Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:14][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 7-nitro-1,2,3,4-tetrahydroquinoline (4.5 g, 25.25 mmol) in DMF (50 mL) was added potassium carbonate (15 g) followed by iodomethane (5.54 g, 39.0 mMol) and the mixture was agitated overnight at ambient temperature. The mixture was poured onto water and extracted with ether (3×200 mL). The combined ethereal extracts were washed with brine, dried and concentrated to give the crude product which was purified by column chromatography on silica-gel to obtain the title compound as an orange liquid.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[NH4+].[Cl-]>C1COCC1.[Zn]>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:2][C:3]1=[O:11]
Reactant: O=C1Nc2ncccc2C1(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: O=C1Cc2cccnc2N1
Reaction time: 2 h

Procedure:
A solution of 3,3-dibromo-7-azaoxindole (2.0 g, 7.2 mmol) in THF (50 mL) is stirred at room temperature and a saturated aqueous solution of NH4Cl is added. Activated zinc powder is added and the reaction mixture is stirred for 2 h. The zinc is removed by filtration through a pad of diatomaceous earth and the organic layer is separated. The aqueous layer is extracted with THF (10 mL) and the combined organic layers are dried over anhydrous MgSO4, filtered and evaporated. The residue is slurried in 10:1 CHCl3:MeOH (15 mL) and filtered through a pad of silica gel and the filtrate is evaporated. The residue is triturated with water and the solid is collected by filtration and dried under vacuum to give 7-azaoxindole, 0.668 g (70%). 1H NMR (DMSO-d6) δ 10.94 (s, 1H), 8.02 (d, 1H, J=5.2 Hz), 7.52 (d, 1H, J=6.8 Hz), 6.90 (dd, 1H, J=6.8, 5.2 Hz), 3.53 (s, 2H). MS(AP−ve) 133 (100) (M−H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:23])=[N:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[N:35]=[C:36]=[O:37]>CN(C=O)C.C1COCC1.O>[NH2:23][C:13]1[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:36]([NH:35][C:26]4[CH:27]=[C:28]([C:31]([F:32])([F:34])[F:33])[CH:29]=[CH:30][C:25]=4[F:24])=[O:37])=[CH:7][CH:6]=3)=[CH:9][S:10][C:11]=2[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:15][N:14]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(-c2csc3c(-c4ccncc4)cnc(N)c23)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc(-c2ccncc2)c2scc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Yield: 46.2 %

Procedure:
A −20° C. solution of Example 121B (0.18 g, 0.57 mmol) in DMF (3 mL) and THF (3 mL) was treated dropwise with 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (0.085 mL, 0.57 mmol) and warmed to room temperature over 1.5 hours. The resulting mixture was diluted with water and extracted twice with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, concentrated and the residue was purified by flash column chromatography on silica gel with 3-5% methanol/dichloromethane to provide 138 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 5.74 (s, 2H), 7.44 (d, J=8.48 Hz, 3H), 7.51 (d, J=10.85 Hz, 1H), 7.55 (s, 1H), 7.64 (d, J=8.82 Hz, 2H), 7.71-7.72 (m, 1H), 7.74 (d, J=1.70 Hz, 1H), 8.10 (s, 1H), 8.64 (dd, J=7.29, 2.20 Hz, 1H), 8.67-8.69 (m, 1H), 8.70 (d, J=1.70 Hz, 1H), 8.98 (d, J=2.71 Hz, 1H), 9.40 (s, 1H); MS (ESI(+)) m/e 524 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[Br:11]Br>CC(O)=O>[Br:11][CH:5]1[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]1=[O:9]
Reactant: BrBr
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(Br)C(=O)C1

Procedure:
To a stirred solution of 5,5-dimethylcyclohexane-1,3-dione (1.4 g, 10 mmol) in AcOH (20 mL) at r.t. was added bromine (1.6 g, 0.51 mL, 10 mmol) dropwise. The reaction was carried out according to Method A to give the title compound in quantitative yield as a light brown solid, which was used without further purification. LCMS (ES+) 218.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O>>[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: O=Cc1ccccc1O
Reactant: COC(=O)CN
Product: COC(=O)CNCc1ccccc1O
Yield: 40 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 2-hydroxybenzaldehyde. Yield 40%. MS M+H calculated 196.1. Found 196.1
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[N:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29].C(N(CC)CC)C>C(Cl)Cl.O>[C:22]([C:20]1[C:19]2[N:24]=[N:25][N:26]([CH3:27])[C:18]=2[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:5][C:1](=[O:3])[CH3:2])=[C:11]([C:28]([F:30])([F:29])[F:31])[CH:12]=2)[N:21]=1)#[N:23]
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCCN)c(C(F)(F)F)c3)cc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCCCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.5 %

Procedure:
Acetyl chloride (18.3 mg) was added to a mixture of 6-(4-(3-aminopropoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (100 mg) and triethylamine (294 μl) in DCM (2 ml). The mixture was stirred at room temperature for 2 hours then diluted with water, the organic layer was separated, dried over magnesium sulphate, and solvent was removed under reduced pressure. The residue was purified by HPLC to give the expected product (4.4 mg). 1H NMR (CD3OD) δ: 8.56 (s, 1H), 8.38-8.45 (m, 2H), 7.33 (d, 1H), 4.45 (s, 3H), 4.23 (t, 2H), 3.40 (t, 2H), 2.05 (quin, 2H), 1.95 (s, 3H). MS m/z 419 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25](Br)=[O:26].[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>>[C:1]1([CH2:7][CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][CH2:11][N:10]2[CH2:24][C:25]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[F:28])=[O:26])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc2c(cc1OC)C(CCc1ccccc1)NCC2
Reactant: NCc1ccccc1F
Reactant: O=C(Br)CBr
Product: COc1cc2c(cc1OC)C(CCc1ccccc1)N(CC(=O)NCc1ccccc1F)CC2

Procedure:
prepared by reaction of 1-(2-Phenyl-ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-fluorobenzylamine
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[CH3:12][S:13]([O:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])(=[O:15])=[O:14]
Reactant: COc1ccc(C=O)cc1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)cc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.4 %

Procedure:
3-hydroxy-4-methoxybenzaldehyde (2.5 g, 16.4 mmol) was dissolved in DCM (50 ml), then methanesulfonyl chloride (2 g, 17.5 mmol) and TEA (4 ml, 28.6 mmol) were added, and the reaction was stirred at RT for 12 hours. DCM was evaporated, and the mixture was dissolved in ethyl acetate and extracted with HCl 1M, dried over Na2SO4 and evaporated under vacuum to yield 3.3 g of the desired product. (Yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].CI.C(OCC)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COC(=O)c1cc(SC)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a solution of 2-chloro-5-methylsulfanylbenzoic acid (20.2 g, 100 mmol) in N,N-dimethylformamide (200 ml) were added potassium carbonate (15.2 g, 110 mmol) and methyl iodide (6.8 ml, 110 mmol). After stirring at room temperature for 3 hr, diethyl ether (300 ml) was added. The organic layer was washed successively with water (200 ml×3) and saturated brine (200 ml), and dried over magnesium sulfate. Filtration and concentration gave methyl 2-chloro-5-methylsulfanylbenzoate (18.5 g, yield 86%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[CH:47]=[C:17]2[N:18]([CH:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[CH:47]=[C:17]2[N:18]([CH:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:30][CH:31]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2cc(C)nn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOCC2)c2cc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.33 g), sodium hydrogen carbonate (0.54 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.15 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.062 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.053 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate 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 as colorless crystals (0.079 g, 47%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[N:34][C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])=[N:36]2)=[CH:31][CH:30]=1.[OH:52][C@@H:53]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:54](O)=[O:55].C(N(CC)CC)C>CN(C=O)C>[OH:52][C@@H:53]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:54]([N:49]1[CH2:50][CH2:51][N:46]([C:33]2[C:32]3[C:37](=[CH:38][C:29]([CH3:28])=[CH:30][CH:31]=3)[N:36]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])[N:34]=2)[CH2:47][CH2:48]1)=[O:55]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(C(=O)[C@@H](O)CC(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an N2 atmosphere, BOP (137 mg, 0.31 mmol) was added in a single portion to a stirring solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (100 mg, 0.31 mmol), (S)-2-hydroxy-4-methylpentanoic acid (41 mg, 0.31 mmol), and triethylamine (43 μL, 0.31 mmol) in DMF (0.5 ml). After stirring the mixture for 1 h at room temperature, it was partitioned between H2O and ether. The organic phase was washed with H2O (3×20 mL), dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 1:1 ethyl acetate/hexane gave (S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one as a white solid. LC/MS: m/z 435.3 (M+H)+ at 2.62 min (10-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J=8.2, 1.7 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.40-7.36 (m, 2H), 6.96-6.93 (m, 2H), 4.92 (d, J=7.2 Hz, 1H) 4.41-4.36 (m, 1H), 4.06-3.67 (m, 8H), 2.51 (s, 3H), 1.85-1.73 (m, 1H), 1.49-1.35 (m, 2H), 0.93-0.91 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][C:7](=[O:10])[O:8][CH2:9][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:16]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]([CH3:16])[C:7](=[O:10])[O:8][CH2:9][C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=C1Nc2ncc(Br)cc2CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)OCc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one (Stage 170.1.3, 0.707 mmol) in DMF (1.4 ml) was added 55% sodium hydride in oil (0.778 mmol). The RM was stirred for 5 min at rt then was added iodomethane (0.778 mmol) and the RM was stirred for 30 min at rt. The RM was diluted with EtOAc, washed with saturated NaHCO3, with brine (3×), dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and separated by flash chromatography (heptane/EtOAc 0% to 70%). The fractions containing product were evaporated together to give the title compound as a yellow solid. (HPLC: tR 2.64 min (Method A).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:13])[CH:12]=1)[O:9][CH2:8][C@H:7]([NH2:14])[CH2:6]2.C(OC(=O)[NH:21][CH2:22][CH2:23][C:24](=O)[CH2:25]O[Si](C(C)(C)C)(C)C)(C)(C)C.[S-:36][C:37]#[N:38].[K+].O.C(O)(=O)C>C(OCC)(=O)C>[ClH:1].[NH2:21][CH2:22][CH2:23][C:24]1[N:14]([C@@H:7]2[CH2:6][C:5]3[C:10](=[C:11]([F:13])[CH:12]=[C:3]([F:2])[CH:4]=3)[O:9][CH2:8]2)[C:37](=[S:36])[NH:38][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)CO[Si](C)(C)C(C)(C)C
Reactant: N[C@H]1COc2c(F)cc(F)cc2C1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: NCCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture of (R)-6,8-difluorochroman-3-ylamine hydrochloride (1.68 g, 7.58 mmol), [4-(tert-butyldimethylsilanyloxy)-3-oxobutyl]carbamic acid tert-butyl ester (3.13 g, 9.85 mmol), potassium thiocyanate (0.96 g, 9.85 mmol), water (0.18 mL, 10 mmol) and acetic acid (3.0 mL, 50 mmol) in ethyl acetate (30 mL) was refluxed for 7 hours, cooled to room temperature, washed by sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography on silica using ethyl acetate—petroleum ether mixture as eluent. The resulting oil (2.15 g) was dissolved in ethyl acetate (20 ml), 2M HCl solution in ethyl acetate was added (20 mL, 40 mmol) and the mixture was stirred for 2 hours at room temperature. The precipitate was removed by filtration and washed with ethyl acetate to give crystals, which decomposed without melting.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[NH:6][C:5](=[O:16])[CH:4]=1.[F-].[Cs+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[NH2:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([O:16][CH:22]([CH3:24])[CH3:23])[CH:4]=[C:3]2[C:2]([F:18])([F:17])[F:1]
Reactant: CC(C)I
Reactant: O=c1cc(C(F)(F)F)c2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(F)(F)F)c2cc(N)ccc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
In a 250-mL r.b. flask, a solution of 4-trifluoromethyl-6-nitroquinolinone (structure 1 of Scheme I) (3.78 g, 14.6 mmol) in DMF (75 mL) was treated with CsF (12.41 g, 73 mmol, 5.0 equiv.) and 2-iodopropane (11.09 g, 73 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature (rt) for 18 h. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (3×200 mL). The combined EtOAc extracts were washed with saturated aqueous NH4Cl solution (300 mL), H2O (300 mL) and brine (300 mL). Dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 5×20 cm, 2% EtOAc in hexane as eluent) to afford 3.94 g (90%) of the 2-isopropoxyquinoline as a white solid. Rf 0.81 (SiO2, 10% EtOAc-hexane). 1H NMR (400 MHz, CDCl3) 8.93 (s, 1H), 8.47 (dd, 1H, J=9.2, 2.5), 7.98 (d, 1H, J=9.2), 7.32 (s, 1H), 5.62 (septet, 1H, J=6.2), 1.45 (d, 1H, J=6.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:3]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1ccc(Cl)cc1Sc1ccncc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Sc2ccncc2)cc1

Procedure:
4-Mercaptopyridine (1.1 1 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) were suspended in DMF (10 mL) and stirred at room temperature for 15 min. The mixture was treated with 4-chloro-2-fluoro-1-nitro-benzene (1.75 g, 10 mmol) and heated at 50° C. for 16 h. After cooling to room temperature, water (50 mL) was added and the mixture extracted 3 times with ethyl acetate. The organic layer was combined the ethyl acetate and then reduced in vacuo. The residue was dissolved in DMF (30 mL) and treated with SnCl2.2H2O. The mixture was heated at 50° C. for 16 hr. The DMF was distilled off under vacuum and the reduction product was purified by flash chromatography on silica gel column (50-100% EtOAc/hexane) to afford 4-chloro-2-(pyridin-4-ylsulfanyl)-phenylamine as light yellow solid. The title sulfonamide compound was prepared according to the general procedure using 118 mg of 4-chloro-2-(pyridin-4-ylsulfanyl)-phenylamine prepared above and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.33 (s, 9H), 7.06 (d, 2H, J=6.8 Hz), 7.45 (d, 2H, J=8.4 Hz), 7.51 (m, 2H), 7.66 (d, 2H, 8.4 Hz), 7.71 (d, 1H, J=9.2 Hz), 8.43 (d, 2H, J=6.4 Hz). MS: m/z 433.9 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9](Br)[CH:10]=1)=[O:4].[C:18]1(B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21][CH2:20][CH:19]=1>>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:18]2[CH2:22][CH2:21][CH2:20][CH:19]=2)[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:7][CH:6]=1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C2=CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 2a using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester (CAN 1211589-51-3) and 2-(1-cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9) as starting materials; MS (ESI) 302.0 (M+H)+.
Reaction SMILES: C1(C2[O:12][C@H:11]3[CH2:13][C@H:14]([N:17]4[CH:22]=[CH:21][N:20]=[C:19]([C:23](OC)=[O:24])[C:18]4=[O:27])[CH2:15][O:16][C@@H:10]3[CH2:9][O:8]2)C=CC=CC=1.[NH3:28]>C(O)(=O)C.CO>[OH:12][C@@H:11]1[C@@H:10]([CH2:9][OH:8])[O:16][CH2:15][C@@H:14]([N:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:28])=[O:24])[C:18]2=[O:27])[CH2:13]1
Reactant: COC(=O)c1nccn([C@@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)c1=O
Reactant: N
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1nccn([C@@H]2CO[C@H](CO)[C@@H](O)C2)c1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In 5.0 mL of 80% aqueous solution of acetic acid was dissolved 80 mg of methyl 4-[(4aR,7S,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. The solution was heated at 80° C. for 2 hours and then allowed to cool, and the solvent was removed under reduced pressure. The residue was diluted with 20 mL of water and washed with diethyl ether, and water was distilled off from the aqueous layer. The residue thus obtained was dissolved in 4.0 mL of methanol, and gaseous ammonia was introduced until saturation at an ice-cooled temperature. After stirring the reaction mixture at room temperature for 2 hours, the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography [eluent: chloroform:methanl=10:1] to obtain 24 mg of 4-[(3S,5S,6R)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide as a solid product.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH:13]([C:20]1(CN)[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:27][N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCN(C(C)C)C(C)C>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[C:3]=1[C:4]([NH:12][CH:13]([C:20]1([NH:28][CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: NCC1(C(N)c2ccccc2)CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC1(C(NC(=O)c2c(C)cccc2C)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
To a solution of 2,6-dimethylbenzoic acid (0.100 g; 0.668 mmol) in DMF (5 ml) and DIPEA (0.12 ml) was added {[amino(phenyl)methyl]cyclopentyl}methylamine D31 enantiomer 2 (0.124 g; 0.608 mmol) and HATU (0.254 g; 0.668 mmol). The resulting mixture was allowed to stir at room temperature for 3 days and then the DMF was evaporated off under reduced pressure. Residual material was partitioned between ethyl acetate and water, washed with water and the organic layer was dried (Na2SO4) and evaporated. The residual material was dissolved in DCM (2 ml) and loaded onto an SCX cartridge. Washing with DCM, then methanol followed by elution with 1 M ammonia in methanol afforded the title product (155 mg; 76%). 1H NMR (CDCl3) δ: 1.3-1.8 (9H, m), 2.21 (3H, s), 2.28 (6H, s), 5.07 (1H, m), 7.0 (2H, m), 7.1-7.4 (7H, m). Mass Spectrum (Electrospray LC/MS). Found 337 (MH+). C22H28N2O requires 336. Ret. time: 1.86 min.