Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=3[C@H:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=1>>[CH3:35][O:34][C:30]1[CH:29]=[C:28]([N:23]2[CH2:24][CH2:25][CH2:26][C@@H:22]2[C:10]2[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[C:14]3[C:9]=2[O:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][C:15]3=[O:17])[CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1cc([C@H]2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: COc1cccc(Br)c1
Product: COC(=O)c1cc([C@H]2CCCN2c2cccc(OC)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Yield: 56 %

Procedure:
Methyl 2-morpholino-4-oxo-8-[(2R)-pyrrolidin-2-yl]chromene-6-carboxylate, preparation described in Example 1.03b, 125 mg, 0.35 mmol) was reacted with 1-bromo-3-methoxybenzene (0.049 ml, 0.38 mmol) using a procedure similar to that described in Example 1.0 to afford methyl 8-[(2R)-(1-(3-methoxyphenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylate (90 mg, 56%) as a yellow gum. Mass Spectrum: m/z [M+H]+=465.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:5])[C:3]#[N:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:1])[CH2:3][NH2:4]
Reactant: CC(C)(C#N)c1ccccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(CN)c1ccccn1
Reaction time: 10 h

Procedure:
To a solution of 2-methyl-2-(2-pyridyl)-propionitrile (1.018 g, 6.97 mmol) in 25 mL of anhydrous diethyl ether under a blanket of Argon was added LiAlH4 (0.538 g, 14.17 mmol) portionwise. After 1 h the reaction was quenched with the addition of water (1 mL), NaOH (1.0 mL, 1N), water (8 mL) then diethyl ether (20 mL) and let stir for 10 h. The solution was filtered through a plug of celite and washed with diethyl ether:MeOH (1:1) (200 mL). The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (30×150 mm column of SiO2, CH2Cl2 /CH2Cl2 saturated with NH3 /MeOH gradient elution 60:39:1 to 60:38:2 to 60:37:3) to give the title compound as a resin:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:4][CH:5]([C:11]([F:14])([F:13])[F:12])[CH2:6][CH2:7][CH2:8][CH2:9]I.C(O)C.[S-:25][C:26]#[N:27].[K+]>C(O)(=O)C>[F:1][C:2]([F:21])([F:20])[C:3]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:4][CH:5]([C:11]([F:14])([F:13])[F:12])[CH2:6][CH2:7][CH2:8][CH2:9][S:25][C:26]#[N:27]
Reactant: N#C[S-]
Reactant: FC(F)(F)C(CCCCI)CC(F)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CSCCCCC(CC(F)(C(F)(F)F)C(F)(F)F)C(F)(F)F
Yield: 99.5 %

Procedure:
According to scheme (16) above, in a flask that can be equipped with an agitator, thermocouple and a reflux condenser, 30 grams (67 mmol) of 1,1,1,2-tetrafluoro-2,4-bis(trifluoromethyl)-8-iodooctane (see, e.g. Published International Patent Applications), 35 ml of absolute ethanol, 9.8 grams of potassium thiocyanate (KSCN) and 1.4 ml of glacial acetic acid (HOAc) can be placed to form a mixture. The mixture can be heated to reflux (about 84.7 C) and maintained for overnight while stirring. The mixture can be observed as a light yellow slurry and can be concentrated in vacuo to afford a viscous yellow slurry. The slurry cab be extracted with 300 mL of diethyl ether, (decanted twice) and filtered to afford a wet cake and a filtrate. The wet cake can be washed with three 100 mL portions of diethyl ether wherein the collected washings can be combined with the filtrate and concentrated in vacuo to afford 25.28 grams (99.5% yield) of the 1,1,1,2-tetrafluoro-2,4-bis(trifluoromethyl)-8-thiocyanatooctane product that can be observed as a light yellow oil. The product structure can be confirmed by NMR and/or chromatographic analysis.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]23[CH2:15][CH:14]2[CH2:13][O:12][C:11]3=[O:16])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:17]>>[OH:12][CH2:13][CH:14]1[CH2:15][C:10]1([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:11]([NH2:17])=[O:16]
Reactant: O=C1OCC2CC12c1cccc([N+](=O)[O-])c1
Reactant: N
Product: NC(=O)C1(c2cccc([N+](=O)[O-])c2)CC1CO
Temperature: 60 °C
Reaction time: 84 h
Yield: 85.9 %

Procedure:
A mixture of (1SR,5RS)-1-(3-nitrophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (intermediate B5a) (11.47 g, 52.3 mmol, Eq: 1.00) in ammonia (7 M in MeOH) (140 ml, 980 mmol, Eq: 18.7) was stirred in 10 sealed tubes at 60° C. for 3.5 days, but still not complete (ca. 75% conversion). Evaporated all volatiles, coated on silica gel and the crude material was purified by flash chromatography (silica gel, 200 g, 70% to 100% EtOAc in heptane to EtOH/THF 3:1->2:1) to give recovered (1SR,5RS)-1-(3-nitrophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (1.957 g, 16%, which was converted under the same conditions to product) and (1SR,2RS)-2-(hydroxymethyl)-1-(3-nitrophenyl)cyclopropanecarboxamide (10.61 g, 44.9 mmol, 85.8% yield) as a light brown solid. MS (ISN): m/z=235.1 [(M−H)−].
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:22]C(=O)OC(C)(C)C)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:11][CH:10]=1.O1CCOCC1.[ClH:36]>>[ClH:36].[NH2:22][CH:16]([CH2:15][C:12]1[CH:13]=[N:14][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])=[CH:10][CH:11]=1)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18]
Reactant: CN(C)C(=O)C(Cc1ccc(-c2cccc(F)c2F)nc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)C(N)Cc1ccc(-c2cccc(F)c2F)nc1
Reaction time: 1 h
Yield: 50 %

Procedure:
tert-Butyl [1-{[6-(2,3-difluorophenyl)pyridin-3-yl]methyl}-2-(dimethylamino)-2-oxoethyl]carbamate (60 mg, 0.10 mmol) was dissolved in 4 M of hydrogen chloride in 1,4-dioxane (2 mL, 8 mmol) at r.t. The reaction was stirred for 1 h., and concentrated under reduced pressure to give crude 2-amino-3-[6-(2,3-difluorophenyl)pyridin-3yl]-N,N-dimethylpropanamide HCl salt (0.040 g, 50%) as colorless oil. Analytical LCMS (M+H)+: m/z=306.0.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:13])[O:8][CH:7]([CH2:9][OH:10])[CH:6]([CH2:11][OH:12])[O:5]1.Cl[CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:16](=[O:23])[CH2:15][O:10][CH2:9][CH:7]1[CH:6]([CH2:11][O:12][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:5][C:4]([CH3:13])([CH3:3])[O:8]1)[CH3:22]
Reactant: CC1(C)OC(CO)C(CO)O1
Reactant: CCOC(=O)CC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCC1OC(C)(C)OC1COCC(=O)CC(=O)OCC
Temperature: 25 °C
Yield: 43.7 %

Procedure:
To a suspension of sodium hydride (4.0 g, 60% dispersion in oil) in tetrahydrofuran (150 mL) under a nitrogen atmosphere was added a solution of 2,2-dimethyl-[1,3]dioxolane-4,5-dimethanol (VII, 4.05 g) in tetrahydrofuran (25 mL) over 2 min at room temperature, followed by solid tetrabutylammonium hydrogen sulfate (0.4 g). The resulting mixture was cooled in an ice bath and a solution of ethyl 4-chloroacetoacetate (VIII, 8.1 g) in tetrahydrofuran (25 mL) was added dropwise over a period of 15 min. The reaction mixture was warmed to room temperature over 1 h then refluxed for 6 h. On cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid (20 mL) and volatile materials were removed under reduced pressure. The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic fractions was washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (grade 9385, Merck, 230-400 mesh, 60 Å) using a mixture of hexane and ethyl acetate (8:2, 7:3 and 6:4; 500 mL each) as eluent, thereby affording the title compound (IX 4.5 g) as an oil and the mono O-alkylated compound, 4-(2-chlorophenyl)-2-(5-hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy-methyl-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester (X, 1.95 g). Compound IX. IR (neat, cm-1): 1723, 1636; MS (CI): 436 (100%, [M+NH4 ]+). Compound X. IR (neat, cm-1): 3455, 1734;
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2ccncc2-c2cccs2)CC1
Yield: 91 %

Procedure:
General procedure D (See Example 4) was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol), thiophene-2-boronic acid (13 mg, 0.11 mmol), tetrakis (triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (23 mg, 91%), LC-MS (ESI) Rt 1.17 min, m/z 288 (100%, [M+H]+); m/z (ESI) C15H18N3OS requires 288.1165 found [M+H]+ 288.1163.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:15][N+:16]([O-])=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1>C(O)C.[Ni]>[NH2:16][CH2:15][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1cccc(Cl)c1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)CC(CN)c1cccc(Cl)c1
Temperature: 0 °C
Yield: 78 %

Procedure:
In a 2 L pressure jar, under inert atmosphere, 196 g (733 mmoles) of ethyl 3-(3-chlorophenyl)-4-nitrobutanoate 377 are dissolved in 200 ml of ethanol. A suspension of 200 g of predried (3×, ethanol) Raney Nickel in 700 ml of ethanol is added and the mixture hydrogenated on a Parr hydrogenator at a maximum of 20 psi H2 pressure (STRONGLY EXOTHERMIC REACTION, ice/water cooling required). The mixture is degassed, filtered on a Celite/Norite pad, and the filtrate concentrated in vacuo, to give 136.7 g of crude 378, 78% yield, used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:23]=[N:24][NH:25][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1nnc2ccc(C#Cc3ccc(F)cc3F)nn12
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)c1nnc2ccc(-c3[nH]nnc3-c3ccc(F)cc3F)nn12
Temperature: 80 °C

Procedure:
A 50 mL round-bottomed flask equipped with a condenser outfitted with a nitrogen inlet was charged with 6-((2,4-difluorophenyl)ethynyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.500 g, 1.67 mmol, Preparation #J.1) in DMA (15 mL) to give a yellow solution. Sodium azide (0.327 g, 5.03 mmol) was added in one portion. The reaction mixture was heated at about 80° C. for about 16 h. The reaction mixture was partitioned between EtOAc and water. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. One-half of the aqueous mixture was purified via RP-HPLC (Table 1, Method f) to provide the title compound after lyophilization (0.080 g, 14%): LC/MS (Table 1, Method b) Rt=1.8 min; MS m/z: 342.2 (M+H)+.
Reaction SMILES: Br.[CH2:2]([N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13](Cl)[C:12]=2[N:11]=[C:10]1[NH2:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH3:24]>CO>[CH2:2]([N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:24])[C:12]=2[N:11]=[C:10]1[NH2:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1nc2c(Cl)nc3ccccc3c2n1Cc1ccccc1
Reactant: N
Agent: Br
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc(N)n2Cc1ccccc1
Temperature: 170 °C

Procedure:
Crude 1-benzyl-4-chloro-1H-imidazo[4,5-c]quinoline-2-amine hydrobromide (0.500 g) and ammonia (20 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 170° C. for six days. The resulting solution was concentrated under reduced pressure, and the residue was purified by automated flash chromatography on silica gel (eluting with 0-10% methanol in dichloromethane with 1% ammonium hydroxide added) to provide 42 mg of 1-benzyl-1H-imidazo[4,5-c]quinoline-2,4-diamine as a brown powder, mp 254-256° C.
Reaction SMILES: C[O-].[Na+].C([O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:12]=1)(=O)C>CO>[CH3:18][N:17]([CH3:19])[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][CH2:9][CH2:8][OH:7]
Reactant: CC(=O)OCCOc1cccc(N(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)c1cccc(OCCO)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A catalytic amount of sodium methoxide (enough to insure a basic solution) was added to a solution of 2-(3-(dimethylamino)phenoxy)ethyl acetate (39A) (0.545 g, 2.44 mmol) in anhydrous MeOH (7 mL). The reaction mixture was stirred at rt for 2.5 hours before a small amount of acidic resin (Dowex 50WX8-200) was added. The reaction mixture was filtered, concentrated under reduced pressure and the crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 66:34-50:50, to provide the desired compound 2-(3-(dimethylamino)phenoxy)ethanol (39B).
Reaction SMILES: CCN=C=NCCCN(C)C.[I:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:24][CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19].[CH:35]1([C:38](O)=[O:39])[CH2:37][CH2:36]1.COC(C1CCC(C(N2CCN(C3C=CC(C(=O)NC4C=CC=C(C(C)(C)C)C=4)=CN=3)CC2)=O)CC1)=O>>[CH:35]1([C:38]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([NH:20][C:15]4[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([I:12])[CH:14]=4)=[O:34])=[CH:23][N:24]=3)[CH2:33][CH2:32]2)=[O:39])[CH2:37][CH2:36]1
Reactant: O=C(O)C1CC1
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)C4CC4)CC3)nc2)cc1I

Procedure:
6-(4-Cyclopropanecarbonyl-piperazin-1-yl)-N-(3-iodo-4-methyl-phenyl)-nicotinamide was synthesized by the EDCI coupling of N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and cyclopropanecarboxylic acid in a manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid methyl ester, above. LCMS calcd for C21H23IN4O2 (m/e) 490, obsd 491 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8]CC2C=CC(OC)=CC=2OC)=[CH:4][C:3]=1[CH3:20].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:20]
Reactant: COc1ccc(CNc2cc(C)c(Cl)nn2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nnc1Cl
Reaction time: 8 h

Procedure:
To a solution of (6-chloro-5-methyl-pyridazin-3-yl)-(2,4-dimethoxy-benzyl)-amine from above (680 mg) in DCM (8 ml) was added TFA (8 ml). The resulting solution was allowed to stand for overnight. The mixture was concentrated to give the titled compound which was used directly for next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(C1C=CC([N+]([O-])=O)=CC=1OCCN1CCCCC1)(C)(C)C>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[C:8]([CH:9]=1)[O:10][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(O)c1
Reactant: ClCCN1CCCCC1
Agent: CC(C)(C)c1ccc([N+](=O)[O-])cc1OCCN1CCCCC1
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCCN2CCCCC2)c1

Procedure:
1-[2-(5-Nitro-2-pentafluoroethyl-phenoxy)-ethyl]-piperidine was prepared from 5-nitro-2-pentafluoroethylphenol and 1-(2-chloroethyl)piperidine by a procedure similar to that described in the preparation of 1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[NH:32][C:31]3[CH:33]=[C:34]([C:37]([O:39]C)=[O:38])[CH:35]=[CH:36][C:30]=3[N:29]=2)[CH2:24][CH:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[NH:32][C:31]3[CH:33]=[C:34]([C:37]([OH:39])=[O:38])[CH:35]=[CH:36][C:30]=3[N:29]=2)[CH2:24][CH:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc2nc(N3CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c4cccc5ccccc45)C(c4cccc(F)c4)C3)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2nc3ccc(C(=O)O)cc3[nH]2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a solution of 48 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1H-benzimidazole-6-carboxylate in 2.0 mL of THF and 1.0 mL of methanol was added 1.00 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight, and then stirring at 80° C. for 6 hours. The reaction mixture was cooled to room temperature, neutralized by addition of 1.00 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 19 mg of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1H-benzimidazole-6-carboxylic acid as a pale yellow amorphous compound. ESI+: 623
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].FC(F)(F)C([N:12]([C:27]1[CH:42]=[CH:41][C:30]([C:31](ON2C(=O)CCC2=O)=[O:32])=[CH:29][CH:28]=1)[CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=O.[OH-].[Na+].Cl>O.C(O)C.C(N(CC)CC)C>[CH2:13]([NH:12][C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:32])=[CH:41][CH:42]=1)[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NCCS(=O)(=O)O
Reactant: CCCCCCCCCC=CCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)NCCS(=O)(=O)O)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of 2.50 g. of taurine and 5.6 ml. of triethylamine in 22.5 ml. of water is added 5.55 g. of N-{p-[2,2,2-trifluoro-N-(4-tetradecenyl)acetamido]benzoyloxy}succinimide as a solution in 45 ml. of ethanol. After 24 hour, the mixture is treated with 20 ml. of 2.0M sodium hydroxide and 25 ml. of water. After stirring for 10 minutes, the mixture is acidified with dilute hydrochloric acid, and the crude product is collected by filtration. Recrystallization affords the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]([NH:11][CH3:12])=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=1.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:22]=[C:23]([C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[F:29][C:27]([F:28])([F:30])[C:25]1[CH:24]=[C:23]([C:31]([CH3:35])([CH3:36])[C:32]([N:11]([C:10]2[C:5]([O:4][C:3]3[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=3[Cl:1])=[N:6][C:7]([S:13][CH3:14])=[N:8][CH:9]=2)[CH3:12])=[O:33])[CH:22]=[C:21]([C:20]([F:19])([F:37])[F:38])[CH:26]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(SC)nc1Oc1ccccc1Cl
Product: CSc1ncc(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Oc2ccccc2Cl)n1

Procedure:
The resulting [4-(2-chloro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl]-methyl-amine was treated with 2-(3,5-bis-trifluormethyl-phenyl)-2-methyl-propionyl chloride as described in Example 43e) to give 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl]-N-methyl-isobutyramide as a white foam, MS (ISP): 564.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN1CCN(C2CCN(c3ccc(N)cc3C#N)CC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 17.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.7 g) and 5-amino-2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]benzonitrile (2.0 g), the title compound (0.6 g) was obtained, melting point: 240° C. (decomposition).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:11]1[C:15]2[C:16]([NH2:25])=[C:17]([Cl:24])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=2[N:13]=[C:12]1[CH3:26])[CH3:10].C1(S(O)(=O)=O)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH:1](=[N:25][C:16]1[C:15]2[N:11]([CH2:9][CH3:10])[C:12]([CH3:26])=[N:13][C:14]=2[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[C:17]=1[Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(C)nc2cc(C(F)(F)F)c(Cl)c(N)c21
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: CCn1c(C)nc2cc(C(F)(F)F)c(Cl)c(N=Cc3ccccc3)c21
Temperature: 25 °C
Yield: 94 %

Procedure:
Benzaldehyde (0.78 g.; 7.35 mmole) was reacted with 1-ethyl-2-methyl-5-trifluoromethyl-6-chloro-7-aminobenzimidazole (1.0 g.; 3.66 mmole) in the presence of 7 ml. of xylene and a few crystals of benzenesulfonic acid. The mixture was refluxed for 1 hour, removing water from the reaction mixture. Upon cooling to room temperature, the product crystallized out of solution to give 1.24 g. (94% yield). After recrystallization from benzene, the product melts at 183°-185.5° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]4[C:19]([CH3:24])=[N:20][CH:21]=[N:22][CH:23]=4)=[O:17])=[CH:11][C:10]=3[F:25])[N:7]=[C:6]([C:26]([F:29])([F:28])[F:27])[CH:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:32]I>C1COCC1>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([N:15]([CH3:32])[C:16]([C:18]4[C:19]([CH3:24])=[N:20][CH:21]=[N:22][CH:23]=4)=[O:17])=[CH:11][C:10]=3[F:25])[N:7]=[C:6]([C:26]([F:28])([F:27])[F:29])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ncncc1C(=O)Nc1ccc(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncncc1C(=O)N(C)c1ccc(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-fluorophenyl}-4-methylpyrimidine-5-carboxamide (300 mg, 0.74 mmol) was dissolved in THF, cooled to 0° C., added sodium hydride (35 mg, 1.48 mmol) and stirred the mixture for 30 mins at the same temperature. Methyl Iodide (120 mg, 0.84 mmol) was added and heated the reaction mixture to rt. After 3 h, reaction mixture quenched with water. Work up (H2O/AcOEt) and purification afforded the title compound (120 mg) as a pale-yellow solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.99 (s, 1H), 8.41 (s, 1H), 7.46 (t, J 8.1, 1H), 7.08-7.01 (m, 2H), 6.21 (s, 1H), 3.53 (s, 3H), 2.58 (s, 3H), 1.60-1.51 (m, 1H), 0.98-0.88 (m, 2H), 0.70-0.60 (m, 2H). MS (m/z): 418.35 [M−H]−.