Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[C:5]([CH3:9])[N:4]=[CH:3]1.[H-].[Na+].[CH2:12]([C:16]1[N:20]([C:21]2[N:26]=[C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:24]([CH3:32])=[CH:23][N:22]=2)[N:19]=[CH:18][C:17]=1[CH2:33]Cl)[CH2:13][CH2:14][CH3:15]>CN(C=O)C>[CH2:12]([C:16]1[N:20]([C:21]2[N:26]=[C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:24]([CH3:32])=[CH:23][N:22]=2)[N:19]=[CH:18][C:17]=1[CH2:33][O:8][CH2:7][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[CH3:9])[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ncn(C)c1CO
Reactant: CCCCc1c(CCl)cnn1-c1ncc(C)c(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1c(COCc2c(C)ncn2C)cnn1-c1ncc(C)c(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.9 %

Procedure:
To a 20 mL vial was added (1,4-dimethyl-1H-imidazol-5-yl)methanol (32 mg, 0.26 mmol), NaH (10 mg, 60% in oil, 0.12 mmol) and 4 mL of DMF. The reaction mixture was stirred at room temperature for 30 minutes, at which time the reaction was cooled to 0° C., the crude intermediate 2-(5-butyl-4-(chloromethyl)-1H-pyrazol-1-yl)-5-methyl-4-(thiophen-2-yl)pyrimidine (60 mg, 0.17 mmol) was added, warmed to room temperature and stirred for an additional 2 hours. The crude reaction was partitioned between water and EtOAc, the organic layer was concentrated and was purified by reverse phase preparative HPLC to provide 1.4 mg of 24 as a clear film. 1H NMR (400 MHz, MeOD-d3) δ 0.851 (t, J=5.9 Hz, 3H), 1.35 (q, J=5.9 Hz, 2H), 1.57 (t, J=6.2 Hz, 2H), 2.38 (s, 3H), 2.67 (s, 3H), 3.35 (t, J=4.8 Hz, 2H), 3.91 (s, 3H), 4.61 (s, 2H), 4.67 (s, 2H) 7.31 (t, J=3.6 Hz, 1H), 7.76 (s, 1H), 7.78 (d, J=4.1 Hz, 1H), 7.96 (d, J=3.1 Hz, 1H), 8.71 (s, 1H), 8.81 (s, 1H). LCMS (ES+) m/z 437 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([C:8]([F:11])([F:10])[F:9])([OH:7])[CH3:6].[OH-].[NH4+:14]>CO>[F:9][C:8]([F:11])([F:10])[C:5]([OH:7])([CH3:6])[CH2:4][C:3]([NH2:14])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)CC(C)(O)C(F)(F)F
Agent: [OH-]
Solvent: CO
Product: CC(O)(CC(N)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 40 h
Yield: 100 %

Procedure:
To a solution of the crude 4,4,4-trifluoro-3-hydroxy-3-methylbutyric acid (1.90 g, 10.0 mmol) in methanol (5 ml) was added concentrated aqueous ammonium hydroxide (10 ml), and the reaction stirred for 40 h at room temperature then evaporated to dryness to afford crude 4,4,4,-trifluoro-3-hydroxy-3-methyl butyramide (1.77 g, 100%) as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)(=[O:31])=[O:30])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[NH:25])=[CH:22][CH:21]=1)=[CH:12]2)=[O:6])[CH3:3].Cl[C:43]([O:45][CH3:46])=[O:44].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)(=[O:30])=[O:31])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH2:26])=[N:25][C:43]([O:45][CH3:46])=[O:44])=[CH:27][CH:28]=1)=[CH:12]2)=[O:6])[CH3:3]
Reactant: CCOC(=O)CN(c1ccc2c(c1)cc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(c1ccc2c(c1)cc(Cc1ccc(C(N)=NC(=O)OC)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride, methyl chloroformate and potassium carbonate in tetrahydrofuran.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH3:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=S.Cl.C(O)(=[O:35])C>C(OCC)(=O)C.C(OCC)C>[ClH:1].[CH3:2][CH:3]([CH3:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=[O:35]
Reactant: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reactant: CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)CCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2

Procedure:
Mercuric acetate (0.668 g) is added with stirring to a suspension of N-(3-methylbutyl)-10-[(2RS)-1-(1-pyrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide hydrochloride (1 g) in acetic acid (20 cc), and the mixture is left to react for 5 hours 30 minutes at a temperature in the region of 20° C. The reaction mixture is diluted with ethyl acetate (150 cc) and distilled water (50 cc) and then treated with caustic soda (d=1.33) to pH 13. The organic phase is separated and the aqueous phase is extracted again with ethyl acetate (2×50 cc). The combined organic phases are washed with saturated aqueous sodium hydrogen carbonate solution (100 cc) and then with saturated aqueous sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.53 g) is purified by chromatography on a column (height: 30 cm; diameter: 2.5 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting successively with a mixture (97.5:2.5 by volume) (100 cc) of methylene chloride and methanol and then with a mixture (95:5 by volume) (200 cc) of methylene chloride and methanol and collecting 15-cc fractions. Fractions 12 to 34 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oil obtained is dissolved in ethyl acetate (10 cc) and a 3N solution (0.5 cc) of hydrochloric acid in ethyl ether is added. The solid formed is drained, washed with ethyl ether (2×2 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-(3-Methylbutyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (0.37 g) is thereby obtained in the form of a pale yellow solid, m.p. about 100° C. (melts forming a paste), the NMR spectrum of which is identical to that of the product described below in Example 26.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](=[O:29])SC2C=CC=CN=2)=[CH:3]1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH2:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=1>C(Cl)Cl>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH:41][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4](=[CH:3][C:2](=[O:1])[CH2:19][CH2:18]2)[CH2:5][CH2:6]4)=[O:29])([CH3:39])[CH3:40])=[CH:34][CH:33]=1
Reactant: COc1ccc(C(C)(C)N)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Solvent: ClCCl
Product: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
610 mg of S-2-pyridyl 3-oxo-4-androstene-17β-thiocarboxylate [prepared as described in step (a) above] were dissolved in 1 ml of dry methylene chloride, and 630 mg of 1-(4-methoxyphenyl)-1-methylethylamine (prepared as described in Preparation 10a) were added to the resulting solution. The mixture was then stirred at room temperature for 3 days. At the end of this time, the reaction mixture was subjected, without further treatment, to silica gel column chromatography using a gradient elution method, with mixtures of methylene chloride and acetone in ratios ranging from 3:2 to 1:1 by volume as the eluent, and the product was recrystallized from diisopropyl ether, to give 670 mg of the title compound as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CN(C=O)C.C(OCC)(=O)C>[C:17]([O:16][C:14]([CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: OCc1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
The solution of 5-hydroxy-2-hydroxymethylpyridine (5.0 g) in DMF (10 ml) was titrated under ice-cooling in the suspension of sodium hydride (60% purity, 1.6 g) in DMF (10 ml). After 10 minutes, the mixture was heated to room temperature and stirred for 15 minutes. After t-butyl bromoacetate (6 ml) was added to the mixture under ice-cooling, the resulting mixture was stirred under ice-cooling for 10 minutes and at room temperature for 45 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine and dried over anhydrous magnesium sulfate. After the solvents were removed by distillation, the residue was purified by column chromatography on silica gel with an eluent system of chloroform→chloroform:methanol=50:1 to give 8.16 g of 5-(t-butoxycarbonylmethyl)oxy-2-hydroxymethylpyridine (yield, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].[CH2:14](Br)[CH:15]=[CH2:16].CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH2:16]([O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN1CCCC1=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1[N+](=O)[O-]
Temperature: 55 °C
Yield: 93.2 %

Procedure:
A mixture of 2,5-dinitrophenol (7.36 g, 40 mmol), allyl bromide (4.84 g, 40 mmol), acetone (75 mL), 1-methylpyrrolidinone (3 mL) and potassium carbonate (11.0 g, 80 mmol) was heated to 50-60° C. for 22 h. The mixture was cooled to room temperature and filtered and the solid rinsed with ethyl acetate. The filtrate was concentrated and recrystallized from isopropanol-hexane (1:1) to give 2-allyloxy-1,4-dinitrobenzene as yellow crystals (8.36 g, mp 66.5-68° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]=O)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[NH:16][CH:14]=[C:11]([C:12]#[N:13])[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:21]
Reactant: CCOC(N)=O
Reactant: COc1ccc(C(C#N)C=O)cc1OC
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)NC=C(C#N)c1ccc(OC)c(OC)c1

Procedure:
To the mixture of 2-(3,4-dimethoxy-phenyl)-3-oxo-propionitrile (20.5 g, 0.1 mol), urethane (8.9 g, 0.1 mol) in toluene (400 mL) was added concentrated sulfuric acid (0.5 mL, 10 mmol). The mixture was refluxed and was concentrated by slow distillation to a volume to about 50 mL. The cooled mixture was filtered and the precipitate was washed with benzene and dried. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 20% methylenechloride) afforded [2-cyano-2-(3,4-dimethoxy-phenyl)-vinyl]-carbamic acid ethyl ester as a solid: LC-MS m/e calcd for C14H16N2O4 (MH+) 277. found 277. 1H NMR (300 MHz) compatible.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[C:12]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:21][C:12]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:7]
Reactant: CC(C)(N)c1ccccc1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)NC(C)(C)c2ccccc2)c1
Yield: 98.2 %

Procedure:
In a similar manner to Step 1 of Example 16, 3-methoxybenzoylchloride (8.00 g, 46.9 mmol) was dissolved in dichloromethane (160 mL), and the solution was treated with cumylamine (7.40 mL, 51.6 mmol), triethylamine (9.80 mL, 70.4 mmol) and DMAP (573 mg, 4.69 mmol), followed by purification by slurry using diisopropylether to obtain 3-methoxy-N-(1-methyl-1-phenylethyl)benzamide (12.4 g, yield 98%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH2:11][CH:12]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:13][CH:14]([OH:36])[CH2:15][CH2:16][CH:17]1[CH:26]2[C:21](=[CH:22][CH:23]([CH3:34])[CH2:24][CH:25]2[O:27][C:28](=[O:33])[CH:29]([CH3:32])[CH2:30][CH3:31])[CH:20]=[CH:19][CH:18]1[CH3:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:1]([NH:8][C:9]([CH2:11][CH:12]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])[CH2:13][C:14](=[O:36])[CH2:15][CH2:16][CH:17]1[CH:26]2[C:21](=[CH:22][CH:23]([CH3:34])[CH2:24][CH:25]2[O:27][C:28](=[O:33])[CH:29]([CH3:32])[CH2:30][CH3:31])[CH:20]=[CH:19][CH:18]1[CH3:35])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(O)CC(CC(=O)NCc3ccccc3)O[Si](C)(C)C(C)(C)C)C21
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(=O)CC(CC(=O)NCc3ccccc3)O[Si](C)(C)C(C)(C)C)C21

Procedure:
To a stirred solution of 2.9 g (4.6 mmol) 2-methyl-butyric acid 8-[6-benzylcarbamoyl-5-(tert.-butyl-dimethyl-silanyloxy)-3-hydroxy-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester and 5.2 ml (37 mmol) triethyl amine in 22 ml DMSO is added a solution of 4.4 g (28 mmol) SO3.pyridine complex in 22 ml DMSO. After 2 hours at room temperature the mixture is poured on ice and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent evaporated. The residue is chromatographed over silica gel (hexane/ethyl acetate 9/1 to 7/3) to afford 2-methyl-butyric acid 8-[6-benzylcarbamoyl-5-(tert.-butyl-dimethyl-silanyloxy)-3-oxo-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester as an oil. MS (FAB) m/z 630 ([M+Li]+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[N:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=1)[C:7](=[O:12])[CH:6]=2
Reactant: Fc1cccc(CBr)c1
Reactant: Oc1cc2ncc(Br)cc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc2ncc(Br)cc2cn1Cc1cccc(F)c1

Procedure:
The alkylation of 7-bromo-3-hydroxy-5-azaisoquinoline (1.00 g, 4.40 mmol) using 3-fluorobenzyl bromide (1.27 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 2-(3-fluorobenzyl)-7-(3-phenyl-prop-1-ynyl)-2H-5-azaisoquinolin-3-one
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5](OC)=[O:6].[CH3:23][NH:24][CH3:25]>CO>[CH3:23][N:24]([CH3:25])[C:5](=[O:6])[C:4](=[N:3][O:2][CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNC
Reactant: CON=C(C(=O)OC)c1ccccc1OCc1ccccc1
Solvent: CO
Product: CON=C(C(=O)N(C)C)c1ccccc1OCc1ccccc1
Yield: 66 %

Procedure:
A solution of 4.9 g (16.4 mmol) of methyl 2-methoxyimino-2-(2-benzyloxyphenyl)acetate and 0.9 g (20 mmol) of dimethylamine in 20 ml of methanol was stirred at about -25° C. for 60 hours. After removal of the solvent, the crude product was purified by chromatography on silica gel (methyl tert-butyl ether/n-hexane mixture as eluent). Yield: 66%;
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:36])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:35])[C:24]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:35][N+:23]1[C:24]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:36])[CH3:16])[N:22]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCCC3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCNc1n[n+]([O-])c2c3c(ccc2[n+]1[O-])CCCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.6 %

Procedure:
H2O2 (70%, 0.12 mL, ca. 2.4 mmol) was added dropwise to a stirred solution of TFAA (0.34 mL, 2.4 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 172 (70 mg, 0.2 mmol) and TFA (95 μL, 1.2 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 173 (38 mg, 52%) as a red solid: mp (MeOH/EtOAc) 139-142° C.; 1H NMR δ 8.06 (d, J=8.9 Hz, 1H, H-5), 7.51 (d, J=8.9 Hz, 1H, H-6), 7.38 (br s, 1H, NH), 3.59-3.66 (m, 2H, CH2N), 3.49-3.55 (m, 2H, CH2), 2.83-2.92 (m, 2H, CH2), 2.61-2.65 (m, 2H, CH2N), 2.32 [s, 6H, N(CH3)2], 1.80-1.88 (m, 4H, 2×CH2).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][OH:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: OCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OCCCO)cc1
Temperature: 67.5 °C

Procedure:
To a flask was added 4-hydroxybenzonitrile (50 g, 0.41 mol, 1 eq.) and toluene (400 mL). The resulting mixture was heated to 65° C.±5° C. To the stirring reaction mixture was added 3-bromo-1-propanol (72.90 g, 0.51 mol, 1.25 eq.) and then, over the course of 20 minutes, sodium hydroxide (210 mL, 2.5 M, 0.52 mol, 1.25 eq.). The reaction was heated to 65 to 70° C. for 17 hours. The aqueous layer was separated from the organic layer at 60 to 65° C. The organic layer was then employed directly in the next step without further purification. LC purity 95.3%.
Reaction SMILES: CN(C)C=O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:28](#[N:31])[CH:29]=[CH2:30].[NH2:32][C:33]1[C:42]2[N:43]=[C:44]([CH2:51][O:52][CH3:53])[N:45]([CH2:46][C:47]([CH3:50])([OH:49])[CH3:48])[C:41]=2[C:40]2[CH:39]=[CH:38][C:37](Br)=[CH:36][C:35]=2[N:34]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:32][C:33]1[C:42]2[N:43]=[C:44]([CH2:51][O:52][CH3:53])[N:45]([CH2:46][C:47]([OH:49])([CH3:50])[CH3:48])[C:41]=2[C:40]2[CH:39]=[CH:38][C:37]([CH:30]=[CH:29][C:28]#[N:31])=[CH:36][C:35]=2[N:34]=1
Reactant: C=CC#N
Reactant: COCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CN(C)C=O
Product: COCc1nc2c(N)nc3cc(C=CC#N)ccc3c2n1CC(C)(C)O
Temperature: 120 °C
Yield: 74.7 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (225 mg, 1.00 mmol), acetonitrile (50 mL), N,N-dimethylformamide (20 mL) triethylamine (8.25 mL, 59.3 mmol), tri-o-tolylphosphine (900 mg, 2.97 mmol), acrylonitrile (770 mg, 21.8 mmol) and 1-[4-amino-7-bromo-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (7.50 g, 19.8 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath for 18 hours. The reaction was cooled to ambient temperature and then concentrated under reduced pressure. The resulting solid was partitioned between chloroform (300 mL) and aqueous 1% sodium carbonate (100 mL). The fractions were separated and the aqueous fraction was extracted with chloroform (4×100 mL). The combined organic fractions were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-7% gradient of methanol in dichloromethane) to provide 5.2 g of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enenitrile as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.O.Cl>N1C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Yield: 77.7 %

Procedure:
After adding 4-nitrobenzoyl chloride (34, 7.534 g, 185.57 mmol) to p-anisidine (33, 5.00 g, 40.60 mmol) dissolved in pyridine (50 mL), the reaction mixture was heated for 2 hours at 100° C. After adding water and aqueous 4 N HCl (300 mL), extracting with ethyl acetate and removing water using sodium sulfate, column chromatography yielded the target compound N-(4-methoxyphenyl)-4-nitrobenzamide (36, 8.594 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH:14]=[O:15])[C:5]2=[CH:4][N:3]=1.CC(=CC)C.Cl([O-])=[O:28].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[C:14]([OH:28])=[O:15])[C:5]2=[CH:4][N:3]=1
Reactant: COc1ccc(C=O)cc1-c1nn(C)c2nc(N)ncc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(C(=O)O)cc1-c1nn(C)c2nc(N)ncc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-benzaldehyde (Example 75) (0.5 g, 1.77 mmol) is suspended in t-butanol (12 ml) and 2-methyl-2-butene (0.562 ml, 5.31 mmol). To this is added a solution of sodium chlorite (0.367 g, 4.06 mmol) and sodium dihydrogen phosphate (0.848 g, 7.06 mmol) in water (5 ml). The reaction mixture is stirred at room temperature for 48 hours and the resulting precipitate is collected by filtration, dissolved in saturated aqueous NaHCO3 (100 ml) and washed with EtOAc (2×50 ml). The aqueous portion is acidified to pH1 with 2M HCl resulting in an off-white solid which is collected by filtration and dried under vacuum for 72 hours to afford the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[S:14][N:13]=[C:12]([CH3:15])[C:11]=1[N+:16]([O-:18])=[O:17])#[N:9].[CH2:19]([S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[OH-].[Na+]>O1CCCC1>[C:8]([C:10]1[S:14][N:13]=[C:12]([CH2:15][C:38](=[O:39])[C:37]2[CH:36]=[CH:35][C:34]([S:31]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])=[CH:42][CH:41]=2)[C:11]=1[N+:16]([O-:18])=[O:17])#[N:9]
Reactant: Cc1nsc(C#N)c1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)Cc2nsc(C#N)c2[N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 23.5 %

Procedure:
Triethylamine (20.2 grams, 0.200 mol) was added to 200 ml of a tetrahydrofuran (THF) solution of 16.9 grams (0.100 mol) of 5-cyano-3-methyl-4-nitroisothiazole, and 74.6 grams (0.200 mol) of 4-dodecylsulfonylbenzoyl chloride was added dropwise. After heating under reflux for 8 hours, 200 ml of 1N aqueous sodium hydroxide solution was added dropwise. After heating under reflux for 3 hours, the reaction mixture was left to cool, poured into ice water and extracted with ethyl acetate. 5-Cyano-3-(4-dodecylsulfonylbenzoylmethyl)-4-nitroisothiazole (11.9 grams, 23.5 mmol) was obtained on refinement using silica gel column chromatography.