Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:49][C:50]([Si:53]([CH3:64])([CH3:63])[O:54][C:55]1[CH:56]=[C:57]([CH2:61][NH2:62])[CH:58]=[CH:59][CH:60]=1)([CH3:52])[CH3:51]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:62][CH2:61][C:57]2[CH:58]=[CH:59][CH:60]=[C:55]([O:54][Si:53]([C:50]([CH3:52])([CH3:51])[CH3:49])([CH3:63])[CH3:64])[CH:56]=2)=[O:7])[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Reactant: Cc1cc(C(=O)O)cc(Cl)c1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
A suspension of 3-chloro-4-hydroxy-5-methylbenzoic acid (4.7 g, 25.2 mmol) in dichloromethane (50 mL) was cooled to 0° C. and BOP reagent (12.3 g, 27.8 mmol) was added, followed by diisopropylethylamine (13.2 mL, 75.6 mmol). A solution of 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzene-methanamine (Example 8; 6.59 g, 27.8 mmol) in dry dichloromethane (10 mL) was added by syringe and the resulting solution was stirred at −0° C. for 3 h. The solvent was evaporated and ethyl acetate (200 mL) was added. The solution was washed with 1 M HCl (2×50 mL), aqueous sodium hydrogen carbonate (100 mL), brine (100 mL), and water (100 mL) dried (MgSO4), filtered, evaporated, and chromatographed (30% ethyl acetate/hexanes) to give 2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylphenol (6.03 g, 59%) as a pale pink solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:5]=1[NH2:6].[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1>>[CH3:14][N:15]1[CH:19]=[C:18]([C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:3][C:2]([F:13])([F:12])[F:1])[CH:10]=2)[CH:17]=[N:16]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Product: Cn1cc(-c2ccc(N)c(OC(F)(F)F)c2)cn1

Procedure:
The title compound was prepared according to the method described for Preparation 98 using 2-trifluoromethoxy-4-bromoaniline and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: OC1C(C)=C(O)C=CC=1C=O.C(Cl)C=C.C(N(CC)C(C)C)(C)C.C([O:28][C:29]1[C:36]([CH3:37])=[C:35]([O:38][CH2:39][CH:40]=[CH2:41])[CH:34]=[CH:33][C:30]=1[CH:31]=[O:32])C=C>>[CH2:39]([O:38][C:35]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([OH:28])[C:36]=1[CH3:37])[CH:40]=[CH2:41]
Reactant: C=CCOc1ccc(C=O)c(OCC=C)c1C
Agent: Cc1c(O)ccc(C=O)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C=CCCl
Product: C=CCOc1ccc(C=O)c(O)c1C

Procedure:
By following Example 2 procedure, 5.0 g of 2,4-dihydroxy-3-methylbenzaldehyde was reacted with 8.35 g of allyl chloride and 5.1 g of N,N-diisopropylethylamine to get 8.41 g of crude title product containing 12% of 2,4-bis(allyloxy)-3-methylbenzaldehyde by GC. Crude product was purified by column chromatography to get the title compound as liquid. IR (neat): 3280, 3088, 3024, 2988, 2926, 2838, 2748, 1645, 1585, 1499, 1452, 1427, 1388, 1353, 1330, 1290, 1250, 1182, 1110, 1022, 990, 928, 891, 788, 758, 715, and 646 cm−1. 1H-NMR (CDCl3, 400 MHz): δ 11.45 (s, 1H, exch. with D2O, OH), 9.70 (s, 1H, CHO), 7.34 (d, J=8.8 Hz, 1H, H-6), 6.53 (d, J=8.8 Hz, 1H, H-5), 6.06 (m, 1H, CH═CH2), 5.44 (dq, J=1.6, 19.2 Hz, 1H, CH═CH2), 5.32 (dq, J=1.2, 10.8 Hz, 1H, CH═CH2), 4.64 (dt, J=1.6, 4.8 Hz, 2H, CH2═CHCH2), 2.13 (s, 3H, ArCH3). 13C NMR (CDCl3, 100 MHz): δ 194.60 (CHO), 163.17 (C-4), 160.99 (C-2), 133.00 (CH2═CH); 132.38 (C-5), 117.55 (CH2═CH), 113.48 (C-1), 103.75 (C-5), 68.90 (OCH2), 7.30 (ArCH3). Mass (EI-MS): 192.1 (M), 191.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.O[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:3]([CH2:9][O:10][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCc1nc(Cl)ccc1Cl
Product: COC(=O)c1ccc(OCc2nc(Cl)ccc2Cl)cc1

Procedure:
The title compound was prepared from the intermediate from Step A and methyl 4-hydroxybenzoate using the Mitsunobu conditions described in EXAMPLE 4. 1H NMR (500 MHz, CDCl3): δ 8.054 (d, J=8.8 Hz, 2H); 7.74 (d, J=8.4 Hz, 1H); 7.35 (d, J=8.4 Hz, 1H); 7.07 (d, J=8.7 Hz, 2H); 5.31 (s, 2H); 3.93 (s, 3H). LCMS2 2.29 min. (M+H)=312
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][NH2:18])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[N:20]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH:18][C:24]([C:22]3[CH:23]=[N:19][NH:20][CH:21]=3)=[O:25])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1cn[nH]c1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1cc(CN2CCCCC2)ccn1)c1cn[nH]c1
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
A solution of 1.0 g of 3-(4-piperidinomethyl-2-pyridyloxy)propylamine and 0.45 g of 4-pyrazolecarboxylic acid dissolved in 15 ml of dimethylformamide was stirred for 5 minutes, whilst ice-cooling, after which 734 mg of diethyl cyanophosphonate and 0.68 ml of triethylamine were added to the resulting mixture. The mixture was then stirred at room temperature for 3 hours, after which it was diluted with water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and chloroform as the eluent, to give 1.2 g (yield 85%) of the title compound as a white powder, melting at 117°-119° C.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([CH:10]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[CH:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1)=O.[NH3:32]>>[NH2:32][C:4]1[N:9]=[C:8]([CH:10]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[CH:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CS(=O)c1nccc(C(c2cccc(C#N)c2)C(c2cccnc2)c2cccnc2)n1
Reactant: N
Product: N#Cc1cccc(C(c2ccnc(N)n2)C(c2cccnc2)c2cccnc2)c1
Temperature: 100 °C

Procedure:
The solution of diastereomeric mixture of (±)-3-{1-[2-(methylsulfinyl)pyrimidin-4-yl]-2,2-dipyridin-3-ylethyl}benzonitrile (0.11 g, 0.25 mmol) in NH3 saturated DMSO(2 mL) was heated to 100 ° C. in microwave for 2 h. The mixture was concentrated and the residue was purified by silica gel chromatography (5% MeOH in CH2Cl2) to give (±)-3-[1-(2-aminopyrimidin-4-yl)-2,2-dipyridin-3-ylethyl]benzonitrile. 1H-NMR (500 MHz, DMSO-d6) δ 8.68 (d, 1H, J=1.5), 8.60 (d, 1H, J=1.5), 8.29 (d, 1H, J=4.6), 8.23 (d, 1H, J=4.6), 8.00 (d, 1H, J=4.8), 7.95 (s, 1H), 7.90(t, 2H, J=9.4), 7.80(d, 1H, J=8.0), 7.55 (d, 1H, J=7.6), 7.40 (t, 1H, J=7.8), 7.25(dd, 1H, J=7.8, 4.6), 7.19(dd, 1H, J=8.0, 4.6), 6.67(d, 1H, J=5.1), 6.54(s,2H), 5.25 (d, 1H, J=12.5), 5.20 (d, 1H, J=12.4). LRMS m/z (M+H) Calcd: 379.4, found: 379.2.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.I[C:22]1[NH:26][N:25]=[CH:24][CH:23]=1.C(Cl)Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:22]1[NH:26][N:25]=[CH:24][CH:23]=1
Reactant: Ic1ccn[nH]1
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-c2ccn[nH]2)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
To methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 800 mg, 2.9 mmol) in dioxane (30 mL) was added 5-iodo-1H-pyrazole (674 mg, 3.5 mmol), and Pd(dppf)Cl2.DCM (237 mg, 0.29 mmol). The mixture was degassed with argon and stirred for 10 minutes then an aqueous potassium carbonate solution (2 M, 8 mL) was added. The mixture was heated at 90° C. for 18 h, then cooled and diluted with EtOAc and filtered through Celite®. The filtrate was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; 0-30% EtOAc in hexanes) to yield 258 mg (41%) of the title compound as a solid. m/z (ES+) 217 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=2[F:31])[C:13]2[C:14]([CH3:22])=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[N:17][CH:18]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C=O.[OH-].[Na+].[C:36](OCC)(=[O:38])C>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=2[F:31])[C:13]2[C:14]([CH3:22])=[CH:15][C:16]([C:19]([NH:21][CH2:36][OH:38])=[O:20])=[N:17][CH:18]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(F)c(F)c1
Reactant: CCOC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(F)c(F)c1
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of 5-[[(3,4-difluorophenyl)sulfonyl](2,3,6-trifluorophenyl)methyl]-4-methylpyridine-2-carboxamide (160 mg, 0.350 mmol) in ethylene glycol dimethyl ether (3 ml), an aqueous solution of formaldehyde (37%, 78.9 μl) and 1 N aqueous sodium hydroxide (17.5 μl) were added at room temperature, and the mixture was stirred for 18 hours. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed with saturated aqueous ammonium chloride. Subsequently, 1 N hydrochloric acid was added to the organic layer, and the mixture was stirred for 1 hour. After the organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of ethyl acetate and diethyl ether, and then was collected by filtration, to obtain the title compound (100 mg, 0.206 mmol, 59%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)C(C)C)(C)C.[NH:53]1[C:57]([CH2:58][NH2:59])=[N:56][N:55]=[N:54]1>CN(C)C=O.[Cl-].[NH4+]>[NH:53]1[C:57]([CH2:58][NH:59][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([CH:4]([NH:5][C:6]3[CH:7]=[CH:8][C:9]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=4)=[CH:10][CH:11]=3)[CH2:3][CH:2]([CH3:1])[CH3:31])=[N:23][CH:24]=2)=[N:56][N:55]=[N:54]1
Reactant: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Reactant: NCc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCc2nnn[nH]2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a solution of 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino) butyl)nicotinic acid (0.100 g, 0.233 mmol) in N,N-dimethylformamide (3.0 mL) was added 1,1′-carbonyldiimidazole (75.6 mg, 0.466 mmol) and N,N-diisopropylethylamine (181 mg, 1.40 mmol). The reaction was stirred for 30 minutes at 80° C. (1H-tetrazol-5-yl)methanamine (80.2 mg, 0.466 mmol) was added and the reaction continued to stir at 80° C. overnight. The reaction was diluted with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by preparative HPLC (column: Boston Analytics Symmetrix ODS-H 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient: 10 to 80% MeCN in water) gave N-((1H-tetrazol-5-yl)methyl)-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinamide (15.7 mg, 13%) as a light yellow solid. 1H NMR (400 MHz, CD3OD, δ): 9.35 (m, 1H), 8.98 (s, 1H), 8.15 (d, 1H), 7.72 (d, 4H), 7.50 (d, 1H), 7.35 (d, 2H), 6.64 (m, 3H), 4.75 (d, 2H), 4.55 (m, 1H), 1.75 (m, 2H), 1.55 (m, 1H), 0.95 (d, 3H), 0.85 (d, 3H). MS (M+1): 510.4.
Reaction SMILES: C[C:2]1([N:23]=[N+]=[N-])[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:3]1[O:4][C:5](=[O:7])[CH3:6].[H][H].O1CCC[CH2:29]1>O=[Pt]=O>[CH3:29][NH:23][CH:2]1[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:3]1[O:4][C:5](=[O:7])[CH3:6]
Reactant: [H][H]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)C(C)(N=[N+]=[N-])O[C@@H]1C(=O)O
Reactant: C1CCOC1
Agent: O=[Pt]=O
Product: CNC1O[C@H](C(=O)O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
Next, 6.17 g, that is, 17 mmol methyl 2,3,4-tri-O-acetylglucopyranuronosyl azide was added to 50 ml of dry tetrahydrofuran containing 400 mg of PtO2. The mixture was shaken under 40 psi of hydrogen for 2 hours, filtered, concentrated to dryness, to produce methyl 2,3,4-tri-O-acetylglucopyranuronosyl amine. ##STR8##
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:23][C:24]([F:38])([F:37])[O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[CH:33][N+]([O-])=O)=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:15]([N:22]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:32]([C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:37])[F:38])=[CH:31][CH:30]=2)=[CH:33]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1

Procedure:
The title compound (0.28 g) was prepared from 0.50 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 274 μL of benzylamine, and 0.59 g of 1-trifluoromethoxy-4-(2-nitro-vinyl)-benzene using CH2Cl2 as the solvent. MS (ESI): exact mass calculated for C21H19F3N2O, 372.14; found, m/z 373.2 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.44-7.41 (m, 2H), 7.37-7.26 (m, 5H), 7.19-7.17 (m, 3H), 5.15 (s, 2H), 4.37 (s, 2H), 3.51 (t, J=6.3 Hz, 2H), 2.87 (t, J=6.3 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Cl[C:11]1[CH:16]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]=1[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.N#N.C(OCC)(=O)C>[CH:18]([O:17][C:15]1[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]([CH3:24])=[C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:16]=1)([CH3:20])[CH3:19]
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1Cl
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1-c1ccncc1
Temperature: 150 °C

Procedure:
4-Pyridineboronic acid (147 mg, 1.20 mmol, 1.1 equiv.) is dissolved in a 2:1 v/v mixture of dioxane and H2O (15 mL) and N2 is bubbled through for 5 minutes. Tris(dibenzylidene acetone)dipalladium (0) (100 mg, 0.109 mmol, 0.1 equiv.), 2-dicyclohexylphosphine-2′-6′-dimethoxy biphenyl (112 mg, 0.272 mmol, 0.25 equiv.), 1-chloro-5-isopropoxy-2-methyl-4-nitro-benzene (Intermediate 4, 250 mg, 1.09 mmol, 1.0 equiv.) and K3PO4 (462 mg, 2.18 mmol, 2.0 equiv.) are added under a N2 blanket. The reaction vessel is sealed and heated with microwave irradiation to 150° C. for 20 min. After cooling to room temperature, the reaction is diluted with ethyl acetate and washed with 1 N aqueous NaOH (2×), the organic layer is then dried over Na2SO4 and filtered. After concentration, the crude product is purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-pyridine as a brown solid: ESMS m/z 273.1 (M+Ft).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.Cl[CH2:43][C:44]([NH2:46])=[O:45].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:18][CH2:19][N:20]([CH2:43][C:44]([NH2:46])=[O:45])[CH2:21][CH2:22]2)=[CH:5][N:4]([C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: NC(=O)CCl
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(CC(N)=O)CC3)c2c1
Temperature: 115 °C
Reaction time: 5 h
Yield: 68.8 %

Procedure:
A mixture of 54 mg 6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-piperazin-1-yl-quinoline obtained in Example 187, 9.4 mg 2-chloroacetamide, 16 mg potassium carbonate and 3 mL dimethylformamide was stirred at 115° C. for 5 hours. 3 mg of 2-chloroacetamide was added thereto, and the mixture was stirred at the same temperature for 3 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, then washed twice with water and then with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 41 mg of the title compound as a colorless amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18]CC4C=CC=CC=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][N:37]3[CH3:42])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][N:37]3[CH3:42])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: CN1CCCCC1CCOc1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CN1CCCCC1CCOc1ccc(CC2c3ccc(O)cc3CCN2c2ccc(F)cc2)cc1
Yield: 13.9 %

Procedure:
The title compound was prepared as described in Example 44.G, using 2-(4-fluorophenyl)-1-(4-[2-(1-methyl(2-piperidyl))ethoxy]benzyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (0.043 g, 0.076 mmol). The product was purified by radial chromatography (100% CH2Cl2, then CH2Cl2/MeOH, 95:5) to yield the title compound (0.005 g, 14% yield): ES−MS (m/z) 475 [M+H]+.
Reaction SMILES: [F:1][C@@:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[S:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C@:2]([F:1])([CH3:6])[C:3]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:4])=[CH:8][CH:9]=1)(=[O:16])=[O:15]
Reactant: C[C@](F)(C(=O)O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@](F)(C(=O)NS(C)(=O)=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of 3 (0.5 g, 1.6 mmol) in dry CH2Cl2 (10 ml), N,N-carbonyldiimidazole (0.33 g, 2.0 mmol) was added under vigorous stirring. After 1 h methanesulfonamide (0.19 g, 2 mmol) and triethylamine (0.28 mL, 2 mmol) were added and the resulting mixture was left stirring overnight at room temperature. The organic mixture was washed with a saturated solution of NaHCO3 (2×10 mL) and brine (3×10 mL), dried over Na2SO4 and evaporated under vacuum to give pure 17 as a colourless oil (0.60 g, yield 95%). [α]b=+9 (c=1; CH3OH). 1H-NMR (DMSO-d6) δ 7.70 (d, 2H, J=7 Hz), 7.55 (d, 2H, J=7 Hz), 3.05 (s, 3H), 1.85 (d, 3H, J=23 Hz).
Reaction SMILES: [OH:1][C:2]([CH3:31])([CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[NH:15][CH:16]=[C:17]([S:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)=[O:13])=[CH:7][C:6]=1[O:28][CH3:29].Br[CH2:33][CH2:34]Br.[OH-].[Na+]>ClC(Cl)C.CCOC(C)=O>[OH:1][C:2]([CH3:31])([CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:34][CH2:33][N:15]3[CH:16]=[C:17]([S:19][CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[C:14]3[C:12]2=[O:13])=[CH:7][C:6]=1[O:28][CH3:29]
Reactant: COc1cc(NC(=O)c2cc(SCCc3ccccc3)c[nH]2)ccc1OCC(C)(C)O
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc(N2CCn3cc(SCCc4ccccc4)cc3C2=O)ccc1OCC(C)(C)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
A mixture of N-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(phenethylthio)-1H-pyrrole-2-carboxamide (20.0 mg, 0.0450 mmol), 1,2-dibromoethane (20.0 μL, 0.227 mmol), NBu4Br (43.5 mg, 0.135 mmol) and 1N NaOH (0.227 mL, 0.227 mmol) in dichloroethane (0.227 mL) was allowed to stir at 50° C. for 4 h. The reaction mixture was cooled to rt, diluted with EtOAc (20 mL), washed with water (×2, 15 mL), brine, dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC: PHENOMENEX® Luna AXIA 5μ C18 21.2×100 mm, 15 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 5 min hold; 20 mL/min, UV detection at 220 nm, 8.949 min retention time to afford 11.5 mg of the title compound as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 6 H), 2.86-2.91 (m, 2 H), 2.92-2.98 (m, 2 H), 3.83 (s, 2 H), 3.85 (s, 3 H), 4.05-4.11 (m, 2 H), 4.24-4.28 (m, 2 H), 6.78-6.84 (m, 2 H), 6.93 (d, J=8.2 Hz, 1 H), 6.96 (d, J=2.2 Hz, 1 H), 7.07 (s, 1 H), 7.18 (d, 7=8.2 Hz, 2 H), 7.21 (d, 7.1 Hz, 1 H), 7.26-7.32 (m, 2 H); HPLC a) column: PHENOMENEX® Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 3.470 min retention time, (>95%); HPLC b) column: PHENOMENEX® Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 3.461 min retention time; MS (ESI) 467 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[Br:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:12][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1ncc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a mixture of 5-trifluoromethyl-pyridine-2-ylamine (65 g) and chloroform (100 mL), N-bromosuccinimide (71 g) was added in 5 parts under ice-cooling. The mixture was heated to room temperature, and stirred for 1 hour, then heated to 80° C., and stirred with heating for 30 minutes. After the mixture was allowed to cool to room temperature, into the mixture, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogen carbonate solution were poured, and extracted with chloroform. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 96 g of 3-bromo-5-trifluoromethyl-pyridine-2-ylamine.