Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C1COCC1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Chloro-3-iodobenzene (10.0 g, 41.9 mmol) was dissolved in 100 mL dry THF and 17.5 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (329 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I)iodide (239 mg, 1.25 mmol) and trimethylsilylacetylen (6.28 g, 6.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel (heptane/ethyl acetate 100:0->80:20 gradient). The desired product was obtained as a light yellow oil (7.38 g, purity ˜70%, yield ˜59%).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH:19](C(O)=O)[C:20]([OH:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)=O>>[C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccc2c(CC(C(=O)O)C(=O)O)c[nH]c12
Agent: O=C=O
Product: O=C(O)CCc1c[nH]c2c(C(=O)c3ccccc3)cccc12
Yield: 100 %

Procedure:
A 2.4 g (0.07 mole) sample of 2-[(7-benzoyl-1H-indol-3-yl)methyl]propanedioic acid was heated at 190° C. under vacuum until carbon dioxide evolution ceased (1/2 hr). The syrup was cooled to give 2.1 g (100%) of a yellow solid, m.p. 166.5°-168-5° C.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1.S([O-])([O-])(=O)=O.[Mg+2].COC1C=C[N+:22]([O-])=[CH:21]C=1.C[Si](C#N)(C)C.CN(C)C(Cl)=O>C(Cl)(Cl)Cl.ClCCl>[C:21]([C:8]1[CH:9]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][N:7]=1)#[N:22]
Reactant: COc1cc[n+]([O-])cc1
Agent: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a slurry of 4-methoxypyridine N-oxide hydrate, 50 g, in 250 mL of chloroform was added 20 g of magnesium sulfate. The slurry was stirred for 1 hour at ambient temperature, then filtered and concentrated to dryness. To a solution of the residue, 4-methoxypyridine N-oxide, 43 g (350 mmol) in 350 mL of dichloromethane was added 65 mL (490 mmol) of trimethylsilylcyanide. The solution was cooled to 10° C. and 45 mL (490 mmol) of N,N-dimethylcarbamyl chloride was added dropwise such that the reaction warmed to a gentle reflux. Upon completion of the addition, the reaction mixture was stirred overnight at ambient temperature, then carefully quenched at 0° C. dropwise with 10% aqueous potassium carbonate. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was triturated with ether. Filtration of the solid provided 31.4 g (67%) of the desired product as a white solid. 1H—NMR is consistent with structure; MS (ion spray) 135.1 (M+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:21][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[N:18][C:17](Br)=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[OH-:22].[Na+]>C1COCC1>[OH:22][C:17]1[N:18]=[CH:19][C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:3])=[O:5])=[N:13]2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1nn(-c2cnc(O)cn2)c2c1C[C@H]1C[C@@H]21
Temperature: 120 °C
Yield: 70.4 %

Procedure:
To a mixture of (1aR,5aR)-2-(5-bromopyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (100 mg, 0.286 mmol) in THF was added 1 N NaOH solution (1.43 mL, 1.43 mmol). The reaction was heated at 120° C. for 1 h under microwave irradiation. The solvent was removed. The residue was added water and acidified with HCl solution to give the title compound (52 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:40])([CH3:39])[C:3]([NH:5][CH2:6][C@@H:7]([C@@H:9]([NH:31]C(=O)OC(C)(C)C)[CH2:10][C@H:11]([CH2:15][NH:16][C:17](=[O:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:12]([CH3:14])[CH3:13])[OH:8])=[O:4].[ClH:41]>>[ClH:41].[NH2:31][C@H:9]([C@@H:7]([OH:8])[CH2:6][NH:5][C:3](=[O:4])[C:2]([CH3:40])([CH3:39])[CH3:1])[CH2:10][C@@H:11]([CH:12]([CH3:14])[CH3:13])[CH2:15][NH:16][C:17](=[O:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29]
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)C(C)(C)C)C(C)C
Agent: Cl
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](N)[C@@H](O)CNC(=O)C(C)(C)C)C(C)C

Procedure:
The solution of 0.030 g of tert-butyl (1(S)-[2-(2,2-dimethylpropionylamino)-1(S)-hydroxyethyl]-3(S)-{[2-(3-methoxypropoxy)benzoylamino]methyl}-4-methylpentyl)carbamate in 1 ml of 4M HCl (in dioxane) is stirred at 0° C. to 20° C. over 2 hours, subsequently concentrated by evaporation to dryness—the residue is dissolved in 1 ml of tert-butanol, frozen and lyophilized under high vacuum. The title compound is obtained as a white powder. Rf=0.20 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=3.55 (gradient I).
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[C:8]([C:13](=[O:15])[CH3:14])=[N:9][N:10]([CH3:12])[CH:11]=1.C([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=O)(OC(C)(C)C)=O>CO>[CH3:12][N:10]1[CH:11]=[C:7]2[O:6][C:26]3([CH2:27][CH2:28][NH:23][CH2:24][CH2:25]3)[CH2:14][C:13](=[O:15])[C:8]2=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: CC(=O)c1nn(C)cc1O
Solvent: CO
Solvent: C1CCNC1
Product: Cn1cc2c(n1)C(=O)CC1(CCNCC1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (3.0 g, 3.5 mL, 42 mmol) was added to a solution of 1-(4-hydroxy-1-methyl-1H-pyrazol-3-yl)ethanone (5.93 g, 42.3 mmol) in methanol (50 mL). The mixture was stirred at room temperature for 2 hours before addition of N-Boc-piperidone (8.43 g, 42.3 mmol). The mixture was stirred at room temperature overnight before concentration to dryness. The crude material was purified by CombiFlash (120 g column, 30-50% EtOAc/hexanes gradient) to afford desired product containing unreacted starting material. This material was triturated with 30% EtOAc/hexanes, the solids were filtered and air dried to afford tert-butyl 2′-methyl-7′-oxo-6′,7′-dihydro-1H,2′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazole]-1-carboxylate (6.8 g, 50%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reaction time: 0.5 h

Procedure:
2,2-Dimethyl-4-hydroxymethyl-1,3-dioxolan (3.96 g, 30 mmol) and triethyl amine (5 mL) were dissolved in CH2Cl2 (50 mL). p-Toluenesulphonyl chloride (3.8 g, 20 mmol) was added. The solution was stirred for 3 h after which 4-dimethylaminopyridine (0.05 g, 0.04 mmol) was added. The solution was stirred for 0.5 h after which the solution was concentrated in vacuo. The residue was taken up in CH2Cl2 and the organic phase was washed with H2O, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford the title compound.
Reaction SMILES: [I:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.O.[OH-].[Na+]>C(O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCCCCOc1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCOc1ccc(I)cc1
Yield: 93 %

Procedure:
Ethyl 6-(4-iodophenoxy)hexanoate (3.62 g, 10 mmol), in ethanol (30 ml), water (30 ml) was treated with sodium hydroxide (1 g, 25 mmol) and the reaction was stirred under reflux for 3 h. The reaction was then allowed to cool and concentrated in vacuum to a solid. The solid was then treated cautiously with ethyl acetate (100 ml) and 1N hydrochloric acid (100 ml) and the reaction stirred at room temperature for 10 min. The ethyl acetate layer was separated dried over sodium sulfate and concentrated in vacuum to give a pale yellow solid (3.11 g, 9.3 mmol, 93%), δH (CDCl3) 1.48-1.82 (6H, m, 3,4,5-CH2), 2.40 (2H, t, 2-CH2), 3.91 (2H, t, 6-CH2O), 6.67 (2H, dd, 2,6-ArH), 7.53 (2H, dd, 3,5-ArH), δc (CDCl3) 24.31, 25.50, 38.75, 33.89, 82.54, 116.87, 138.14, 158.83 and 179.97
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH2:34]Cl)=[CH:31][C:24]=3[S:23]4)=[CH:16][CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:37]([O:39][C:40](=[O:43])[CH2:41][NH2:42])C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:37][O:39][C:40](=[O:43])[CH2:41][NH:42][CH2:34][CH2:33][O:32][C:30]1[CH:29]=[CH:28][C:25]2[N:26]3[CH:27]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([NH:13][C:11]([NH:10][C:7]5[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][N:8]=5)=[O:12])=[CH:15][CH:16]=4)[N:21]=[C:22]3[S:23][C:24]=2[CH:31]=1
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCCl)ccc34)cc2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)CNCCOc1ccc2c(c1)sc1nc(-c3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)cn12

Procedure:
Alternatively, [2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yloxy)-ethylamino]-acetic acid methyl ester is prepared in the following manner. To a stirred mixture of 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-chloro-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (1 equivalent), glycine ethyl ester hydrochloride (1-3 equivalents) and potassium carbonate (2-6 equivalents) in anhydrous acetone is added tetrabutylammonium iodide (0.1-1 equivalent) and the mixture is stirred and heated under reflux until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is partitioned between water and either dichloromethane or a mixture of isopropanol and dichloromethane. The organic layer is separated and the aqueous layer is further extracted with dichloromethane or a mixture of isopropanol and dichloromethane. The combined extracts are washed with water or brine, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford [2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yloxy)-ethylamino]-acetic acid methyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]Br>II>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([F:11])=[C:9]([Br:12])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(F)cc1
Reactant: BrBr
Agent: II
Product: CC(C)(C)c1ccc(F)c(Br)c1
Yield: 48.5 %

Procedure:
In this example 5-t-butyl-2-fluorophenol, the starting material for the dealkylation process of this invention, was prepared by first alkylating 480 grams of fluorobenzene with 370 grams of t-butylchloride in the presence of 16.6 grams of aluminum chloride and 33 grams of nitromethane as solvent for the reaction at a temperature ranging from about 0° to 2° C., the t-butylchloride being added incrementally to the mixture of fluorobenzene, aluminum chloride and nitromethane in about 2.5 hours and maintained for about an additional hour at this temperature. The resulting 4-t-butyl-fluorobenzene was recovered by treating the reaction mixture with 150 ml water at 0°-10° C. followed by washing with 5% aqueous NaOH, and the organic layer was then separated, followed by fractionation at about 5 mm reduced pressure and 547 grams of product collected from about 48°-52° C. to yield about a 70% conversion and 86% selectivity to p-t-butylfluorobenzene via gas liquid chromatographic analysis. Following this 304 grams of 4-t-butylfluorobenzene so prepared and a catalyst comprising 12.3 grams of iodine were placed in another reaction apparatus and brominated by incrementally adding about 372 grams of bromine during a period of about 3 hours while maintaining the temperature of the reaction at about 60°-65° C., and then maintaining the reaction mixture for about an additional 9 hours. Upon completion of the bromination the organic layer was washed with saturated sodium thiosulfate solution and then with water, dried and the recovered 312 grams of product was fractionated under a reduced pressure of about 3 mm to isolate about 224 grams of the desired 4-t-butyl-2-bromofluorobenzene distilling at about 40°-77° C. The heart cut of this distillate of about 171 grams analyzed about 90% pure via gas liquid chromatography. To obtain the next product comprising 5-t-butyl-2-fluorophenol the thus formed 4-t-butyl-2-bromo-fluorobenzene (20.0 grams) was hydrolyzed by treatment with 160 ml of water in the presence of 18.6 grams of potassium fluoride and 1.0 grams of cuprous oxide plus 40 grams of sulfolane as a co-solvent, said reaction being effected at an elevated temperature of 250° C. and under a nitrogen atmosphere at a total pressure of about 525 pounds per square inch. At the end of about eight hours of reaction period, the autoclave and contents thereof were allowed to return to room temperature, the excess pressure was discharged, and the product recovered from the mixture by extraction with toluene. Distillation under reduced pressure provided about 11.4 grams of the desired product comprising 5-t-butyl-2-fluorophenol corresponding to a conversion of about 85% and a selectivity of about 70%. N-methylpyrrolidone may also be effectively used as the co-solvent in this hydrolysis.
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[C:9]([NH:14][C:15](=[O:24])[C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)=[N+]=[N-].[C:25]1([P:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)(=O)C>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:15]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[CH:6][CH:5]=[C:4]2[N:1]=[P:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24]
Reactant: [N-]=[N+]=Nc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2c(N=P(c3ccccc3)(c3ccccc3)c3ccccc3)ccnc12)c1c(Cl)cccc1Cl
Temperature: 45 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a suspension of 4-azido-8-(2,6-dichlorobenzoylamino)quinoline (518 mg) in ethyl acetate (5 ml) was added triphenylphosphine (383 mg), and the mixture was stirred for 3 hours at 45° C. The resulting precipitates were collected by filtration, and the residue was recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-[(triphenylphosphoranylidene)amino]quinoline (846 mg) as white crystal.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[I-:15].[Na+]>C(#N)CC>[I:15][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(Cl)n1
Reactant: [I-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CCC#N
Product: N#Cc1cccc(I)n1
Temperature: 90 °C
Yield: 55.6 %

Procedure:
6-Chloro-pyridine-2-carbonitrile (5.0 g, 36 mmol) was taken up in propionitrile (35 mL). To this was added TMSCl (4.6 mL, 36 mmol) and sodium iodide (16.0 g, 108 mmol) and the solution was heated to 90° C. for 16 h. The solution was cooled and quenched by the addition of 2M sodium hydroxide (35 mL) The mixture was extracted with ethyl acetate (3×30 mL) and washed with water (1×50 mL) and saturated aqueous sodium bisulfate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica-gel) using 0-100% ethyl acetate in hexanes to afford 4.6 g of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=O)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[CH3:27][NH2:28]>>[CH3:27][NH:28][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Reactant: CN
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)NC
Temperature: 70 °C
Reaction time: 8 h

Procedure:
The method described in Part D of Example 3 was used to treat ethyl 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (5.0 g, 14 mmol) with methylamine (8 mL of a 40% solution). The reaction was complete after being stirred overnight at 70° C. Following the work-up procedure, 3.42 g of N-methyl-6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide were obtained.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]2[N:15]=[CH:14][N:13]([CH2:16][C:17]3[CH:33]=[CH:32][C:20]4[N:21]=[C:22]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:23][C:19]=4[CH:18]=3)[C:10]2=[N:11][CH:12]=1)(C)C.C([O-])([O-])=O.[K+].[K+]>CO>[C:6]([C:7]1[CH:8]=[C:9]2[N:15]=[CH:14][N:13]([CH2:16][C:17]3[CH:33]=[CH:32][C:20]4[N:21]=[C:22]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:23][C:19]=4[CH:18]=3)[C:10]2=[N:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((6-((trimethylsilyl)ethynyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.21 mmol) from Step 3 of this Example in MeOH (5 mL) was added excess K2CO3 (150 mg). The resulting mixture was stirred at rt for 30 min. LCMS analysis showed that the reaction was complete. The reaction mixture was filtered through a Celite plug and the filtrate was purified by preparative HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a tan powder (40 mg, 47%). 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.23 (d, J=1.7 Hz, 1H), 8.02 (d, J=6.6 Hz, 1H), 7.66 (s, 1H), 7.26-7.34 (m, 1H), 7.15-7.26 (m, 1H), 5.49 (s, 2H), 4.29 (s, 1H), 3.26-3.38 (m, 2H), 2.03 (d, J=10.4 Hz, 1H), 1.85 (br s, 1H), 1.62 (d, J=4.7 Hz, 2H), 1.00-1.38 (m, 4H). LCMS (ESI) m/z 404 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[S:11]([OH:14])(=O)=[O:12].O=S(Cl)[Cl:17]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[S:11]([Cl:17])(=[O:14])=[O:12]
Reactant: Cc1cccc([N+](=O)[O-])c1S(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cccc([N+](=O)[O-])c1S(=O)(=O)Cl

Procedure:
In a similar fashion using route 39 general procedure 96, 2-methyl-6-nitro-benzenesulfonic acid 451 (7.2 g crude), SOCl2 (16 ml) and DMF (0.35 ml) at 90° C. for 3 h gave the title compound (3.5 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.Cl.[C:19]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)#[CH:20].[O-]S([O-])(=O)=O.[Mg+2]>>[N:24]1[CH:25]=[CH:26][C:21]([C:19]#[C:20][C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)=[CH:22][CH:23]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: C#Cc1ccncc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: C(#Cc1cccc2c3c([nH]c12)C1CCN(CC1)C3)c1ccncc1

Procedure:
The product of Example 1B (100 mg, 0.34 mmol), 4-ethynylpyridine hydrochloride (144 mg, 1.03 mmol; Aldrich) and MgSO4 (83 mg, 0.69 mmol) were combined and processed as described in Example 3 to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.05-2.16 (m, 4 H), 3.03-3.14 (m, 2 H), 3.18-3.22 (m, 1 H), 3.22-3.29 (m, 2 H), 4.26 (s, 2 H), 7.03 (t, J=7.6 Hz, 1 H), 7.29 (dd, J=7.5, 0.8 Hz, 1 H), 7.41 (dd, J=7.9, 0.9 Hz, 1 H), 7.62-7.66 (m, 2 H), 8.53-8.58 (m, 2 H); MS (APCI) m/z 314 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[N:9]O)[CH2:7][O:8][C:4]=2[CH:3]=1.[H][H]>O1CCCC1.CO.[Ni]>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[CH:6]([NH2:9])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: ON=C1COc2cc(F)ccc21
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: NC1COc2cc(F)ccc21
Yield: 33.7 %

Procedure:
A mixture of the above described 6-fluoro-benzofuran-3-one oxime (5.38 g, 32 mmol; HPLC 1.489 min) and Raney-Nickel (2.4 g) in tetrahydrofuran (125 mL) and methanol (125 mL) was hydrogenated at 100 bar hydrogen-pressure at 50° C. for 18 h. Filtered the catalyst off, washed with methanol and tetrahydrofuran, all volatiles very removed in vacuum to give the crude product which was purified by Si—NH2 column chromatography with n-heptane/ethyl acetate to give the title compound as a light brown liquid (1.65 g, 34%, HPLC 0.367 min 100%), MS (ISP) m/e=154.0 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[OH:4].[CH3:15][NH:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[CH3:15][N:16]([CH2:9][C:8]1[CH:11]=[CH:12][C:5]([CH:3]([OH:4])[C:2]([F:14])([F:13])[F:1])=[CH:6][CH:7]=1)[CH3:17]
Reactant: CNC
Reactant: O=Cc1ccc(C(O)C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(C)Cc1ccc(C(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
4-(2,2,2-Trifluoro-1-hydroxyethyl)benzaldehyde (295 mg, 1.4 mmol) obtained in Step 1 of Reference Example 8-70 was dissolved in acetonitrile (15 mL). To this, dimethylamine (a 1.0 mol/L solution in tetrahydrofuran, 7.2 mL, 14 mmol) and acetic acid (0.83 mL) were added and the mixture was stirred at room temperature for 30 minutes. To this, sodium triacetoxyborohydride (918 mg, 4.3 mmol) was added and the mixture was stirred at room temperature for 4 hours. Then, an aqueous sodium bicarbonate solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was subjected to slurry purification using a mixed solvent of diisopropyl ether and hexane. Further, purification by silica gel column chromatography (hexane/ethyl acetate=1/0 to 2/1) was performed to give 1-{4-[(dimethylamino)methyl]phenyl}-2,2,2-trifluoroethanol (Compound ER) (284 mg, yield: 85%).