Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[C:3]1[C:12]2[C:7](=CC=C[C:11]=2[N:13]([CH3:15])C)[CH:6]=[CH:5][CH:4]=1.[CH:17]([O:20]C1C=CC(CC(O)=O)=CC=1)([CH3:19])[CH3:18].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:38])C=CC=CC=1>O1CCCC1>[N:13]([CH2:11][C:12]1[CH:3]=[CH:4][C:5]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:6][CH:7]=1)=[C:15]=[O:38]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: CC(C)Oc1ccc(CC(=O)O)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(CN=C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.3 %

Procedure:
1,8-Bis(dimethylamino)-naphtalene (3.19 g, 14.9 mmol) was added to a solution of 4-(isopropoxy)phenyl acetic acid (2.89 g, 14.9 mmol) in dry tetrahydrofuran (18 mL) at rt under argon atmosphere. After 25 minutes stirring at rt diphenylphosphoryl azide (4.10 g, 14.9 mmol) was added dropwise and the mixture refluxed for 6 hours. It was allowed to cool to rt and then stored at −20° C. overnight to precipitate out the ammonium phosphate salt. A mixture of diethyl ether and ethyl acetate (1:1 v/v, 25 mL) was added to the cold reaction mixture. The precipitate was filtered from the reaction mixture and washed with diethyl ether:ethyl acetate (1:1 v/v, 20 mL). The filtrate was evaporated to dryness giving 1-isocyanatomethyl-4-isopropoxybenzene as an oil (3.2 g), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH3:2].[CH3:15]C1C=CC(C)=CC=1O>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=1[CH3:13])[CH3:2]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CCOC(=O)COc1ccccc1C
Product: CCOC(=O)COc1cc(C)ccc1C

Procedure:
The title compound was prepared according to the method described for preparing compound 10.1, using 2,5-dimethylphenol as the starting material. 1H NMR (400 MHz) (CDCl3) δ 7.03 (1H, d, J=7.5 Hz); 6.72 (1H, d, J=7.5 Hz); 6.52 (1H, s); 4.62 (2H, s); 4.27 (2H, q, J=7.1 Hz); 2.30 (3H, s); 2.25 (3H, s); 1.30 (3H, t, J=7.1 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:19]=O)[NH:12][C:11]([CH3:21])=[C:10]1[C:22]([OH:24])=[O:23])#[N:2].Cl.[NH2:26]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C.C(OCC)C>[C:19]([C:13]1[NH:12][C:11]([CH3:21])=[C:10]([C:22]([OH:24])=[O:23])[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[C:14]=1[C:15]([O:17][CH3:18])=[O:16])#[N:26]
Reactant: COC(=O)C1=C(C=O)NC(C)=C(C(=O)O)C1c1ccccc1C#N
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COC(=O)C1=C(C#N)NC(C)=C(C(=O)O)C1c1ccccc1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
To a solution of isopropyl ester of 4-(2-cyanophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (3.90 g) in acetic acid (20 ml) were added hydroxylamine hydrochloride (0.88 g) and sodium acetate (1.30 g), and the mixture was stirred for an hour at ambient temperature. To the reaction mixture was added acetic anhydride (3.97 g) with stirring, and the stirring was continued for an hour at ambient temperature and for additional 4 hours at 95°~100° C. After the reaction mixture was allowed to stand at ambient temperature, the acetic acid was removed by distillation under reduced pressure. The resultant residue was diluted with water, neutralized with an aqueous solution of sodium bicarbonate and then extracted twice with ethyl acetate. After the combined extract was washed twice with water and dried, the solvent was removed by distillation under reduced pressure to give an oil, which was allowed to stand overnight and pulverized with a small amount of ethyl ether. The powder was washed with isopropyl ether and recrystallized from methanol to give yellowish-orange crystals of isopropyl ester of 6-cyano-4-(2-cyanophenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (1.99 g), mp 198°~200° C.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1>C(OCC)(=O)C.[Fe]>[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(F)cc1OCc1ccccc1
Temperature: 76 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a mixture of iron powder (90.36 g, 1.62 mol) and acetic acid (10%, 400 mL) at 80° C. was added a solution of the title compound of Step A (40 g, 0.162 mol) in ethyl acetate (200 mL) dropwise with vigorous stirring. The reaction mixture was stirred further at 76° C. for 1 h. After the reaction was complete, the hot reaction mixture was filtered through Celite® (200 g) and the filter cake was washed with ethyl acetate (1000 mL). The filtrate was washed with water (3×200 mL), sodium bicarbonate solution (5%, 3×200 mL), dried (MgSO4) and concentrated to give the crude product. The product was purified by flash chromatography to give 24.76 g of the title compound of Step B. 1H NMR (CDCl3, 400 MHz): δ 7.41 (m,5H), 6.60 (m,3H), 5.04 (s,2H).
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1.Cl[C:16]1[C:17]2[N:25]=[C:24](Cl)[CH:23]=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:16]2[C:17]3[N:25]=[C:24]([S:1][C:2]4[N:6]=[CH:5][NH:4][N:3]=4)[CH:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[N:9][CH:10]=1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Sc1nc[nH]n1
Reactant: Nc1ccc(F)cn1
Product: Fc1ccc(Nc2ncnc3ccc(Sc4nc[nH]n4)nc23)nc1

Procedure:
The compound of Example 50 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 3-mercapto-[1,2,4]triazole, 2-amino-5-fluoropyridine and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Br:24][C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Br:24][C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(C)ccc2Br)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Bromo-5-methyl-benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[C:13]([Cu])#[N:14].CN(C=O)C.[OH-].[NH4+]>C(Cl)Cl.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: N#C[Cu]
Reactant: Nc1ccc(C(F)(F)F)cc1I
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc(C(F)(F)F)ccc1N

Procedure:
A 2-liter flask was charged with 100 g (0.348 mol) of 4-amino-3-iodobenzotrifluoride, 40 g of CuCN and 750 mL of DMF. The mixture was heated to and then maintained at reflux for 1 hour. The reaction was cooled and poured into 3 L of water containing 300 mL of concentrated ammonium hydroxide. To the mixture was added 1 L CH2Cl2. The mixture was then filtered through Celite. The layers were separated and the aqueous layer was back extracted with CH2Cl2. The organic extracts were combined and the solvent removed under reduced pressure. The residue was dissolved in 1.5 L of ether and the resulting solution was washed with 1N ammonium hydroxide, aqueous sodium bisulfite, 1N aqueous HCl and brine. The solution was dried over anhydrous MgSO4 and filtered through a silica gel plug containing a layer of MgSO4 on top. The plug was washed with 0.5 L ether. The ether solutions were combined and concentrated to 750 mL and let stand at room temperature. After 2 days the resulting solids were collected, washed with hexanes and dried under reduced pressure to afford 2-amino-5-(trifluoromethyl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 7.68 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 4.80 (br s, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](N2CCOCC2)[CH2:3][CH2:2]1.[S:13](Cl)(=[O:16])(=[O:15])[NH2:14].C(NC(C)C)(C)C.C1C[O:28]CC1>>[O:28]=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH:3]1[S:13]([NH2:14])(=[O:16])=[O:15]
Reactant: C1CCOC1
Reactant: NS(=O)(=O)Cl
Reactant: C1=C(N2CCOCC2)CCOC1
Solvent: CC(C)NC(C)C
Product: NS(=O)(=O)C1COCCC1=O
Temperature: -40 °C
Reaction time: 2 h

Procedure:
1.3 g of 4-(3,6-dihydro-2H-pyran-4-yl)morpholine were dissolved under argon in 12 ml of THF, the mixture was cooled to −40° C., and then 1.3 g of sulfamoyl chloride were added, followed by 6 ml of diisopropylamine. The cooling was removed and, after the mixture had come to room temperature, it was stirred for another 2 hours. An oil separated out. The THF was decanted off, and the residue was taken up in methanol and filtered through silica gel. The filtrate was concentrated under reduced pressure and the residue, bound to 12 g of Celite, was purified by means of a silica gel column (50 g): solvent A: dichloromethane, B: methanol, gradient: 0 min 2% B, 3 min 2% B, 5 min 5% B, 35 min 10% B, 45 min 10% B; flow rate 20 ml/min; detection: 220 nm, fraction size: 20 ml. After removal of the solvent under reduced pressure, the product was thus obtained with impurities. The residue (1.09 g) was used further without further workup.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:38])[C:29]2([CH2:35][NH:36][CH3:37])[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]([OH:54])=O)[CH2:47][CH2:46]1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[F:43][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:38])[C:29]2([CH2:35][N:36]([CH3:37])[C:52](=[O:54])[CH2:51][N:48]3[CH2:47][CH2:46][O:45][CH2:50][CH2:49]3)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: CNCC1(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)C=CC=CN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CC1(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)C=CC=CN1)C(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
Into a 50-mL vial, was placed N-(3-(trifluoromethyl)benzyl)-2-(2-(2-((methylamino)methyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (10 mL), 2-morpholinoacetic acid (28.9 mg, 0.20 mmol, 1.20 equiv), EDC.HCl (47.4 mg, 0.25 mmol, 1.50 equiv), and 4-dimethylaminopyridine (30.4 mg, 0.25 mmol, 1.50 equiv). The resulting solution was stirred for 4 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 3×50 mL of aqueous NH4Cl, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 116 mg (59%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 9.12 (m, 1H), 8.86 (d, J=9.2 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.17 (m, 1H), 8.12 (m, 1H), 8.01 (m, 1H), 7.95 (m, 1H), 7.80 (m, 3H), 7.60 (m, 3H), 4.96 (m, 2H), 4.72 (s, 2H), 4.50 (m, 2H), 3.98 (m, 4H), 3.70 (m, 4H), 3.1 (s, 3H), 2.10 (m, 4H), 1.98 (s, 2H). MS (ES, m/z): 730 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].I[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)Cl>[CH:11]([O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])([CH3:13])[CH3:12]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)Oc1cccc(C#N)c1
Reaction time: 8 h

Procedure:
A combination of 32 g (268 mmol, Aldrich) 3-cyanophenol, 26.9 mL (268 mmol) 2-iodopropane, and 88 g (269 mmol) cesium carbonate in 1:1 CH2Cl2:CH3CN was heated to reflux and allowed to stir overnight. HPLC/MS showed pure product so the suspension was filtered, washed with CH3CN and concentrated. The remaining oil was dissolved in CH2Cl2 and filtered thru a short pad of silica with CH2Cl2. The filtrate was concentrated to dryness to give the product. An alternative preparation uses the conditions similar to the above except that potassium carbonate is used as the base.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39]C(OCC3C=CC=CC=3)=O)=[CH:33][C:32]=2[CH3:50])=[C:28]([CH:51]([CH3:53])[CH3:52])[NH:27][N:26]=1)(=[O:3])[CH3:2]>O1CCCC1.[C].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][C:32]=2[CH3:50])=[C:28]([CH:51]([CH3:53])[CH3:52])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCNC(=O)OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(benzyloxycarbonylamino)ethyl]-2-methylphenyl}-methyl)-5-isopropyl-1H-pyrazole (0.3 g) was dissolved in tetrahydrofuran (2 mL). To the solution was added 10% palladium-carbon powder (20 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethyl)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (0.24 g). The obtained 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethyl)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (0.13 g) was dissolved in dichloromethane (2.6 mL). To the solution were added triethylamine (0.042 mL) and 4-nitrophenyl chloroformate (52 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. A ¼ amount of the reaction mixture was separated. To the part of the reaction mixture were added triethylamine (0.028 mL) and L-threonine amide hydrochloride (23 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: ethyl acetate-ethyl acetate/methanol=10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-{3-[(1S,2R)-1-carbamoyl-2-hydroxypropyl]-ureido}ethyl)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (30 mg). This material was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.006 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (0.005 mL). The resulting mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (21 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[CH:30]1([N:36]2[CH2:41][CH2:40][N:39]([C:42]3[CH:47]=[C:46]([CH2:48][NH2:49])[CH:45]=[C:44]([C:50]4[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=4)[N:43]=3)[CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:49][CH2:48][C:46]3[CH:45]=[C:44]([C:50]4[CH:51]=[CH:52][C:53]([C:56]([F:59])([F:57])[F:58])=[CH:54][CH:55]=4)[N:43]=[C:42]([N:39]4[CH2:38][CH2:37][N:36]([CH:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:41][CH2:40]4)[CH:47]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCN(C3CCCCC3)CC2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2cc(-c3ccc(C(F)(F)F)cc3)nc(N3CCN(C4CCCCC4)CC3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 10.3 %

Procedure:
A solution of acid 18 (463 mg, 1.5 mmol) in THF (30 mL) was added with DEPC (0.23 mL, 1.0 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27E (628 mg, 1.04 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (40 mL) and washed with water (50 mL) and brine. The separated organic phase was dried over Na2SO4 and evaporated under reduced pressure and the residue was purified by flash chromatography (9:1 EtOAc:methanol) to afford a white solid (110 mg) after crystallization from diethyl ether. Yield=10%, 1HNMR (DMSO, 200 MHz) δ 1.15 (bm, 9H), 1.80 (bm, 4H), 2.35 (bm, 1H), 2.59 (bm, 4H), 3.37 (bm, 2H), 3.65 (bm, 4H), 4.45 (bd, 2H), 6.89 (s, 1H), 7.35 (m, 2H), 7.60 (d, 1H, J=3.4), 7.82 (d, 2H, J=8), 8.25 (bm, 3H). [M+1] 711.65 (C33H39ClF3N5O3S2 requires 710.27).
Reaction SMILES: C([C:5]1[CH:10]=[C:9](C)[CH:8]=[C:7](C(C)(C)C)[C:6]=1[OH:16])(C)(C)C.C([Mg:21]CCCC)CCC>CCCCCCC.C1CCCCC1>[C:6]1([O-:16])[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]=1.[Mg+2:21].[C:6]1([O-:16])[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]=1
Reactant: CCCC[Mg]CCCC
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCCCCCC
Solvent: C1CCCCC1
Product: [Mg+2]
Product: [O-]c1ccccc1

Procedure:
0.637 g of 2,6-di-tert-butyl-4-methylphenol (from Aldrich) and 2.9 ml of a 1.0 molar solution of dibutylmagnesium (DBM) in heptane (from Aldrich) were combined at 25° C. and stirred for 10 hours in 26 ml of cyclohexane before use.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[OH:13].CCN(C(C)C)C(C)C.[O:23](S(C(F)(F)F)(=O)=O)[S:24]([C:27]([F:30])([F:29])[F:28])(=O)=[O:25]>ClCCl>[F:28][C:27]([F:30])([F:29])[S:24]([O:13][C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:25])=[O:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cccc2c(O)cccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc2c(OS(=O)(=O)C(F)(F)F)cccc12
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
To a solution of 5-methoxynaphthalen-1-ol (above Step-1 intermediate) (19 g, 0.11 mol) in anhydrous dichloromethane (250 mL) at 0° C. was added, DIPEA (23 mL, 0.16 mol) and the mixture was stirred for 15 min. To this, Tf2O (21.7 mL, 0.13 mol) was added slowly at 0° C. and the reaction mixture was stirred for 1.5 h and then quenched slowly with water (100 mL). The aqueous layer was extracted with CH2Cl2 (4×100 mL) and the combined organic layer was washed with water (100 mL), brine (100 mL), dried and filtered. The solvent was then evaporated and the crude product was purified by column chromatography (5% EtOAc:Hexanes) to furnish the desired compound (28.5 g, 85%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[F:14][C:15]([F:25])([F:24])[S:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[CH3:13][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([S:16][C:15]([F:25])([F:14])[F:24])=[CH:18][CH:19]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: Nc1ccc(SC(F)(F)F)cc1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Product: CN(C)c1ccc(CC(=O)Nc2ccc(SC(F)(F)F)cc2)cc1

Procedure:
The product was prepared from 2-(4-(dimethylamino)phenyl)acetic acid (23 mg) and 4-trifluoromethylthioaniline (28 mg) according to Method C: 1H NMR (300 MHz, CDCl3) δ ppm 2.98 (s, 6 H), 3.66 (s, 2 H), 6.72-6.78 (m, 2 H), 7.14-7.19 (m, 2 H), 7.19 (s, 1 H), 7.43-7.51 (m, 2 H), 7.52-7.57 (m, 2 H); MS (ESI-pos) m/z 355.0 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13](Cl)[N:14]3[C:19]([CH:20]=2)=[C:18]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])[C:17](=[O:29])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.C(OCC)(=O)C>[ClH:27].[C:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[Cl:31])[N:14]3[C:19]([CH:20]=2)=[C:18]([C:21]2[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=2[Cl:27])[C:17](=[O:29])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N1CC=C(c2cc(Cl)n3ccc(=O)c(-c4c(Cl)cccc4Cl)c3c2)CC1
Reactant: OB(O)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)N1CC=C(c2cc(-c3ccccc3Cl)n3ccc(=O)c(-c4c(Cl)cccc4Cl)c3c2)CC1
Temperature: 80 °C
Yield: 73.4 %

Procedure:
To a solution of 8-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-6-chloro-1-(2,6-dichlorophenyl)-2H-quinolizin-2-one (57 mg) in DME was added 2-chlorophenylboronic acid (38 mg), palladium tetrakis triphenylphosphine (14 mg) and 2N sodium carbonate (0.36 mL). The mixture was heated to 80° C. for a couple of hours, then cooled to room temperature, and diluted with ethyl acetate/saturated aqueous sodium bicarbonate. The organic layers were dried over magnesium sulfate and concentrated. The residue was purified by silica gel (100% acetone). The free base was dissolved in methylene chloride and 3 eq. of HCl (1N in ethyl ether) was added to give the HCl salt (26 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](O)=O)[CH3:2].C=O.N1C=CC=CC=1.N1CCCCC1>O>[CH2:1]([O:3][C:4](=[O:18])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCOC(=O)C(CCCc1ccccc1)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: C=C(CCCc1ccccc1)C(=O)OCC

Procedure:
50 g of 3-phenylpropylmalonic acid monoethyl ester, 7.5 g of paraformaldehyde, 37.5 ml of pyridine and 2.5 ml of piperidine are stirred together at 50° C. for 5 hours. After cooling, 350 ml of water are added to the reaction mixture, and the mixture is then extracted 3 times with 150 ml of hexane each time. After washing with 1 N hydrochloric acid, water and sodium bicarbonate solution, the organic phase is concentrated and distilled. 5-Phenyl-2-methylenevaleric acid ethyl ester is obtained as a colorless liquid of b.p. 78° to 79° C. under 0.02 mm Hg.