Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][O:6][CH2:5]1.[CH:9]([CH:12]1[C:17]2[N:18]=[CH:19][NH:20][C:16]=2[CH2:15][CH2:14][N:13]1[C:21](OCC(Cl)(Cl)Cl)=[O:22])([CH3:11])[CH3:10]>C1COCC1>[CH:9]([CH:12]1[C:17]2[N:18]=[CH:19][NH:20][C:16]=2[CH2:15][CH2:14][N:13]1[C:21]([O:3][C@H:4]1[CH2:8][CH2:7][O:6][CH2:5]1)=[O:22])([CH3:11])[CH3:10]
Reactant: O[C@H]1CCOC1
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)O[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 1.2 %

Procedure:
NaH (0.40 g, 10.0 mmol, 60% dispersion in mineral oil) was suspended in anhydrous THF (20 mL), cooled to 0° C. and (S)-3-hydroxytetrahydrofuran (0.88 g, 0.68 mL, 10.0 mmol) was added. The suspension was stirred at 0° C. for 30 min then added to a solution of Intermediate 2 (3.30 g, 10.0 mmol, 70% pure) in THF (60 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and (S)-3-hydroxytetrahydrofuran in THF were added after 5 and 29 h, respectively. After 2 d the is reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4% and 5% MeOH in DCM (200 mL each)) and reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 30% to 60% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give (3S)-tetrahydro-furan-3-yl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (34.8 mg, 1.1%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C@@H:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[C:12](=[O:18])[CH2:11]1)[C:5]#[N:6].[Cl-].[C:20]([O:24][C:25](=[O:28])[CH2:26][Zn+])([CH3:23])([CH3:22])[CH3:21]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([C@@H:10]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[C@:12]([CH2:26][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:28])([OH:18])[CH2:11]2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@]1(O)C[C@H](c2ccc(C#N)cc2F)n2cncc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-fluoro-4-(7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (2.0 g, 8.29 mmol) in THF (40.8 mL) was added a solution of 0.5M (2-tert-butoxy-2-oxoethyl)zinc(II) chloride in THF (39.8 mL, 19.90 mmol). The crude was stirred at room temperature for 2 hrs. To the crude was added and additional 0.5M 2-tert-butoxy-2-oxoethyl)zinc(II) chloride solution in THF (16.6 mL, 8.29 mmol). The crude was stirred at room temperature for 0.5 hr. The crude was quenched with saturated NH4Cl and diluted in EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was purified via HPLC 15% to 40% MeCN/H2O, to give 365 mg of the entitled product as the major diastereomer. MS 358.2 (M+H), LCMS condition A, retention time 1.21 min. 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (s, 9H), 2.66-2.74 (m, 1H), 2.76-2.90 (m, 2H), 3.05-3.17 (m, 1H), 5.69 (dd, 1H), 6.96 (s, 1H), 7.12 (t, 1H), 7.31-7.38 (m, 2H), 7.44 (d, 1H).
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([OH:13])[CH2:11][CH2:10][CH2:9][CH:8]2[CH:14](C(O)=O)[C:15]([OH:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(#N)C.[Cu-]=O>[C:1]1([CH:7]2[CH:12]([OH:13])[CH2:11][CH2:10][CH2:9][CH:8]2[CH2:14][C:15]([OH:17])=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(C(=O)O)C1CCCC(O)C1c1ccccc1
Agent: O=[Cu-]
Solvent: CC#N
Product: O=C(O)CC1CCCC(O)C1c1ccccc1
Yield: 89.8 %

Procedure:
A suspension of ca. 700 mg (2.52 mmole) of 2-(SR)-phenyl-3-(SR)-hydroxy-(SR)-cyclohexylmalonic acid in 55 mL of acetonitrile was degassed with nitrogen for 10 min and then 18 mg (0.13 mmole) of copper (I) oxide was added under nitrogen and the mixture was heated at reflux for 40 hr under nitrogen. The solution was cooled and concentrated in vacuo, and the residue was taken up in 50 mL of water containing 0.4 mL of 2N HCl and 45 mL of ether. The layers were separated and the aqueous layer was extracted with 2×50 mL of ether. The pooled organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 67 g of silica eluting with 1 L of 100:3:0.1 methylene chloride:methanol: acetic acid to provide 530 mg (90%) of a light yellow oil that crystallized on standing.
Reaction SMILES: O.[SH-].[Na+].[CH3:4][C:5]1([CH3:15])[O:9][N:8]=[C:7]([S:10]([CH2:13][CH3:14])(=O)=O)[CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].ClCC1[C:31]([O:40][CH3:41])=[N:32][N:33]([CH3:39])[C:34]=1[C:35]([F:38])([F:37])[F:36]>CN(C)C=O.O>[CH3:4][C:5]1([CH3:15])[O:9][N:8]=[C:7]([S:10][CH2:13][C:14]2[C:31]([O:40][CH3:41])=[N:32][N:33]([CH3:39])[C:34]=2[C:35]([F:38])([F:36])[F:37])[CH2:6]1
Reactant: CCS(=O)(=O)C1=NOC(C)(C)C1
Reactant: COc1nn(C)c(C(F)(F)F)c1CCl
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nn(C)c(C(F)(F)F)c1CSC1=NOC(C)(C)C1
Reaction time: 2 h
Yield: 50.1 %

Procedure:
3.1 g of sodium hydrosulfide hydrate (purity: 70%, 22.0 mmoles) was added to a solution of 3.3 g (17.3 mmoles) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto were added 3.1 g (22.0 mmoles) of anhydrous potassium carbonate, 2.7 g (17.5 mmoles) of Rongalit and 4.0 g (17.5 mmoles) of 4-chloromethyl-3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 2.8 g (yield: 52.0%) of 5,5-dimethyl-3-(3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=O)[CH:15]=1)=[CH:12][CH:11]=[C:10]([NH:17]CC1C=CC=CC=1)[C:9]=2[N+:25]([O-])=O)=[O:5])[CH3:2].Cl>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([NH2:25])[C:10]([NH2:17])=[CH:11][CH:12]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(=O)c2ccc(NCc3ccccc3)c([N+](=O)[O-])c2o1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2ccc(N)c(N)c2O1
Reaction time: 12 h
Yield: 96.5 %

Procedure:
A mixture of ethyl-7-benzylamino-8-nitro-4-oxo4H-chromene-2-carboxylate (1.1 g, 3 mmol), Pd/C (0.10 g, 10%), and HCl (12 N 2 mL) in ethanol (90 mL) was hydrogenated for 12 hours. The catalyst was filtered through diatomaceous earth and solvent was removed under vacuum. The residue was dissolved in EtOAc (100 mL) and then washed with saturated NaHCO3 and concentrated to give 684 mg (97%) of product as a thick oil. The product was used without any further purification. 1H NMR (400 MHz), CDCl3)□1.26 (t, J=7.1 Hz, 3H) 2.19 (m, 2H), 2.70 (m, 1H), 3.18) bs, 4H), 4.22 (q, J=7.1 Hz, 2H), 4.66 (m, 1H), 6.30 (d, J=8 Hz, 1H), 6.40 (d, J=8 Hz,1 H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].CS([C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][N:26]=1)(=O)=O.O>C1COCC1>[CH3:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([O:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[N:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)nc1
Yield: 88 %

Procedure:
To 4.75 g of 4-phenoxyphenol dissolved in a 20 ml THF/20 ml DMSO mixture was added 2.9 g of t-BuOK and then 6.0 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture heated at 58° C. for 11/2 hrs. The reaction mixture was cooled overnight and then poured into 200 ml of water and stirred. A pink-white solid precipitated which was recovered and then dried on a porous plate. Recrystallization and ethanol/CH2Cl2 gave purified 5-(methylsulfonyl)-2-(4-phenoxyphenoxy)pyridine, (88% yield), as slightly pink shiny plates, m.p. 136.5°-138° C.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:24]([NH:23][S:21]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:22])[CH2:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C(C)CC=NS(=O)C(C)(C)C
Reactant: COc1cccc(OC)c1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) yellow solution of 2-iodo-1,3-dimethoxybenzene (8.553 g; 32.39 mmol) in anh. THF (175 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (20.25 ml; 32.40 mmol). The resulting slightly yellow solution was further stirred at −78° C. for 15 min. A yellow solution of ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate (6.410 g; 25.91 mmol) in anh. THF (15 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 30 min. The resulting yellow reaction mixture was treated successively with aq. sat. NH4Cl (80 ml), Et2O (250 ml) and water (75 ml). The separated yellow organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded ethyl 4-(2,6-dimethoxyphenyl)-4-(1,1-dimethylethylsulfinamido)-2-methylbutanoate as an orange oil. LC-MS (conditions B): tR=0.88 min. and [M+H]+: 386.15 g/mol; tR=0.89 min. and [M+H]+: 386.14 g/mol (mixture of diastereoisomers).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[NH:25][C:24]5[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=5[N:22]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C(O)(=O)C>C1COCC1.[Pd]>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[NH:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: C1=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4[nH]3)cc2)CCOC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4[nH]3)cc2)c(C2CCOCC2)c1

Procedure:
To a round bottomed flask was added N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.0784 g, 0.204 mmol), palladium, 10% wt. on activated carbon (0.043 g, 0.041 mmol), and acetic acid (0.023 mL, 0.408 mmol) in THF (a few drops of MeOH was added to help solubility). To remove oxygen from the round bottomed flask, the flask was flushed by nitrogen and the placed under vacuum repeatedly. Hydrogen gas was then introduced to the reaction and allowed to stir. Upon completion, the reaction was filtered through celite. The crude product was run through a SCX cartridge. Impurities were removed from column using DCM and MeOH. The product was flushed from the cartridge using 2.0 ammonia in MeOH to provide N-(4-(3-(Tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 387.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>C(Cl)Cl.CCOCC>[CH3:29][O:28][N:27]([CH3:26])[C:10](=[O:12])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(CC(=O)O)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
To a solution of 4-(methylthio)phenylacetic acid (18.3 g, 0.100 mol) in methylene chloride (200 mL) was added 1,1'-carbonyldiimidazole (16.3 g, 0.100 mol) portionwise. The mixture was stirred at room temperature for 20 minutes, and N,O-dimethylhydroxylamine hydrochloride (9.8 g, 0.100 mol) was added. The reaction mixture was stirred overnight at room temperature, diluted with ether (500 mL) and washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to give 20.9 g of N-methoxy-N-methyl-4-(methylthio)-benzeneacetamide as a clear oil (93%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[S:29][C:17]2[N:18]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:19](=[O:24])[N:20]([CH3:23])[C:21](=[O:22])[C:16]=2[C:15]=1[S:30][CH:31]([CH3:33])[CH3:32].O>CN(C)C=O>[N:1]1([CH2:13][C:14]2[S:29][C:17]3[N:18]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:19](=[O:24])[N:20]([CH3:23])[C:21](=[O:22])[C:16]=3[C:15]=2[S:30][CH:31]([CH3:33])[CH3:32])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(CCl)sc21
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(Cn3cnc4ccccc43)sc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
Benzimidazole (0.083 g) and sodium hydride (60% dispersion, 0.031 g) were added to 6-(chloromethyl)-3-methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.21 g) in dry dimethylformamide (10 ml) and the reaction was stirred for 2 hours at room temperature. Water was added to the reaction mixture which was then extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with brine and dried, filtered and evaporated. The residue was triturated with diethyl ether to give the title compound (0.163 g).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:26])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[N:6]2[C:12](=[O:25])[CH:13]([NH:14][C:15](=[O:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:5]2[S:4]1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>F[B-](F)(F)F.[Ag+].C(Cl)Cl>[NH:27]([CH2:2][C:3]1([CH3:26])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[N:6]2[C:12](=[O:25])[CH:13]([NH:14][C:15](=[O:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:5]2[S:4]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CBr
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CNc1ccccc1
Yield: 45.3 %

Procedure:
By treating in the similar manner as described in Example 16 using methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.88 g), aniline (0.28 g), silver fluoroborate (0.43 g) and methylene chloride (15 ml), there was obtained oily methyl 2-anilinomethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate (0.41 g) from the fractions of the third to seventh.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>CC(O)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CC(C(=O)O)c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of 2-(4-Aminophenyl)propanoic acid (8.45 g, 51.2 mmol) in AcOH (70 mL) was added HNO3 (60%, 5.66 g) at room temperature. The reaction mixture was refluxed for 4 hrs then cooled to room temperature. The mixture was poured into iced water (200 mL), and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:9]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CCC(Oc2ccc(F)cc2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(Oc4ccc(F)cc4)C3)CC2)cc1
Yield: 30.6 %

Procedure:
The title compound (D196) (50 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(4-fluorophenoxy)pyrrolidin-1-yl)nicotinic acid (D138) (110 mg, 0.320 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (72.86 mg, 0.320 mmol).
Reaction SMILES: C(OC([N:8]([CH3:33])[C:9]1[CH:32]=[CH:31][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19](CNC(=O)OC(C)(C)C)=[N:20][CH:21]=3)[S:15][C:11]=2[CH:10]=1)=O)(C)(C)C.[CH3:34][NH:35]C1N=CC(C2SC3C=C(N)C=CC=3N=2)=CC=1>>[CH3:33][NH:8][C:9]1[CH:32]=[CH:31][C:12]2[N:13]=[C:14]([C:16]3[CH:21]=[N:20][C:19]([NH:35][CH3:34])=[CH:18][CH:17]=3)[S:15][C:11]=2[CH:10]=1
Reactant: CNc1ccc(-c2nc3ccc(N)cc3s2)cn1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2nc(-c3ccc(CNC(=O)OC(C)(C)C)nc3)sc2c1
Product: CNc1ccc2nc(-c3ccc(NC)nc3)sc2c1

Procedure:
tert-Butyl (5-{6-[(tert-butoxycarbonyl)(methyl)amino]-1,3-benzothiazol-2-yl}pyridin-2-yl)methylcarbamate (53 mg, 0.11 mmol) was reacted according to the procedure used for the preparation of 2-(6-methylaminopyridin-3-yl)benzothiazol-6-amine. This gave the title compound (20 mg) as a yellow solid. 1H NMR δ 8.56 (d, 1H) 7.91 (dd, 1H) 7.63 (d, 1H) 7.12 (br q, 1H) 7.00 (d, 1H) 6.75 (dd, 1H) 6.55 (d, 1H) 5.99 (br q, 1H) 2.84 (d, 3H) 2.73 (d, 3H); MS m/z (M+H) 271.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:18]([C:22]1[NH:23][C:24]2[C:29]([C:30](=[O:32])[N:31]=1)=[CH:28][C:27]([CH:33]=[O:34])=[CH:26][CH:25]=2)[CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:18]([C:22]1[NH:23][C:24]2[C:29]([C:30](=[O:32])[N:31]=1)=[CH:28][C:27]([CH:33]([OH:34])[CH:4]1[CH2:5][CH2:6][N:2]([CH3:1])[C:3]1=[O:7])=[CH:26][CH:25]=2)[CH2:19][CH2:20][CH3:21]
Reactant: CN1CCCC1=O
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(O)C3CCN(C)C3=O)ccc2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.834 ml of 1-methyl-2-pyrrolidinone in 10 ml of tetrahydrofuran is added dropwise with stirring 8.69 ml of lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran) at -78° C. Following complete addition, 500 mg of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde is rapidly added and the reactants stirred at -78° C. for 4 1/2 hours. The reaction mixture is quenched with 10 ml of saturated ammonium chloride and allowed to warm to room temperature followed by evaporation of the volatiles in vacuo to a residue. The residue is diluted with 5 ml of water and extracted with ethyl acetate. The extract is washed with water, brine and dried with anhydrous Na2SO4.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CN1CCC(=O)CC1
Reactant: Clc1ccc2cc[nH]c2c1Cl
Product: CN1CC=C(c2c[nH]c3c(Cl)c(Cl)ccc23)CC1
Yield: 94.8 %

Procedure:
Beginning with 0.50 gm (2.7 mMol) 6,7-dichloro-1H-indole and 0.66 mL (5.4 mMol) 1-methyl-4-piperidone, 0.72 gm (95%) of the title compound were recovered as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:13])[CH2:9][CH2:10][C:11]#[CH:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[N:22][OH:23])=[CH:17][CH:16]=1.O>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:12]=[C:11]([CH2:10][CH2:9][CH2:8][OH:13])[O:23][N:22]=2)=[CH:17][CH:16]=1
Reactant: C#CCCCO
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: OCCCc1cc(-c2ccc(Cl)cc2)no1
Yield: 52.1 %

Procedure:
1.6 ml (11.5 mmol) of triethylamine are added dropwise to a solution, cooled with an ice bath, of 1.18 ml (12.6 mmol) of pent-4-yn-1-ol and of 2.0 g (10.5 mmol) of 4-chloro-N-hydroxybenzenecarboximidoyl chloride (J. Med. Chem., 1998, 41, 4556-4566) in 30 ml of dichloromethane. Reaction is allowed to take place at ambient temperature overnight. 50 ml of dichloromethane and 70 ml of water are added. The organic phase is separated and the aqueous phase is extracted with 2 times 50 ml of dichloromethane. The organic phases are subsequently washed with 2 times 70 ml of water and then with 70 ml of a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a mixture of cyclohexane and of ethyl acetate, to produce 1.3 g (5.47 mmol) of product in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN.[CH3:38][N:39](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([NH:39][CH3:38])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1ccc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)C(C(=O)O)c2ccccc2)cc1OC
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CNC(=O)C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(OC)c(OC)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
A mixture of 16.2 mg (0.033 mmol) N-(3,4-Dimethoxy-phenyl)-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-malonamic acid, 15.5 mg (0.049 mmol) methylamine (commercially available), 13.8 mg (0.043 mmol) TBTU and 7.8 mg (0.09 mmol) pyridine in 2 mL DMF was shaken for 4 h at room temperature. The mixture was evaporated to dryness, taken up in methanol, formic acid and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and acetic acid. The combined product fractions were evaporated to dryness to yield 2.7 mg (16%) of the title compound. MS(m/e): 501.3 (MH+), MH+ found: 501.3.
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:16])([F:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].CN([CH:20]=[O:21])C.O>C1COCC1>[Cl:14][C:9]1[C:8]([C:7]([F:6])([F:15])[F:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:20]=[O:21]
Reactant: FC(F)(F)c1ccccc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccc(C(F)(F)F)c1Cl
Temperature: -70 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
BuLi (1.6 M in hexane, 173 mL, 277 mmol) was added to a sol. of 2-trifluoromethyl-chlorobenzene (50.0 g, 277 mmol) in THF (500 mL) at −70° C. The sol. was stirred for 2 h at −70° C., and DMF (21.3 mL, 277 mmol) in THF (100 mL) was added. The mixture was allowed to warm to rt overnight. Water was added (200 mL), and the mixture was extracted with Et2O (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/EtOAc 20:1) yielded the title compound (37.4 g, 65%). LC-MS: tR=0.96 min.