Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([S:27]([C:30]1[CH:35]=[CH:34][C:33](CO)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:26]>O1CCCC1>[CH2:25]([S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH2:20][Cl:24])=[CH:32][CH:31]=1)(=[O:28])=[O:29])[CH3:26]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCS(=O)(=O)c1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
Triphenylphosphine (12.77 g, 481 mmol), carbon tetrachloride (19.0 mL, 197 mmol) and tetrahydrofuran (40 mL) were combined and stirred at room temperature for 15 minutes. A solution of (4-ethanesulfonyl-phenyl)-methanol (4.87 g, 24.4 mmol) in 45 mL tetrahydrofuran was added, then the reaction mixture was heated at 75° C. for 3 hours. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was dried over MgSO4, filtered, and concentrated to give the crude product as an oily solid. A solution of this crude product and dichloromethane was evaporated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (15%-35% ethyl acetate in hexanes) afforded 5.16 g (97%) of 4-(ethanesulfonyl)benzyl chloride as a white, crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.88 (d, J=8.2 Hz, 2 H), 7.70 (d, J=8.2 Hz, 2 H), 4.86 (s, 2 H), 3.29 (q, J=7.4 Hz, 2 H), 1.07 (t, J=7.4 Hz, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:12][CH2:13][OH:14])[C:10]=1[OH:11])[C@H:7]([CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:6][CH2:5]2.C(N(CC)CC)C>[C].[Pd].CO>[OH:11][C:10]1[C:9]([CH2:12][CH2:13][OH:14])=[C:8]2[C:4]([CH2:5][CH2:6][C@H:7]2[CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])=[CH:3][CH:2]=1
Reactant: CCC(=O)NCC[C@@H]1CCc2cc(Br)c(O)c(CCO)c21
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(=O)NCC[C@@H]1CCc2ccc(O)c(CCO)c21
Yield: 91.2 %

Procedure:
A methanol suspension of (S)-N-[2-(5-bromo-6-hydroxy-7-(2-hydroxyethyl)indan-1-yl)ethyl]propionamide (590 mg, 1.66 mmol.), triethylamine (184 mg, 1.82 mmol.) and 5% palladium-carbon (100 mg) was subjected to catalytic reduction under hydrogen atmosphere. At the time when the calculated volume of hydrogen was absorbed, the catalyst was filtered off. The filtrate was made weakly acidic with dilute hydrochloric acid, followed by extracting the organic matter with a mixture of ethyl acetate:butanol=1:1. The extract solution was dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure, followed by washing with diethyl ether to afford the title compound (yield 0.42 g, 91%).
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:9]1[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[N:12][N:13]=1)=[CH:5][N:6](C)C.[NH:19]([C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[N:24]=[CH:23][N:22]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CC[O-].[Na+].C[O-].[Na+]>C(O)C.CO>[N:27]1([C:25]2[N:24]=[CH:23][N:22]=[C:21]([N:19]3[C:3](=[O:18])[C:4]([C:9]4[S:10][C:11]([C:14]([F:15])([F:16])[F:17])=[N:12][N:13]=4)=[CH:5][NH:6]3)[CH:26]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NNc1cc(N2CCCCC2)ncn1
Reactant: COC(=O)C(=CN(C)C)c1nnc(C(F)(F)F)s1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CC[O-]
Agent: C[O-]
Solvent: CO
Solvent: CCO
Product: O=c1c(-c2nnc(C(F)(F)F)s2)c[nH]n1-c1cc(N2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
240 mg (854 μmol) of the compound from Example 2A, 150 mg (776 mmol) of the compound from Example 8A and 18 mg (78 μmol) camphor-10-sulfonic acid are dissolved in 3 ml anhydrous ethanol and the mixture is heated under reflux overnight. After cooling, 64 mg (931 μmol) sodium ethylate are added and the mixture is further stirred overnight at RT. The precipitate formed is filtered off with suction, washed with ethanol and diethyl ether and dried. The filtrate is concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). The two intermediate product fractions obtained in this way are suspended together in 5 ml methanol, 15 mg (278 μmol) sodium methylate are added and the mixture is heated under reflux overnight. After cooling, the reaction mixture is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) and 26 mg (8% of th.) of the title compound are obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:25]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc(C(F)(F)F)c2)o1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-trifluoromethylphenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M in diethyl ether) was added and the solution was evaporated. After drying under vacuum, the hydrochloride salt of the title compound was obtained as a colourless solid; MS (ES+) 365 (MH+).
Reaction SMILES: [F:1][CH:2]([F:30])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40].O>C1COCC1>[F:30][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:24][CH2:25]3)[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)c1nc2ccccc2n1-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A solution of 100 mg (0.24 mmol) of 2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (WO 2006/095906) and 0.51 g (50 mmol) of Et3N in 20 mL of THF was cooled to 0° C. and 41 mg (0.36 mmol) of methanesulfonyl chloride was added. The mixture was allowed to warm to room temperature, and after 1 hr water was added. The precipitate was collected, washed with water, and dried to give 110 mg (93% yield) of 2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp (MeOH) 248-250° C.; 1H NMR (CDCl3) δ 8.30 (br d, J=8.3 Hz, 1H), 7.90 (br d, J=7.3 Hz, 1H), 7.52 (t, JHF=53.6 Hz, 1H), 7.46-7.40 (m, 2H), 4.03 (m, 4H), 3.89 (m, 4H), 3.80 (m, 4H), 3.34 (m, 4H), 2.82 (s, 3H); Anal. Calcd. for C20H24F2N8O4S: C, 48.6; H, 4.9; N, 22.7. Found: C, 48.8; H, 4.9; N, 22.85%.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][O:28][CH3:29])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:30]([N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH2:27][O:28][CH3:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(COC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 32 %

Procedure:
A solution of 4′-{[4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (4.5 g), benzyl bromide (1.5 mL) and cesium carbonate (4.2 g) in N,N-dimethylacetamide (45 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.8 g, 32%) as a colorless liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].O>C1COCC1>[N+:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCOc1ccncc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of tert-butyl 2-hydroxyethylcarbamate (1.1 eq) in THF, NaH (1.3 eq) was added, stirred for 1 hr, and then 4-chloro-3-nitropyridine (1.0 eq) was added. The reaction mixture was stirred at RT overnight, poured into cold water, and extracted with EtOAc. Organic layer was dried over Na2CO3, filtered, and concentrated to yield tert-butyl 2-(3-nitropyridin-4-yloxy)ethylcarbamate. LCMS (m/z): 284.1 (MH+); LC Rt=2.09 min.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=2[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:17][CH:16]=1)[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:23]([C:22]1[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:13]2[N:6]3[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]3=[N:4][C:3]=2[CH2:1][CH3:2])=[CH:20][CH:19]=1)([OH:25])=[O:24]
Reactant: CCc1nc2c(C)cc(C)nn2c1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(C)cc(C)nn2c1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.1 %

Procedure:
To a solution of 0.111 g (0.25 mmol) of the product of Step H and 0.055 g (0.51 mmol) of anisole dissolved in 0.25 mL of methylene chloride was added 0.4 mL of trifluoroacetic acid and the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 14 hours. The reaction mixture was then evaporated in vacuo and purified on a silica gel flash chromatography column eluted with CHCl3 -MeOH-NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.083 g (86%) of the title compound as a white amorphous solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:10]1[NH:11][C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=1)[CH2:8][CH3:9].[C:25]([N:44]1[C:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[C:55]2[CH:62]=[CH:61][C:58]([CH2:59]Br)=[CH:57][CH:56]=2)=[N:47][N:46]=[N:45]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C(=O)C.O>[CH2:7]([C:10]1[N:14]([CH2:59][C:58]2[CH:57]=[CH:56][C:55]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[C:48]3[N:44]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:45]=[N:46][N:47]=3)=[CH:62][CH:61]=2)[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]=1)[CH2:8][CH3:9]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(=O)OCC)c(C(=O)OCC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
0.441 g of potassium t-butoxide was added to a solution of 1.00 g of diethyl 2-propylimidazole-4,5-dicarboxylate (prepared as described in Preparation 12) in 15 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 2.19 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 15 ml of N,N-dimethylacetamide was then added dropwise to the reaction mixture at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. At the end of this time, it was diluted with water and then extracting with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then freed from the solvent by distillation. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent,to give 2.24 g of the title compound as an amorphous solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.CCN(CC)CC>C(Cl)Cl>[CH3:11][O:12][C:13]([CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:19]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl chloride (1.40 mL, 12.1 mmol) was added in a dropwise manner to a mixture of L-proline methyl ester hydrochloride (2.00 g, 12.1 mmol) and Et3N (4.20 mL, 30.2 mmol) in CH2Cl2 (40 mL) and the resulting mixture stirred overnight at rt. The mixture was concentrated in vacuo and the residue treated with water and extracted with EtOAc and the combined extracts dried over Na2SO4. Concentration left a residue which was loaded onto a silica gel column and eluted with MeOH/CH2Cl2 which allowed for isolation of 2.76 g (94%) of the title compound as a white solid. MS(ES): (M+1)+ 234.2 m/z.
Reaction SMILES: [C:1]([C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][N:12]=1)([O:3][CH3:4])=[O:2].[H-].[Na+].[CH3:24]I>O1CCCC1>[CH3:24][N:13]1[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:15][C:11]([C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])=[N:12]1
Reactant: CI
Reactant: COC(=O)C1=C(c2cc(-c3ccccc3)[nH]n2)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2cc(-c3ccccc3)n(C)n2)CCCC1

Procedure:
A mixture of 3.0 g 3-(2-carbomethoxy-1-cyclohexen-1-yl)-5-phenylpyrazole, 0.3 g of 50% sodium hydride-mineral oil slurry, and 1.0 g of methyl iodide in 50 ml of anhydrous tetrahydrofuran is stirred and refluxed overnite. The reaction mixture is filtered, and the solvent is evaporated from the filtrate to give 1-methyl-3-(2-carbomethoxy-1-cyclohexen-1-yl)-5-phenylpyrazole.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:13][C:12]=1[F:21].[OH-].[Na+].Cl>C1COCC1.CO>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)ccc(OC)c2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.6 %

Procedure:
To a mixture of methyl 6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylate (82.9 mg, 0.279 mmol) in THF (0.3 mL) and MeOH (0.3 mL) was added 1.0 M aq. NaOH (1.39 mL, 1.39 mmol). The reaction mixture was stirred at room temperature for 40 min., neutralized with HCl (12 M) to pH=7 and concentrated under reduced pressure to remove the solvents. The residue was dissolved in THF, dried, filtered and concentrated under reduced pressure to give the sub-title compound as a white powder (53.4 mg, 68%). LCMS calc. for C13H9F3NO3 (M+H)+: m/z=284.1. Found: 284.2.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=4)[CH:26]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C1(OC)C=CC=CC=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>ClCCl>[F:47][C:46]([F:49])([F:48])[C:44]([OH:50])=[O:45].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([S:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=4)[CH:26]=3)(=[O:24])=[O:23])[CH2:20][CH2:21]2)=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CCNCC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a stirring solution of 1-(1-Boc-piperidin-4-yl-carbonyl)-4-(6-chloronaphthalen-2-ylsulfonyl)piperazine (2.2 g, 4.2 mmol) in dichloromethane (25 mL) was added anisole (2 mL) followed by TFA (25 mL). After 90 min, the solvents were removed in vacuo and the residue was dissolved in a few mL of dichloromethane and diluted with diethyl ether (200 mL). After stirring for 2 h, the suspension was sonicated and filtered and then the solid was washed with diethyl ether and dried in vacuo to give 2.25 g (99%) of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][S:22]([O:25]C2C(F)=C(F)C(F)=C(F)C=2F)(=O)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:37])[CH:4]=1.[CH3:38][N:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1.N12CCCN=C1CCCCC2.C(=O)(O)[O-].[Na+]>O1CCCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:37])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][S:22]([N:48]2[CH2:47][CH2:46][N:45]([CH:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[CH2:50][CH2:49]2)(=[O:23])=[O:25])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(C)c1
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)N2CCN(C3CCN(C)CC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Perfluorophenyl 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propane-1-sulfonate (40 mg, 0.07 mmol) and 1-(1-methyl-4-piperidinyl)piperazine (25 mg, 0.14 mmol) were dissolved in tetrahydrofuran (10 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 ml, 0.21 mmol) was added under an inert gas and the mixture was refluxed for 1 h and stirred at room temperature for 15 h. Methylene chloride and saturated sodium bicarbonate solution (10 ml of each) were added, the phases were separated and the aqueous phases were extracted with methylene chloride (20 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/ammonia (25 aq) (200:100:1). Yield: 18 mg (45%). MS, m/z=571.3 [MH]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]2)=[N:21][CH:22]=1>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:24]3)=[N:21][CH:22]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:14])[CH3:13]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(N)cn2)C1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Yield: 50.5 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.0 mmol) was reacted with tert-butyl (1-(5-aminopyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (440 mg, 1.50 mmol) to afford the desired product (273 mg, 51%) as an orange solid. ESI MS m/z 540 [C26H30BrN5O3+H]+
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=O)=[C:4]([OH:26])[CH:3]=1)=[O:9].[NH2:27][CH2:28][CH2:29][OH:30].[BH4-].[Na+].Cl>C(O)C.O>[OH:26][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[C:8](=[O:9])[O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]=1[CH2:24][NH:27][CH2:28][CH2:29][OH:30]
Reactant: NCCO
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(CNCCO)c1O2

Procedure:
To a stirring solution of psoromic acid (1 mmol) in ethanol (25 mL) was added 2-amino-ethanol (1 mmol). The reaction was stirred for half an hour. The reaction was added with sodium borohydride (4 mmol) under ice bath, and stirred for additional 15 min under ice bath and then allowed to react overnight at room temperature. Water (3 mL) was added, the solution was acidified to a pH of 6 with dilute HCl. All of the solvent was removed by rotary evaporation. The residue was redissolved in ethanol and dried over anhydrous magnesium sulfate, filtered, and evaporated by a rotary evaporator to give a white solid product.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[Cl:16].[F-].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:8][C:7]1[C:2]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[C:15]([Cl:16])[CH:14]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Clc1nccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2nccnc2Cl)cc1Cl
Temperature: 25 °C
Yield: 23 %

Procedure:
Dissolve 2,3-dichloropyrazine (2.42 g, 2.03 mmol) and 3,4-dichlorobenzene boronic acid (0.406 g, 2.13 mmol) in toluene (6 mL). Add a solution of potassium fluoride (0.36 g; 6.2 mmol) in deionized water (5 mL). Add tetrakis triphenylphosphine (0.124 gm; 0.11 mmol). Reflux the reaction for 17 hr.s, cool to ambient temperature, and add EtOAc (10 mL) and water (10 mL). Separate the organic layer, re-extract the aqueous layer with EtOAc (2×40 mL), and combine the organic layers. Wash the organic solution with saturated aq NaHCO3 and brine (2×), dry over MgSO4, filter and concentrate. Purify via chromatography on silica gel eluting 0-40% ethyl acetate/hexanes to give the title preparation (0.124 g, 23% yield). MS (ES) m/z: 274, 276 (M)+.