Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[Sn](CCCC)(CCCC)CCCC)=[CH:12]\[C@@H:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:16](=[O:29])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:44]1[N:49]=[C:48]([O:50][CH3:51])[C:47]([CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[CH:46][CH:45]=1.[F-].[Cs+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:44]2[N:49]=[C:48]([O:50][CH3:51])[C:47]([CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[CH:46][CH:45]=2)=[CH:12]\[C@H:13]2[CH2:14][CH2:15][C:16](=[O:29])[N:17]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[O:27][CH3:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1nc(Br)ccc1CCC(=O)OC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC)c1ccc(C(C)(C)C)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(=O)OC(C)(C)C)c(OC)n2)c(OC)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (80 mg) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-26 (471 mg), tert-butyl 3-(6-bromo-2-methoxypyridin-3-yl)propanoate obtained in Reference Example 4-41 (436 mg), cesium fluoride (209 mg) and copper iodide (144 mg) in N,N-dimethylformamide (4.5 mL) in a nitrogen atmosphere, and the mixture was stirred at 65° C. for one hour. The reaction solution was left to cool, and then water and ethyl acetate were added, followed by filtration through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give tert-butyl 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)propanoate as a brown oil (293 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[CH:5]=[CH:4][N:3]=1.[C:10]([NH:12][C:13](=[N:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1)OC1C=CC=CC=1)#[N:11].C(=O)(O)[O-].[Na+].C(#N)C>CN1C(=O)CCC1.CCN(C(C)C)C(C)C>[NH2:11][C:10]1[N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[N:9]=[C:13]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=2)[N:12]=1
Reactant: CC(=O)Nc1ccc(N=C(NC#N)Oc2ccccc2)cc1
Reactant: NNc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)Nc1ccc(Nc2nc(N)n(-c3ccnc(Cl)c3)n2)cc1
Temperature: 220 °C
Yield: 85.3 %

Procedure:
A microwave reaction vessel was charged with 1.34 g of (2-Chloro-pyridin-4-yl)-hydrazine (7.48 mmol, 1.1 equiv) and 2.00 g of N-cyano-N′-(4-acetamidophenyl)-O-phenylisourea (6.80 mMol, 1 equiv). The solids were dissolved in 40 mL of NMP and 8 mL of DIEA. The sealed vessel was warmed to 220° C. for 6 min via microwave irradiation. Upon cooling, the resulting solution was poured into 200 mL of saturated sodium bicarbonate. The precipitate was collected and washed with 3×100 mL of water. After azeotropic drying (3×50 mL of acetonitrile) the dark yellow solid (2.0 g, 5.80 mMol, 85% yield) was used without further purification. 1H NMR (500 Mhz, DMSO-d6) δ 9.68 (1 H, s), 9.00 (1 H, s), 8.40 (1 H, d), 7.67 (2 H, m), 7.50 (2 H, d), 7.40 (2 H, d), 6.95 (2 H, s), 2.0 (3 H, s) ppm. LCMS: 2.16 minutes/343.95 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[OH:20][C:13]1([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:15][N:10]([C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:7]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C(c1cccc(Br)n1)N1CCC(O)(C(F)(F)F)CC1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1cccc(N2CCCCC2)n1)N1CCC(O)(C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
(6-Bromopyridin-2-yl)(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methanone (61 mg, 0.172 mmol), piperidine (0.02 ml, 0.189 mmol), Pd2(dba)3 (3 mg, 0.003 mmol), xantphos (6 mg, 0.010 mmol), and sodium-tert-butoxide (25 mg, 0.258 mmol) were suspended in toluene (1.5 ml), and then stirred at 100° C. under nitrogen stream for 2 hours. Distilled water (5 ml) was added to the resulting reaction liquid, followed by extraction with 5% MeOH/MC (10 ml×2). The organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (50% EtOAc/Hexanes), to obtain 37 mg of yellow solid (61%). MS (ESI): 358 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][N:4]=1.[OH:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CN(C=O)C.O>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:18][C:16]2[CH:15]=[CH:14][NH:13][C:12](=[O:11])[CH:17]=2)=[N:4][CH:5]=1
Reactant: COc1ccc(CBr)nc1
Reactant: Oc1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc[nH]c(=O)c2)nc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromomethyl-5-methoxy-pyridine (preparation 11a, 2.00 g crude material), 2,4-dihydroxypyridine (1.06 g, 9.5 mmol) in acetonitrile (20 mL) and DMF (5 mL) is added K2CO3 and the mixture is stirred for 4 h at 50° C. and overnight at room temperature. The reaction mixture is diluted with water (60 mL) and extracted several times with ethyl acetate. The organic layer is dried over Na2SO4, concentrated under reduced pressure and purified via reverse phase HPLC chromatography (Waters XBridge 5 μm, gradient 25%→95% methanol in water+0.3% NH4OH).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:18]([CH3:21])[C:19]#[N:20]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:6]([C:5]([O:10][CH:18]([C:19]#[N:20])[CH3:21])=[CH:4][CH:3]=1)[CH:7]=[O:8]
Reactant: CC(Cl)C#N
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C#N)Oc1ccc(Cl)cc1C=O

Procedure:
A mixture of 5-chlorosalicylaldehyde (78 g., 0.5 mole), finely powdered anhydrous potassium carbonate (103.5 g., 0.75 mole) and acetone (500 ml.) is stirred under reflux and 2-chloropropionitrile (33.6 g., 0.375 mole) is added over a period of about 5 minutes. The mixture is heated under reflux for 1.5 hours and then treated with potassium carbonate (34.5 g., 0.25 mole) followed by more 2-chloropropionitrile (11.2 g., 0.125 mole). Heating and stirring are continued for 31/2 hours, after which the reaction mixture is filtered and the filter-cake washed with acetone. Evaporation of the combined filtrate gives 3-chloro-6-(1-cyanoethoxy)-benzaldehyde which is recrystallized from aqueous methanol.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([N:12]1[CH2:17][CH2:16][C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][O:26][CH2:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])=[CH:21][CH:20]=2)(O)[CH:14]([CH2:33][O:34][C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[CH2:5]([N:12]1[CH2:17][CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][O:26][CH2:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])=[CH:21][CH:20]=2)[CH:14]([CH2:33][O:34][C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC[C@H](C)COCc1ccc(C2(O)CCN(Cc3ccccc3)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC[C@H](C)COCc1ccc(C2=CCN(Cc3ccccc3)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
102.636 mmol of thionyl chloride are slowly added to a solution of 85.53 mmol of 1-benzyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-3-(R,S)-trityloxymethyl -piperidin-4-(R,S)-ol in 250 ml of pyridine at 0° C., taking care that the internal temperature stays below 10° C. After 5 minutes, the reaction mixture is quenched by adding 50 ml of 4N NaOH solution and concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf=0.28 (EtOAc-heptane-25% ammonia conc. 100:200:1); Rt=5.64 (gradient I).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:11]=2[C:12](OC)=[O:13])[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:11]=2[CH2:12][OH:13])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(F)c1NCCN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cccc(F)c1NCCN1CCOCC1
Temperature: 0 °C
Yield: 77.8 %

Procedure:
Methyl 2-(2-morpholinoethylamino)-3-fluorobenzoate (943 mg, 3.340 mmol) was dissolved in Et2O (˜40 mL) and cooled to 0° C. The mixture was treated with LAH (203 mg, 5.35 mmol) and stirred at 0° C. The reaction was quenched with NaF (5 g) and water (5 mL), then decanted, dried over Na2SO4, and solvent was removed under vacuum. The mixture was diluted with CH2Cl2 and EtOAc, dried over MgSO4, filtered and the solvent was evaporated. The crude product was purified on an ISCO system with EtOAc/Hex (20-80% over 20 column volumes on 12 g redisep column) to give (2-(2-morpholinoethylamino)-3-fluorophenyl)methanol (661 mg, 2.599 mmol) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][Si](C)(C)C)[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[F:18])=[O:5])[CH3:2].O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:19])[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[F:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2F)nnn1C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Br)cc2F)nnn1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57.6 %

Procedure:
In a 250 mL round-bottomed flask, 5-(4-bromo-2-fluoro-phenyl)-3-trimethylsilanylmethyl-3H-[1,2,3]triazole-4-carboxylic acid ethyl ester (616 mg, 1.54 mmol) and water (55.4 mg, 55.4 μL, 3.08 mmol, Eq: 2) were combined with tetrahydrofuran (13 mL) to give a light yellow solution. The reaction was cooled to 0° C. and 1M TBAF in THF (1.85 ml, 1.85 mmol, Eq: 1.2) was added. The reaction was stirred for 20 mins at 0° C. then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc in heptane) to afford 291 mg (58%) of the desired product as a white solid. (M+H)+=327.9/329.9 m/e; 1H NMR (DMSO-d6) δ ppm 7.73 (dq, J=9.9, 0.7 Hz, 1H), 7.50-7.62 (m, 2H), 4.29 (s, 3H), 4.25 (q, J=7.1 Hz, 2H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH2:17][CH:16]([CH3:18])[CH2:15][CH2:14][CH:13]2[CH:19]([CH3:21])[CH3:20])=[O:11])=[C:5]([N+:22]([O-])=O)[CH:4]=1>[Pd].C1COCC1.[OH-].[OH-].[Pd+2]>[NH2:22][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:10]([CH:12]1[CH2:17][CH:16]([CH3:18])[CH2:15][CH2:14][CH:13]1[CH:19]([CH3:21])[CH3:20])=[O:11]
Reactant: COc1ccc(NC(=O)C2CC(C)CCC2C(C)C)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)C2CC(C)CCC2C(C)C)c(N)c1

Procedure:
2-Isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxy-2-nitrophenyl)-amide (4.9 g) was dissolved in a suspension of 10% Pd—C (5 g) and THF (150 mL). The reaction mixture was hydrogenated over 20% Pd(OH)2 for 48 h with a balloon. The reaction mixture was filtered and concentrated to give the desired compound in sufficient purity to use in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:28])[C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:7]2.[Cl:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:29][CH2:30][CH2:31][CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:28])[C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:7]2)=[O:34]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(NC(=O)CCCCl)c2NC1=O

Procedure:
tert-Butyl (2R)-1-(8-amino-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylcarbamate (300 mg) was dissolved in ethyl acetate (5 mL), and 4-chlorobutyryl chloride (0.1 mL) and saturated aqueous sodium bicarbonate solution (5 mL) were added thereto. The mixture was stirred under cooling on ice for 45 minutes and then subjected to extraction with water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, and was dried over sodium sulfate. The solvent was evaporated under reduced pressure, whereby the title compound (377 mg) was yielded.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][N:3]=1.B1(C=C)OB([CH:17]=[CH2:18])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6]1[C:5]([CH3:10])=[CH:4][N:3]=[C:2]([CH:17]=[CH2:18])[CH:7]=1
Reactant: COc1cc(Cl)ncc1C
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: O
Product: C=Cc1cc(OC)c(C)cn1
Temperature: 80 °C
Reaction time: 15 h
Yield: 62.9 %

Procedure:
To a solution of 2-chloro-4-methoxy-5-methyl-pyridine (2.91 g, 18.5 mmol) in DME (75 mL), 2,4,6-trivinylcyclotriboroxane pyridine complex (3.13 g, 13.0 mmol) followed by 2 M aq. K2CO3 solution (25 mL) is added. The mixture is degassed and put under argon before Pd(PPh3)4 (384 mg, 0.332 mmol) is added. The mixture is stirred at 80° C. for 15 h before it is cooled to rt, diluted with water and extracted with diethyl ether. The org. extract is washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 4-methoxy-5-methyl-2-vinyl-pyridine (1.22 g) as a white solid; LC-MS: tR=0.52 min, [M+1]+=150.08.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.Cl.[NH2:20][C@@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([NH:20][C@@H:21]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: Cl
Product: O[C@H]1CC[C@@H](Nc2ncc(C#Cc3ccccc3)cn2)CC1

Procedure:
The title compound, MS: m/e=294.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and cis-4-aminocyclohexanol hydrochloride.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19])[CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][N:4]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[C:32]([F:35])([F:34])[F:33])[CH2:3]1.C1COCC1.[BH4-].[Na+]>CO>[NH2:29][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([N:4]2[CH2:5][CH2:6][N:7]([S:8]([C:11]3[CH:12]=[C:13]([C:17]([OH:23])([CH3:22])[C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:15][CH:16]=3)(=[O:10])=[O:9])[C@H:2]([CH3:1])[CH2:3]2)=[C:25]([C:32]([F:33])([F:34])[F:35])[CH:26]=1
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C(C)(O)C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN(c2ccc(CN)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C(C)(O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a flask containing 4-((3R)-3-methyl-4-{[3-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]sulfonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile (50 mg, 0.10 mmol) and 2 mL of THF was added CoCl2 (32.5 mg, 0.25 mmol) at 0° C., then NaBH4 (28.4 mg, 0.75 mmol) was added, followed by adding 1 mL of MeOH. The reaction mixture was stirred at 0° C. for 0.5 hr. Reaction was complete as determined by TLC. The reaction mixture was filtered, washed with EtoAc. The filtrate washed with H2O, then washed with sat. brine and dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography to yield 2-[3-({(2R)-4-[4-(aminomethyl)-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]-1,1,1-trifluoropropan-2-ol as a white solid. Yield 29%. HRMS: calcd for C22H25F6N3O3S+H+, 526.15936. found (ESI-FTMS, [M+H]1+), 526.15985.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:10]=3[NH:11]2)=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[CH:20]=2)[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[CH2:28]([S:25]([C:21]1[CH:20]=[C:19]([C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=[C:12]3[C:8]=2[C:9]2[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:10]=2[NH:11]3)[CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:26])[CH3:29]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)O)cc3[nH]c4ncc(C)cc4c23)c1
Yield: 90.3 %

Procedure:
Compound 132 (260 mg, 0.64 mmol) was stirred 1N NaOH (1 mL) in MeOH (2 mL) at 60° C. for 2 h. The reaction was allowed to cool, and was acidified with 1 N HCl and extracted with CHCl3. Organics were dried (MgSO4) and concentrated to give 228 mg (90%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (br s, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 8.11 (d, 1H, J=7.6 Hz), 8.01 (d, 1H, J=7.6 Hz), 7.90 (t, 1H, J=7.6 Hz), 7.87 (s, 1H), 7.79 (s, 1H), 3.31 (q, 2H, J=7.2 Hz), 2.35 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C21H18N2O4S, 395; found 395.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](O)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19].C(Cl)(=O)C([Cl:23])=O.CN(C)C=O>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:23])=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19]
Reactant: COc1cc2c(O)c(C#N)cnc2cc1OCCCl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCl
Yield: 70.4 %

Procedure:
A solution of 8 g (28.7 mmol) of 7-(2-Chloro-ethoxy)-4-hydroxy-6-methoxy-quinoline-3-carbonitrile and 18.2 g (143.5 mmol) of oxalyl chloride in 80 ml of methylene chloride containing 0.26 g of dimethylformamide was stirred at reflux for 2.5 hr. The solvent was removed. The residue was mixed with cold dilute sodium hydroxide and extracted several time with ethyl acetate and tetrahydrofuran. The combined extracts were dried over magnesium sulfate and the solution was passed through a short silica gel column. The solvents were removed giving 6.0 g of the title compound as an off-white solid that is used without additional purification.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C=Cc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A suspension of 4-formylcinnamic acid (1.76 g), p-methoxybenzyl chloride (1.63 ml) and potassium carbonate (2.76 g) in 20 ml dimethylformamide was stirred at 80° C. for 7 hours, and then allowed to cool. The reaction mixture was extracted with ethyl acetate and washed with water. The combined organic layers were dried over magnesium sulfate. The drying agent was filtered off and the filtrate was evaporated under reduced pressure and dried to give p-anisyl 4formylcinnamate of interest (2.96 g, 100%) as a pale yellow solid.
Reaction SMILES: [C:1]1([NH:11][C:12](=S)[NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>C(O)C>[CH3:25][C:23]1[NH:14][N:13]=[C:12]([NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: NNC(=S)Nc1cccc2ccccc12
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2cccc3ccccc23)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
A suspension of 15.0 g (0.069 mole) of 4-(1-naphthalenyl)-3-thiosemicarbazide and 11.4 g (0.069 mole) of ethyl 2-chloroacetoacetate in 100 mL of absolute ethanol was stirred at room temperature for 1 hr. Alcoholic hydrogen chloride (2N, 50 mL) was added, the mixture refluxed for 1 hr, filtered while hot and the filtrate evaporated under reduced pressure. The residue was recrystallized twice from 190 ethanol then twice from absolute ethanol to give 6.2 g of product, mp 199°-202° C. The sample was dried at 56° C./4 hr/0.1 mmHg then at 25° C./0.1 mmHg/for ~16 hr.
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[Na].Cl[C:12]([O:14][CH3:15])=[O:13]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:12](=[O:13])([O:9][C:3]1([C:1]#[CH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[O:14][CH3:15]
Reactant: COC(=O)Cl
Reactant: C#CC1(O)CCCCC1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: C#CC1(OC(=O)OC)CCCCC1
Temperature: 25 °C

Procedure:
A solution of 36.0 gm of 1-ethynylcyclohexanol in 50 ml of benzene was slowly added drop-by-drop to an agitated suspension, cooled to 0° to 5° C, of 5.5 gm of finely distributed sodium in 50 ml of absolute toluene and 250 ml of benzene, and was agitated at room temperature until reaction had been completed. 26.0 gm of methyl chloroformate were added under cooling to the sodium salt which has been formed. The mixture was allowed to react for 12 hours at room temperature and was washed several times with water and dried. After distilling off the solvent, the raw ester was fractionated by means of a 20 cm Vigreux column. The methyl 1 -ethynylcyclohexyl carbonate thus obtained constitutes a colorless liquid having a fruity, herbal, complex odor and a distinctive fragrance of dill, and has the following characteristic values;