Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:24])[CH:9]=2)[C:4]2[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:48].Cl>>[ClH:48].[ClH:48].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:24])[CH:9]=2)[C:4]2[CH2:25][CH2:26][NH:27][CH2:28][C:3]1=2
Reactant: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CN(C(=O)OC(C)(C)C)CC5)c(=O)c2)nc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CNCC5)c(=O)c2)nc1
Yield: 15 %

Procedure:
tert-Butyl 9-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (138 mg, 0.27 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (18 mg, 15%) as a yellow solid: mp 303-310° C.; 1H NMR (500 MHz, CD3OD) δ 8.59 (s, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.87 (d, J=6.5 Hz, 1H), 7.80 (d, J=7.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.56 (d, J=1.4 Hz, 1H), 7.24 (d, J=1.6 Hz, 1H), 7.15-7.12 (m, 2H), 4.57 (s, 2H), 3.74 (s, 3H), 3.61 (t, J=6.0 Hz, 2H), 3.14 (t, J=6.1 Hz, 2H), 2.46 (s, 3H); ESI MS m/z 371 [M+H]+; HPLC (Method B)>99% (AUC), tR=11.0 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]([CH3:29])([CH3:28])[CH2:9][N:10]1[C:15](=[O:16])[NH:14][C:13](=[O:17])[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])[C:11]1=[O:27])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:37][C:38]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[C:39]=1[CH2:40]Br>CN(C=O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]([CH3:29])([CH3:28])[CH2:9][N:10]1[C:15](=[O:16])[N:14]([CH2:40][C:39]2[C:42]([C:46]([F:47])([F:49])[F:48])=[CH:43][CH:44]=[CH:45][C:38]=2[F:37])[C:13](=[O:17])[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])[C:11]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Reactant: COc1cccc(-n2c(=O)[nH]c(=O)n(CC(C)(C)NC(=O)OC(C)(C)C)c2=O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-n2c(=O)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(CC(C)(C)NC(=O)OC(C)(C)C)c2=O)c1F
Reaction time: 14 h

Procedure:
{2-[3-(2-Fluoro-3-methoxy-phenyl)-2,4,6-trioxo-[1,3,5]triazinan-1-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (370 mg) was dissolved in 7 mL of anhydrous DMF. To this solution was added K2CO3 (2.0 eq, 226 mg) and 2-fluoro-6-(trifluoromethyl)benzyl bromide (1.0 eq, 222 mg). The reaction was complete by LC/MS after 14 hours. The DMF was removed in vacuo. The residue was partitioned between EtOAc and H2O. The EtOAc layer was collected and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography and eluted with 30% EtOAc/hexanes to yield 399 mg (76%). Rf=0.36 in 30% EtOAc/hexanes. 1H NMR (CDCl3) δ: 7.51 (d,1H), 7.39 (m,1H), 7.27 (d,1H), 7.15 (dt,1H), 7.06 (dt,1H), 6.88 (dt,1H), 5.42 (q,2H), 5.15 (bs,1H), 4.14 (q,2H), 3.9 (s,3H), 1.4 (s,9H), 1.39 (d,6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:16]([O-])=O)=[C:4]([NH:8][C@@H:9]([CH3:15])[C:10](OCC)=[O:11])[CH:5]=[CH:6][CH:7]=1.CCO.Cl.CCOC(C)=O>[Cl-].[Na+].O.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:16][C:10](=[O:11])[C@H:9]([CH3:15])[NH:8]2
Reactant: CCOC(=O)[C@H](C)Nc1cccc(Br)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1Nc2cccc(Br)c2NC1=O
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
To a 2-L, 3-necked round-bottomed flask equipped with a mechanical stirrer, nitrogen gas inlet, and temperature probe was sequentially added (S)-ethyl 2-((3-bromo-2-nitrophenyl)amino)-propanoate (50 g, 158 mmol), EtOH (750 mL), and iron powder (325 mesh, Aldrich; 39.6 g, 709 mmol). The resulting slurry was cooled to 0-5° C. on an ice water bath, and HCl (6.0 N, aq.; 342 mL, 2050 mmol) was added, dropwise, such that the internal reaction temperature did not exceed 5° C. After 1 h, brine (500 mL) and EtOAc (1500 mL) were added, such that the internal reaction temperature was kept below 10° C. The resulting mixture was vacuum filtered, and the collected solid was washed with EtOAc. The organic phase of the filtrate was separated and sequentially washed with brine (300 mL), saturated aq. NaHCO3 (500 mL; repeated until aq. layer pH ≧7), and EDTA trisodium salt solution (1 N, aq.; 300 mL). The organic layer was then concentrated in vacuo to provide (S)-8-bromo-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (126c; 40.0 g, 165.9 mmol, 105% yield) as a light-brown oil, which was used without further purification in the subsequent step: m/z (ESI, +ve) 241.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:14][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][O:6][CH2:5][C:4]3[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=3)[N:13]=2)(=[O:26])=[O:27])=[CH:21][C:20]=1[C:29]([F:32])([F:30])[F:31]
Reactant: Nc1cccc(COCc2cccc(F)c2)n1
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Product: O=S(=O)(Nc1cccc(COCc2cccc(F)c2)n1)c1ccc(F)c(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(3-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.06 g) and 4-fluoro-3-(trifluoromethyl)-benzenesulfonyl chloride (0.075 g) as a light yellow solid (0.1 g). MS (ESI−): 457.2 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:21]2[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:20]=2[C:19]2[C:18]3[CH:17]=[C:16]([O:27]C)[CH:15]=[CH:14][C:13]=3[N:12]([CH2:29][CH2:30][C:31]([NH2:33])=[O:32])[C:11]=2[CH:10]=1.O1CCCC1>C(OCC)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:21]2[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:20]=2[C:19]2[C:18]3[CH:17]=[C:16]([OH:27])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:29][CH2:30][C:31]([NH2:33])=[O:32])[C:11]=2[CH:10]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4c(Cl)cccc4Cl)cc1n2CCC(N)=O)C(=O)NC3=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)CCn1c2ccc(O)cc2c2c3c(c(-c4c(Cl)cccc4Cl)cc21)C(=O)NC3=O
Yield: 59 %

Procedure:
Reaction of methyl ether (250) (80 mg, 0.17 mmol)) prepared as described in example 210 according to The procedure described in example 80, followed by chromatography on silica eluting with ethyl acetate then tetrahydrofuran and trituration from ethyl acetate, gave amide (258) (47 mg, 59%) as an orange powder, mp 327–329° C. 1H NMR δ [(CD3)2SO] 11.12 (br s, 1H), 9.39 (s, 1H), 8.36 (d, J=2.4 Hz, 1H), 7.82 (s, 1H), 7.61 (m, 3H), 7.51 (dd, J=8.8, 7.4 Hz, 1H), 7.38 (br s, 1H), 7.15 (dd, J=8.9, 2.4 Hz, 1H), 6.87 (br s, 1H), 4.65 (t, J=6.7 Hz, 2H), 2.55 (t, J=6.7 Hz, 2H). Found: C, 57.75; H, 3.83; N, 8.50. C23H15Cl2N3O4.3/4H2O requires: C, 57.33; H, 3.45; N, 8.72.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[NH:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(Cl)(Cl)Cl>[CH:8]1[CH:9]=[C:10]2[C:5](=[C:6]([S:11]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21]3)(=[O:13])=[O:12])[CH:7]=1)[CH:4]=[CH:3][N:2]=[CH:1]2
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: C1CNCCNC1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1cccc2cnccc12)N1CCCNCC1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
40 liters of a chloroform solution containing 5.0 kg of 5-isoquinolinesulfonyl chloride was added dropwise to 40 liters of a chloroform solution containing 8.8 kg of homopiperazine over 1 hour while cooling with ice, to obtain a mixture. Subsequently, the obtained mixture was stirred for 1 hour while cooling with ice, to effect a reaction and then the resultant reaction mixture was subjected to extraction with a 2N aqueous solution of HCl, followed by separation of an aqueous phase. The aqueous phase was adjusted to a pH value of 10 with a 10% aqueous solution of NaOH to thereby obtain a solution having a pH value of 10. The obtained solution was subjected to extraction with 80 liters of chloroform, followed by separation of a chloroform phase. The resultant chloroform phase was washed with water and then dried over anhydrous sodium sulfate, and subsequently, the solvent was removed by distillation under reduced pressure to obtain a residue. The obtained residue was subjected to column chromatography using 150 kg of silica gel (Wakogel C-200, manufactured and sold by Wako Pure Chemical Industries, Ltd., Japan) and a mixed solvent of methanol and chloroform (5 v/v % methanol) as a developing solvent, and purified to obtain 6.01 kg of fasudil (yield 89%). The results of elemental analysis of fasudil: found (calculated) C: 57.59 (57.71), H: 5.92 (5.88), N: 14.29 (14.42), S: 10.83 (11.00) (wt %)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccnc1C
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1ccc[n+]([O-])c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the 2,3-dimethylpyridine (15.0 g, 140 mmol) in CHCl3 (40 mL) at 0° C. was slowly added a CHCl3 (200 mL) solution of m-chloroperbenzoic acid (21.5 g, 154 mmol). The mixture was stirred 1 hour at 0° C., the ice bath was removed and stirring continued another hour. Calcium hydroxide (26 g, 350 mmol) was added and the slurry was vigorously stirred 4.5 hours before filtering through celite. The cake was thoroughly washed with CH2Cl2. Evaporation of the solvents left an oily solid that was swished in Et2O giving 8.71 g of desired product which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[NH3:13]>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[C:8]([NH2:13])=[O:9]
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: N
Product: NC(=O)c1c(F)cccc1C(=O)O

Procedure:
reacting the fluorophthalic anhydride with ammonia to form an ammonium salt of a fluorophthalamic acid, and
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC(=O)OCC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(CC(=O)OCC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-ethoxycarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [H-].[Na+].CS(C)=O.Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[Cl:16].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>O>[Cl:16][C:10]1[CH:11]=[C:12]([O:15][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: Nc1ccc(O)cc1Cl
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
Sodium hydride (60 wt %, 0.72 g) was added to dimethyl sulfoxide (10 ml). The mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-3-chlorophenol hydrochloride (1.61 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue. The precipitated crystal was collected by suction filtration to give 0.89 g (yield 60%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH2:6])=[CH2:4].[C:7]1(=[O:12])[CH2:11][CH2:10][CH:9]=[CH:8]1>C1(C=CC(O)=CC=1)O>[CH3:1][O:2][C:3]1[CH2:4][CH:10]2[CH:11]([CH2:6][CH:5]=1)[C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: O=C1C=CCC1
Reactant: C=CC(=C)OC
Agent: Oc1ccc(O)cc1
Product: COC1=CCC2C(=O)CCC2C1
Yield: 21.7 %

Procedure:
2-Methoxybutadiene (69.9 g), 2-cyclopentenone (68.22 g) and hydroquinone (0.2 g) were heated together at 190° C. for 2 hours. The product was then distilled in vacuo, to give 3-methoxybicyclo[4,3,0]non-3-en-7-one (30 g), b.p. 74°-92° C./1.5 mmHg.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:12])=[CH:8][C:9]=2[OH:11])[O:4][C@H:3]([C:13]2[CH:18]=[C:17](O)[C:16]([OH:20])=[C:15]([OH:21])[CH:14]=2)[C@@H:2]1[O:22]C(C1C=C(O)C(O)=C(O)C=1)=O.N[C@H](C(=O)O)CC[S+](C)C[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O>>[CH:18]1[C:13]([CH:3]2[O:4][C:5]3[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([OH:11])[C:10]=3[CH2:1][CH:2]2[OH:22])=[CH:14][C:15]([OH:21])=[C:16]([OH:20])[CH:17]=1
Reactant: O=C(O[C@@H]1Cc2c(O)cc(O)cc2O[C@@H]1c1cc(O)c(O)c(O)c1)c1cc(O)c(O)c(O)c1
Agent: C[S+](CC[C@H](N)C(=O)O)C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Product: Oc1cc(O)c2c(c1)OC(c1ccc(O)c(O)c1)C(O)C2

Procedure:
The purified enzyme is suspended in a buffer having a pH of 4.5 to 8.5, preferably 6.5 to 8. To this suspension, EGCG or ECG is added along with S-adenosyl-L-methionine (SAM) and the reaction is allowed to proceed at 5 to 60° C., preferably at 20 to 40° C., to form a methylated catechin.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(I)cc1N
Yield: 99.8 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (2.18 g, 6.0 mmol) by reduction with SnCl2.2H2O (6.77 g, 30 mmol) according to the general procedure G (method b). Obtained as a brown-yellow solid (2.0 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)=[CH:13][CH:12]=1.FC1C=CC(C(=O)C)=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:58][CH2:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:77])[F:76])[CH:70]=2)[CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[O:61]=[C:60]([N:62]1[CH2:63][CH2:64][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:76])[F:77])[CH:70]=2)[CH2:66][CH2:67]1)[CH2:59][NH:58][C:22]([C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=2)[NH:21][N:20]=1)=[O:24]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)[nH]n1
Agent: CC(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccc(F)cc2)[nH]n1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
DIPEA (131 mg, 1.0 mmol) was added to a stirred solution of 5-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (60 mg, 0.29 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from 4′-fluoroacetophenone) in DMF (2 mL) followed by HOBt (41 mg, 0.305 mmol) and EDCI.HCl (59 mg, 0.306 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (98 mg, 0.294 mmol) (prepared according to Step 1 and 5 of the General Scheme) 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, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by washing with 1% MeOH in EtOAc to afford 97 mg (68.3% Yield) of 5-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 491, 92.85%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.1 (t, 1H), 7.9 (m, 2H), 7.5 (t, 1H), 7.24 (m, 5H), 7.1 (d, 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: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([C:24](=O)[C:25](OC)=[O:26])=[C:15]1[CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])([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.S(C)C>C1COCC1>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][OH:26])=[C:15]1[CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c(CO[Si](C)(C)C(C)(C)C)n(C(c2ccccc2)c2ccccc2)c2ccc(Cl)cc12
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)[Si](C)(C)OCc1c(CCO)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Methyl [1-benzhydryl-2-({[tert-butyl(dimethyl)silyl]oxy }methyl)-5-chloro-1H-indol-3-yl](oxo)acetate (1 eq) was dissolved in THF (0.46M), then BH3.Me2S (2M in THF) (2 eq) was added to it. The resulting mixture was refluxed with stirring overnight under N2. The reaction mixture was cooled to rt, then quenched slowly with 1N NaOH(aq). Followed by regular work-up (eg. EtOAc extraction, brine wash, etc.). Removed the solvent and purified using a column with CH2Cl2 as eluent to give 2-[1-benzhydryl-2-({[tert-butyl(dimethyl)silyl]oxy }methyl)-5-chloro-1H-indol-3-yl]ethanol (yellow solid) in 72% yield.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+].C(O)(=O)C.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>CO>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:6][CH:7]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CC(C)(C)N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)NCC(O)c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
50 g (0.289 mol) of α-chloro-p-fluoroacetophenone are dissolved in 900 ml of methanol. The mixture is cooled to -5° C. and 5.80 g of NaBH4 are added. It is left in contact for 1 hour then 10 ml of acetic acid are added. 151 ml of tertiary-butylamine are added and the mixture is refluxed for 12 hours. It is evaporated to dryness and the residue of evaporation is taken up in distilled water. The free base which has crystallised is filtered off and, by recrystallisation in hexane, 39 g (yield 63%) of 1-(4-fluorophenyl)-2-tertiary-butylamino-1-ethanol are obtained. m.p. 117° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[CH3:9][C:10]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])[CH3:11].C([O-])(O)=O.[Na+]>>[C:10]([Si:13]([CH3:15])([CH3:14])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[N:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:9]
Reactant: Oc1ccc(F)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A mixture of 2-fluoro-5-hydroxypyridine (1.00 g, 8.84 mmol) and BDCS reagent (0.5 TBSCl, 1.0 imidazole in DMF) (35.4 mL, 17.7 mmol) was stirred at rt for 1 h. The reaction was poured into satd. aqueous NaHCO3 solution. The aqueous layer was extracted with ether. The combined extracts were washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% ethyl acetate/hexanes to give the title compound (1.96 g, 98%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[N:21]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:25]([C:23]3[CH:24]=[N:20][NH:21][CH:22]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCCOc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1cn[nH]c1
Product: O=C(NCCCCOc1cc(CN2CCCCC2)ccn1)c1cn[nH]c1
Yield: 71 %

Procedure:
Following a procedure similar to that described in Example 64, but using 4-(4-piperidinomethyl-2-pyridyloxy)butylamine and 4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 145°-147° C., in a 71% yield.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19](O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19]([N:43]=[N+:44]=[N-:45])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(O)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(N=[N+]=[N-])c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
Compound 2 (0.600 g, 1.61 mmol) was dissolved in toluene (15 mL), and diphenylphosphoryl azide (0.696 mL, 3.23 mmol) and DBU (0.483 mL, 3.22 mmol) was added to the solution, followed by stirring at 60° C. for 4 hours. The reaction mixture was diluted with toluene, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain [4-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)phenyl]phenylmethylazide (0.590 g, yield 92%).