Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CC=CC(C)(C)N1.[C:11]1(=[O:27])[CH2:23][CH2:22][CH:21]2[CH2:24][CH2:25][CH2:26][N:19]3[C:20]2=[C:12]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=13.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:35]2[C:39]([CH3:40])=[C:38]([CH:41]=O)[N:37]=[CH:36]2)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCC.O1CCCC1.C(O)(=O)C>[CH3:41][C:38]1[NH:37][CH:36]=[N:35][C:39]=1[CH:40]=[C:23]1[CH2:22][CH:21]2[CH2:24][CH2:25][CH2:26][N:19]3[C:20]2=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=23)[C:11]1=[O:27]
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC2CCCn3c2c1c1ccccc13
Agent: CC1(C)C=CCC(C)(C)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: O
Product: Cc1[nH]cnc1C=C1CC2CCCn3c2c(c2ccccc23)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
6.88 mmol butyllium in hexane (4.3 ml; 1.6M) were added dropwise at -78° C. to a solution of 1.2 ml (6.88 mmol) of 2,2,6,6-tetramethylpyridine in 14 ml of dry tetrahydrofuran. The mixture was then stirred for 30 minutes at 0° C., cooled to -70° C., and added dropwise to a solution of 1-4 g (6.23 mmol) of 2,3,3a,4,5,6-hexahydro-1H-pyrido[3,2,1-jk]carbazol-1-one in 42 ml of dry tetrahydrofuran. The mixture was stirred for 90 minutes under nitrogen at -70° C. A solution of 2.4 g (6.88 mmol) of 1-triphenylmethyl-5-methyl-1H-imidazole-4-carboxaldehyde in 14 ml of dry tetrahydrofuran was then added dropwise to the reaction mixture at -70° C., and the mixture was stirred for 2 hours at -10° C. The mixture was then cooled to -70° C. and 16.8 ml of acetic acid was added dropwise. After the temperature had raised to -10° C., 8.1 g of p-toluenesulfonic acid hydrate were added. This mixture was boiled for 18 hours and evaporated in vacuum. The residue was shaken with methylene chloride and with 2N sodium hydroxide. The organic layer was separated, washed with brine, dried and evaporated. The residue was chromatographed over silicagel using methylene chloride/methanol/ammonia (92.5/7/0.5) as an eluent. 1.2 g (60%) of 2,3,3a,4,5,6-hexahydro-2-[(5-methyl-1H-imidazol-4-yl)-methylene]-1H- pyrido[3,2,1jk]carbazol-1-one were obtained. This product dissolved in 100 ml of ethanol and hydrogenated at room temperature at 1 atmosphere with palladium on carbon as a catalyst. The catalyst was removed by filtration after disappearance of the starting material, the filtrate was evaporated in vacuum, and the residue was purified by flash chromatography over silicagel using methyene chloride/methanol/ammonia (92.5/7/0.5) as an eluent. 0.49 g of the desired compound were obtained after evaporating the desired fractions.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH2:3][C:4]#[N:5].CSC>C1COCC1>[NH2:5][CH2:4][CH2:3][CH:2]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[OH:1]
Reactant: N#CCC(O)c1cccc(O)c1
Solvent: C1CCOC1
Solvent: CSC
Product: NCCC(O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the nitrile 127 (25.0 g, 153 mmol) in THF (400 mL), cooled to 0° C., was added BH3.DMS (49.5 mL, 460 mmol), following which the cooling bath was removed. The resulting mixture was gradually warmed to reflux and maintained overnight. This was then cooled in an ice-bath and quenched by the slow addition of large excess of MeOH. After stirring at RT for about 2 h, the excess solvent was removed under reduced pressure. The residue was again treated with MeOH and evaporated. The process was repeated thrice. The brown oil was then applied onto a flash silica gel column and eluted (0 to 15% (9:1 MeOH—NH3)-DCM gradient) to give 3-(3-amino-1-hydroxypropyl)phenol (128) as a brown solid. Yield (25.0 g, 97%): 1H NMR (400 MHz, DMSO-d6) δ 7.04-7.09 (m, 1H), 6.74 (s, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.58 (dd, J=8.0, 2.0 Hz, 1H), 4.55 (dd, J=7.2, 5.6 Hz, 1H), 2.57-2.66 (m, 2H), 1.56-1.62 (m, 2H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[N:6]=[CH:5][C:4]([C:3]([N:26]4[CH2:31][CH2:30][S:29][CH2:28][CH2:27]4)=[O:2])=[CH:9][CH:8]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Reactant: C1CSCCN1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 95 %

Procedure:
As described for example 117, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72 mg, 0.2 mmol) was converted, using thiomorpholine instead of 2,2,2-trifluoroethylamine, to the title compound (82 mg, 95%) which was obtained as a white solid. MS: m/e=430.5 [M+H]′.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)C.CC(C[AlH]CC(C)C)C.[Cl-].[NH4+].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.C(OCC)C>[F:16][C:15]([F:17])([F:18])[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCCCc1ccc(C(F)(F)F)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=CCCCCc1ccc(C(F)(F)F)cc1
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 73.3 %

Procedure:
The above 5-(4-trifluoromethylphenyl)pentanoic acid ethylester 12.2 g (44.5 mmol) was stirred in toluene 70 ml while the temperature was cooled to −60° C., and a 1.01 M of toluene solution 46.0 ml (46.5 mmol) of DIBAL was added dropwise, and the mixture was stirred at −60° C. for 15 minutes. At the same temperature, a saturated ammonium chloride aqueous solution 40 ml was added dropwise to the reactant, and the mixture was heated to room temperature and stirred for 30 minutes. Diethyl ether 100 ml was added to the reactant, and the mixture was stirred at room temperature for one hour, and magnesium sulfate was added, and the suspension was filtered with cerite. The filtrate was washed with water, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 5-(4-trifluoromethylphenyl)pentanal 7.50 g (32.6 mmol). The yield was 73.3% from 5-(4-trifluorophenyl)pentanoic add ethylester.
Reaction SMILES: C([Cu])#N.[C:4]([Mg]Br)([CH3:7])([CH3:6])[CH3:5].Br[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:16]=1>C1COCC1>[C:4]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:16]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Mg]Br
Reactant: CC(C)[Si](OCc1cncc(Br)c1)(C(C)C)C(C)C
Agent: N#C[Cu]
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1cncc(C(C)(C)C)c1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 22.9 %

Procedure:
A mixture of anhydrous CuCN (3.41 g, 38.03 mmol) in 150 mL of anhydrous THF, and ethereal tert-butylmagnesium bromide (38 mL, 76.1 mmol) was stirred under N2 at −78° C. for 20 min. 3-bromo-5-((triisopropylsilyloxy)methyl)pyridine (3.274 g, 9.51 mmol) in THF was added, and the reaction mixture was stirred for 2-3 h at −78° C. and then overnight at room temperature. The reaction mixture was quenched by dropwise addition of saturated aqueous NH4OH and the pH was adjusted to 10 by using 1 M aqueous NaOH, and the resulting solution was extracted with extracted with EtOAc (3×75 mL). The combined organic extracts were dried (Na2SO4,), and concentrated under vacuum to get a residue which was purified by flash column chromatography to give 3-tert-butyl-5-((triisopropylsilyloxy)methyl)pyridine (0.7 g). 1H NMR shows the products contain the desired product and bromine-removed product. 1H NMR (CDCl3): d: 1.124 (m, 22H), 1.369 (s, 5H), 4.878 (s, 2H), 7.298 (m, 0.5H), 7.738 (m, 1H), 8.414 (s, 0.6H), 8.607 (m, 1.5H).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:22]C)[N:13]3[CH2:16][CH:17]3[CH2:21][CH2:20][O:19][CH2:18]3)=[C:9]([NH2:24])[N:8]=2)[CH2:3][CH2:2]1.NC1N=C(NCCCC)N=C2C=1NC(=O)N2CC1CCOC1.Cl.[OH-].[Na+]>CO.O1CCOCC1.O>[NH2:24][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:22])[N:13]2[CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOC1
Agent: CCCCNc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(OCCC2CC2)nc2c1[nH]c(=O)n2CC1CCOC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 2-[(2-cyclopropylethyl)oxy]-8-(methoxy)-9-[tetrahydro-3-furanylmethyl]-9H-purin-6-amine, Isomer 2 (1.45 g) in dry methanol (50 ml) at room temperature and under nitrogen, was added 4.0M hydrochloric acid in 1,4-dioxane (14 ml) in one go. The reaction was stirred at room temperature for 4 hours. The reaction was neutralised by the addition of 2M aqueous sodium hydroxide solution and concentrated in vacuo to yield an off white residue. This was taken up in water (40 ml) and filtered to afford a sand coloured solid. This was recrystallised from water:ethanol, 1:1 (75 ml) to afford a beige solid (765 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[Li]CCCC.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[CH:27]1([NH:33][C:34]([C:11]2[N:12]([CH3:13])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:10]=2)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C=NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
A solution of 5.5 g (16.2 mmol) of 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-1-methyl-imidazole in 70 mL of THF was cooled in a −78° C. bath and 15 mL of 1.6 M n-BuLi was slowly added. After stirring for 1 h, 5.2 mL (40.7 mmol) of cyclohexylisocyanate was added. The cooling bath was removed and the solution was stirred for 3 h. The reaction mixture was poured into a mixture of water/EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The residue was purified on a flash column using a gradient of 2-10% EtOAc-hexane. The isolated product was crystallized from EtOAc-hexane (˜1:10) to obtain the title compound as a white solid with a melting point of 165° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:17](=[O:18])[O:16][CH2:15]2)#[N:11].[NH4+].[Cl-]>O1CCCC1.COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]([C:19]2[CH:20]=[CH:21][C:12]([C:10]#[N:11])=[CH:13][C:14]=2[CH2:15][OH:16])=[O:18])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: N#Cc1ccc2c(c1)COC2=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: N#Cc1ccc(C(=O)c2ccc(F)cc2)c(CO)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
1048 g of a 10% solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran are added to a suspension of 60.0 g of 5-cyanophthalide in 390 ml of 1,2-dimethoxyethane at −10° C. within three hours. After stirring for 30 minutes at −10° C., the cold reaction mixture is poured into 1 L of aqueous NH4Cl (180 g in 1000 ml of water, 20° C.) in about 5 minutes. The layers are separated and the aqueous layer is extracted with 300 ml of tetrahydrofuran. The organic layers are combined and volatiles are removed under reduced pressure at 45° C. The residue is dissolved in a mixture of 1000 mL of CH2Cl2 and 200 ml of water containing 2.5 g of sodium carbonate (pH of 9). The layers are separated and the organic phase is dried with 40 g of sodium carbonate. The dry CH2Cl2 solution is treated with 6 g of charcoal, stirred for 10 minutes and the charcoal is removed by filtration. The filter cake is washed with 50 mL of CH2Cl2. Filtrate and washing liquid are combined and the solvent is removed under reduced pressure. 300 mL of diisopropylether are added to the residue. After stirring for 1 hour at 22° C. the crystal suspension is cooled to 0° C. and stirred for another two hours, then cooled to −10° C. and stirred for 14 hours. The product is isolated by filtration and washed with 40 mL of chilled diisopropylether, 80 mL of a 1:1 mixture of diisopropylether/cyclohexane and 80 mL of cyclohexane. After drying for 3 hours at 50° C. in vacuo 83.0 g (86.2% of theory, purity (HPLC): 99.8 area %) white, crystalline powder of the title compound are obtained (mp. 85° C.).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>COCCOCCOC.O.C(O)C.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:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34]([CH2:2][C:3]2[N:4]=[C:5]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[S:6][C:7]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: COCCOCCOC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1Cc1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Yield: 31.1 %

Procedure:
To a solution of ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (0.25 g, 0.63 mmol) in 4 ml of 2-methoxyethyl ether was added tetrakis(triphenylphosphine)palladium(0), (0.02 g, 0.019 mmol) and then sodium carbonate (0.13 g, 1.2 mmol) in 0.5 ml water. After brief stirring, 4-(trifluoromethyl)phenyl boronic acid (0.13 g, 0.7 mmol) in 1 ml ethanol was added. After heating at 110° C. for 15 hours, the reaction was complete by HPLC and was treated with water (5 ml) and extracted with tert-butyl methyl ether (2×30 ml). The organic layers were dried with magnesium sulfate and immediately loaded onto silica to give a crude residue which was purified on a Biotage FlashElute with a 40M silica cartridge, eluting with 10% ethyl acetate in hexanes to yield ethyl 4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate as a white solid (0.09 g, 35%).
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:18][C:19]1[CH:20]=[C:21]([C:26](=[C:31]2[CH2:34][NH:33][CH2:32]2)[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:23]([F:25])[CH:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:2]([N:33]2[CH2:34][C:31](=[C:26]([C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=3)[C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:32]2)[C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[CH:12][CH:13]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CC(C)(C)C(=C1CNC1)c1cc(F)cc(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1)c1cc(F)cc(F)c1

Procedure:
A mixture of 99 mg (0.32 mmol) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile, 80 mg (0.216 mmol) of 3-[1-(3,5-difluorophenyl)-2,2-dimethylpropylidene]azetidine and 113 uL (0.65 mmol) of N,N-diisopropylethylamine in 3 mL of acetonitrile was heated at reflux for 3 h. Then the reaction was concentrated and the residue was dissolved in 5 ml of hexane/ether. A solution of 1 mL of 1N HCl in ether was added to above solution to make the salt. The mixture was filtered and the solids were washed with hexane/ether. The residue was neutralized with NaOH and the free base was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR (CDCl3) δ 1.07 (s, 9H), 3.37 (m, 2H), 4.06 (m, 2H), 4.50 (s, 1H), 6.58 (d, J=8 Hz, 2H), 6.74 (m, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.39 (t, J=7.7 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.72 (s, 1H); Mass Spectrum: m/e=463 (M+1 35Cl) and 465 (M+1 37Cl).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]([F:21])([F:20])[C:5]([F:19])([F:18])[O:6][C:7]([F:17])([F:16])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Cl.[CH2:24]([C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[N:36][N:35]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:24]([C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8][C:7]([O:6][C:5]([F:19])([F:18])[C:4]([F:21])([F:20])[O:3][C:2]([F:23])([F:22])[F:1])([F:17])[F:16])=[CH:41][CH:40]=2)=[N:36][N:35]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCc1nnc(-c2ccc(O)cc2)s1
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCCCl
Product: CCCCCCCCCCc1nnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)s1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)pentyl chloride (2.4 g, 5.7 mmol, prepared from 1,5-dichloropentane and 2-(2-(trifluoromethoxy)tetrafluoroethoxy)-2,2-difluoroethanol) with 5-decyl-2-[4-hydroxyphenyl]-1,3,4-thiadiazole (1.4 g, 4.4 mmol, prepared essentially as described by C. Tschierske and D. Girdzivnaite in J. Prakt. Chem. 1991, 135-37). The reaction mixture was quenched by addition of water, and the resulting crude product was recrystallized from ethanol and further purified by Kugelrohr distillation (215-25° C. at 0.01 torr) to provide a yield of 2.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:26])[CH:25]=1)[CH2:20][Mg]Br.CC(O)CC.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(OCC)C.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[CH:14]([NH2:15])[CH2:20][C:19]2[CH:18]=[C:17]([F:16])[CH:25]=[C:24]([F:26])[CH:23]=2)=[CH:6][CH:7]=1
Reactant: Cn1cnc(C#N)c1-c1ccc(Cl)cc1
Reactant: Fc1cc(F)cc(C[Mg]Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCC(C)O
Solvent: CO
Product: Cn1cnc(C(N)Cc2cc(F)cc(F)c2)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-(4-chlorophenyl)-1-methyl-1H-imidazole-4-carbonitrile (520 mg, 2.4 mmol) in toluene (13 mL) at 0° C. was added (3,5-difluorobenzyl)magnesium bromide (12.5 mL of a 0.25 M solution in diethylether). The reaction was stirred 20 min at 0° C. then let warm to ambient temperature. After stirring for 40 min, the reaction was cooled to 0° C. 2-Butanol (8 mL) and MeOH (4 mL) were added followed by addition of NaBH4 (135 mg, 3.6 mmol) and stirred for 20 min. The reaction was quenched by addition of saturated aqueous NH4Cl and extracted with EtOAc. The organics were separated, washed with saturated aqueous NaHCO3, and dried with saturated aqueous NaCl. Solvents were removed in vacuo and the residue purified by column chromatography on silica to provide the desired product. MS (m/z) 348.3 [M+H]+.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=[O:12])[C@H:5]([C:8](=[O:11])[O:9][CH3:10])[NH:6][CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([OH:63])=O)=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>[Cl-].[Na+].O.CN(C=O)C>[CH3:46][O:47][CH2:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]2[CH:56]=[CH:57][C:58]([C:61](=[O:63])[N:6]([CH:5]([C:4]([NH:3][CH3:2])=[O:12])[C:8]([O:9][CH3:10])=[O:11])[CH3:7])=[CH:59][CH:60]=2)=[CH:53][CH:54]=1
Reactant: CNC(=O)[C@@H](NC)C(=O)OC
Reactant: COCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(COC)cc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Intermediate 5-2 (0.39 g), HATU (0.57 g) and DIPEA (0.80 mL) were added to a DMF (6.0 mL) solution of 4′-(methoxymethyl)biphenyl-4-carboxylic acid (0.36 g) as obtained in Example 3-(3), and the mixture was stirred for 30 minutes at 80° C. Then, brine was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH type silica gel chromatography (gradient elution with hexane/ethyl acetate=50/50→0/100) to obtain 4-(methoxymethyl)-4′-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (yellow oil) (0.40 g, 69%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[CH:8][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3)nc2c1
Reactant: C1CCNCC1
Product: Cc1ccn2cc(-c3ccc(OCCCN4CCCCC4)cc3)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (0.2 g) and piperidine (2.0 mL) were heated at reflux temperature for 5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with additional ethyl acetate (10 mL) and the organic portions combined. The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (0.21 g). This compound can also be named as 7-(methyl-2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-imidazo[1,2-a]pyridine. Treatment with 2M HCl in ether afforded the dihydrochloride. 1H NMR (CD3OD) δ 8.67 (d, J=7.5 Hz, 1H), 8.41 (s, 1H), 7.84 (m, 2H), 7.71 (s, 1H), 7.36 (dd, J=6.9 Hz, J=1.4 Hz, 1H), 7.16 (m, 2H), 4.22 (t, J=5.8 Hz, 2H), 3.64 (d, J=12.5 Hz, 2H), 3.35 (m, 2H), 3.04 (m, 2H), 2.62 (s, 3H), 2.34 (m, 2H), 1.99 (m, 2H), 1.86 (m, 3H), 1.59 (m, 1H); 13C NMR (CD3OD) δ 161.0, 147.1, 141.1, 136.2, 128.5, 128.2, 120.3, 119.3, 115.8, 110.6, 109.9, 65.8, 55.0, 53.8, 24.5, 23.6, 22.1, 21.2, MS (M+H)=350.2 Analysis: Calc'd for C22H27N3O 2HCl (2H2O) C, 57.64; H, 7.26; N, 9.17; Found: C, 57.68; H, 7.13; N, 9.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH:17]12[CH2:23][CH:20]([NH:21][CH2:22]1)[CH2:19][O:18]2>>[CH:17]12[CH2:23][CH:20]([N:21]([C:14]([C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][C:8]=4[CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:16])[CH2:22]1)[CH2:19][O:18]2
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Reactant: C1OC2CNC1C2
Product: COc1ccc(C(=O)N2CC3CC2CO3)c2c(C)cccc12

Procedure:
4-Methoxy-8-methyl-1-naphthoic acid (Step-5 of Intermediate-22) was reacted with 2-oxa-5-azabicyclo[2.2.1]heptane by following the similar procedure as described in Step-6 of Intermediate-22.