Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:7])[CH3:2].C(O)(=O)C.[N:20]([O-])=[O:21].[Na+]>O>[CH2:1]([O:3][C:4](=[O:15])[C:5](=[N:20][OH:21])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cccc(F)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-(3-fluoro-phenyl)-3-oxo-propionic acid ethyl ester (4.85 mmol) in acetic acid (1.90 mmol) is cooled to 10° C. and a solution of sodium nitrite (5.63 mmol) in water (0.68 mL) is added dropwise. The mixture is allowed to reach RT, stirred for 2 h, poured into water (10 mL) and cooled to 0° C. The precipitate is filtered off and dried by azeotropic removal of water with toluene to give crude 3-(3-fluoro-phenyl)-2-hydroxyimino-3-oxo-propionic acid ethyl ester which is dissolved in a mixture of acetic anhydride (1.38 mL) and acetic acid (1.80 mL). Sodium acetate (0.30 mmol), HgCl2 (0.01 mmol) and zinc powder (14.6 mmol) are added successively. The mixture is stirred under reflux for 1 h, cooled to RT and filtered and the residue is washed with ether. The filtrate is washed three times with water and once with aq. K2CO3 solution (1.0 M). The organic layer is dried over MgSO4 and concentrated in vacuo to give the desired crude product which is purified by FC (heptane to heptane/EtOAc 3/7). LC-MS: tR=0.82 min; [M+H]+=268.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31]C1C=C(F)C=CC=1C[Mg]Br>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:31])=[CH:20][C:21]=2[F:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: Fc1ccc(C[Mg]Br)c(F)c1
Product: OC(Cc1ccc(F)cc1F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 18a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2,4-difluorobenzyl magnesium bromide as starting material (available from Rieke Metals) was followed making non-critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+=410 @ Rt 3.19 min. major peak.
Reaction SMILES: [C:1]1([N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N(C2C=CC=CC=2)/[C:28](/[C:36]2[CH:41]=[CH:40]C=CC=2)=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C=CC=CC=1>C(OCC)(=O)C.CO>[C:15]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:40][C:41]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]=[CH:28][CH:36]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Reactant: C(=C(\c1ccccc1)N(c1ccccc1)c1ccccc1)\c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: C(=C(c1ccccc1)N(c1ccccc1)c1ccccc1)c1cccc2ccccc12

Procedure:
This compound was synthesized from diphenylbenzylamine and N-phenyl-1-naphthaldimine under the same conditions outlined for (E)-1-(diphenylamino)-1-phenyl-2-phenylethylene above. Recrystallizatiom from ethyl acetate/methanol gave small crystals mp 170-2° C. 1H NMR (200 MHz, CDCl3) δ (assignment): 6.60-6.90 (m, 2 H, aromatic), 6.80-7.38 (m, 15 H, aromatic), 7.52-7.85 (m, 6 H, aromatic). MS [m/e (70 eV, % of base peak] C10H7CHCPhNPh2 397 (M+., 43.1), 180 (PhCNPh+, 100), 77 (Ph+, 43.2); HRMS (m/z) for C30H23N (M+.), calcd. 397.183 found 397.195.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][N:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:25]4[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]4=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Reactant: Oc1ccnc(O)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccc(O)cc3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 9.4 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (66 mg, 0.15 mmol), 2,4-dihydroxypyridine (45 mg, 0.41 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the titled compound (6 mg). MS 427.0 and 429.0 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][C:10]=1[O:16][CH3:17])([CH3:8])[CH3:7].[CH2:24](C([Sn])=C(CCCC)CCCC)[CH2:25]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3](=[O:23])[C:4]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:24]=[CH2:25])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:8])[CH3:7]
Reactant: COC(=O)C(O)(CC(C)(C)c1ccc(I)cc1OC)C(F)(F)F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C)(C)CC(O)(C(=O)OC)C(F)(F)F)c(OC)c1
Yield: 43.7 %

Procedure:
1 g of 2-hydroxy-4-(4-iodo-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid methyl ester, 860 mg of tributylvinyl tin, 103 mg of palladium-dibenzylidene acetone complex and 30 mg of triphenylphosphine in 17 ml of THF are refluxed under argon atmosphere for 57 hours. It is filtered through diatomaceous earth and completely concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->2%), 339 mg of 2-hydroxy-4-(2-methoxy-4-vinylphenyl)-4-methyl-2-trifluoromethylvaleric acid methyl ester is obtained. The latter is stirred with 56 mg of lithium aluminum hydride in 11 ml of diethyl ether at room temperature for 10 hours. It is added to saturated bicarbonate solution, filtered through diatomaceous earth and extracted with ethyl acetate. The organic phase is washed with bicarbonate solution and brine, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->10%), 148 mg of 2-hydroxy-4-(2-methoxy-4-vinylphenyl)-4-methyl-2-trifluoro-methylpentanol is obtained. The latter is hydrogenated in 4.3 ml of ethyl acetate with 14 mg of palladium on activated carbon under normal pressure with hydrogen. The batch is filtered through diatomaceous earth and completely concentrated by evaporation. 127 mg of 4-(4-ethyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanol is obtained. The diol that is obtained is reacted with 0.29 ml of triethylamine and 280 mg of sulfur trioxide-pyridine complex in 1.3 ml of DMSO at room temperature in 10 hours of reaction time. It is added to saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0->3%), 94 mg of the title compound is obtained as a colorless oil.
Reaction SMILES: C(NC(C1SC(NC(N(CC(OC)OC)CC2C=CC(F)=CC=2)=O)=NC=1C)=O)C1C=CC=CC=1.CO[CH:37]([O:70]C)[CH2:38][N:39]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][CH:61]=1)[C:40](=[O:58])[NH:41][C:42]1[S:43][C:44]([C:48]([NH:50][CH2:51][C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[O:49])=[C:45]([CH3:47])[N:46]=1>>[OH:70][CH:37]1[N:41]([C:42]2[S:43][C:44]([C:48]([NH:50][CH2:51][C:52]3[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=3)=[O:49])=[C:45]([CH3:47])[N:46]=2)[C:40](=[O:58])[N:39]([CH2:59][C:60]2[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][CH:61]=2)[CH2:38]1
Reactant: COC(CN(Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1nc(C)c(C(=O)NCc2cccnc2)s1)OC
Agent: COC(CN(Cc1ccc(F)cc1)C(=O)Nc1nc(C)c(C(=O)NCc2ccccc2)s1)OC
Product: Cc1nc(N2C(=O)N(Cc3ccc(C(F)(F)F)cc3)CC2O)sc1C(=O)NCc1cccnc1
Yield: 98 %

Procedure:
Following the procedure as described in Example 16, making variations as required to replace N-benzyl-2-(3-(2,2-dimethoxyethyl)-3-(4-fluorobenzyl)ureido)-4-methylthiazole-5-carboxamide with 2-(3-(2,2-dimethoxyethyl)-3-(4-(trifluoromethyl)-benzyl)ureido)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 98% yield: mp 171-172° C. (ethyl acetate/hexanes): 1H NMR (300 MHz, CDCl3) δ 8.45-8.42 (m, 2H), 7.69-7.62 (m, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 7.27-7.22 (m, 1H), 6.08-6.05 (m, 1H), 4.56-4.37 (m, 4H), 3.65-6.59 (m, 1H), 3.33-3.25 (m, 1H), 2.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 157.1, 154.0, 153.1, 148.4, 139.4, 135.8, 135.0, 134.2, 130.1, 128.6, 125.9, 123.7, 121.8, 117.5, 50.2, 46.9, 41.4, 17.2; MS (ES+) m/z 492.2 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.S([O-])([O-])(=O)=O.[Mg+2].Cl.[CH2:18](Cl)[Cl:19]>>[CH2:1]([O:8][CH2:18][Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: ClCCl
Agent: C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Product: ClCOCc1ccccc1
Reaction time: 0.17 h

Procedure:
A mixture of 216.28 g. of benzyl alcohol, 61.44 g. of paraformaldehyde, 481.6 g. of anhydrous magnesium sulfate and 1200 ml. of methylene chloride is cooled to a temperature of between -50° to -55°C in a dry ice-acetonitrile bath, and the stirred cold solution is saturated with anhydrous hydrogen chloride gas. The reaction mixture is kept at -50° to -55°C for 10 minutes further, and then excess of hydrogen chloride is eliminated by passing a stream of nitrogen during 30 minutes. The reaction mixture is filtered and the solid material washed well with pentane, and the combined filtrates are evaporated to dryness at a temperature below 30°C, to produce an oil which is distilled under reduced pressure to yield chloromethyl benzyl ether.
Reaction SMILES: O.FC1C=CC(C2NN=C(C(N3CCNCC3)=O)C=2C2C=CN=CC=2)=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[NH:39][N:38]=[C:37]([CH2:40][CH:41]3[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]3)[C:36]=2[C:54]2[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:36]([C:54]3[CH:55]=[CH:56][N:57]=[CH:58][CH:59]=3)=[C:37]([CH2:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[NH:38][N:39]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2n[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Agent: O=C(c1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)N1CCNCC1
Solvent: O
Product: Fc1ccc(-c2n[nH]c(CC3CCNCC3)c2-c2ccncc2)cc1

Procedure:
4-[3-(4-Fluorophenyl)-5-(4-piperidinylmethyl)-1H-pyrazol-4-yl]pyridine was prepared using the same method as described for Example A-314, step 1 by replacing 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine, monohydrate with the pyrazole of step 5 of the present Example. Anal. Calc'd for C20H21N4F.2TFA.1.25H2O: C, 49.11; H, 4.38; N. 9.54; Found: C, 48.74; H, 4.02; N, 9.57. MS (MH+): 337 (base peak).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]2[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:9]=[CH:8][C:7]1=2)(=[O:4])=[O:3].[H-].[Na+].I[CH3:25]>CN(C=O)C>[CH3:1][S:2]([N:5]([CH3:25])[CH:6]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]2[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:9]=[CH:8][C:7]1=2)(=[O:4])=[O:3]
Reactant: COC(=O)c1cccc2c1CC(C)(C)CC2NS(C)(=O)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1CC(C)(C)CC2N(C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 0.5 g (1.6 mmol) of methyl 5-methanesulfonylamino-7,7-dimethyl-5,6,7,8-tetrahydro-1-naphthalenecarboxylate in 5 ml of DMF was added dropwise to a suspension of 0.05 g (1.8 mmol) of 80 percent sodium hydride in 4 ml of DMF. After stirring at room temperature for 1 hr., 0.23 g (1.6 mmol) of iodomethane was added and the mixture was stirred at room temperature for 4 h. The reaction mixture was completely concentrated in vacuo and the residue was then taken up in EA and water and the organic phase was washed with dilute hydrochloric acid and sodium bicarbonate solution. After drying over magnesium sulfate and concentrating in vacuo; 0.5 g of methyl 5-(methanesulfonyl-methyl-amino)-7,7-dimethyl-5,6,7,8-tetrahydronaphthalene-1-carboxylate was obtained; m.p. 98-99° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cnn(C)c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1-c1cnn(C)c1
Yield: 100.3 %

Procedure:
A mixture of 4-(2-methoxy-4-nitro-phenyl)-1-methyl-1H-pyrazole (240 mg, 1.03 mmol) and palladium on carbon 10% (55 mg, 0.052 mmol) in methanol (15 mL) was stirred for 2 hours at under hydrogen atmosphere. The mixture was filtrated and the solvent evaporated to afford the title compound (210 mg, 100%) as a white solid. MS ISP (m/e): 204.3.0 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.76 (s, 1H), 7.70 (s, 1H), 7.28 (d, 1H), 6.32 (d, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.68 (s broad, 2H). Mp 129-131° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: BrCc1ccccc1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(Cc2ccccc2Cc2ccccc2)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2,6-Difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(45 mg, 0.202 mmol), potassium carbonate (42 mg, 0.304 mmol) and 1-(bromomethyl)-2-(phenylmethyl)benzene (for a preparation see Intermediate 3)(64 mg, 0.245 mmol) were weighed into a vial with a stirrer. DMF (1 ml) was added, the vial was capped and the mixture was stirred at room temperature for 17 h. The reaction mixture was filtered, washing with MeOH to give a total volume of 2 ml. This solution was purified by MDAP (Sunfire column, formic acid buffer) (Method B). The solvent was removed to give the title compound as a colourless solid (10 mg); LCMS: (System 4) MH+=404, tRET=3.23 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:19][C:20]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH:17][C:22]([C:21]2[C:20]([CH3:19])=[N:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:23])[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Product: CCOC(=O)C(C)(C)Oc1cccc(CCNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 55C]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[3-(2-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently-saponified to yield the title compound as colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:22][C:23]#[N:24])[CH2:16][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:14]3)[CH:12]=2)[N:5]2[CH:25]=[CH:26][N:27]=[C:4]2[CH:3]=1.[CH2:28]([N:30]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31]1)[CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>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].O1CCOCC1>[CH2:28]([N:30]1[CH:34]=[C:33]([C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]([C:13]4([CH2:22][C:23]#[N:24])[CH2:14][N:15]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:16]4)[CH:12]=3)[N:5]3[CH:25]=[CH:26][N:27]=[C:4]3[CH:3]=2)[CH:32]=[N:31]1)[CH3:29]
Reactant: CCn1cc(B(O)O)cn1
Reactant: N#CCC1(n2cc(-c3nc(Cl)cc4nccn34)cn2)CN(CC(F)(F)F)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)(F)F)C4)c3)n2)cn1
Temperature: 80 °C
Yield: 81.6 %

Procedure:
In a flask containing 2-(3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile (0.015 g, 0.038 mmol), 1-ethyl-1H-pyrazol-4-ylboronic acid (0.0080 g, 0.057 mmol), and K3PO4 (0.057 mL, 0.11 mmol) was added 1 mL of dioxane and argon was bubbled through for 10 minutes before dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.0036 g, 0.0076 mmol) and tris(dibenzylideneacetone)dipalladium (0.0035 g, 0.0038 mmol) were added and the reaction was then sealed and heated to 80° C. for 6 hours. The reaction mixture was loaded directly onto a silica gel column and eluted with EtOAc containing 0.5% NH4OH to afford the title compound (0.015 g, 0.031 mmol, 83% yield). MS (apci) m/z=456.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:3]=1[C:24]([OH:26])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:60]1([CH:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)[CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:16])([F:15])[F:17])[CH:8]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:3]=1[C:24]([N:68]1[CH2:69][CH2:70][CH:65]([N:60]2[CH2:64][CH2:63][CH2:62][CH2:61]2)[CH2:66][CH2:67]1)=[O:26]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1c(C(=O)O)c(-c2ccncc2)nn1-c1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)c(-c2ccncc2)nn1-c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
5-Methyl-3-pyridin-4-yl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid (76 mg, 0.21 mmol) in 2.5 ml DMF was treated with iPr2NEt (0.11 ml, 0.63 mmol) and HATU (79 mg, 0.21 mmol), then after 20 min a solution of 4-(1-pyrrolidinyl)piperidine (32 mg, 0.21 mmol) in 1.5 ml DMF was added. The reaction mixture was stirred 0.5 h at room temperature, diluted with EtOAc and washed with three portions of saturated solution of NaHCO3 and brine. The aqueous phases were extracted with EtOAc the combined organic layers were dried over magnesium sulfate and evaporated. A column chromatography (amino-phase silica gel, EtOAc:MeOH, 19:1) afforded the title compound as a foam (74 mg, 71%). MS: 500.0 (MH+).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[Hg]Cl)(=[O:3])[CH3:2].[Cl:12][C:13](=[CH2:16])[C:14]#[N:15].[BH4-].[Na+]>C(O)C>[C:1]([NH:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:16][CH:13]([Cl:12])[C:14]#[N:15])(=[O:3])[CH3:2]
Reactant: C=C(Cl)C#N
Reactant: CC(=O)N[C@@H]1CCC[C@H]1[Hg]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N[C@@H]1CCC[C@H]1CC(Cl)C#N
Reaction time: 1 h

Procedure:
16.1 g of trans-1-acetamido-2-chloromercuriocyclopentane are suspended in 200 ml of ethanol. 10.7 ml of 2-chloroacrylonitrile are added, followed by 1.7 g of sodium borohydride in 40 ml of ethanol as rapidly as possible while cooling in ice. After 1 hour at room temperature, the mixture is filtered with suction through kieselguhr, the filtrate is evaporated, the residue is taken up with methylene chloride, this solution is washed twice with 1N sodium hydroxide solution, and the organic phase is dried over sodium sulfate and evaporated. Chromatography on silica gel (mobile phase ethyl acetate) produces 2.2 g of crystalline product, melting point 114°-117° C.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[N:29]1(C(OC(C)(C)C)=O)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[N:7]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCNCC5)n4)n[nH]c3cn2)cn1
Yield: 61 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl 1-piperazinecarboxylate were reacted. The product was deprotected to give 234 as a white solid (61% over two steps). 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.53 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.45 (d, J=7.2 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 3.91 (s, 3H), 3.63 (s, 4H), 2.94 (s, 4H); two protons not seen. LC/MS: m/z 361.1 [M+1]
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH2:60][CH2:61][C:62]([O:64][CH3:65])=[O:63]>CN(C)C=O>[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]([CH2:60][CH2:61][C:62]([O:64][CH3:65])=[O:63])[C:11]([C:7]1[N:6]=[C:5]2[N:4]=[C:3]([CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=3)[N:2]([CH3:1])[C:10]2=[CH:9][CH:8]=1)=[O:12]
Reactant: Cn1c(COc2ccc(C#N)cc2)nc2nc(C(=O)O)ccc21
Reactant: COC(=O)CCNc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CCN(C(=O)c1ccc2c(n1)nc(COc1ccc(C#N)cc1)n2C)c1ccccn1
Temperature: 0 °C

Procedure:
308 mg (1.0 mMol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-5-carboxy-imidazo[4,5-b]pyridine were suspended in 5 ml of dimethylformamide and mixed with 303 mg (3.0 mMol) of N-methyl-morpholine and 321 mg (1.0 mMol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium tetrafluoroborate. After 10 minutes at room temperature a solution of 215 mg (1.2 mMol) of methyl N-(2-pyridyl)-3-amino-propionate in 2 ml of dimethylformamide was added, whereupon a clear solution was obtained. After 12 hours at room temperature the reaction solution was stirred into ice-water. After extracting 3 times with ethyl acetate the combined organic extracts were washed with a saline solution, dried over sodium sulphate and evaporated down. The residue obtained was chromatographed on silica gel with dichloromethane/ethanol (90:1 to 25:1).