 g, 3.18 mmol) in DCM and in the presence of 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3.18 mmol). After aqueous work-up and isolation, and purification by silica gel flash chromatography afforded 0.16 g (20% yield) of the title compound (34) as a semi-solid material. 1H NMR (CDCl3, 400 MHz, all rotamers): δ 6.95-6.69 (m, 2H), 6.63 (br. m, 1H), 4.73 (s, 2H), 3.99 (d, J=4.8 Hz, 2H), 3.83 (s, 3H), 1.48 (s, 9H). MS (ESI): m/z 324.05 (M+Na+)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:33][CH2:34][CH3:35])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([C:29]([O:31]C)=[O:30])=[O:28])=[CH:17][CH:16]=2)[C:8]=1[C:9]([O:11]CC)=[O:10])([CH3:3])=[CH2:2].O.[OH-].[Li+]>O1CCOCC1.O>[C:1]([C:4]1[N:5]=[C:6]([CH2:33][CH2:34][CH3:35])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([C:29]([OH:31])=[O:30])=[O:28])=[CH:17][CH:16]=2)[C:8]=1[C:9]([OH:11])=[O:10])([CH3:3])=[CH2:2]
Reactant: C=C(C)c1nc(CCC)n(Cc2ccc(-c3ccccc3C(=O)C(=O)OC)cc2)c1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1nc(CCC)n(Cc2ccc(-c3ccccc3C(=O)C(=O)O)cc2)c1C(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.2 %

Procedure:
A solution of 279 mg of ethyl 4-isopropenyl-1-[(2'-methoxalylbiphenyl-4-yl)methyl)-2-propylimidazole-5-carboxylate [prepared as described in step (a) above] dissolved in 3 ml of dioxane was mixed with a solution of 123 mg of lithium hydroxide monohydrate dissolved in 3 ml of water, and the resulting mixture was stirred at 80° C. for 5 hours. At the end of this time, the dioxane was removed by distillation under reduced pressure, and 2.94 ml of 1N aqueous hydrochloric acid were added to the residual aqueous solution. The crystals which precipitated were collected by filtration, to give 214 mg of the title compound, melting at 150°-151° C.