Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](OC)(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37](=[O:54])[CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:41]=2)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C.[OH-].[Na+]>C1COCC1>[CH2:47]([O:46][C:42]1[CH:41]=[C:40]([CH2:39][CH2:38][C:37]2([CH2:36][CH2:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:30]=3)[O:54][C:13](=[O:18])[CH:14]=[C:15]([OH:16])[CH2:17]2)[CH:45]=[CH:44][CH:43]=1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1cccc(OCc2ccccc2)c1)CCc1cccc(OCc2ccccc2)c1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1C=C(O)CC(CCc2cccc(OCc3ccccc3)c2)(CCc2cccc(OCc3ccccc3)c2)O1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A solution of 3.3 mL of diisopropylamine (23.5 mmol) in dry THF (500 mL) was cooled to 0° C. under nitrogen, treated with 14.3 mL of 1.64M n-butyllithium (22.8 mmol), and stirred at 0° C. for 25 minutes. To this solution was added 1.2 mL (11.1 mmol) of methyl acetoacetate, and the mixture was stirred for 30 minutes. The solution was then cooled to -78° C. A solution of 5.00 g (11.1 mmol) of 1,5-bis-(3-benzyloxy-phenyl)-pentan-3-one (prepared in Example J) dissolved in dry THF (100 mL) was added dropwise, and the mixture was stirred at low temperature for 3 hours. Dilute acetic acid (2 equivalents) was added, and the mixture was extracted with EtOAc. The extracts were dried (MgSO4) and concentrated. The residue that was obtained was dissolved in THF (250 mL), treated with 0.1N NaOH (500 mL), and stirred overnight at room temperature. The mixture was cooled in an ice bath, quenched with 50% acetic acid, and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. The residue was chromatographed on silica gel, eluting with MeOH:CH2Cl2 (2:98), to give 6,6-bis-[2-(3-benzyloxy-phenyl)-ethyl]-5,6-dihydro-4-hydroxy-pyran-2-one. 1H NMR (DMSO-d6) δ 1.93 (m, 4 H), 2.56 (m, 4 H), 3.35 (s, partially obscured by H2O, 2 H), 4.99 (s, 1 H), 5.02 (s, 4 H), 6.72-6.78 (m, 4 H), 6.82 (br s, 2 H), 7.14 (t, 2 H), 7.26-7.39 (m, 10 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9](C(OCC)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CCO.O=[Pt]=O>[CH2:1]([O:3][C:4]([N:6]1[C:12]2=[CH:13][CH:14]=[CH:15][CH2:16][C:11]2=[C:10]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=Cc2ccccc2N(C(=O)OCC)CC1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)C1=C2CC=CC=C2N(C(=O)OCC)CCC1
Yield: 155.4 %

Procedure:
A solution of 9 (5.5 g, 19 mmoles) in EtOH (55 ml) containing PtO2 (300 mg) was reduced (9 Atm, 25° C.) in a steel bomb for 10 hours. The catalyst was filtered and the solvent was evaporated to dryness. The residue was chromatographed [Silica gel: 120 g; eluent CHCH2Cl3 /EtOAc (95/5)] to give pure 11 (4.3 g, 80%) mp 60° C. (Calc. for C16H21NO4 : C 65.96; H 7.27; N 4.81 Found C 65.76; H 7.55; N 4.82) 1H NMR (CDCl3) δ=1.2 (6H, 2 overlapped t, J=7 Hz) 1.8-2.2 (2H, m) 2.3-2.7 (1H, m) 2.8-3.05 (2H, m) 3.2-3.7 (1H, m) 3.8-4.3 (5H, 2 overlapped q, J=7 Hz) 7.1 (4H, s). IR (CHCl3) 2980 (m) 2930 (m) 1725 (s) 1690 (s) 1610 (w) 1590 (w) 1490 (w) 1440 (w) 1410 (w) 1385 (w) 1310 (m). Mass spectrum m/z 291.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]#[N:22]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:21]([C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)=[NH:22])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: N#Cc1cccs1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(NC(=N)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10.4 g, 61.1 mmol) in toluene (400 ml) at 0° C., trimethylaluminum (2M solution in toluene, 46.8 ml, 91.6 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of 2-thiophenecarbonitrile (10.0 g, 91.6 mmol) in toluene (200 ml) was added over 10 minutes and the mixture was heated to 80–85° C. After 16 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later with methanol. The combined filtrates were concentrated and the resulting yellow solid was stirred with ethyl acetate and filtered. The pale yellow solid (9.8 g, 57%) was used in the next reaction without further purification: m.p. (DSC) 182° C. Anal. Calcld. for C12H12N2S2O2: C, 51.41, H. 4.31, N, 9.99, S, 22.87. Found: C, 51.02, H, 4.37, N, 9.80, S, 22.93.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[C:9]#[C:10][C:11]2([OH:21])[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]#[C:10][C:11]2([OH:21])[CH2:20][CH2:19][C:14]3([O:15][CH2:16][CH2:17][O:18]3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: OC(C#CC1(O)CCC2(CC1)OCCO2)c1ccc(Cl)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(C#CC1(O)CCC2(CC1)OCCO2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a solution of 8-(3-(4-chlorophenyl)-3-hydroxypropyn-1-yl)-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 5) (7.70 g, 23.9 mmol) in dichloromethane (120 mL), manganese dioxide (10.4 g, 119 mmol) was added, and the obtained solution was stirred at room temperature for 18 hours. The reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (5.45 g, 17.0 mmol, 71%) as an oily product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]C)=[CH:14][CH:15]=2)[CH:10]([CH3:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(O)(=O)C.C([O-])(O)=O.[Na+]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]([CH3:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(C)CN2Cc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1CN(Cc2ccccc2)c2ccc(O)cc21
Temperature: 105 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To 1-benzyl-5-methoxy-3-methylindoline (78.5 mg, 0.310 mmol) was added a solution of 50% hydrogen bromide-acetic acid solution (0.80 mL) at room temperature. After the reaction mixture was stirred at 105° C. overnight, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution, and the solution was extracted with ethyl acetate. The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain the title compound (59.5 mg, 80%).
Reaction SMILES: [CH:1]1[C:13]2C[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]([Cl:18])(Cl)(Cl)[Cl:15]>>[Cl:15][C:14]1([Cl:18])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:13][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: ClC(Cl)(Cl)Cl
Product: ClC1(Cl)c2ccccc2-c2ccccc21

Procedure:
To the reactor which has been purged with nitrogen is charged a volume of carbon tetrachloride (400 mL) such that its level just comes to the bottom of the sixth stage. NaOH solution (the same solution used in Recycle run #1, 25 percent by weight, 6.14 moles, 245.6 g dry weight, 983 g solution weight, 774.0 mL) is then charged to the reactor, and fills all six of the stirred zones. The stirrer is started and its speed adjusted to 1500 rpm. Fluorene (0.185 moles, 30.75 g) dissolved in carbon tetrachloride (2.24 moles, 344.8 g, 225.35 mL) is fed into the catalyst saturator containing the catalyst solution using a metering pump at a rate of 5.5 mL/min. The product solution is collected at the overflow, washed and dried as in Part A. The total product solution collected in this fashion amounts to 1006 g which is evaporated to dryness on the rotary evaporation leaving 42.23 g of very light yellow crystals, 9,9-dichlorofluorene (97.1 percent of the theoretical yield of 43.49 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=O)[CH2:15][CH2:16][N:17]1[CH2:22][CH:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C(O)C.B.[Na].Cl>O1CCCC1>[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[CH:14]=[CH:15][CH2:16][N:17]1[CH2:18][CH:19]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1
Reactant: Cc1c(C(=O)CCN2CC=C(c3ccccc3)CC2)cnn1-c1ncccn1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C=CCN2CC=C(c3ccccc3)CC2)cnn1-c1ncccn1
Temperature: 0 °C
Reaction time: 7 h
Yield: 26 %

Procedure:
207 mg of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-phenyl-1,2,3,6-tetrahydro-1-pyridyl]-1-propanone hydrochloride was dissolved in a solvent mixture comprising 10 ml of ethanol and 10 ml of tetrahydrofuran. After ice-cooling to 0° C., 319 mg of sodium boron hydride was added thereto in portions for 7 hours. After decomposing the sodium boron hydride by adding conc. hydrochloric acid, the solvent was removed by evaporation. Then the residue was neutralized by adding an aqueous solution of sodium hydroxide and extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was dissolved in 7 ml of tetrahydrofuran. Then 250 mg of tosic acid monohydrate was added and the mixture was heated under reflux for 60 minutes. After evaporating the solvent, the residue was neutralized by adding an aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform:methanol=100:1-3). Then the product was converted into hydrochloride by adding 0.3 ml of a 1N hydrochloric acid/ethanol solution and recrystallized from methanol/ethyl acetate. Thus 47 mg of the title compound was obtained in the form of a pale yellow solid product.
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH2:14][CH2:15]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:20]>ClC(Cl)(Cl)Cl>[O:1]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH2:14][CH2:15][Br:20])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCOc1ccc(Oc2ccccc2)cc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCCCOc1ccc(Oc2ccccc2)cc1
Temperature: 40 °C
Yield: 192.9 %

Procedure:
24.4 g of 3-(4-phenoxyphenoxy)-propan-1-ol is added in portions to a solution of 9.5 g of phosphorus tribromide in 65 ml of tetrachloromethane. When the exothermic reaction has subsided, the mixture is heated for 4 hours at 40° C. After the mixture has cooled, the solvent is removed under reduced pressure, the residue is dissolved in 300 ml of methyl tert-butyl ether, and the organic phase is washed thoroughly with water and dried over sodium sulfate. The crude product remaining after removal of the solvent is purified by silica gel filtration with toluene/methyl tert-butyl ether (2:1). There is obtained 20.8 g (67%) of 3-(p-phenoxyphenoxy)-1-bromopropane; m.p.: 54°-55° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:3][CH2:2]1.[CH2:24](Br)[CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:5][CH2:6]1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCNCC1
Reactant: OCCBr
Product: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(CCO)CC1

Procedure:
In similar way as in Preparation Example 31, the title compound was synthesized from 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone and ethylene bromohydrin.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14]Cl)[C:8](=[O:16])[C:7](=[O:17])[NH:6]2.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:21]1[NH:20][CH:24]=[CH:23][N:22]=1)[C:8](=[O:16])[C:7](=[O:17])[NH:6]2
Reactant: c1c[nH]cn1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n(CCCl)c1=O
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n(CCc2ncc[nH]2)c1=O

Procedure:
392 mg (1 mmol) of 2-[(6 trifluoromethylquinoxaline-2,3-dion-1-yl)ethyl chloride is heated with 150 mg (2.2 mmol) of imidazole for 3 hours to 150° C. bath temperature. The organic phase is concentrated by evaporation with dispersion in 10 ml of ethyl acetate and 10 ml of water, and the residue is chromatographed on silica gel with methanol:butanol:water:ammonia=75:25:17:3 as eluant. 54 mg (17% of theory) of 2-((6 trifluoromethylquinoxaline-2,3-dion-1-yl)ethylimidazole of melting point>250° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][O:6][C:7]1[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]([S:18][CH3:19])[N:8]=1.[OH-].[Na+].Cl>O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([S:18][CH3:19])[N:8]=1
Reactant: CCOC(=O)c1cnc(SC)nc1OCc1ccc(OC)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2nc(SC)ncc2C(=O)O)cc1Cl

Procedure:
Ethyl 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylate (3.0 g, 8.15 mmol) and sodium hydroxide (652 mg, 16.3 mmol) were dissolved in 10 mL of water and 50 mL of THF, reacted at room temperature for 5 h. The diluted hydrochloric acid was added to adjust to pH=6, extraction was performed with dichloromethane (30 mL×3), the extract was dried and concentrated to obtain a white solid, and this product was directly used in the next reaction without purification.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[N:16]1([C:22]([CH:24]2[CH2:26][CH:25]2[CH3:27])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:19]3[CH2:20][CH2:21][N:16]([C:22]([CH:24]4[CH2:26][CH:25]4[CH3:27])=[O:23])[CH2:17][CH2:18]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC1CC1C(=O)N1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Product: CC1CC1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-methylcyclopropyl)methanone, the title compound was obtained as a white solid (88% yield). 13C NMR (75 MHz, CDCl3) δ 177.1, 163.5, 159.5, 144.9, 131.3, 126.4, 115.1, 49.7, 45.2, 39.5, 37.5, 37.2, 35.3, 34.6, 29.9, 28.5, 26.5, 23.4, 8.6, 4.2. MS (ES+) m/z 360 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([Br:23])[C:19](Br)([F:21])[F:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr.C(OCCCCCCCCC=C(F)F)(=O)C1C=CC=CC=1.[H-].[Na+]>O1CCCC1>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([Br:23])=[C:19]([F:21])[F:20])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCCCCCCCCC(Br)C(F)(F)Br)c1ccccc1
Agent: BrBr
Agent: O=C(OCCCCCCCCC=C(F)F)c1ccccc1
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(OCCCCCCCCC(Br)=C(F)F)c1ccccc1

Procedure:
After ester formation, additional reactions, most of which are described above, were utilized to further modify the esters themselves. For example, 9,10-dibromo-10,10-difluorodecyl benzoate (XXVI) was prepared by adding elemental bromine to 10,10-difluoro-9 decenyl benzoate (XXV). Subsequently, 9,10-dibromo-10,10-difluorodecyl benzoate was dehydrobrominated using sodium hydride in tetrahydrofuran, yielding 9-bromo-10,10-difluoro-9-decenyl benzoate (XXVII). In order to extend a hydrocarbon chain by three carbon atoms, an unsaturated ester, e.g., 9-decenyl acetate, was reacted with borane-tetrahydrofuran complex and then with acrolein in the presence of hydrochloric acid, producing 13-oxotridecyl acetate (XXIX). As an alternative to catalytic hydrogenolysis to remove a bromine atom, a brominated compound, e.g., 2,4-dibromo-4,4-difluorobutyl acetate (XXXVI), tributyltin hydride, and 1,1'-azobisisobutyronitrile were heated at 120° C., yielding 4-bromo-4,4-difluorobutyl acetate. These reactions are detailed in Examples 12-23.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8](=O)[NH:9][NH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[N:14]=1)=[O:12].CCN(C(C)C)C(C)C.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>C(#N)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:27]([CH3:28])[CH3:29])=[O:26])=[CH:30][CH:31]=2)=[N:6][C:7]=1[C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[N:14]=2)=[N:10][N:9]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=O)c3cccc(N)n3)n2)cc1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(N)n4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
To a suspension of 4-[5-amino-6-[[(6-aminopyridine-2-carbonyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide (80 mg, 0.1903 mmol) in anhydrous acetonitrile (1.600 mL) cooled in an ice bath, was added DIPEA (73.78 mg, 99.43 μL, 0.5709 mmol) followed by dibromo(triphenyl)phosphorane (104.4 mg, 0.2474 mmol) portionwise. The resulting mixture was stirred at room temperature for 30 min. The precipitate was isolated by filtration, washed with small amount of acetonitrile giving a pale yellow solid. The solid was triturated in hot acetonitrile, cooled, filtered and washed acetonitrile then ether to give the pure product (36.1 mg, 54% yield); 1H NMR (400 MHz, DMSO) d 2.98-3.02 (m, 6H), 6.53 (br s, 2H), 6.69 (m, 1.5H), 7.16 (m, 0.51H), 7.16 (m, 1H), 7.53-7.66 (m, 3H), 8.11 (m, 2H) and 8.94 (s, 1H) ppm; MS (ES+) 403.29
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH3:14][S:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.S([O-])(O)=O.[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:11])[F:12])[CH:7]=[C:8]2[N:9]=[C:18]1[C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[S:15][CH3:14]
Reactant: CSc1ccccc1C=O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: O=S([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 80 °C
Yield: 32.6 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (1.34 g), 2-methylsulfanylbenzaldehyde (1.28 g), sodium hydrogen sulfite (2.19 g), and DMF (14 ml) was stirred with heating at 80° C. for 1 hour, and then heated to 120° C., and stirred with heating for further 3 hours. Into the reaction mixture cooled to room temperature, saturated aqueous ammonium chloride solution was poured, and extracted with ethyl acetate 3 times. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.74 g of 3-methyl-2-(2-methylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:7]=[CH:8][C:9]=1[O:10][S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])([O-])=O.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:7]=[CH:8][C:9]=1[O:10][S:11]([C:14]([F:17])([F:15])[F:16])(=[O:13])=[O:12]
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(N)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
Iron powder (2.5 g) was added to a stirred mixture of methyl 3-nitro-4-trifluoromethanesulfonyloxyphenylacetate (2.97 g) and conc. hydrochloric acid (7.3 ml) in methanol (22 ml) at 0° C. in some small portion. The reaction mixture was stirred at 20° C. for 2 hours, then poured into a mixture of ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give methyl 3-amino-4-trifluoromethanesulfonyloxyphenylacetate (2.34 g) as colorless crystals.
Reaction SMILES: Cl[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][CH3:21].[SH:22][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[CH2:20]([C:7]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][S:22][C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[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]=1)[CH3:21]
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCCl
Reactant: Sc1ncccn1
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCSc1ncccn1
Yield: 80.1 %

Procedure:
Using the general method of Example 20 Part A, 1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.30 mmol) was reacted with 2-mercaptopyrimidine (0.59 g, 5.3 mmol) to provide 1.0 g of 2-ethyl-1-[4-(pyrimidin-2-ylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine as an off white powder, m.p. 182-185° C.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:3][CH:2]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:4]2[CH:5]=[CH:6][C:1]([CH3:12])=[CH:2][CH:3]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(C2CCCN2)cc1
Product: Cc1ccc(C2CCCN2S(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 112° C. and MS: m/e=319 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-p-tolyl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: ClCCCC([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=O.[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1>>[CH3:18][C:19]1[N:23]2[CH2:9][CH2:8][CH:7]=[C:12]([C:11]3[CH:12]=[CH:7][C:8]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:10]=3)[C:22]2=[CH:21][N:20]=1
Reactant: Cc1ncc[nH]1
Reactant: CS(=O)(=O)Nc1ccccc1C(=O)CCCCl
Product: Cc1ncc2n1CCC=C2c1ccc(NS(C)(=O)=O)cc1

Procedure:
Combine 100 g (0.36 mol) of N-[(4-chloro-l-oxobutyl)phenyl] methanesulfonamide with 400 g (4.88 mol) of 2-methylimidazole and heat to 175° C. for 22 hr under argon. Crystallization from methylene chloride provides the title compound.