Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[N+:5]([O-])=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)c(F)c[n+]1[O-]
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1cc(Cl)c(F)cn1
Reaction time: 0.17 h
Yield: 142.1 %

Procedure:
4-Chloro-5-fluoro-2-picoline-N-oxide (12.43 g, 76.93 mmol), from Step 7, was dissolved in 52 mL of glacial acetic acid in a 3-necked flask equiped with a mechanical stirrer, a condenser and a thermometer. Iron powder (6.45 g, 115.5 mmol) was added to the solution at ambient temperature and the reaction mixture was carefully heated to 35°-40° C. After 10 min at 30° C., an exothermic reaction took place which caused the reaction temperature to rise to 120° C. and the reaction mixture became a very dark brown-colored solution. The flask was transferred to a cold water bath and the temperature of the solution brought down to ambient. The reaction mixture was then poured over ice. The resultant aqueous mixture was adjusted to pH 9 with potassium carbonate and steam distilled. The aqueous distillate collected at 92°-96° C. was extracted with three portions of methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and distilled to afford 15.91 g (71% yield) of the title compound, b.p. 138°-140° C.; MS GC-MS M/Z:146 (M+H)+ ; 1H NMR (CDCl3) d 2.53 (s, 3H), 7.23 (d, 1H, J=6.0 Hz), 8.37 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[CH:27]=1)(=[O:25])=[O:24])(=[O:14])=[O:13].[CH3:35][O-:36].[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:35][O:36][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[CH:27]=1)(=[O:25])=[O:24])(=[O:14])=[O:13]
Reactant: C[O-]
Reactant: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)ccc1Cl)c1cc2ccccc2s1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid [2-(2-chloro-5-trifluoromethylbenzenesulfonylamino)phenyl]-amide (0.5 mmol) in dioxane (5 mL), solid sodium methoxide (2 mmol) was added in one portion and the resulting reaction mixture was then heated to reflux for ca. 4 h. After the completion of the reaction, the reaction mixture was cooled to RT and concentrated in vacuo. The residue obtained was redissolved in EtOAc (10 mL) and was washed with water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 204 mg of benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-5-trifluoromethyl-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.20 min; MS: 544.1 (M+1)+.
Reaction SMILES: C([O:5][C:6]([C@:8]1([NH:28]C(OC(C)(C)C)=O)[CH2:13][C@@H:12]([S:14][C:15]2[NH:19][C:18]([CH3:20])=[N:17][N:16]=2)[C@@H:11]2[C@H:9]1[C@H:10]2[C:21]([O:23]C(C)(C)C)=[O:22])=[O:7])(C)(C)C>O>[NH2:28][C@@:8]1([C:6]([OH:7])=[O:5])[CH2:13][C@@H:12]([S:14][C:15]2[NH:19][C:18]([CH3:20])=[N:17][N:16]=2)[C@@H:11]2[C@H:9]1[C@H:10]2[C:21]([OH:23])=[O:22]
Reactant: Cc1nnc(S[C@@H]2C[C@@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]3[C@@H](C(=O)OC(C)(C)C)[C@@H]32)[nH]1
Solvent: O
Product: Cc1nnc(S[C@@H]2C[C@@](N)(C(=O)O)[C@@H]3[C@@H](C(=O)O)[C@@H]32)[nH]1
Temperature: 160 °C
Yield: 80.8 %

Procedure:
Dissolve ditert-butyl(1R,2S,4R,5R,6R)-2-(tert-butoxycarbonylamino)-4-[(5-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]bicyclo[3.1.0]hexane-2,6-dicarboxylate (85 mg, 0.166 mmol) acetic acid (1 mL) and water (1 mL). Heat the mixture to 160° C. at approximately 40 Watts in a BIOTAGE® Initiator microwave for 6 minutes. Concentrate reaction mixture under reduced pressure. Add water and remove under reduced pressure twice to remove excess acetic acid to give the title compound as a white solid (40 mg, 88.6%). MS (m/z): 299 (M+1).
Reaction SMILES: C1(S([CH:10]2[CH2:16][C:15]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:17]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:11]2[CH2:12][CH2:13][CH:14]3[NH:31]OC)(=O)=O)C=CC=CC=1.[Na]>C1COCC1>[CH2:18]([N:17]1[CH:11]2[CH2:10][CH2:16][C:15]1([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:14]([NH2:31])[CH2:13][CH2:12]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CONC1CCC2C(S(=O)(=O)c3ccccc3)CC1(c1ccccc1)N2Cc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: NC1CCC2CCC1(c1ccccc1)N2Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A flame dried 3/N round bottom flask equipped with an NH3 (g) inlet, dry ice condenser and magnetic stir bar was cooled to −78° C. and ammonia gas was introduced. A solution of 464 mg (1.0 mmol) of the N-(6-Benzenesulfonyl-8-benzyl-1-phenyl-8-aza-bicyclo[3.2.1]oct-2-yl)-O-methyl-hydroxylamine in 10 ml of THF was added followed by 323 mg (14.05 mmol) sodium metal portionwise. A deep blue color was evident and the reaction mixture was stirred at −78° C. for 30 min. The reaction was quenched by the addition of solid ammonium chloride and the ammonia was allowed to evaporate. The residue was taken up in water and methylene chloride. The aqueous phase was washed once again with methylene chloride. The combined organic layers were washed with brine, dried of sodium sulfate and evaporated in vacuo. There was obtained 203 mg (68%) of a clear oil. Enantiomeric separation was completed on a 5 cm×50 cm Chirlpak AS column eluting at 25 ml/min with 93/7 hexane/ethanol containing 0.025% diethyl amine. The retention times were 4.6 minutes and 6.6 minutes respectively. 1H NMR (CDCl3, 400 MHz) δ 7.49–7.41 (m, 2H), 7.37–7.27 (br.m., 5H), 7.24–7.18 (br.m., 3H), 3.97 (d, 1H, J=15 Hz), 3.26–3.24 (br.s., 1H), 2.97 (d, 1H, J=15 Hz), 2.54–2.53 (br.s., 1H), 2.40 (br.s., 2H), 2.33–2.15 (br.m., 3H), 2.03–1.86 (br.m., 2H), 1.72–1.64 (br.m., 2H), 1.33–1.28 (br.m., 1H) ppm. Mass spectrum APCI m/z 293 (p+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=1)[C:16]#[N:17])#[CH:10]>>[OH:8][C:4]1[CH:3]=[C:2]([C:10]#[C:9][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(I)c1
Reactant: C#Cc1cncc(C#N)c1
Product: N#Cc1cncc(C#Cc2cccc(O)c2)c1
Yield: 16.6 %

Procedure:
Prepare essentially as described in EXAMPLE 10 using 3-iodophenol (0.69 g, 3.0 mmol) and 5-ethynylnicotinonitrile (0.4 g, 3.0 mmol) to give the title compound (110 mg, 17%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:4]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:55]([N:62]([CH3:66])[CH2:63][CH2:64][NH2:65])([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]>C(Cl)Cl>[CH3:66][N:62]([CH2:63][CH2:64][NH:65][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:5]2[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=2)=[CH:16][CH:15]=1)[C:55](=[O:56])[O:57][C:58]([CH3:61])([CH3:59])[CH3:60]
Reactant: O=C(O)c1ccc(-c2noc(C(F)(F)F)n2)cc1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCNC(=O)c1ccc(-c2noc(C(F)(F)F)n2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a suspension of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (1 g, 3.87 mmol) in DCM (10 ml) was added COMU (1.825 g, 4.26 mmol) and DIPEA (0.812 ml, 4.65 mmol). The yellow solution was stirred for 2 min at rt and turned red. N-Boc-N-methyl-ethylenediamine (0.810 g, 4.65 mmol) was added and the reaction mixture was stirred at reflux for 1 hr, allowed to cool to rt and washed with water, saturated aqueous NH4Cl, and extracted with EtOAc. The organic layer was dried over Na2SO4 and the solvent was removed in vacuum. The final product was purified according to Method B in Examples 124-156 general method.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:53][OH:54])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:53][OH:54])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:51])([F:50])[F:52])=[CH:43][CH:42]=1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Reaction time: 2 h
Yield: 61.1 %

Procedure:
[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 7m (20 mg, 0.03 mmol) was dissolved in 10 mL of mixed solution (THF and MeOH, v:v=1:1), followed by addition of o-dichlorobenzene (31 μL, 0.27 mmol) and Palladium/carbon (20 mg, 10%) in turn. The mixture was exchanged with H2 three times and was stirred for 2 hours. Thereafter, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound (1S,2S,3S,4R,5S)-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 7 (9 mg, white solid), yield: 69.2%. MS m/z (ESI): 491.1 [M+1]; 1H NMR (400 MHz, CD3OD): δ 7.48 (m, 1H), 7.40-7.38 (m, 2H), 7.18-7.16 (d, 2H), 6.93-6.91 (d, 2H), 4.51-4.45 (q, 2H), 4.17-4.15 (d, 1H), 4.08 (s, 2H), 3.81-3.78 (d, 1H), 3.78-3.71 (d, 1H), 3.69-3.67 (m, 2H), 3.62-3.57 (m, 2H).
Reaction SMILES: FC(F)(F)C1C=CC=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[F:36].[F:37][C:38]([F:51])([F:50])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([N:47]=[C:48]=[S:49])=[O:46]>C1(C)C=CC=CC=1.C(O)C>[F:50][C:38]([F:37])([F:51])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([N:47]=[C:48]=[S:49])=[O:46].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:48]([NH:47][C:45](=[O:46])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:38]([F:37])([F:51])[F:50])=[S:49])=[CH:31][C:30]=1[F:36]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C(N=C=S)c1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C(F)(F)F)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
2-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (63 mg, yield 73%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:35][N:36]([CH3:40])[C:37]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])=[O:38]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 99.8 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0806 g, 0.175 mmol) was dissolved in dichloromethane (2.0 mL), and the solution was treated with 4-dimethylaminopyridine (0.0850 g, 0.699 mmol) and dimethylcarbamoyl chloride (0.0640 mL, 0.699 mmol) to obtain 4-dimethylcarbamoyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0930 g, yield 99%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]1([O:23][CH3:24])[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]1.[CH:25](=[O:27])[CH3:26]>C1COCC1.O>[OH:27][CH:25]([C:17]1([C:19]([O:21][CH3:22])=[O:20])[CH2:16][C:15]([O:14][CH3:13])([O:23][CH3:24])[CH2:18]1)[CH3:26]
Reactant: CC=O
Reactant: COC(=O)C1CC(OC)(OC)C1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(C)O)CC(OC)(OC)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
To a solution of diisopropylamine (3.2 mL, 22.67 mmol) in THF (45 mL) was added n-BuLi (2.69 M in hexane, 7.7 mL, 20.71 mmol) at −78° C. under argon. The mixture was stirred for 10 minutes at 0° C., then cooled to −78° C. and added a solution of methyl 3,3-dimethoxycyclobutanecarboxylate (3.0 g, 17.22 mmol) in THF (10 mL). The mixture was stirred for 30 minutes at −78° C., then added a solution of acetaldehyde (1.9 mL, 33.86 mmol) in THF (10 mL). The mixture was stirred for 30 minutes at −78° C., and water was added. The aqueous layer was extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to give methyl 1-(1-hydroxyethyl)-3,3-dimethoxycyclobutanecarboxylate (3.33 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[C:13]([C:17]2[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)[CH:14]=[CH:15][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=2)[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[O:51]=[C:50]([N:52]1[CH2:53][CH2:54][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:66])[F:67])[CH:60]=2)[CH2:56][CH2:57]1)[CH2:49][NH:48][C:22]([C:19]1[CH:18]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([OH:10])[CH:12]=2)[NH:21][N:20]=1)=[O:24]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cc(-c2cccc(O)c2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2cccc(O)c2)[nH]n1
Reaction time: 8 h
Yield: 51.7 %

Procedure:
DIPEA (133 mg, 1.03 mmol) was added to a stirred solution of 5-(3-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid (60 mg, 0.294 mmol) (prepared from 5-(3-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester) in DMF (2 mL) followed by HOBt (41.7 mg, 0.308 mmol) and EDCI.HCl (59 mg, 0.308 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (99 mg, 0.294 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. Washing with ethyl acetate afforded 74 mg (51.7% Yield) of 5-(3-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 489, 96%. 1H NMR (300 MHz, DMSO-d6): δ13.6 (s, 1H), 9.6 (s, 1H), 8.0 (t, 1H), 7.5 (t, 1H), 7.1 (m, 7H), 6.9 (d, 1H), 6.8 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:16]([N:8]([CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC(C)Nc1ccccc1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(C)N(CCCC)c1ccccc1
Yield: 44 %

Procedure:
A mixture of N-(1-methylhexyl)aniline (76 parts), 1-bromobutane (66 parts), anhydrous potassium carbonate (65 parts) and DMF (150 parts) was stirred while heating under reflux for 41 hours. An additional quantity of 1-bromobutane (44 parts) was added and the mixture stirred while heating under reflux for a further 19 hours. The cooled mixture was poured into water (400 parts) and the organic phase separated. The aqueous phase was extracted with toluene, the organic phases and toluene extract were combined and washed with water (2×100 parts) before evaporating to leave N-butyl-N-(1-methylhexyl)aniline (72.8 parts, 44%) which was purified by vacuum distillation to give N-butyl-N-(1-methylhexyl)aniline b.pt 73°-80° C., 2.6 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH:10]1[C:19]2[C:14](=[C:15]([CH:20]([CH2:24][CH3:25])[C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:21](=[O:22])[CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH:13]=[CH:12][N:11]=[CH:10]3)[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(Br)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CCC(C(=O)NCc1ccc(Br)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-bromobenzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 385, 383 (M+H)+; MS (ESI−) m/z 383, 381 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 0.91 (t, J 7.5, 3H), 1.81 (m, 1H), 2.19 (m, 1H), 3.39 (m, 1H), 4.22 (m, 2H), 7.13 (d, J 8.5, 2H), 7.44 (m, 3H), 7.57 (t, J 7.8, 1H), 8.00 (m, 1H), 8.21 (d, J 7.1, 1H), 8.41 (d, J 8.1, 1H), 8.72 (s, 1H), 8.93 (t, J 6.8, 1H), 9.81 (s, 1H), 10.16 (br s, 1H); Anal. Calcd for C20H19BrN2O: C, 62.67; H, 5.00. Found: C, 62.52; H, 4.95.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[C:3]=1[N+:22]([O-])=O>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][CH:16]=2)[C:3]=1[NH2:22]
Reactant: CC(C)(C)Cc1ccc(CCc2cc(F)cc(F)c2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)Cc1ccc(CCc2cc(F)cc(F)c2N)cc1
Reaction time: 3.5 h
Yield: 80.6 %

Procedure:
10% Pd/C (600 mg) was added under nitrogen to a stirred solution of the product from step (c) (10.9 g) in ethanol (150 ml) and the mixture hydrogenated at room temperature at a pressure of 1 atm. H2 for 3.5 hours (uptake 2300 ml). The mixture was filtered, the residue washed with ethanol, and the filtrate evaporated under reduced pressure to give an oil which crystallised on standing to give 8.0 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:6](C#N)=[C:5]([S:9][CH3:10])[N:4]([CH3:11])[N:3]=1.[OH-].[Na+].P([O-])(O)(O)=O.[Na+]>>[NH2:1][C:2]1[CH:6]=[C:5]([S:9][CH3:10])[N:4]([CH3:11])[N:3]=1
Reactant: CSc1c(C#N)c(N)nn1C
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Product: CSc1cc(N)nn1C
Temperature: 50 °C

Procedure:
5.55 g (33.0 mmol) of 3-amino-4-cyano-1-methyl-5-methylmercaptopyrazole are heated to the boil with 50 ml of 32% strength aqueous sodium hydroxide solution for 24 hours. The reaction mixture is cooled, made slightly acidic with sodium dihydrogen phosphate solution, heated at 50° C. for 8 hours and subsequently extracted with ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and purified by column chromatography (silica gel, hexane/ethyl acetate).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].CCCCCCC.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1>>[CH3:1][CH:2]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[CH:3]=[CH2:4]
Reactant: Cc1ccc(C)cc1
Reactant: C=CC=C
Solvent: CCCCCCC
Product: C=CC(C)Cc1ccc(C)cc1
Temperature: 170 °C
Yield: 8 %

Procedure:
7 g of this catalyst was packed into a quartz reaction tube having an inside diameter of 15 mm in a current of argon. The reaction temperature was maintained at 170°C., and a gaseous mixture consisting of p-xylene, butadiene, n-heptane as a diluent, and nitrogen gas in a molar ratio of 1:5:10:5 was passed through the catalyst layer. The contact time of p-xylene was 24 seconds. The conversion of p-xylene was 43%, and the intended 3-methyl-4-(p-tolyl) butene was obtained in a yield of 8%.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:25][C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:35]([F:38])([F:37])[F:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][O:40][C:41](=[O:44])[CH2:42][NH2:43].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(#N)C.O>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]([NH:43][CH2:42][C:41]([O:40][CH3:39])=[O:44])=[O:31])=[CH:33][CH:34]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:35]([F:38])([F:36])[F:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN
Reactant: O=C(O)c1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COC(=O)CNC(=O)c1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 4-{[3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamino]-methyl}-benzoic acid (130 mg, 0.254 nmol), glycine methyl ester (35 mg, 0.279 mmol) morpholine (102 mg, 1.014 mmol), EDCI (58 mg, 0.304 mmol), and HOBT (41 mg, 0.304 mmol) in CH2Cl2 (15 ml) were combined at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 15 hrs. Quenching with brine (15 ml), separation, drying MgSO4 of the organics and concentration in vacuo. RP-HPLC (gradient water:acetonitrile) afforded the ester as an off white powder (88 mg, 61% Yield). MS (ESI) m/z 582.