Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C@H:9]([C:15]1[O:16]C=CC=1)[C@@H:10]([CH3:14])[CH2:11][O:12][CH3:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH2:21].C(Cl)(Cl)(Cl)Cl.CC#N>CC#N.O>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@@H:9]([C@@H:10]([CH3:14])[CH2:11][O:12][CH3:13])[C:15]([OH:16])=[O:21])=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: O
Reactant: COC[C@H](C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC[C@H](C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a stirred solution of NalO4 (969.0 mg, 4.5 mmol, 6.0 equiv) in H2O/CCl4/CH3CN (3/2/3, 21 mL) was added RuCl3 (53.0 mg, 0.26 mmol, 0.34 equiv). After stirring for 15 minutes, a solution of ((1S,2R)-1-furan-2-yl-3-methoxy-2-methyl-propyl methylcarbamic acid tert-butyl ester (214.0 mg, 0.76 mmol) in CH3CN (4 mL) was added. After 15 minutes, the mixture was diluted with water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed successively with saturated aqueous NaHSO3, brine, dried over Na2SO4, and concentrated in vacuo to give (2S,3R)-2-(tertbutoxycarbonyl-methyl-amino)-4-methoxy-3-methyl-butyric acid (180.0 mg).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.B(F)(F)F.[C:29]([OH:32])(=[S:31])[CH3:30]>CCOCC>[C:29]([S:31][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])(=[O:32])[CH3:30]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CC(O)=S
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)S[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (450 mg.) in dry ether (4 ml.) and thioacetic acid (1 ml.) was treated with BF3 etherate (2 drops). The resulting yellow solution was stirred at room temperature for 20 minutes. The solution was partitioned between ethyl acetate (20 ml.) and water (20 ml.) and the aqueous layer was extracted with more ethyl acetate (20 ml.). The combined organic extracts were washed with water (2 × 20 ml.) and dried over sodium sulphate and evaporated to a yellow oil which was purified by preparative t.l.c., in ethyl acetate/petroleum ether (1:1) to give the title compound as a pale yellow foam. [α]D + 93° (c 0.56); Rf 0.15; N.M.R.:-7.65τ (CH3COS--); 6.16τ (2-- and 3--H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10]2)=[CH:5][CH:4]=1.[H][H]>[Pd].CCO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH:11]2[CH2:12][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:10]2)=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: COc1ccc(C2CC(O)(c3ccc(OC)cc3)C2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2CC(c3ccc(OC)cc3)C2)cc1

Procedure:
1.3-bis(p-methoxyphenyl)cyclobutanol (13.2 g., 0.046 mole), 3.0 g. of 10% Pd/c, 1 ml. of 70% HClO4, and 100 ml. of 95% EtOH is shaken under 50 psi of H2 until hydrogen absorption is complete. The catalyst is removed by filtration and the filtrate is evaporated. A solution of the residue in ether is washed (5% Na HCO3, water) and dried (MgSO4). Evaporation of the ether yields a residue (11.4 g.) which is recrystallized (EtOH), affording 6.8 g. (55%) of the desired intermediate.
Reaction SMILES: S([O-])(O)(=O)=O.[K+].C([O:9][C:10]1[O:11][CH2:12][C:13](=O)[C:14]=1C(OCC)=O)C.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH:29][CH2:30][CH:31]([F:33])[F:32])=[CH:24][CH:23]=1>C(#N)CCC>[Cl:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][N:29]([CH2:30][CH:31]([F:33])[F:32])[C:13]2[CH2:12][O:11][C:10](=[O:9])[CH:14]=2)=[CH:24][CH:23]=1
Reactant: FC(F)CNCc1ccc(Cl)nc1
Reactant: CCOC(=O)C1=C(OCC)OCC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCC#N
Product: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Temperature: 25 °C
Yield: 93 %

Procedure:
31.2 g of potassium hydrogensulphate are added at room temperature to a suspension of 46 g of ethyl 2-ethoxy-4,5-dihydro-4-oxofuran-3-carboxylate and 39.3 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethylamine in 705 ml of butyronitrile. The mixture was heated to reflux for 5 hours. Subsequently, it was cooled to room temperature and washed with 890 ml of water. The solvent was removed under reduced pressure. This gave 51 g of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one (this corresponds to a 93% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[CH:12]1([C:15]2[N:16]=[CH:17][C:18]([O:21][CH:22]3[CH2:31][N:25]4[CH2:26][CH2:27][NH:28][C:29](=[O:30])[CH:24]4[CH2:23]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:12]1([C:15]2[N:16]=[CH:17][C:18]([O:21][C@H:22]3[CH2:31][N:25]4[CH2:26][CH2:27][N:28]([C:2]5[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=5)[C:29](=[O:30])[C@@H:24]4[CH2:23]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1
Reactant: O=C1NCCN2CC(Oc3cnc(C4CC4)cn3)CC12
Reactant: FC(F)(F)c1cccc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: O=C1[C@@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN2CCN1c1cccc(C(F)(F)F)n1
Temperature: 110 °C
Yield: 17.5 %

Procedure:
A 4 mL vial was charged with 2-bromo-6-(trifluoromethyl)pyridine (99 mg, 0.437 mmol), 7-(5-cyclopropylpyrazin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one [3:1 (7R,8aS: 7R,8aR) diastereomer ratio](100 mg, 0.365 mmol) from Example 163 Step 3, palladium(II) acetate (4.09 mg, 0.018 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS, 21.09 mg, 0.036 mmol), and cesium carbonate (178 mg, 0.547 mmol). The mixture was purged with nitrogen, and anhydrous dioxane (0.5 mL) was added. The reaction mixture was purged with nitrogen again and was subsequently heated at 110° C. for 16 hours. The mixture was directly loaded and separated by flash chromatography [12 g cartridge, a gradient 0-5% methanol/dichloromethane over 20 minutes] to give crude oily product. The crude product was further purified on 12 g cartridge eluted with a gradient of 0-100% ethyl acetate over 20 minutes to give the title compound (27 mg, 0.064 mmol, 17.66% yield) as the first eluting diastereomer as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (d, J=8.5 Hz, 1H), 8.12 (s, 1H), 7.95 (d, J=1.3 Hz, 1H), 7.85 (dd, J=10.4, 5.6 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 5.50 (d, J=5.0 Hz, 1H), 4.47 (ddd, J=7.1, 4.5, 1.7 Hz, 1H), 4.12-3.91 (m, 2H), 3.34 (dt, J=9.7, 4.8 Hz, 2H), 3.19-3.05 (m, 2H), 2.64 (dt, J=14.6, 7.3 Hz, 1H), 2.57-2.42 (m, 1H), 2.00 (tt, J=7.8, 5.3 Hz, 1H), 1.02-0.90 (m, 4H); MS (ESI+) m/z 420 (M+H)+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][NH:9][C:8]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:7]=2[S:6]1)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O1CCCC1>[OH:2][CH2:3][CH:5]1[CH2:10][NH:9][C:8]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:7]=2[S:6]1
Reactant: COC(=O)C1CNc2ccc(C(F)(F)F)cc2S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OCC1CNc2ccc(C(F)(F)F)cc2S1

Procedure:
2-methoxycarbonyl-7-trifluoromethyl-3,4-dihydro-2H-[1,4]benzothiazine in 50 ml of toluene and about 10 ml of tetrahydrofuran, kept under argon. The reaction mixture is heated for 1 hour under reflux, and then after returning to 20° C. is hydrolysed with 70 ml of a saturated aqueous sodium hydrogen carbonate solution and 40 ml of ethyl acetate. The insoluble matter is removed by filtration and the filtrate is separated after settling out, the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa). The yellow oil obtained is chromatographed on 35 g of 20-45 μm silica gel contained in a column 2 cm in diameter, eluting with an ethyl acetate and cyclohexane mixture (75-25 by volume). 0.72 g of 2-hydroxymethyl-7-trifluoromethyl-3,4-dihydro-2H-[1,4]benzothiazine is thus obtained in the form of a yellow solid melting at 80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[CH2:16]([NH:23][C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(OC)c2c1CCC(=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c2c1C=C(NCc1ccccc1)CC2

Procedure:
A mixture containing 82 mmol of 5,8-dimethoxy-3,4-dihydronaphthalen-2(1H)-one, 82 mmol of benzylamine and 0.20 g of p-toluenesulfonic acid is brought to reflux with azeotropic distillation of the water/toluene mixture. After heating for 2 hours, the mixture is cooled, filtered and the solvent evaporated under vacuum and leads to the expected product in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[NH:17]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[NH2:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of tert-butyl N-[2-bromo-4-[(4-chlorophenyl)carbonyl]phenyl]carbamate (20 g, 48.70 mmol, 1.00 equip) in dichloromethane (300 mL). To the resulting mixture was then added trifluoroacetic acid (38 mL, 10.00 equip) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of saturated sodium bicarbonate (500 mL). The resulting solution was extracted with DCM (500 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:15 to yield 2-bromo-4-[(4-chlorophenyl)carbonyl]aniline as a light yellow solid. LCMS (ES, m/z) 310 [M+H]+
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:12]=1[S-:13].[Na+].[OH-].[Na+]>O>[C:2]1([C:1]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:11]=3[N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1[S-]
Reactant: O=C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc2sc(-c3ccccc3)nc2c1
Temperature: 117.5 °C

Procedure:
PPA (210 g) is added to benzoic acid (12.96 g, 0.104 mol) and sodium 2-amino-4-nitrothiophenoxide (19.98 g, 0.104 mol) (V. L. Guarda, Heterocyclic Comm., 2000, 1.6, 49-54). The mixture is heated at 115-120° C. for 10 minutes, cooled, and water (200 ml) is added dropwise, followed by addition of 32 percent NaOH (pH=5). The product is filtered off and suspended in NaHCO3 ss, filtered off, washed with water and recrystallized from isopropyl ether. Yield: 17.0 g (64%); IR (KBr): 1515, 1341 cm−1; 1H-NMR (d6-DMSO) 8.77 (d, 1H); 8.39 (d, 1H); 8.25 (dd, 1H); 8.11 (dd, 1H); 7.61 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[N:17]=[C:16](O)[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=2)=[CH:10][CH:11]=1)=[O:4].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:34]>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[N:17]=[C:16]([Cl:34])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=2)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(CCl)Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: O=C(CCl)Nc1ccc(-c2nc(Cl)cc(C(F)(F)F)n2)nc1

Procedure:
To a solution of compound of example 53 (0.100 g, 0.301 mmol) in acetonitrile (5 mL), was added benzyl triethyl ammonium chloride (0.274 g, 1.204 mmol), dimethylaniline (0.143 g, 1.183 mmol) and POCl3 (2.3 g, 15.05 mmol). The reaction mixture was refluxed for 3 hours. Acetonitrile was removed under vacuum, reaction mass neutralized by sodium bicarbonate solution and extracted with ethyl acetate (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5 % methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:27]=[C:28]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)[CH:29]=[CH:30][CH:31]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:50]1(B(O)O)[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]=1>>[C:50]1([C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:27]=[C:28]([N:32]6[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:46])[CH3:44])[C:34](=[O:47])[CH2:33]6)[CH:29]=[CH:30][CH:31]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:48][CH:49]=3)=[CH:4][CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]=1
Reactant: OB(O)C1=CCCCC1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)c2)S1(=O)=O
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5=CCCCC5)nn4)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (38 mg, 0.05 mmol) was treated as described in general procedure G using 1-cyclohexen-1-yl-boronic acid (13 mg, 0.1 mmol) to give 5-{3-[2-[4-(6-cyclohex-1-enyl-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[H-].[Na+].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[C:14]1([C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.5 %

Procedure:
Ethyl 1 H-pyrazole-4-carboxylate (1.50 g, 10.7 mmol) was added in portions to a stirred suspension of sodium hydride (353 mg, 80% oil dispersion, 11.8 mmol) in anhydrous tetrahydrofuran (100 ml) under nitrogen at room temperature. After 20 minutes, the mixture was cooled to 0° C. and trityl chloride (3.28 g, 11.8 mmol) was added. The mixture was stirred at 0° C. for 4 h and allowed to warm to room temperature overnight. The mixture was then heated at 50° C. for 3 h, cooled, and further portions of sodium hydride (321 mg, 10.7 mmol) and trityl chloride (1.0 g, 3.59 mmol) were added. The mixture was heated at 50° C. for 2 h, cooled, treated with water (50 ml) and concentrated under reduced pressure. The product was extracted into ethyl acetate (200 ml), the solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate) to give ethyl 1 -(triphenylmethyl)-pyrazole-4-carboxylate (2.273 g, 56%), as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[CH3:19][C:20]1[C:25]([CH2:26][CH2:27]O)=[CH:24][CH:23]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:27][CH2:26][C:25]2[C:20]([CH3:19])=[N:21][C:22]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)=[CH:23][CH:24]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Reactant: CCOC(=O)CCc1ccc(O)c2ccccc12
Product: CCOC(=O)CCc1ccc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc12

Procedure:
In analogy to the procedures described in example 4D] and 4E], 3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester [Helvetica Chimica Acta (2001), 84(8), 2198-2211] was reacted with 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (example 4K]) to give 3-(4-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-naphthalen-1-yl)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][S:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)(=[O:19])=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:30]1([N:33]([CH2:35][C:36]2[C:37]([CH3:44])=[C:38]([CH:42]=O)[NH:39][C:40]=2[CH3:41])[CH3:34])[CH2:32][CH2:31]1>N1CCCCC1.C(O)C>[CH:30]1([N:33]([CH2:35][C:36]2[C:37]([CH3:44])=[C:38](/[CH:42]=[C:23]3\[C:24](=[O:29])[NH:25][C:26]4[C:22]\3=[CH:21][C:20]([S:17]([CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:19])=[O:18])=[CH:28][CH:27]=4)[NH:39][C:40]=2[CH3:41])[CH3:34])[CH2:32][CH2:31]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3OCCN3CCOCC3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CN(C)C1CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4OCCN4CCOCC4)cc32)c(C)c1CN(C)C1CC1
Yield: 45.7 %

Procedure:
5-[2-(2-Morpholin-4-yl-ethoxy)-phenylmethanesulfonyl]-1,3-dihydro-indol-2-one (39 mg, 0.094 mmol) was condensed with 4-[(cyclopropyl-methyl-amino)-methyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (21 mg, 0.1 mmol) and piperidine (1 drop) in ethanol (1.5 mL) at rt for 48 hours. The solvent was removed and the residue was purified on a silica gel column to give 26 mg (46%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])=[CH:6][C:5]([CH3:18])=[CH:4][N:3]=1.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[C:21]([C:20]1[N:3]2[CH:4]=[C:5]([CH3:18])[CH:6]=[C:7]([O:8][CH2:9][C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:17])[C:2]2=[N:1][C:26]=1[CH3:28])([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Cc1cnc(N)c(OCc2c(C)cccc2C)c1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3c(C)cccc3C)cc(C)cn12
Yield: 46.7 %

Procedure:
A mixture of 2-amino-3-(2,6-dimethylbenzyloxy)-5-methylpyridine (1.0 g, 4.13 mmol) and ethyl 2-chloroacetoacetate (0.79 g, 4.55 mmol) in 20 ml abs. ethanol was refluxed for 19 h. More ethyl 2-chloroacetoacetate (0.25 g) was added. The reaction mixture was refluxed for additional 23 h. The solvent was evaporated in vacuo and the residue was dissolved in methylene chloride and washed with aqueous NaHCO3. The organic layer was dried and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using methylene chloride:ethyl acetate (100:10) as eluent to give 0.68 g (47%) of the title compound.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+:26]>O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
88 kg of the recrystallized behenic acid, 461 L of distilled water, 49.2 L of a 5 mol/L aqueous solution of NaOH and 40.3 L of a 10 mass % solution of dodecylthiopolyacrylamide surfactant (BUN-1) were mixed and allowed to react at 80° C. for one hour under stirring to form a sodium behenate solution. Separately, 206.2 L of an aqueous solution (pH 4.0) containing 40.4 kg of silver nitrate was prepared and kept at 10° C. To 635 L of distilled water contained in a reaction vessel kept at 30° C. were added the entire volume of the above-mentioned sodium behenate solution and the entire volume of the aqueous silver nitrate solution under sufficient stirring at constant flow rates over the periods of 93 minutes and 15 seconds, and 90 minutes, respectively; in this operation, only the aqueous silver nitrate solution was added during a period within 11 minutes from the initiation of the addition of the aqueous silver nitrate solution, and then the addition of the sodium behenate solution was started, and then the addition of the aqueous silver nitrate solution was completed, so that only the sodium behenate solution was added during a period within 14 minutes and 15 seconds from the completion of the addition of the aqueous silver nitrate solution. In this operation, the outside temperature was controlled so that the temperature in the reaction vessel was maintained at 30° C. and the liquid temperature was kept constant. The pipe of the addition system for the sodium behenate solution was warmed by circulating warmed water in the space between the outer pipe and the inner pipe of a double pipe, and temperature was controlled such that the liquid temperature at the outlet orifice of the addition nozzle was 75° C. The pipe of the addition system for the aqueous silver nitrate solution was maintained at a constant temperature by circulating cold water in the space between the outer pipe and the inner pipe of a double pipe. The addition position of the sodium behenate solution and the addition position of the aqueous silver nitrate solution were arranged symmetrically with respect to the stirring axis as a center, and the positions had such heights as not to contact with the reaction solution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[NH2:15])[N:11]=[C:10]([CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[CH:9]=2)=[CH:4][CH:3]=1.[CH:30](=O)[CH3:31].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[NH:15][CH2:30][CH3:31])[N:11]=[C:10]([CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: CC1(C)CC(c2cc(-c3ccc(Cl)cc3)n(-c3ccccc3N)n2)CC(C)(C)O1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCNc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
To a solution of 2-(5-(4-chlorophenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-1-yl)aniline (Example 62) (50 mg, 0.12 mmol, 1 eq) in THF (2 mL) was added acetaldehyde (0.028 mL, 0.49 mmol, 4 eq). After 15 min, sodium cyanoborohydride (61 mg, 0.98 mmol, 8 eq) and acetic acid (0.1 mL) were added and the solution stirred 3 days. Water and NaHCO3 were added, extracted with DCM, dried over MgSO4 and concentrated. Purification by column chromatography (8 g) eluting with 15 to 30% EtOAc/hex gave the title compound (28.3 mg, 50%).