Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:3]([C:2]([NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:23][CH:24]=1)([CH3:17])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)#[N:4]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2cc(Cl)cc(Cl)c2n1
Product: CC(C#N)(Cn1nc2cc(Cl)cc(Cl)c2n1)NC(=O)c1ccc(C(C)(C)C)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 15, and 4-tert-butylbenzoyl chloride, the title compound was isolated as a white solid (80 mg). MS (ES): M/Z [M+H]=430. NMR: (400 MHz, DMSO-d6): 1.30 (s, 9H), 1.75 (s, 3H), 5.47 (q, J=17.8 Hz, 2H), 5.51 (d, J=8.3 Hz, 2H), 7.70-7.76 (m, 3H), 8.18 (d, J=1.5 Hz, 1H) and 8.70 (br s, 1H).
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:8]=[C:9]([CH3:12])[CH2:10][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1.Cl>C(COC)OC>[C:3]([C:7]1[CH:8]=[C:9]([CH3:12])[C:10](=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:17]2[CH:27]=[CH:28][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:11]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC1=CC(C(C)(C)C)=CC1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(C)cc1)c1ccc(C)cc1

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 1.56 g of powdery potassium hydroxide (27.8 mmol) and 100 ml of dehydrated dimethoxy ethane were added in a nitrogen atmosphere. To the suspension, 2.46 g of 3-tert-butyl-1-methyl-cyclopentadiene (18.0 mmol) was gradually added dropwise at room temperature and stirred under reflux for 2 hr. To the reaction solution, a solution prepared by dissolving 3.99 g of 4,4′-dimethylbenzophenone (19.0 mmol) in 40 ml of dehydrated dimethoxy ethane was gradually added and stirred under reflux for 3 days. To the reaction mixture, 50 ml of a hydrochloric acid aqueous solution (1N) was gradually added dropwise in an ice bath, and stirred at room temperature for some time. The organic phase was separated by adding diethyl ether and washed with a saturated sodium bicarbonate aqueous solution, water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, and thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a dark red liquid. The liquid was purified by a column chromatography using 170 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure, and thereby the aimed compound was obtained in an amount of 2.55 g (7.76 mmol) as a red solid (yield: 43%).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:22]([OH:24])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH2:26][CH3:27]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:22]([OH:24])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[CH:14]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 52 %

Procedure:
Sodium hydroxide (4.6 g) was finely divided in an argon atmosphere, and thereafter methylene chloride (160 mL), N-tert-butoxycarbonyl-L-tryptophan (10.0 g), iodoethane (13.2 mL), and tetra-n-butylammonium hydrogensulfate (1.1 g) was added thereto, and the mixture was stirred for 64 hours at room temperature. The reaction mixture was washed with a 10% aqueous citric acid solution and saturated sodium chloride solution, and thereafter the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel column chromatography (chloroform:methanol=200:1), to give the captioned compound (5.7 g, 52%) as an oily product.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14](Br)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](N(CC)C(C)C)(C)[CH3:19].C[Si](C#C)(C)C.[OH-].[Li+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:18]#[CH:19])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C#Cc1nc(C)c(C(=O)NCc2ccccc2)s1
Temperature: 35 °C
Yield: 42.7 %

Procedure:
To a solution of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide (0.10 g, 0.32 mmol) in anhydrous toluene (1 mL) was added copper(I) iodide (0.001 g, 0.006 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.005 g, 0.006 mmol), and N,N-diisopropylethylamine (0.17 mL, 0.97 mmol). The reaction mixture was degassed and the reaction flask was filled with nitrogen followed by the addition of trimethylsilylacetylene (0.089 mL, 0.64 mmol). The reaction mixture was heated at 35° C. for 3 hours, cooled to ambient temperature and treated with 1 M aqueous lithium hydroxide (1.0 mL) for 5 minutes, diluted with ethyl acetate (10 mL), washed with water (3 mL) and brine (3 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexanes, 1:1) to afford the title compound as a brown solid (0.035 g, 93%): 1H NMR (300 MHz, CDCl3) δ 7.43-7.21 (m, 5H), 6.17 (t, J=5.7 Hz, 1H), 4.56 (d, J=5.7 Hz, 2H), 3.49 (s, 1H), 2.65 (s, 3H); MS (ES+) m/z 257.2 (M+1).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[C@@H:5]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[CH2:4]1)#[N:2].C(#N)C.[ClH:27]>O1CCOCC1>[ClH:27].[F:23][C:18]1[CH:17]=[C:16]([C@H:5]2[CH2:4][C@H:3]([C:1]#[N:2])[CH2:8][CH2:7][NH:6]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C#N)C[C@@H]1c1ccc(F)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: N#C[C@@H]1CCN[C@@H](c2ccc(F)c(F)c2)C1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A mixture of (±)-1,1-dimethylethyl (2R,4R)-4-cyano-2-(3,4-difluorophenyl)piperidine-1-carboxylate (65 mg, 0.20 mmol), acetonitrile (2 mL), and 4 M hydrogen chloride in 1,4-dioxane (2 mL) was stirred at 70° C. for 15 minutes. The reaction mixture was concentrated and dried to give (±)-(2R,4R)-2-(3,4-difluorophenyl)piperidine-4-carbonitrile hydrochloride salt (50 mg, 96% yield); MS (EI) for C12H12F2N2: 223 (MH+).
Reaction SMILES: CC(C)(C)C([O:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[N:8][C:7]=1[C:21]([O:23]C)=O)=O.CC1C=CC(C#N)=CC=1.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH:42][C:21]([C:7]2[N:8]=[C:9]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[N:10]([CH3:13])[C:11](=[O:12])[C:6]=2[OH:5])=[O:23])=[CH:39][CH:38]=1
Reactant: COC(=O)c1nc(-c2ccc(C)cc2)n(C)c(=O)c1OC(=O)C(C)(C)C
Reactant: NCc1ccc(F)cc1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: Cc1ccc(C#N)cc1
Product: Cc1ccc(-c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (prepared from 4-methylbenzonitrile by procedures similar to those set forth in Examples 2 or 3) in DMF 3 equivalents of 4-fluorobenzylamine were added and mixture was stirred at 90° C. for 2 h. The title product precipitated from the cooled reaction mixture after the addition of 2 N HCl, and was collected by filtration and washed with diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][NH:5][C:6](=[O:31])[N:7]([C@H:9]([CH2:16][O:17][C:18](=[O:30])[NH:19][C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[CH3:8].[Li+:37].[OH-]>O1CCOCC1>[Cl:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][NH:5][C:6](=[O:31])[N:7]([C@H:9]([CH2:16][O:17][C:18](=[O:30])[NH:19][C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:11][C:12]([O-:14])=[O:13])[CH3:8].[Li+:37]
Reactant: COC(=O)CC[C@@H](COC(=O)Nc1cc2ccccc2cn1)N(C)C(=O)NCc1cccc(F)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)[O-])COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-methyl 4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(isoquinolin-3-ylcarbamoyloxy)pentanoate (220 mg, 0.43 mmol) in 1,4-dioxane (5 mL) was added LiOH (2N, 1.3 mL, 2.6 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to give lithium (S)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(isoquinolin-3-ylcarbamoyloxy)pentanoate, which was used without further purification. LRMS (M+H+) m/z 503.2.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:22]1[CH:23]=[C:24]([N:32]2[CH2:36][CH:35]([CH3:37])[O:34][C:33]2=[O:38])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.CCOC(C)=O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:2]1([C:1](=[N:14][C:22]2[CH:23]=[C:24]([N:32]3[CH2:36][CH:35]([CH3:37])[O:34][C:33]3=[O:38])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(c2cc(Br)cc(C(F)(F)F)c2)C(=O)O1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1CN(c2cc(N=C(c3ccccc3)c3ccccc3)cc(C(F)(F)F)c2)C(=O)O1
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
Add benzophenone imine (3.56 g, 2 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 43 mg, 0.069 mmol), tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 90 mg, 0.098 mmol] and cesium carbonate (858 mg, 2.63 mmol) to the solution of 3-(3-bromo-5-(trifluoromethyl)phenyl)-5-methyloxazolidin-2-one (430 mg, 1.32 mmol) in dioxane (5 mL). Stir the mixture under nitrogen atmosphere at 100° C. overnight. TLC (PE:EtOAc=1:1) shows the reaction is complete. Filter the mixture and concentrate the filtrate to yield the crude product. Purify by flash chromatography (silica gel, PE:EtOAc=1:1) to afford the product (500 mg, 89%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])#[N:2].[OH-:21].[Na+].OO>C(O)C>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[NH:2][C:1](=[O:21])[C:3]2[C:4](=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:10]=1
Reactant: [OH-]
Reactant: COc1ccccc1C(=O)Nc1cc(C)ccc1C#N
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-c1nc2cc(C)ccc2c(=O)[nH]1
Temperature: 80 °C
Yield: 56 %

Procedure:
To a mechanically stirred suspension of N-(2-cyano-5-methylphenyl)-2-methoxybenzamide (180 g, 0.67 mol) in 1.8 L ethanol under an N2 atmosphere was added 6 N sodium hydroxide solution (310 g in 1.25 L water). To the above mixture, 30% hydrogen peroxide (350 mL, 3.64 mol) was slowly added. The solution was then slowly heated to 80° C. and maintained at this temperature for 4 h. The reaction mixture was concentrated under reduced pressure to remove ethanol, giving a suspension which was quenched with ice cold water (1.8 L) and acidified with acetic acid to pH 5-6 to give a solid residue. The solid was filtered and washed with water, then dissolved in 5.5 L CH2Cl2 and washed with water (2×18 L). The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure to give a light yellow solid (100 g, 54%). mp 165-170° C.
Reaction SMILES: [C:1]1([CH:7]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]([OH:11])[CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([O:23][CH2:24][CH3:25])=[CH2:22].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1.C(Cl)Cl>[C:1]1([CH:7]([NH:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]([O:11][CH:21]([O:23][CH2:24][CH3:25])[CH3:22])[CH:9]=[CH2:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(O)C(NC(=O)c1ccccc1)c1ccccc1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(OC(C)OCC)C(NC(=O)c1ccccc1)c1ccccc1
Yield: 91 %

Procedure:
708 mg (2.65 mmol) of 1-phenyl-1-benzoylamino-2-hydroxybut-3-ene, syn form, 13.5 cm3 of dry methylene chloride, 2.53 cm3 (1.911 g, 26.5 mmol) of ethyl vinyl ether and 66.5 mg (0.265 mmol) of pyridinium p-toluenesulphonate (PPTS) are introduced successively into a 50 cm3 single-necked flask placed under an argon atmosphere and equipped with a magnetic stirring system. The resulting homogeneous reaction mixture is left to react for 4 hours at a temperature of about 20° C. When the reaction is complete, 1 drop of pyridine is added and the reaction mixture is then diluted in 20 cm3 of methylene chloride. The organic phase is washed once with 20 cm3 of water. The aqueous phase is extracted twice with 20 cm3 of methylene chloride. The combined organic phases are washed twice with 20 cm3 of water and once with 10 cm3 of a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulphate. After filtration, the solvents are driven off under reduced pressure on a rotary evaporator. The residue obtained (992 mg) is chromatographed on a column of silica gel. Elution with a hexane/ether mixture (6/4 by volume) gives 1-phenyl-1-benzoylamino-2-(1-ethoxyethoxy)but-3-ene, syn form, with a yield of 91% (818 mg, 2.41 mmol). The product obtained is in the form of an equimolar mixture of the two epimers (determination by the proton nuclear magnetic resonance spectrum).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1F.[CH2:16]([S-:18])[CH3:17].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:18][CH2:16][CH3:17]
Reactant: N#Cc1ccc(C2OCCCO2)c(F)c1
Reactant: CC[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1cc(C#N)ccc1C1OCCCO1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
The reaction was carried out under argon. 4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (4.14 g, 20 mmol) and sodium ethanethiolate (1.68 g, 20 mmol; 1 eq.) were initially charged in DMF (100 ml). Potassium carbonate (6.91 g, 50 mmol; 2.5 eq.) was added at RT, and the mixture was stirred at 100° C. for 5 h. TLC control then showed complete conversion. The mixture was concentrated and the residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 4:1). The title compound was obtained as a solid (4.8 g, 97% of theory).
Reaction SMILES: [O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][OH:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][C:26]1[C:27]([CH3:32])=[N:28][O:29][C:30]=1[CH3:31]>>[CH3:32][C:27]1[C:26]([CH2:25][O:23][CH2:22][CH2:21][N:20]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:17]=3[N:18]=[CH:19]2)=[C:30]([CH3:31])[O:29][N:28]=1
Reactant: Cc1noc(C)c1CCl
Reactant: OCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Product: Cc1noc(C)c1COCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Yield: 52.9 %

Procedure:
Using the general method of Example 13 Part F, 2-(4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (0.82 g, 2.69 mmol) was reacted with 4-(chloromethyl)-3,5-dimethylisoxazole (0.43 g, 2.95 mmol) and purified to provide 0.59 g of 1-{2-[(3,5-dimethylisoxazol-4-yl)methoxy]ethyl}-4-phenoxy-1H-imidazo[4,5-c]quinoline as a white foamy solid.
Reaction SMILES: Cl.[CH:2](=[C:9]1[C:14](=O)[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][N:11]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:31][C:32]([F:37])([F:36])[CH2:33][NH:34][NH2:35]>CO>[C:3]1([CH:2]2[CH:9]3[CH2:10][N:11]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:12][C:13](=[CH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]3=[N:35][N:34]2[CH2:33][C:32]([F:37])([F:36])[F:31])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NNCC(F)(F)F
Reactant: O=C1C(=Cc2ccccc2)CN(CCc2ccccc2)CC1=Cc1ccccc1
Agent: Cl
Solvent: CO
Product: FC(F)(F)CN1N=C2C(=Cc3ccccc3)CN(CCc3ccccc3)CC2C1c1ccccc1
Yield: 114.6 %

Procedure:
Ten grams of 3,5-dibenzylidene-1-(2-phenylethyl)-4-piperidone monohydrochloride and 4.4 g of 70% aqueous 2,2,2-trifluoroethylhydrazine are reacted in 150 ml of methanol at reflux for 4 hours. The solvent is removed on a rotary evaporator leaving 13.1 g of brittle residue. The material is converted to 10.7 g of free base using potassium carbonate and ether extractions. The free base is dissolved in 50 ml of warm isopropyl ether and diluted with 20 ml of hexane. After the solution is cooled to room temperature, seeded and rubbed, the crystalline base gradually separates. After cooling overnight, the solid is filtered, washed with cold 5:2 isopropyl ether-hexane and dried to yield 3.6 g of product, melting point 113°-114° C, sintering at 105° C.
Reaction SMILES: [Br:1][CH:2]([C:4]1([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[C:21]=3[Br:25])[CH:16]=2)O[C@@H](C(O)=O)[C@H](C(O)=O)[O:5]1)[CH3:3].S(=O)(=O)(O)O>>[Br:1][CH:2]([CH3:3])[C:4]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[C:21]=2[Br:25])[CH:16]=1)=[O:5]
Reactant: COc1ccc2cc(C3(C(C)Br)O[C@@H](C(=O)O)[C@H](C(=O)O)O3)ccc2c1Br
Agent: O=S(=O)(O)O
Product: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Br
Reaction time: 0.33 h
Yield: 43 %

Procedure:
A mixture of diastereoisomers of 2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-4(R),5(R)-dicarboxy-1,3-dioxolane (RRS:RRR=93:7; 2.52 g; 5 mmoles) and 96% sulphuric acid (15 ml) is kept at 20° C. for 20 minutes. The reaction mixture is processed as described in Example 1. In this manner, pure 2-bromo-1-(5-bromo-6-methoxy-2-naphthyl)-propan-1-one is obtained (0.8 g; 2.15 mmoles; yield 43%).
Reaction SMILES: [CH:1]([N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[N:15]=[N:16][N:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:18]=3[CH3:19])[CH:10]=2)[C:5]1=[O:26])([CH3:3])[CH3:2].[H][H]>[C].[Pd].C(O)C>[CH:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[N:15]=[N:16][N:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:18]=3[CH3:19])[CH:10]=2)[C:5]1=[O:26])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: Cc1c(-c2ccc3c(=O)n(C(C)C)ccc3c2)nnn1-c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(-c2ccc3c(c2)CCN(C(C)C)C3=O)nnn1-c1cccnc1
Yield: 91.5 %

Procedure:
After adding 50 mg of palladium carbon to 10 ml solution of ethanol with 25 mg of 4-(2-isopropyl-1-oxo-isoquinoline-6-yl)-1-(pyridine-3-yl)-5-methyl-1H-[1,2,3]triazole, hydrogen was added under 4 atm of hydrogen pressure. 8 hours later, the reaction solution was filtrated, the solvents of the filtrate were distilled outunder reduced pressure, and the residues were separated and purified by thin-layer chromatography (chloroform/methanol=10/1) to obtain 23 mg of the above compound as a white solid.
Reaction SMILES: [Li+].[OH-].C([O:6][C@@H:7]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][C@H:26]([OH:33])[C@@:25]2([CH3:34])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[CH2:8]1)(=O)C>O.C1COCC1.CO>[CH3:24][C@@H:17]([C@@H:16]1[C@@:25]2([CH3:34])[C@@H:26]([OH:33])[CH2:27][C@@H:28]3[C@@:29]4([CH3:32])[CH2:30][CH2:31][C@@H:7]([OH:6])[CH2:8][C@H:9]4[CH2:10][CH2:11][C@H:12]3[C@@H:13]2[CH2:14][CH2:15]1)[CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 91.8 %

Procedure:
A solution of LiOH (187 mg, 4.4 mmol) in H2O (2.0 mL) was added to a solution of compound 2.1a (500 mg, 1.11 mmol) in THF (8 mL) and MeOH (8 mL). The resulting mixture was stirred for 3-4 h at 50° C. Upon complete disappearance of the starting material by TLC, the reaction mixture was concentrated under vacuum. A mixture of water (10 mL) and 3 N HCl (1 mL) were combined and cooled to 0° C. and then added to the crude product. After stirring for 1 h at 0° C., the precipitated solids were filtered and then washed with water (10 mL) and hexane (20 mL). Drying under vacuum at room temperature provided deoxycholic acid (DCA, 400 mg, 91% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=O)[O:17]C3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:15][C:16]([NH:45][S:42]([C:39]3[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][CH:40]=3)(=[O:43])=[O:44])=[O:17])=[CH:11][CH:12]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: Nc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-amino-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 4 of Example 80) and 4-chlorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.85-7.80 (2H, m), 7.51-7.27 (11H, m), 6.08-6.03 (1H, m), 3.99 (2H, br.s), 3.50-3.44 (2H, m), 2.88-2.84 (2H, m).
Reaction SMILES: Br.Br.[C:3]1([CH3:21])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:3]1([CH3:21])[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][N:15]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][CH2:17][N:18]([CH2:21][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:19][CH2:20]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCNCCNCC2)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)N2CCN(Cc3ccccc3)CCN(Cc3ccccc3)CC2)cc1

Procedure:
From N-(p-toluenesulfonyl-1,4,7-triazacyclononane (1.3.13.31), sodium hydride and benzyl bromide.