Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C>C1COCC1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([B:24]([OH:25])[OH:23])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
To a solution of 4-phenoxybromobenzene (98.2 g, 0.39 mol) in dry THF (800 mL) under nitrogen at −78° C. was added n-BuLi (2.5M solution in hexanes) (172 mL, 0.43 mol) dropwise. A temperature rise to −65° C. was observed. On complete addition, the mixture was allowed to stir at −78° C. for 15 min. Triisopropylborate (109.2 mL, 0.473 mol) was added dropwise over 30 min. On complete addition, a suspension was observed. The mixture was allowed to warm to 0° C. over 1 hr, stirred at 0° C. for 4 hrs. The reaction was quenched by the dropwise addition of water (300 mL) such that the internal temperature<20° C. (ice-cooling required). The mixture was allowed to warm to room temperature overnight then evaporated to dryness. The residue was suspended in water (600 mL) and acidified by the cautious addition of conc. HCl. The resulting precipitate was collected by filtration and dried in vacuo at 45° C. The solid was ground to a fine powder and triturated with petroleum ether (40-60° C.). The pale solid was filtered and dried to give 4-phenoxyphenylboronic acid (68.8 g, 83%). 1H NMR (250 MHz, d6-DMSO):7.99 (1H, m), 7.91 (1H, t), 7.83 (1H, d), 7.4 (2H, m), 7.14 (1H, m), 6.92-7.07 (5H, m). Microanalysis:Req. C(71.4%), H(5.45%), Found C(70.25%), H(4.7%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27]>CCOC(C)=O>[O:29]=[C:28]1[NH:26][N:27]=[C:1]([C:3]2[N:4]=[C:5]([O:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2nc(C#N)cc3ccccc23)C1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 175 °C

Procedure:
To crude (R)-tert-butyl 3-((3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate was added ethyl hydrazinecarboxylate (1.104 g, 10.60 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled and diluted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and concentrated to give the title compound, which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)=[O:6])[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:31])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]2[CH:22]=[C:21]([CH2:29][SH:30])[CH:20]=[CH:19][C:18]1=2>>[CH3:16][C:17]1([CH3:31])[CH2:26][CH2:25][C:24]([CH3:27])([CH3:28])[C:23]2[CH:22]=[C:21]([CH2:29][S:30][C:11]([C:10]3[CH:9]=[CH:8][C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:15][CH:14]=3)=[O:13])[CH:20]=[CH:19][C:18]1=2
Reactant: C=CCOC(=O)c1ccc(C(=O)O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(CS)ccc21
Product: C=CCOC(=O)c1ccc(C(=O)SCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 2 g (10 mmol) of 4-(allyloxycarbonyl)benzoic acid with 2.34 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethanethiol, 3.4 g (81%) of the expected allyl ester, melting point 79°-80° C., are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:17]=[O:18]>>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([CH:17]=[O:18])=[CH:5][CH:4]=1)[CH3:9]
Reactant: CN(C)C=O
Reactant: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1ccc(C=O)cc1

Procedure:
N,N-Di(loweralkyl)anilines, preferably N,N-dimethyl aniline, are reacted with phosphorus oxychloride in dialkyl formamide, preferably dimethyl formamide (DMF), according to the Vilsmeier Reaction to give 4-(N,N-di-loweralkylamino)benzaldehydes, preferably 4-(N,N-dimethylamino)benzaldehyde. The reaction is conducted using essentially two molar proportions of the N,N-dialkylaniline, essentially one molar proportion (or a slight excess) of phosphorus oxychloride, and essentially two molar proportions (or a slight excess) of dimethyl formamide. The phosphorus oxychloride is slowly added, with cooling, to the mixture of N,N-dialkylaniline and dimethyl formamide, keeping the temperature in the range of about 50°-70° C., preferably about 55°-65° C. The 4-(di-loweralkylamino)benzaldehyde thus formed may be isolated at this point for subsequent reaction with an N,N-di(loweralkyl)aniline and the sulfinic acid or the reaction may be continued without isolation in what is referred to herein as the "in situ" process.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:33]([F:35])[F:34])[N:3]=1.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])=[O:38].CCN(C(C)C)C(C)C>C1COCC1>[F:35][CH:33]([F:34])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([N:43]3[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]3)[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:5]=2)[C:18]2[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Yield: 79.4 %

Procedure:
A mixture of tert-butyl 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate (0.333 g, 0.65 mmol), 1-(methylsulfonyl)piperazine (0.32 g, 2 mmol), and DIPEA (0.17 g, 1.3 mmol) in THF (50 mL) was heated under reflux for 3 hrs. The solution was concentrated and then diluted with 100 mL of water containing 1% HOAc to give a solid, which was collected and dried. Chromatography on silica eluting with CH2Cl2/EtOAc (4:1), followed by recrystallization from MeOH, gave 0.33 g (79% yield) of tert-butyl 2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate: mp 223° C. (decomp.); 1H NMR (CDCl3) δ 8.63 (br s, 1H), 7.44 (t, JHF=53.6 Hz, 1H), 6.62 (br s, exchangeable with D2O, 1H), 6.35 (d, J=1.7 Hz, 1H), 4.09-3.80 (m, 15H), 3.35 (m, 4H), 2.80 (s, 3H), 1.52 (s, 9H); Anal. Calcd. for C26H35F2N9O6S: C, 48.8; H, 5.5; N, 19.7. Found: C, 48.9; H, 5.6; N, 19.9%.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH2:15]>C1COCC1>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH:15][CH:1]=[O:3]
Reactant: O=CO
Reactant: COc1ccc([N+](=O)[O-])cc1N
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1NC=O
Temperature: 55 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
A mixture of formic acid (0.45 ml, 0.012 mole) and acetic anhydride (1.06 ml, 0.011 mole) was stirred at 55° C. under Ar for 2 h, and cooled to room temperature. Dry THF (10 ml) was added. To this solution was added 2-methoxy-5-nitroaniline (0.69 g, 0.004 mole). After stirring for 1 h, the suspension was evaporated in vacuo to leave the title compound as a brown solid (0.80 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29].Br[C:34]1[C:35]([CH3:43])=[N:36][C:37]([O:41][CH3:42])=[CH:38][C:39]=1[CH3:40].F.[K]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([C:34]2[C:35]([CH3:43])=[N:36][C:37]([O:41][CH3:42])=[CH:38][C:39]=2[CH3:40])[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1cc(C)c(Br)c(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: F
Agent: [K]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(-c2c(C)cc(OC)nc2C)cc1F
Temperature: 110 °C

Procedure:
A mixture of ethyl 5-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate synthesized in accordance with Example 53 (430 mg), 3-bromo-6-methoxy-2,4-dimethylpyridine obtained in Preparation Example 23 (223 mg), potassium hydrogen fluoride (254 mg), Pd(PPh3)4 (90 mg) and tripotassium phosphate n-hydrate (400 mg) in DME (8 mL) and water (2 mL) was heated under reflux at 110° C. for seven hours. The reaction mixture was cooled to room temperature and partitioned by adding ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane: 16% to 37% to 46%) and silica gel column chromatography (ethyl acetate/n-heptane: 28% to 49% to 54%) to give the title compound (144 mg). This compound was used for the next reaction without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C>ClCCl>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:12][C:9]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)([CH3:10])[CH3:11])=[O:22]
Reactant: CC(C)(N)c1ccc(Cl)cc1
Reactant: O=C(Cl)CCCCCCCBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)CCCCCCCBr)c1ccc(Cl)cc1

Procedure:
1-(4-Chlorophenyl)-1-methylethylamine hydrochloride (4.0 g) was reacted with 8-bromooctanoyl chloride (4.7 g) in dichloromethane (50 ml) containing triethylamine (8.1 ml), in a similar manner to Example 52b, to give 8-bromo-N-[1-(4-chlorophenyl)-1-methylethyl]octanamide which was used directly in part c).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][N:9]=[C:8]([I:12])[C:7]2=[O:13].[CH3:14][O:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:18][CH2:17][C:16]([O:15][CH3:14])([CH3:21])[CH3:20])[N:9]=[C:8]([I:12])[C:7]2=[O:13]
Reactant: COC(C)(C)CCO
Reactant: O=c1c(I)n[nH]c2c(F)cccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(C)(C)CCn1nc(I)c(=O)c2cccc(F)c21
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A mixture of 0.72 g of 8-fluoro-3-iodocinnolin-4(1H)-one and 0.48 ml of 3-methoxy-3-methylbutan-1-ol in 20 ml of THF is cooled to 5° C., 0.97 g of triphenylphosphine is added and then 0.65 g of diethyl azodicarboxylate is slowly added, and the mixture is left stirring overnight at AT. The reaction mixture is concentrated under vacuum and the residue is chromatographed on silica gel, elution being carried out with the cyclohexane/AcOEt mixture (75/25; v/v) and then with AcOEt. The expected compound is obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([CH2:19]O)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.O=S(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][CH2:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:21])[F:1])[CH:4]=1)[CH:18]=[CH:17]2
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12
Solvent: ClCCl
Product: FC(F)(F)c1cccc(-c2ccc3cccc(CCl)c3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of (2-(3-(trifluoromethyl)phenyl)quinolin-8-yl)methanol (0.67 g, 2.2 mmol) in CH2Cl2 (20 ml) was added SOCl2 (0.32 ml, 4.4 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 2 h, and then concentrated. The residue was purified by column chromatography (1:15 ethylacetate in pentane) to give the product as a white solid (0.668 g, 94% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])(O)[CH2:14][CH2:13]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:8][CH2:9][C:10]([N:12]1[CH2:13][CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[CH2:16][CH2:17]1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COCc1ccccc1)N1CCC(O)(c2ccc(Cl)cc2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(COCc1ccccc1)N1CC=C(c2ccc(Cl)cc2Cl)CC1
Yield: 27.8 %

Procedure:
A solution of 2-benzyloxy-1-[4-(2,4-dichloro-phenyl)-4-hydroxy-piperidin-1-yl]-ethanone (0.035 g, 0.09 mmol) in trifluoroacetic acid (1 mL) was stirred at RT for 48 h. Ethyl acetate (2 mL) and saturated aqueous sodium bicarbonate (2 mL) were added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The isolated residue was chromatographed on silica gel using dichloromethane/ethyl acetate to 100% to 90% dichloromethane in a gradient fashion, to give the title compound as a gum (0.0094 g, 28%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][CH2:23][CH3:24].[C:25](O)(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CO>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][CH2:23][CH3:24])[N:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1OCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCCOn1c(CCCC)nc2c(N)nc3ccccc3c21

Procedure:
The 1-(4-aminobutoxy)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine was dissolved in dichloromethane (20 mL) and methanol (5 mL). Stearic acid (0.71 g) was added and the reaction was stirred to dissolve the stearic acid. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl (EDC, 0.45 g) was added and the reaction was stirred at ambient temperature for 16 hours. An additional portion of EDC was added (0.23 g) and the reaction was stirred for an additional 24 hours. Final portions of stearic acid (0.22 g) and EDC (0.37 g) were added to drive the reaction to completion and the reaction was stirred at ambient temperature for another 24 hours. The reaction was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography using a Biotage chromatography system (Si40+M2358-1 SiGel column, 85:15 dichloromethane/methanol isocratic elution). The semi-pure product was purified by flash column chromatography two more times using a 90:10 dichloromethane/methanol isocratic elution, followed by a 95:5 dichloromethane/methanol isocratic elution The fractions containing product were concentrated to yield 1.12 g of N-(4-{[4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl]oxy}butyl)octadecanamide as an off white waxy solid. 1H-NMR (CDCl3): δ 0.89 (t, 3H), 1.01 (t, 3H), 1.14-1.42 (m, 28H), 1.50 (m, 2H), 1.65 (m, 2H), 1.74-1.94 (m, 4H), 2.02 (m, 2H), 2.20 (t, 2H), 2.95 (t, 2H), 3.40 (q, 2H), 4.33 (t, 2H), 5.59 (t, 1H), 6.10 (broad s, 2H), 7.39 (m, 1H), δ 7.57 (m, 1H), 7.83 (d, 1H), 8.07 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:13]=1[C:14]#[N:15]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:13]=2[C:14]#[N:15])=[O:7])=[CH:9][CH:10]=1
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: COc1cc(C#N)c(NC(=O)c2ccc(Cl)nc2)cc1OC

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2-amino-4,5-dimethoxybenzonitrile as a white solid as described in Example 1. 1H NMR (CDCl3): 8.97 (d, J=2.7, 1H), 8.18-8.15 (m, 3H), 7.52 (d, J=8.4, 1H), 7.02 (s, 1H), 4.01 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[S:6][C:7]([CH:11]=O)=[C:8]([Cl:10])[N:9]=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[Cl:4][C:5]1[S:6][C:7]([CH:11]=[N:2][OH:3])=[C:8]([Cl:10])[N:9]=1
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1sc(Cl)nc1Cl
Reaction time: 0.03 h
Yield: 99 %

Procedure:
First 153 g (2.2 mol) of hydroxylamine hydrochloride in portions, then a solution of 364 g (2 mol) of 2,4-dichloro-5-thiazolecarboxaldehyde (II) in 1 liter of ethanol are added to a solution of 185 g (2.2 mol) of sodium bicarbonate in 5 liters of water at room temperature, with stirring. A voluminous, colourless precipitate separates out after 1 to 2 minutes. After stirring for 1 hour, the solid is filtered off with suction, washed with water and dried. 390 g (=99% of theory) of 2,4-dichloro-5-thiazolecarboxaldehyde oxime (IV) of melting point about 160° C. are obtained. It can be dehydrated to give the nitrile without further purification.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][CH2:23][OH:24]>CN(C=O)C.C(OCC)(=O)C>[C:4]([Si:1]([O:24][CH2:23][CH2:22][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[F:14])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCc1ccccc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCc1ccccc1F
Reaction time: 0.75 h

Procedure:
tert-Butyldimethylsilyl chloride (3.19 g) was added to a solution of imidazole (3.6 g) and 3-(2-fluorophenyl)propan-1-ol (example 88, step a) (2.72 g) in dry DMF (30 mL) cooled in an ice bath. After 45 min, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×100 mL) and evaporated. The resulting gum was purified by silica gel chromatography eluting with isohexane. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 4.4 g.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[C:10](=[NH:20])(OCC)[CH2:11][C:12](=[NH:16])OCC.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[NH2:16][C:12]1[CH:11]=[C:10]([NH2:20])[N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=N)CC(=N)OCC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cc(N)n(-c2ccccc2)n1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (6 ml) was added over 5 minutes to a stirred suspension of diethyl malonimidate dihydrochloride (5 g) in ethanol (50 ml). Phenylhydrazine (2.1 ml) was added, then the mixture was stirred at ambient temperature for 4 hours and at 95° C. for 30 minutes. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was separated, washed with water (50 ml), dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 19:1 mixture of dichloromethane and methanol as eluant, appropriate fractions were combined, and the solvents were removed in vacuo to give 3,5-diamino-1-phenylpyrazole as a red-brown oil (0.76 g).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:19]=[C:18]([C:20]2[O:24][CH:23]=[N:22][CH:21]=2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:25][C:23]1[O:24][C:20]([C:18]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([F:11])[CH:19]=2)=[CH:21][N:22]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: N#Cc1ccc(-c2cnco2)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cnc(Cl)o2)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
LiHMDS (1.06 M in THF, 1.32 mL, 1.40 mmol) was added to a solution of 2-fluoro-4-(oxazol-5-yl)benzonitrile 38 (0.22 g, 1.17 mmol) in THF (20 mL) at −78° C., and the mixture was stirred at −78° C. for 1 h. A solution of hexachloroethane (0.415 g, 1.75 mmol) in THF (5 mL) was added at −78° C., and the mixture was stirred at −78° C. for 2 h and allowed to warm to room temperature and stirred for 14 h. The reaction was quenched by adding EtOAC:H2O (50 mL:15 mL), and then extracted with Ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. The product was purified by column chromatography (Acetone/hexane as an eluent) to provide 4-(2-chlorooxazol-5-yl)-2-fluorobenzonitrile 39 (0.18 g, 70% yield) as white solid. MS (ES) m/z 223 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([CH:31]=O)[CH:21]=1>>[CH3:19][C:20]1[N:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:23]=[C:22]([CH2:31][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)[CH:21]=1
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Product: Cc1cc(CNCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1-c1ccccc1
Yield: 59.6 %

Procedure:
Compound 49 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][S:9][C:10](=[NH:12])[NH2:11].[NH2:13][C:14]1[C:15]([C:24](OC(C)=CC(=O)NC(C)(C)C)=[O:25])=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2>C1COCC1>[NH2:13][C:14]1[C:15]([C:24]([NH:12][C:10]([S:9][CH3:8])=[NH:11])=[O:25])=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: CC(=CC(=O)NC(C)(C)C)OC(=O)c1nc2ccccc2nc1N
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSC(=N)NC(=O)c1nc2ccccc2nc1N

Procedure:
To NaOH (1 mol/l in water; 45.7 ml; 45.7 mmol) is added S-methylisothiourea sulphate (10.6 g; 38.1 mmol). The mixture is stirred until complete solution is achieved. The resulting solution is added to a suspension of 1-(tert-butylcarbamoyl)prop-1-en-2-yl 3-aminoquinoxaline-2-carboxylate (example 4) (5.00 g; 15.2 mmol) in THF (80 ml). The mixture is stirred at r.t. for 3 h, then volatiles are evaporated. Ice-water (100 ml) is added. The precipitate formed is filtered off with suction, washed with water and then dried at 50° C. (C11H11N5OS).