Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[CH3:16][C:17]([NH2:21])([C:19]#[CH:20])[CH3:18].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:8][C:6](=[CH2:7])[CH2:5][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:3][CH2:2][NH:21][C:17]([CH3:18])([C:19]#[CH:20])[CH3:16]
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Reactant: C#CC(C)(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(C)(C)NCCC(O)(CC(=C)C)c1ccccc1
Temperature: 80 °C
Yield: 42.6 %

Procedure:
A stirred mixture of 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (550 mg, 2.45 mmol), 1,1-dimethylpropargylamine (204 mg, 2.45 mmol), KI (447 mg, 2.7 mmol), i-Pr2NEt (05 mL, 2.7 mmol) and dry DMF (3 mL) was heated at 80° C. in an oil bath for 24 h. The mixture was concentrated to leave a brown oil which was purified by chromatography on a 12-g silica cartridge eluted with a 0-10% MeOH in CH2Cl2 gradient to afford 5-methyl-1-(2-methylbut-3-yn-2-ylamino)-3-phenylhex-5-en-3-ol (283 mg, 42%) as a brown solid which was used in the next step without further purification. LC-MS Method 1 tR=1.08 min, m/z=272.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:22]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=O)=O)=CC=1.[C:34]([O-])(=[O:36])[CH3:35].[Na+]>CS(C)=O.CCOC(C)=O>[C:34]([O:11][CH2:12][C:13]12[CH2:18][CH2:17][C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:22]=3)([CH2:19][CH2:20]1)[O:15][CH2:14]2)(=[O:36])[CH3:35]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4cccc(Oc5ccccc5)c4)(CC2)OC3)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)OCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 70 °C
Reaction time: 72 h

Procedure:
A mixture of (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate (0.1 g, 0.215 mmol) and sodium acetate (0.212 g, 2.58 mmol) in DMSO (5 mL) was stirred at 70° C. in a seal tube for 3 days. The reaction was diluted with EtOAc (5 mL) and washed with water (3×5 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl acetate. The mixture of the above acetate (0.076 g, 0.216 mmol) and 1 M NaOH (0.65 mL, 0.647 mmol) in THF/MeOH (1:1 of a 2 mL solution) was stirred at rt for 18 h. The reaction was diluted with EtOAc (5 mL) and washed with water (3×5 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 50% EtOAc:hexanes) to afford the title compound (0.05 g, 75% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.39-7.26 (m, 3H), 7.21-7.14 (m, 2H), 7.14-7.08 (m, 1H), 7.05-7.00 (m, 2H), 6.88 (ddd, J=8.1, 2.5, 1.0 Hz, 1H), 3.99-3.89 (m, 2H), 3.38 (s, 2H), 2.16-2.00 (m, 4H), 1.84-1.71 (m, 3H), 1.71-1.57 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([CH2:9][CH2:10][CH3:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:30].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:29](=[O:30])[CH2:28][N:7]2[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][CH2:10][CH3:11])[N:3]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)[C:2]2=[O:1])=[CH:32][CH:33]=1
Reactant: CCCc1cc(=O)[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a mixture of 4′-[(2,4-dioxo-6-propyl-3,4-dihydropyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.4 g) and N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.076 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.63 g, 81%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:15][C:12]1[CH:13]=[N:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[CH3:27]
Reactant: Oc1ccc(OCc2ccccc2)nc1
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OCc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To an ice-cold solution of 0.5 g (2.5 mmol) 6-benzyloxy-3-hydroxypyridine (commercially available) in 5 mL tetrahydrofuran 0.12 g (2.7 mmol) sodium hydride (55% dispersion in mineral oil) was added. After the vigorous gas evolution had ceased the reaction mixture was stirred for 15 min. and then 0.41 mL (3.72 mmol) ethyl bromoacetate were added dropwise. The light brown suspension was stirred for 1 h at room temperature, poured on water and extracted three times with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting solid is purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) with a gradient of heptane:ethyl acetate (100:0 to 70:30) to give the desired product as a colorless oil (90%). MS (Turbo Spray): m/z=288.0 [M+H].
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:15]=[C:16]([Cl:32])[C:17]([CH2:29][C:30]#[N:31])=[C:18]([C:27]#[N:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:32][C:16]1[C:17]([CH2:29][C:30]#[N:31])=[C:18]([C:27]#[N:28])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:15]=1
Reactant: CC(N)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Temperature: 90 °C
Yield: 34.3 %

Procedure:
A mixture of 6-bromo-9H-purine (22 mg, 0.11 mmol), 6-(1-aminoethyl)-4-chloro-3-(cyanomethyl)-3′-fluorobiphenyl-2-carbonitrile (17 mg, 0.054 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.18 mmol) in isopropyl alcohol (0.4 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (8 mg, 30%). LCMS calculated for C22H16ClFN7 (M+H)+: m/z=432.1. found: 432.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH2:19][O:20][CH2:21][CH2:22][NH2:23].N1C=CC=CC=1>C(O)C>[ClH:1].[NH2:23][CH2:22][CH2:21][O:20][N:19]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15]
Reactant: CCOCCCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOCCCC(=NOCCN)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 4.6 mmol (1.20 g) of 3', 4'-dichloro-4-ethoxybutyrophenone (melting point 52°-54° C), 4.7 mmol (0.70 g) of 2-aminooxyethylamine dihydrochloride, 2.5 ml of pyridine and 5 ml of absolute ethanol was refluxed for 2.5 hours. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in 40 ml of water. This solution was washed twice with 15 ml of petroleum ether (boiling point 40°-60° C), rendered alkaline with 10 ml of 2N sodium hydroxide solution and then extracted three times with 20 ml of ether. After washing the collected ether extracts with 10 ml of water and drying over sodium sulphate, the ether was evaporated in vacuo. The resulting base was then evaporated to dryness three times with 20 ml of toluene. Subsequently the hydrochloride was prepared by means of alcoholic hydrochloric acid. This was recrystallized from an ether/petroleum ether mixture. The melting point of the resulting above entitled compound was 92°-94° C.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[S:10][C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[CH:12][C:13]=2[CH3:14])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[Cl:27][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[S:10][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methanol (1.3 g) in toluene (20 mL) was added thionyl chloride (0.4 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (1.3 g, 100%) as an amorphous compound.
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][NH2:22])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].FC(F)(F)C(O)=O>C(#N)C>[I:1][C:15]1[CH:16]=[C:17]([O:18][CH3:19])[C:12]([O:11][CH3:10])=[CH:13][C:14]=1[CH2:20][CH2:21][NH2:22]
Reactant: NC(=O)CCC(=O)NI
Reactant: COc1ccc(CCN)cc1OC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(I)c(CCN)cc1OC
Yield: 70 %

Procedure:
To a solution of N-iodosuccinamide (NIS) (4.95 g, 22 mmol) in dry acetonitrile (50 mL) was added 2-(3,4-dimethoxyphenyl)ethanamine (3.32 mL, 20 mmol) and trifluoroacetic acid (3.85 mL, 50 mmol) with stirring. The mixture was stirred at room temperature in a 250 mL round bottom flask for two hours. The acetonitrile was removed and the remaining solid was taken up in water. The water solution was treated with saturated sodium bisulfite aqueous solution until the purple color disappeared. The pH was adjusted to 8 and the aqueous solution was extracted with dichloromethane (3×50 mL) The organic layers were combined and dried over sodium sulfate. The solvent was evaporated to yield 2-(2-iodo-4,5-dimethoxyphenyl)ethanamine (4.3 g, 70%). The crude product was dried under dynamic vacuum overnight and was sufficiently pure for subsequent steps.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[C:8]2[N:9]([N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=2)[CH:10]=[CH:11][CH:12]=1.C([O-])(O)=O.[Na+].[CH2:24](O)[CH3:25]>>[CH2:24]([O:17][C:16]([C:14]1[CH:15]=[C:8]2[C:7]([NH2:6])=[CH:12][CH:11]=[CH:10][N:9]2[N:13]=1)=[O:18])[CH3:25]
Reactant: CCO
Reactant: Nc1cccn2nc(C(=O)O)cc12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc2c(N)cccn2n1
Temperature: 75 °C

Procedure:
50% Aqueous H2SO4 (60 mL) is added to 4-Aminopyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid dimethyl ester (1.47 g, 5.90 mmol) under air. The mixture is warmed to 80° C. After 6.5 h, the solution is cooled to 0° C. and then neutralized with 10 N aq. NaOH. The resulting slurry is acidified to pH 3 with 1 M aq. HCl. The volatiles are removed under reduced pressure. The residue is washed with 30% EtOH in CH2Cl2. The volatiles are removed under reduced pressure to afford 4-aminopyrazolo[1,5-a]pyridine-2-carboxylic acid in Na2SO4. LC-MS m/z (M+H+): 178.01. A solution of conc. H2SO4 (6.0 mL) and ethanol (120 mL) is added to the crude 4-aminopyrazolo[1,5-a]pyridine-2-carboxylic acid. The mixture is warmed to 75° C. for 3.5 h. After cooling to rt, the mixture is made basic with dropwise addition of sat. aq. NaHCO3. The volatiles are removed under reduced pressure. The aqueous mixture is filtered (EtOAc rinse). The aqueous solution is extracted with EtOAc (3×250 mL). The combined organics are dried over Na2SO4, filtered, and concentrated to afford the title compound as dark brown solid. LC-MS m/z (M+Na+): 228.03.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[C:7](/[C:12](/[CH2:16][CH2:17][CH3:18])=[CH:13]/[CH2:14][CH3:15])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[C:2]1[C:10]2[C:6](=[C:7](/[C:12](/[CH2:16][CH2:17][CH3:18])=[CH:13]/[CH2:14][CH3:15])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC/C=C(\CCC)c1c2cccc(Br)c2nn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC/C=C(\CCC)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of 7-bromo-2-methyl-3-((E)-1-propyl-but-1-enyl)-2H-indazole (1.47 g, 4.79 mmol), 2,4-dichlorophenyl boronic acid (1.32 g, 6.94 mmol), 18 mL of ethylene glycol dimethyl ether, tetrakis(triphenylphosphine)palladium(0) (0.166 g, 0.143 mmol), and 20 mL of a 2 M aqueous Na2CO3 solution was stirred at 85° C. overnight, then allowed to cool. Ethyl acetate (50 mL) was added, and the mixture was washed with two 40 mL portions of a saturated aqueous NaCl solution. The combined aqueous layers were extracted with 20 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a brown oil. Column chromatography (0→5% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-3-((E)-1-propyl-but-1-enyl)-2H-indazole (15a; 1.57 g; 88%) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[OH:29])[CH2:22][CH2:21]4)[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][Cl:41]>C(#N)C>[Cl:41][CH2:40][CH2:39][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1([NH:19][C:15]2[C:14](=[O:30])[N:13]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=3[CH3:12])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:31])[CH:18]=[CH:17][N:16]=2)[CH2:22][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Temperature: 95 °C

Procedure:
To N-Cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 167d, 0.34 g) in acetonitrile (5 mL) under nitrogen was added potassium carbonate (1.13 g) followed by 1-bromo-2-chloroethane (1.35 mL) and the reaction heated at 95° C. for 15 h. After cooling to rt the mixture was filtered through celite, and the solid cake washed with further acetonitrile. The filtrates were collected and the solvents removed in vacuo to give the subtitle product as a brown-orange solid (0.373 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[O:28])[C:17]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=3[O:45][CH2:46][CH3:47])=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH2:4][CH:3]([OH:5])[C:2]([F:7])([F:6])[F:1])[CH2:31][CH2:30]3)=[O:28])[C:17]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:37][C:36]=3[O:45][CH2:46][CH3:47])=[N:16]2)=[CH:13][CH:14]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Reactant: FC(F)(F)C1CO1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(O)C(F)(F)F)CC1
Reaction time: 8 h

Procedure:
1,1,1-trifluoro-2,3-epoxypropane (9 uL, 0.10 mmol) was added to a mixture of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[piperazin-1-yl]-methanone (30 mg, 0.048 mmol) and triethylamine (20 uL, 0.144 mmol) in anhydrous methanol (1.0 mL). The reaction was stirred overnight. Evaporation of the solvent and chromatography of the residue over silica gel using 0-5% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-2-trifluoromethyethyl)-piperazin-1-yl]-methanone, which was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-2-trifluoromethyethyl)-piperazin-1-yl]-methanone hydrochloride as an off-white powder (38 mg, 84%). LR-MS (APCI): 703.5 [(M+H)+].
Reaction SMILES: B.CSC.[CH2:5]([N:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:25][CH2:26][CH2:27][NH:28][CH:29]=O)[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[C:16]([CH3:31])[CH:17]=2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[CH2:5]([N:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:25][CH2:26][CH2:27][NH:28][CH3:29])[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[C:16]([CH3:31])[CH:17]=2)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccc2c(c1)c1c(OCCNC=O)cccc1n2Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CNCCOc1cccc2c1c1cc(C)ccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
Borane-methyl sulfide (0.12 mL, 0.0013 mol) is added to a mixture of 2-[(9-benzyl-6-methyl-9H-carbazol-4-yl)oxy]ethylformamide (0.1565 g, 0.0013 mol) in dry THF (3 mL) and the mixture is stirred overnight at room temperature. The excess borane is cautiously quenched with methanol and the mixture is concentrated under reduced pressure. Methanol and dichloromethane are added to the residue and the solution is again concentrated under reduced pressure (repeated twice). The solids are then dissolved in methanol/dichloromethane and conc. HCl (27 drops) is added. After the mixture had stirred for 1.3 h, the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The combined organic layers are dried over sodium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (40 mL) using acetone/dichloromethane/0.25% NH4OH (10/90, 20/80 and 50/50) to give 0.1300 g (86%) of the title compound; mp 96-96.75° C.; MS (ESI+) for C23H24N2O m/z 345.2 (M+H)+; IR (drift) 1600, 1580, 1467, 1449, 1341, 1307, 1268, 1242, 1151, 1128, 794, 779, 744, 718, 708 cm−1; 1H NMR (CDCl3) δ2.54, 2.61, 3.22, 4.39, 5.48, 6.68, 6.96, 7.11, 7.24, 7.31, 8.09. Anal. Calcd for C23H24N2O: C, 80.20; H, 7.02; N, 8.13. Found: C, 79.88; H, 7.15; N, 8.12.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[NH2:2].[F:12][C:13]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:14]=1[CH:15]=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:14]=1[CH:15]=[N:2][NH:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: NNc1cccc(C(=O)O)c1
Reactant: O=Cc1cc(I)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(NN=Cc2cc(I)ccc2F)c1
Yield: 97.6 %

Procedure:
3-Hydrazinylbenzoic acid (1.52 g, 10 mmol)), 2-fluoro-5-iodobenzaldehyde (2.5 g, 10 mmol) and caesium carbonate (3.26 g, 10 mmol) were stirred in DMF (10 mL) at room temp under argon atmosphere for 2.5 h. Water (40 mL) was added and the clear solution was acidified with aqueous HCl (1.7 M). The beige-orange precipitate that formed was collected by, filtration, washed with water and dried in vacuo to give the title compound (3.75 g, 98%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=1[O:56][C:57]1[CH:63]=[CH:62][C:60]([NH2:61])=[CH:59][CH:58]=1>CN(C)C=O>[CH3:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[C:11]([NH:61][C:60]1[CH:59]=[CH:58][C:57]([O:56][C:49]2[CH:50]=[C:51]([O:54][CH3:55])[CH:52]=[CH:53][C:48]=2[CH3:47])=[CH:63][CH:62]=1)=[O:13]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(C)c(Oc2ccc(N)cc2)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: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
To a solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (89 mg, 0.471 mmol) in dry N,N-dimethylformamide (5 mL), DIPEA (0.103 mL, 0.589 mmol) then HATU (179 mg, 0.471 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature under argon. Then 4-{[2-methyl-5-(methyloxy)phenyl]oxy}aniline (Intermediate 14, 90 mg) was added and the reaction mixture was stirred at 60° C. under argon for 1 hour 30 min. The reaction mixture was evaporated. The residues obtained was purified by silica gel chromatography (Companion instrument, 40 g silica cartridge) eluting with a gradient cHex/EtOAc 100/0 to 75/25 during 15 min and then 75/25 during 30 min to afford the title compound (155 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:22](OC)(OC)(OC)[CH2:23][CH2:24][CH2:25][CH3:26].C(OC)(OC)(OC)CCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[CH2:23]([C:22]1[N:12]([CH2:13][C:14]([CH3:20])([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(OC)(OC)OC
Reactant: CCOC(=O)C(C)(C)CNc1c(N)cnc2ccccc12
Agent: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-(3-aminoquinolin-4-ylamino)-2,2-dimethylpropanoate (see Example 26 Parts A through D, 9.0 g, 31.3 mmol) was treated according to a modification of the method described in Part B of Example 8 using trimethyl orthovalerate in lieu of trimethyl orthobutyrate. Prior to the addition of trimethyl orthovalerate (6.1 mL, 35 mmol) and pyridinium p-toluenesulfonate (0.050 g), the reaction was heated at reflux for 15 minutes and then cooled slightly. The reaction was heated at reflux for five hours, allowed to cool to ambient temperature, stirred overnight, and concentrated under reduced pressure to provide 11.2 g of ethyl 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]1([S:14]([CH:17]=[C:18]2[CH2:21][O:20][CH2:19]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[C:8]1([S:14]([CH2:17][C:18]2([N:1]3[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]3)[CH2:21][O:20][CH2:19]2)(=[O:16])=[O:15])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC1CCNCC1
Reactant: O=S(=O)(C=C1COC1)c1ccccc1
Solvent: CO
Product: O=S(=O)(CC1(N2CCC(O)CC2)COC1)c1ccccc1

Procedure:
A solution of piperidin-4-ol (100 mg, 0.989 mmol) and 3-((phenylsulfonyl)methylene)oxetane (prepared according to a published literature procedure: Wuitschik et al. J. Med. Chem. 53(8) 3227-3246, 2010, 416 mg, 1.977 mmol) in methanol (5 mL) was heated at 50° C. for 20 h. Solvent was evaporated in vacuo and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-8% 2 N ammonia in methanol/dichloromethane). 1-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperidin-4-ol (300 mg) was obtained as a colorless oil.