Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]([CH3:8])[CH:6]=[CH2:7].[CH2:9]1[O:12][C@H:10]1[CH3:11]>C1COCC1.[Cu](Br)Br.II>[CH3:8][CH:5]([CH:6]=[CH2:7])[CH2:4][CH2:3][CH2:9][C@H:10]([OH:12])[CH3:11]
Reactant: C[C@H]1CO1
Reactant: C=CC(C)CCBr
Agent: Br[Cu]Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)CCC[C@@H](C)O
Reaction time: 8 h
Yield: 236.9 %

Procedure:
Magnesium turnings (1.3 g, 55.2 mmol) were suspended in dry THF (50 mL) and to the mixture was added a pinch of iodine (20 mg) at room temperature. To this reaction mass was added a solution of 5-bromo-3-methylpent-1-ene (6 g, 36.8 mmol) in THF (200 mL). The reaction mass was heated with hot air gun to initiate the reaction. When the reaction was judged complete, the solution was cannulated to a solution of (S)-propylene oxide (3.21 g, 55.2 mmol) and copper bromide (0.528 g, 3.68 mmol) in THF (50 mL) at −78° C. The reaction mass was allowed to come to room temperature and stirred overnight. The reaction mass was quenched with saturated ammonium chloride solution and extracted with diethyl ether (200 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated at room temperature to get crude compound. The crude compound was purified by column chromotography (Silica gel, 10% TBME in pet ether) to get (2R)-6-methyloct-7-en-2-ol (12.4 g, 92%) as oily liquid. 1H NMR (400 MHz, CDCl3): δ ppm 5.82-5.69 (m, 1H), 4.98-4.91 (m, 2H), 4.27-4.26 (m, 1H), 3.65-3.39 (m, 1H), 2.15-1.98 (m, 1H), 1.36-1.19 (m, 5H), 1.18-1.1 (m, 1H), 1.08-0.95 (m, 5H), 0.89-0.78 (m, 1H).
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-])=[O:2].C1(N=C=O)C=CC=CC=1.[C:15]([Sn:17]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])#[CH:16].CCN(CC)CC>C1C=CC=CC=1>[CH3:5][C:4]1[CH:16]=[C:15]([Sn:17]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:26][CH2:27][CH2:28][CH3:29])[O:2][N:1]=1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: CC[N+](=O)[O-]
Solvent: O=C=Nc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Temperature: 50 °C
Reaction time: 14 h
Yield: 85 %

Procedure:
A solution of nitroethane and phenyl isocynate in 8 ml of benzene was stirred at 50° C. for 5 minutes before ethynyltri-n-butyltin in 8 ml of benzene containing one droplet of Et3N was added. The mixture was stirred at 50° C. for 14 hours. The reaction mixture was then quenched with water and filtered through celite. The filtrate was extracted with EtOAc, dried with Na2SO4. Silica Chromatography using Hexance/EtOAc afforded 3-methyl-5-(tributylstannyl)isoxazole, 6.30 g, 85% yield.
Reaction SMILES: N1CCC(CO)CC1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.O[CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.C(Br)(Br)(Br)[Br:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(#N)C>[Br:40][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: BrC(Br)(Br)Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: OCC1CCNCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reaction time: 8 h

Procedure:
To a solution of 5.792 g (50.287 mM) of 4-piperidylmethanol in 150 ml of dichloromethane was added 12.1 g (55.3 mM) of di-tert-butyl dicarbonate dropwise at room temperature and the mixture was stirred at the prevailing temperature overnight. The solvent was then distilled off under reduced pressure to recover crude tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. This crude product was not purified but used as it was in the next reaction. To a solution of the above crude tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate and 18.3 g (55.3 mM) of carbon tetrabromide in 100 ml of acetonitrile was added 14.5 g (55.3 mM) of triphenylphosphine at room temperature and the mixture was stirred at the prevailing temperature for 3 hours. The solvent was then distilled off under reduced pressure. To the residue was added diethyl ether, and after stirring, the resulting precipitate (triphenylphosphine oxide) was filtered off and washed with diethyl ether. The filtrate and washes were combined and concentrated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1 to 15/1 to 9/1) to provide the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:11]1[C:12]2[C:8](=[C:7]([F:6])[CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)[CH:3]1[O:5][CH2:4]1
Reactant: Fc1cccc2[nH]ccc12
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc2c1ccn2CC1CO1
Temperature: 60 °C

Procedure:
Epibromohydrin (0.64 ml, 7.5 mmole) was added to a stirred solution of 4-fluoroindole (1.0 g, 7.4 mmole) and sodium hydride (0.32 g, 8.1 mmole) in anhydrous DMF (20 ml), and the mixture was heated at 60° C. under nitrogen for 15 hours. Water (100 ml) was added and the product extracted into CH2Cl2 (3×25 ml). The combined organics were washed with water (25 ml), brine (25 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a yellow colored oil (1.34 g). This was purified by flash silica gel chromatography (30% ethyl acetate in hexane) to afford the titled product as a light oil (1.27 g, 90% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:28]O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:28])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OO
Reactant: CC(C)(C)c1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1
Product: CC(C)(C)c1ccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-tert. butylphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[SH:10].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.O>CO.CCCCCC>[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[S:10][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: ClCc1ccccn1
Reactant: Cc1occc1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: O
Product: Cc1occc1SCc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 25 ml 3 neck round bottom flask equipped with magnetic stirrer, pot thermometer, Y tube, nitrogen inlet tube, reflux condenser and heating mantle is placed a solution of 0.54 g (0.01 moles) of sodium methoxide dissolved in 3 ml absolute methanol. The reaction mass is maintained at 25° -30° C and a solution of 0.57 g (0.005 moles) of 2-methyl-3-furan thiol in 3 ml absolute methanol is added to the reaction mass. While maintaining the reaction mass at 25° C, picolyl chloride hydrochloride (0.82 g; 0.005 moles) dissolved in 2 ml absolute methanol is added to the reaction mass. The reaction being exothermic, the reaction mass warms up to 42° C and a white solid precipitate forms. The reaction mass is then allowed to cool to 25° C (with stirring) over a period of 30 minutes. The reaction is then heated to reflux (60° - 65° C) under nitrogen and reflux is continued for a period of 1 hour. The reaction mass is cooled to 25° C. After remaining at room temperature for a period of 12 hours, 10 ml of water is added to the reaction mass with stirring, causing the reaction mass to now exist in two phases; an aqueous phase and an organic phase. The pH of the reaction mixture is 5. 7 ml of n-hexane is then added to the reaction mass with stirring and transferred to a separatory funnel. The aqueous layer is separated from the organic phase and extracted with 8 ml n-hexane after first diluting the aqueous phase with another 10 ml of water. The hexane extracts are combined, washed with 7 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, gravity filtered, then concentrated on a rotary evaporator using water-aspirator vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([CH3:33])[CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][C:26]=2[CH3:33])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccccc2)c1Cl
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: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccccc2)c1-c1ccc(F)cc1C
Temperature: 75 °C
Reaction time: 15 h
Yield: 84.5 %

Procedure:
A solution of 1-benzyl-4-chloro-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (4.56 g, 0.0144 mol) in toluene (80 mL) and EtOH (40 mL) was degassed 3 times before Pd(PPh3)4 (0.834 g, 0.722 mmol), 4-fluoro-2-methylphenylboronic acid (2.67 g, 0.0173 mol) and an aqueous solution of Na2CO3 (2N, 14.4 mL, 0.0288 mol) were added. The reaction mixture was stirred at 75° C. for 15 hours, cooled down to RT, filtered and the volatiles evaporated under vacuo. The residue was taken up in EtOAc and washed with aqueous NaOH (1N). The organic phase was dried over Na2SO4, concentrated under vacuo, before a purification on column chromatography (SiO2, EtOAc/Heptane, 1/4) yielded 4.74 g (84%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9](=[CH:15][C:16]2[O:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[CH:5][CH:4]=1.[NH2:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>CCCCO.C1COCC1>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]2[N:24]=[C:25]3[NH:26][N:27]=[C:28]([CH3:30])[C:29]3=[C:15]([C:16]3[O:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CCOC(=O)C(=Cc1ccc(C)o1)C(=O)c1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)nc2[nH]nc(C)c2c1-c1ccc(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
A mixture of 0.76 g (2.41 mmol) of ethyl 2-(4-methoxybenzoyl)-3-(5-methylfuran-2-yl)acrylate and of 0.23 g (2.41 mmol) of 3-amino-5-methyl-pyrazole is heated to 140° C. in 6 ml of n-BuOH for 24 h. The mixture is then cooled to room temperature and 0.55 g (2.4 mmol) of DDQ in 6 ml of THF is added. The mixture is stirred at room temperature for 1 h. The mixture is then poured onto a saturated solution of NaHCO3 then extracted with ethyl acetate. The organic phase is washed in a saturated solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated. The mixture is then purified using reverse-phase HPLC to yield 146 mg (15%) of ethyl 6-(4-methoxyphenyl)-3-methyl-4-(5-methylfuran-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in the form of a yellow solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:14])[C:12]=1[CH3:13].[C:15]([N:19]=[C:20]=[O:21])([CH3:18])([CH3:17])[CH3:16].[NH4+].[Cl-]>CCCCCC>[Br:14][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([C:12]=1[CH3:13])[C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21]
Reactant: Cc1c(Br)cncc1Br
Reactant: CC(C)(C)N=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: Cc1c(Br)cncc1C(=O)NC(C)(C)C
Temperature: -100 °C
Reaction time: 0.17 h

Procedure:
Under argon, an n-butyllithium solution in hexane (1.55N, 6.6 ml) is added dropwise to a solution of 3,5-dibromo-4-methylpyridine (intermediate 10.1, 2.51 g, 10 mmol) kept at −100° C. After stirring for 10 min, tert-butyl isocyanate (2.28 ml, 20 mmol) is added. The stirring is maintained for 20 min at −100° C. and then for 1 h at −78° C. and at room temperature overnight. An aqueous NH4Cl solution is added to the reaction mixture. Extraction with AcOEt/H2O gives a brown solid which is taken up in an AcOEt/petroleum ether mixture. The compound obtained is isolated by filtration.
Reaction SMILES: ClC12[O:8]C1CCC(Cl)(F)C2.[CH3:11][C:12]1(O)[C:17]([Cl:19])([Cl:18])[CH2:16][CH2:15][CH2:14][C:13]1([Cl:21])Cl.[OH-].[Na+]>O>[Cl:21][C:13]12[O:8][CH:14]1[CH2:15][CH2:16][C:17]([Cl:19])([Cl:18])[CH:12]2[CH3:11]
Reactant: CC1(O)C(Cl)(Cl)CCCC1(Cl)Cl
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1C(Cl)(Cl)CCC2OC21Cl
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
The same procedure was employed as for the preparation of 2e in Example 17: it was performed with 3.97 g (15.75 mmol) of crude alcohol 1j, 20 cm3 of distilled water and 2.4 g (60 mmol) of sodium hydroxide; reaction time was 1 h 15 min; ether extraction (5×40 cm3); 3.29 g of epoxide 2h were obtained having a 95.5% yield based on the ketone (macrobore GC purity>99%)
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)([CH3:4])=[O:3].C(O)(C(F)(F)F)=O>ClCCl>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CP(C)(C)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CP(C)(=O)CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl 4-[(dimethylphosphoryl)methyl]piperazine-1-carboxylate (1.01 g, 3.66 mmole) was dissolved in 7 mL of anhydrous dichloromethane. At 0° C., 7 mL of TFA:DCM=1:1 solution was added in 3 portions. The reaction mixture was stirred at this temperature for 15 minutes before another 3.5 mL of TFA was added, and then continued to stir at room temperature for 2 hours. Volatile components were evaporated and yield light yellow oil. The crude mixture was directly carried into next step. MS (LC/MS): 199.2 [M+Na]
Reaction SMILES: S([Cl:11])(C1C=CC(C)=CC=1)(=O)=O.[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N+:14]=1[O-].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(CCl)c(C)c1
Yield: 66.2 %

Procedure:
Tosyl chloride (12.5 g, 65.6 mmol) was added to a solution of 2,3,5-trimethylpyridine 1-oxide (6.0 g, 43.7 mmol), and triethylamine (6.6 g, 65.6 mmol) in DCM (60 ml) at RT under an atmosphere of nitrogen. The reaction mixture was heated to reflux and reflux was maintained 4 h (reaction was monitored by TLC). The reaction was quenched with water and extracted with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexanes and silica gel (230-400 Mesh) to afford 2-(chloromethyl)-3,5-dimethylpyridine (4.5 g, 66.1%) as a brown thick syrup. 1H NMR: 200 MHz, CDCl3: δ 8.15 (s, 1H), 7.45 (s, 1H), 4.75 (s, 2H), 2.35 (s, 3H), 2.25 (s, 3H). MS: [M+H]+: m/z=156.3.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reaction time: 2 h
Yield: 98 %

Procedure:
The intermediate obtained in Step G was dissolved in absolute ethanol (50 mL) under argon, treated with 10% palladium on carbon (140 mg, 0.1 eq), then stirred under a hydrogen atmosphere for 2 hr. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the product dried in vacuo to afford the title compound as a white solid (1.4 g, 3.9 mmol, 98%). 1H NMR (300 MHz, CDCl3 ): δ7.15 (m, 4 H), 4.33 (d, J=4.4 Hz, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.23 (sept, J =6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J=6.6 Hz, 6 H), 1.30 (d, J=6.6 Hz, 6 H), 1.27 (m, 2 H), 1.13 (m, 5 H), 0.79 (t, J=6.6 Hz, 3 H). FAB-MS: calculated for (C23H32FNO) 357, found 358 (M+H). Anal. calcd for C23H32FNO: C, 77.27; H, 9.02; N, 3.92. Found: C, 77.46; H, 8.95; N, 3.78. Rf=0.3 (20% ethyl acetate/hexane). mp 100-101° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[C:27]2[C:19](=[CH:20][C:21]3[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=2)[CH:18]([NH:28][CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1.Cl>ClCCl>[CH:8]([O:11][C:12]([N:14]1[C:27]2[C:19](=[CH:20][C:21]3[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=2)[CH:18]([N:28]([C:1](=[O:3])[CH3:2])[CH2:29][C:30]2[CH:31]=[C:32]([C:40]([F:43])([F:41])[F:42])[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc3c(cc21)CCC3
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc3c(cc21)CCC3
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.2 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (187 mg, 0.77 mmol) followed by titanium isopropoxide (835 mg, 2.94 mmol) to 9-Oxo-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester (200 mg, 0.7 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 3 days. Add methanol (3 mL) and sodium borohydride (40 mg, 1.05 mmol) and stir the mixture under nitrogen at room temperature for 16 hours. Add sodium bicarbonate saturated solution. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by silica cartridge, eluting with hexanes/ethyl acetate 9:1, to afford of (+/−)-9-(3,5-bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester (220 mg). Add acetic anhydride (0.22 mL, 2.33 mmol) dropwise to a solution of the amine (80 mg, 0.155 mmol) and pyridine (0.18 mL, 2.33 mmol) in dichloromethane (1 mL). Stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by silica gel cartridge, eluting with hexanes/ethyl acetate 4:1, to afford the title compound (64 mg, 74%); MS (ES+): 579 (M+H+Na).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([CH:32]1[CH2:34][CH2:33]1)[NH2:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][S:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:27][N:29]=2)[CH2:34][CH2:33]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: O=C(N1CCSCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 164 mg (1.640 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted Yield: 352 mg (47% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[CH:5]=[CH:6][CH:7]=1.[Cl:16][CH2:17][C:18](O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:15]=[C:18]2[CH2:17][Cl:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1Nc1cccc(F)c1
Reactant: O=C(O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cccc(-n2c(CCl)nc3ccccc32)c1
Temperature: 130 °C

Procedure:
A mixture of N-(3-fluorophenyl)-o-phenylenediamine (0.8 g, 4 mmol) prepared in the preceding step (a), polyphosphoric ester (2.7 g) and monochloroacetic acid (0.4 g, 4.2 mmol) was heated for 1 hour at 130° C. and water was added to the reaction mixture to decompose an excess of polyphosphoric ester, then neutralized with sodium carbonate and the occurred oily substance was extracted with chloroform and the extract was washed, dried and concentrated in vacuo.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.[NH2:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21]>>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:18][C@@H:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][OH:21])=[O:17])=[CH:13][CH:14]=1)(=[O:8])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccc(C(=O)c2ccccc2)cc1
Yield: 67 %

Procedure:
3 g (13 mmol) of benzophenone-4-carboxylic acid were reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 3.2 g (67%) of the product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:26][C:27]1([CH3:34])[CH:32]([OH:33])[CH2:31][CH2:30][NH:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:29]3[CH2:30][CH2:31][C@H:32]([OH:33])[C:27]([CH3:34])([CH3:26])[CH2:28]3)=[O:10])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:13])=[O:14])=[CH:16][C:17]=1[C:22]([F:24])([F:25])[F:23]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC1(C)CNCCC1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
General synthesis of amides: A 10 mL scintillation vial was charged with the 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (164 mg, 0.4 mmol), freshly prepared 3,3-dimethylpiperidin-4-ol (0.56 mmol) ((M+H+), 130.1), HATU (192 mg, 0.5 mmol), DIEA (260 mg, 2 mmol) and anhydrous DMF (1.5 mL). The resultant solution was heated to 70° C. and stirred for 2 h. After cooled to room temperature, the mixture was purified via preparative HPLC and dried (lyophilizer) to afford (S)-4-chloro-N-(5-chloro-2-(4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)pyridine-3-yl)-3-(trifluoromethyl) benzenesulfonamide (1:2 mixture of rotamers): 1H NMR (400 MHz, CDCl3) (major rotamer) δ 9.54 (s, 1 H), 8.26 (d, 1 H), 8.12 (d, 1 H), 8.00 (d, 1 H), 7.88 (dd, 1 H), 7.62 (d, 1 H), 4.05 (m, 1 H), 3.70 (d, 1 H), 3.50 (m, 2H), 3.40 (m, 1 H), 3.10 (d, 1 H), 1.82 (m, 2H), 1.00 (s, 3H), 0.92 (s, 3H); MS (ES) (M+H)+ expected 526.0, found 526.0.