Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[C:11]([O:12][CH3:13])=[C:10]([OH:14])[C:9]([CH3:15])=[CH:8][C:6]=1[OH:7]>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[C:11]([O:12][CH3:13])=[C:10]([OH:14])[C:9]([CH3:15])=[C:8]([Br:1])[C:6]=1[OH:7]
Reactant: BrBr
Reactant: COc1c(O)cc(C)c(O)c1OC
Solvent: ClC(Cl)Cl
Product: COc1c(O)c(C)c(Br)c(O)c1OC
Reaction time: 3 h
Yield: 100.7 %

Procedure:
A solution of 39.5 g of bromine in 70 ml of chloroform was added dropwise at about 5° C. to a solution of 46.0 g of 2,3-dimethoxy-5-methylhydroquinone in 500 ml of chloroform, under a nitrogen atmosphere. Stirring was continued at the same temperature for 3 hours, and then the reaction mixture was washed with water until the washings were colorless. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to provide 65.5 g of 2,3-dimethoxy-5-methyl-6-bromohydroquinone.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[C:14]([CH3:20])=[CH:13][N:12]=2)[C:3]=1[NH2:21].[N:22]([O-])=O.[Na+]>>[Cl:1][C:2]1[C:3]2[N:21]=[N:22][N:9]([CH2:10][C:11]3[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[C:14]([CH3:20])=[CH:13][N:12]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: O=N[O-]
Reactant: COc1c(C)cnc(CNc2nc(N)nc(Cl)c2N)c1C
Agent: [Na+]
Product: COc1c(C)cnc(Cn2nnc3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of 6-chloro-N4-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-pyrimidine-2,4,5-triamine was treated with a cold aqueous solution of NaNO2, following the general procedure 2. HPLC RT was 3.597 min. 1HNMR (CDCl3): δ 8.22 (s, 1H), 7.12 (broad t, 1H), 4.61 (s, 2H), 4.56–4.55 (d, 2H), 3.80 (s, 3H), 3.00 (s, 2H), 2.29 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:53]=[C:54]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)[CH:55]=[N:56][CH:57]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:53]=[C:54]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)[CH:55]=[N:56][CH:57]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1cncc(-c2cccc(N)c2)c1
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: COc1cncc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)c1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(5-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.020 g of product in 79% yield: LCMS (ESI) m/z 403 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c12
Product: Cc1csc2nc(-n3cccn3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(O[C@H:5]1[C@H:10]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[N:16][C:17]#[N:18])[C:9]2[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:8]=2[O:7][C:6]1([CH3:26])[CH3:25])(=O)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:17]([N:16]=[C:12]1[NH:13][CH2:14][CH2:15][N:11]1[C:10]1[C:9]2[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:8]=2[O:7][C:6]([CH3:26])([CH3:25])[CH:5]=1)#[N:18]
Reactant: CC(=O)O[C@H]1[C@H](N2CCNC2=NC#N)c2cc(C#N)ccc2OC1(C)C
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)C=C(N2CCNC2=NC#N)c2cc(C#N)ccc2O1
Yield: 58.5 %

Procedure:
To a suspension of trans-3-acetoxy-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.35 g) in toluene (7 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 ml) and the mixture was stirred under reflux for 2.5 hours. The solvent was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ethanol to give 4-(2-cyanoiminoimidazolidin-1-yl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.17 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26]Cl)[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]([O-:48])(=[O:47])[CH3:46].[Na+]>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26][O:48][C:45](=[O:47])[CH3:46])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCOC(C)=O)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 40 °C
Reaction time: 17 h
Yield: 32.4 %

Procedure:
To the product of Example 145 (21 mg, 32 μmol) in acetone (2 mL) was added tetra-n-butylammonium iodide (24 mg, 65 μmol). The solution was stirred at 40° C. for 17 h prior to the addition of sodium acetate (50 mg, 0.64 mmol). The reaction solution was heated at 75° C. for 48 h. After cooling the solution was diluted with EtOAc (25 mL), washed with saturated NaHCO3 (20 mL) and water (2×20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude sample was chromatographed (silica gel, DCM) to provide the title compound (7 mg, 33%). 1H-NMR (CDCl3) δ 7.87 (1H, s), 7.60 (1H, dd), 7.30–7.35 (3H, m), 7.17–7.22 (3H, m), 6.60 (1H, dd), 6.48 (1H, d), 5.27 (2H, s), 4.72 (1H, s), 4.39 (2H, t), 4.16 (2H, t), 3.69 (2H, q), 3.16 (2H, s), 3.08 (3H, s), 2.43 (6H, s), 2.06 (3H, s), 0.91 (3H, t); MS(ESI): 675 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[N:42]=[CH:41][CH:40]=[CH:39][N:38]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Clc1ncccn1
Product: C[C@@H](c1ccc(-c2ncccn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-chloropyrimidine following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.401, m/z=436.1; 1H NMR (CDCl3) 1.53 (d, 3H), 1.62 (m, 1H), 1.81-1.98 (m, 3H), 2.15 (m, 2H), 2.31 (m, 1H), 2.76 (m, 1H), 3.51 (t, 2H), 5.67 (m, 1H), 6.92 (m, 4H), 7.11 (m, 1H), 7.19 (m, 1H), 8.15 (d, 2H), 8.71 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[H-].[Na+].Br[CH2:11][Cl:12]>CN(C)C=O.O>[Cl:12][CH2:11][S:7][C:4]1[S:3][C:2]([CH3:1])=[N:6][N:5]=1
Reactant: ClCBr
Reactant: Cc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(SCCl)s1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a solution of 2-methyl-1,3,4-thiadiazole-5-thiol (2.64 g: 20 mMol.) in dimethylformamide (40 ml) is added under ice cooling sodium hydride (880 mg: 60% dispersion in oil: 1.1 equivalents: 22 mMol.) in portions, and the mixture is stirred for 10 minutes. To the resulting solution is added bromochloromethane (40 ml), and the mixture is stirred at the same temperature for another 1 hour and 30 minutes. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and purified by silica gel chromatography (toluene: ethyl acetate=10:1) to give 5-chloromethylthio-2-methyl-1,3,4-thiadiazole (3.3 g) as colorless oil. Yield: 91%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.C1C(=O)N([Cl:21])C(=O)C1>C(#N)C>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9](=[O:13])[NH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Solvent: CC#N
Product: COc1ccc2c(=O)[nH]cc(Cl)c2c1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a solution of 6-methoxyisoquinolin-1(2H)-one (2.5 g, 14.27 mmol) in acetonitrile (10 ml) was added NCS (2.54 g, 14.27 mmol) at 80° C. for overnight. The reaction mass was cooled to room temperature and the precipitated solid was filtered to get crude compound (2 g, 55.2%). The crude compound was taken to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.41 (s, 1H), 8.17-8.15 (d, J=8 Hz, 1H), 7.53 (s, 1H), 7.19-7.11 (m, 2H), 3.93 (s, 3H); MS: MS m/z 210.02 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8](Cl)=[O:9].[Cl:37][C:38]1[CH:39]=[C:40]([OH:47])[CH:41]=[CH:42][C:43]=1[N+:44]([O-:46])=[O:45].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]([O:47][C:40]1[CH:41]=[CH:42][C:43]([N+:44]([O-:46])=[O:45])=[C:38]([Cl:37])[CH:39]=1)=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)Oc4ccc(C(=O)Cl)c(Cl)c4)cc3)cc2)CC1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)Oc4ccc(C(=O)Oc5ccc([N+](=O)[O-])c(Cl)c5)c(Cl)c4)cc3)cc2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid 3-chloro-4-(chlorocarbonyl)phenyl ester obtained was dissolved in 150 ml of benzene and then added dropwise to a solution of 1.2 g of 3-chloro-4-nitrophenol in 110 ml of dry pyridine. The mixture was stirred at 65° C. overnight, then poured into a mixture of 500 ml of ice-water and 100 ml of concentrated hydrochloric acid and extracted with diethyl ether. The extract was washed three times with 100 ml of 3N hydrochloric acid each time and three times with 200 ml of water each time, then dried and evaporated. The crude 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid 3-chloro-4-[(3-chloro-4-nitrophenoxy)carbonyl]phenyl ester obtained was chromatographed on silica gel with toluene/acetone (volume ratio 19:1). The fractions which were almost pure according to thin-layer chromatography (2.8 g) were recrystallized twice from ethyl acetate; m.p. (C-N) 132° C., cl.p. >250° C. (decomposition).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1>CN(C=O)C.O>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:15]=1
Reactant: Brc1cncc(Br)c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1cncc(Br)c1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
To a slurry of sodium hydride (60% dispersion in mineral oil, 0.54 g, 14 mmol) in DMF (15 mL) was added commercially available 2,2,2-trifluoroethanol (0.97 mL, 14 mmol) at room temperature. After stirring for 15 minutes, a solution of 3,5-dibromopyridine (3.2 g, 14 mmol) in 5 mL of DMF was added dropwise. The reaction mixture was heated overnight at 70° C. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate. The extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was chromatographed on silica (5% ethyl acetate/hexanes) to give the title compound (1.6 g, 46% yield) as clear oil. 1H NMR (CDCl3) δ 8.42 (d, 1H, J=1.7 Hz), 8.32 (d, 1H, J=2.5 Hz), 7.46 (m, 1H), 4.42 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:7][C:6]2=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Br>O1CCCC1>[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][N:12]1[C:11]2[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([O:2][CH3:1])[CH:4]=2
Reactant: COc1ccc2[nH]c3c(c2c1)CC(NC(=O)C(C)C)CC3
Reactant: Clc1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c1c(n2Cc2ccccc2Cl)CCC(NC(=O)C(C)C)C1
Reaction time: 0.42 h
Yield: 68.8 %

Procedure:
Dissolve N-(6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 6) (100 mg, 0.35 mmol) in anhydrous tetrahydrofuran (4 mL) under nitrogen. Add dropwise potassium bis(trimethylsilyl)amide (0.77 mL, 0.385 mmol, 0.5N in toluene) and stir 25 min. Add slowly 2-chlorobenzylbromide (0.050 mL, 0.385 mmol) and stir at ambient temperature for 18 h. Quench with saturated ammonium chloride solution (0.5 mL) and dilute with a volume of dichloromethane and water (1 mL). Pass over a Varian Chem Elut column to remove aqueous portion and concentrate in vacuo. Alternatively, workup with ethyl acetate/water and dry over MgSO4. Purify the resulting residue by flash chromatography, eluting with dichloromethane with a gradient up to 10% ethyl acetate/dichloromethane to obtain 99 mg (69%) of a white solid. MS (ES): m/z 411, 413 (M+1); 1H NMR(DMSO-d6): δ 7.86 (d, 1H, J=7.5 Hz), 7.52 (d, 1H, J=8.4 Hz), 7.28 (t, 1H, J=7.7 Hz), 7.17 (m, 2H), 6.97 (d, 1H, J=2.2 Hz), 6.68 (dd, 1H, J=8.8, 2.2 Hz), 6.24 (d, 1H, J=7.9 Hz), 5.36 (s, 2H), 4.02 (m, 1H), 3.77 (s, 3H), 2.98 (dd, 1H, J=15.2, 5.1 Hz), 2.75-2.61 (m, 2H), 2.41 (m, 1H), 1.96 (m, 1H), 1.81 (m, 1H), 2.52 (m, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1.[OH-].[Na+]>CN(C=O)C.O>[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:10][C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH:17]=1
Reactant: Oc1ccc(F)cc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Oc2cncc(Br)c2)cc1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
Sodium hydride (1.53 g of 80% in mineral oil, 51 mmol) was slowly added to a solution of 4-fluorophenol (5.6 g, 50 mmol) in DMF (100 mL) as it was stirred and cooled (ice water bath) under a nitrogen atmosphere. The resulting mixture was warmed to ambient temperature and stirred for 1 h. 3,5-Dibromopyridine (5.9 g, 25 mmol) was added and the mixture was then heated at 90° C. (bath temperature) for 62 h. The mixture was cooled, diluted with water (150 mL), poured into 5N sodium hydroxide (150 mL), and extracted with diethyl ether (2×150 mL). The combined ether extracts were washed with water, dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography on silica gel, using 5% ethyl acetate: hexane as eluent, to yield 1.4 g (21%) of a colorless oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6].[C:24]([NH:31][CH2:32][CH2:33][CH2:34][NH2:35])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][CH:10]([CH3:12])[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]([C:4]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:2]([NH:35][CH2:34][CH2:33][CH2:32][NH:31][C:24](=[O:25])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:3]=1)=[O:6]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1
Yield: 96 %

Procedure:
A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (1.6 g, 1 eq), N-Boc-1,3-diaminopropane (0.9 g, 1.2 eq) and potassium carbonate (1.35 g, 2 eq) in acetonitrile (80 ml) is heated under reflux for 5 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (100 ml) and water (40 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent:heptane/ethyl acetate 8:2 to 6:4) produces the expected compound in the form of a yellow oil (2.2 g; 96% yield).
Reaction SMILES: [OH-].[NH4+:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[O-][N+:15]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[N:25]([CH2:31][CH2:32][CH2:33][O:34][N:35]3C(=O)C4C(=CC=CC=4)C3=O)[C:26]([CH2:28][CH2:29][CH3:30])=[N:27][C:17]=2[CH:16]=1>C(Cl)(Cl)Cl>[NH2:35][O:34][CH2:33][CH2:32][CH2:31][N:25]1[C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[N:15]=[C:16]([NH2:2])[C:17]=2[N:27]=[C:26]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCON1C(=O)c2ccccc2C1=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCON
Reaction time: 1 h

Procedure:
Ammonium hydroxide (75 mL) and p-toluenesulfonyl chloride (4.87 g, 25.6 mmol) were added to a solution of 2-[3-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione (10.0 g, 23.2 mmol) in chloroform (100 mL), and the resulting mixture was stirred vigorously for one hour.) A white precipitate was removed by filtration, and the filtrate layers were separated. The organic solution was washed with brine (2×150 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a yellow solid. The solid was purified by column chromatography on silica gel (eluting with dichloromethane:methanol:ammonium hydroxide ranging in ratios from 94:5:1 to 91:8:1) to provide 4.31 g of 1-[3-(aminooxy)propyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a beige powder, melting point (mp) 145-148° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=O)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O)[CH3:2].O.[NH2:16][NH2:17]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[NH:17][N:16]=1)=[O:14])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)C1CCCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1n[nH]c2c1CCCC2

Procedure:
A solution of oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester [7.5 g, Reference Example 19(a)] in acetic acid (150 ml) was treated dropwise with hydrazine monohydrate (1.65 ml). The mixture was refluxed for 8 hours, then cooled and then evaporated. The residue was partitioned between ethyl acetate (200 ml) and saturated sodium bicarbonate solution (200 ml) and the organic layer was dried over sodium sulfate and then evaporated. The residual orange oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:1, v/v) to give 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester (606 mg) as an orange oil which solidified on standing. LC-MS (METHOD B): RT=2.79 minutes; 195 (M+H)+. (b) 5-Isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:14](/[N+:11]([O-:13])=[O:12])\[CH3:15])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: CC[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C/C(=C\c1ccc(Cl)cc1F)[N+](=O)[O-]
Temperature: 25 °C
Yield: 76.4 %

Procedure:
4-Chloro-2-fluorobenzaldehyde (10 g, 63.1 mmol), nitroethane (54.6 mL, 757 mmol) and piperidine (1.869 mL, 18.92 mmol) were dissolved in toluene (150 mL) and refluxed under Dean Stark conditions overnight. The reaction mixture was cooled to room temperature and the solvents were evaporated. The crude product was purified by column chromatography (silica, heptane/EtOAc 98:2) to give the desired product (10.4 g, 76%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[S:17][CH2:16][CH2:15][N:14]=[C:13]([C:18]2[C:19](=[O:26])[O:20][C:21]([CH3:25])=[CH:22][C:23]=2[OH:24])[CH2:12]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[S:17][CH2:16][CH2:15][N:14]=[C:13]([C:18]2[C:19](=[O:26])[O:20][C:21]([CH3:25])=[CH:22][C:23]=2[OH:24])[CH:12]=1
Reactant: COc1ccc(C2CC(c3c(O)cc(C)oc3=O)=NCCS2)c(OC)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CC(c3c(O)cc(C)oc3=O)=NCCS2)c(OC)c1
Temperature: 80 °C
Yield: 24 %

Procedure:
3-[7-(2,4-Dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one (150 mg, 0.39 mmol), prepared as in Reference 5, was dissolved in toluene (2 ml) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.3 mL, 35 wt % in water) was added to the solution. The mixture was stirred at 80° C. The reaction was monitored by analytical HPLC and after reaction was complete (20 minutes) the solvent was then removed in vacuo. Product was purified by preparative HPLC (RPC18 column, 2-80% acetonitrile/water containing 0.1% HCl) to provide 3-[7-(2,4-dimethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one (35 mg) as an orange powder. LCMS: MH+ 373.0.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=O)=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=[N:12][OH:13])=[CH:4][N:3]=1
Reactant: Cc1ncc(C=O)c(N)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ncc(C=NO)c(N)n1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a mixture of 8.6 g of 2-methyl-4-amino-5-formylpyrimidine and 340 ml of methanol, while stirring at room temperature, was added dropwise gradually 40 ml of an aqueous solution of 5.20 g of hydroxylamine hydrochloride and 7.80 g of sodium carbonate. As the reaction proceeded, crystals precipitated. Four hours later, the crystals were collected by filtration, washed with methanol and water, followed by drying under reduced pressure to give 7.84 g (82.3%) of 2-methyl-4-amino-5-pyrimidine aldoxime. The mother liquor was subjected to high performance liquid chromatography to quantitatively determine 2-methyl-4-amino-5-pyrimidine aldoxime (by absolute calibration curve method) to confirm that 1.41 g (14.8%) of the object compound was produced. The total yield of the crystals and the object compound in the mother liquor was 97.1%. The mother liquor was concentrated to dryness under reduced pressure, followed by recrystallization from a mixture solvent of methanol/ether to isolate 0.8 g of 2-methyl-4-amino-5-pyrimidine aldoxime.