Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])[CH2:3][CH2:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH2:9][OH:10])=[O:6]>C1C=CC=CC=1.CS(C)=O.C(N(CC)CC)C>[O:1]=[C:2]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])[CH2:3][CH2:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH:9]=[O:10])=[O:6]
Reactant: O=C1CCCN1C(=O)CCC(=O)N1CCC[C@H]1CO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@@H]1CCCN1C(=O)CCC(=O)N1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-[(4-Oxo-4-(2-oxo-1-pyrrolidinyl)butanoyl]-L-prolinol (105 mg) was dissolved in a mixed solvent of benzene (0.25 ml), DMSO (0.79 ml) and triethylamine (0.25 ml), and sulfur trioxide pyridine complex (285 mg) was added thereto under ice-cooling. After 0.5 hour's stirring at a temperature of 10°-15° C., the reaction mixture was poured into ice water, and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine in sequence. The organic layer was dried over magnesium sulfate, followed by concentration. The residue was purified by PLC (chloroform:methanol=49:1) using silica gel to give 65 mg of N-[(4-oxo-4-(2-oxo-pyrrolidinyl)butanoyl]-L-prolinal.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=O)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[N+:29]([O-])=O)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCOCC1>[NH2:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15][CH2:16]1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Nc1cc(F)ccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a solution of lithium aluminum hydride (4.01 g, 105.7 mmol) in anhydrous 1,4-dioxane (40 mL) at reflux was added N-(1-benzylpiperidin-4-yl)-4-fluoro-2-nitrobenzamide (9.87 g, 30.2 mmol) in anhydrous 1,4-dioxane (125 mL) dropwise under nitrogen over 30 minutes. The resulting mixture was heated at reflux for 3 h under nitrogen. After cooling to room temperature, the reaction was carefully quenched with ice water (10 mL), sodium hydroxide (50% in water, 50 mL), and extracted with diethyl ether (2×500 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo to afford the title compound (8.64 g, 100% yield) as a yellow oil, which was pure enough for use in the next step. 1H-NMR (CD3OD, 400 MHz) δ 7.52-7.40 (m, 5H), 7.28-7.18 (m, 1H), 6.53 (dd, J=11.2, 2.4, 1H), 6.48-6.38 (m, 1H), 4.33 (s, 2H), 4.18 (s, 2H), 3.68-3.46 (m, 3H), 3.25-3.10 (m, 2H), 2.50-2.42 (m, 2H), 2.16-1.93 (m, 2H). Mass spec.: 314.21 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37])=O)(C)(C)C>CN(C=O)C>[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:18](=[O:20])[C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 18 %

Procedure:
To a solution of 4-(4-t-butoxycarbonylpiperazin-1-yl)benzoic acid (1.0 g, 3.3 mmol) and 1-(t-butoxycarbonylamino)-2-aminobenzene (Method 17, 0.68 g, 3.3 mmol) in DMF (10 ml) was added 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride (1.1 g, 4.0 mmol) (Method 18). The mixture was stirred at ambient temperature for 20 hours. The mixture was concentrated in vacuo and the residue partitioned between water and ethyl acetate. The organic phase was separated and the aqueous reextracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (eluting with 4:1-1:1 isohexane/ethyl acetate). The product was dissolved in 1,4-dioxane (2.5 ml) and treated with a 4M solution of hydrogen chloride in 1,4-dioxane (2.5 ml). The mixture was stirred at ambient temperature for 4 hours. The resulting solid was collected by filtration, trated with a 2M aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate to afford the title compound as a colourless solid (176 mg, 92%); NMR Spectrum: (DMSO-d6) 2.89 (t, 4H), 3.25 (t, 4H), 4.90 (s, 2H), 6.66 (t, 1H), 6.84 (d, 1H), 7.01 (m, 3H), 7.21 (d, 1H), 7.92 (d, 2H), 9.48 (s, 1H); Mass Spectrum: M+H+ 297.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH:8]=[CH:9][O:10]C.Cl>CC(C)=O.O.C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]=[O:10]
Reactant: COC=Cc1ccc(C(C)(C)O)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(O)c1ccc(CC=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a room temperature solution of 2-{3-fluoro-4-[2-methoxyvinyl]phenyl}propan-2-ol (100 mg, 0.48 mmol) in acetone (5 mL) was added dropwise 4 M aqueous hydrochloric acid (5 mL, 20 mmol). The reaction was stirred at room temperature for two hours. The mixture was then diluted with 25 mL of water and 50 mL of diethyl ether. The water phase was extracted with diethyl ether (2×) and the combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried and concentrated in vacuo to afford the title compound.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CCOCC.[C:25](=[O:27])=[O:26]>C1COCC1.C(O)(=O)C.O>[C:6]([O:10][C:11]([NH:13][C:14]1[C:15]([C:25]([OH:27])=[O:26])=[CH:16][N:17]=[CH:18][CH:19]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Temperature: -78 °C
Yield: 54 %

Procedure:
n-Butyl lithium (2.18 M, 24 mL, 52.51 mmol) is added slowly to a solution of 4-(N-t-butoxycarbonylamino)-pyridine (4.08 g, 21 mmol) in THF (50 mL, stirred under N2 at −78° C. The solution is allowed to warm to 0° C., stirred for 3 h, then cooled again to −78° C. and poured into ether (100 mL) containing dry ice. The solution is warmed to room temperature with constant stirring. Water is added and the mixture is neutralized with acetic acid. The resulting solid is collected by vacuum filtration and dried in a vacuum oven to give 4-(N-t-butoxycarbonylamino)nicotinic acid (2.72 g, 54%) as a brown solid. 1H NMR (DMSO) δ 11.75 (1H, brs), 8.95 (1H, s), 8.50 (1H, d, J=6.0 Hz), 8.20 (1H, d, J=6.0 Hz), 1.49 (9H, s)
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([F:11])([F:10])[F:9])=[C:4]([C:12]([O:14]CC2C=CC=CC=2)=[O:13])[S:3]1>C(O)C.[Pd]>[O:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([F:11])([F:9])[F:10])=[C:4]([C:12]([OH:14])=[O:13])[S:3]1
Reactant: O=C(OCc1ccccc1)c1sc(=O)[nH]c1CC(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1sc(=O)[nH]c1CC(F)(F)F
Yield: 34.9 %

Procedure:
Benzyl 2-oxo-4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-thiazole-5-carboxylate (0.6 g) in ethanol was treated with 5% palladium on carbon and hydrogenated at 3 bar for 8 days. After filtration, the solvent was evaporated to yield the title compound as a colourless oil (0.15 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)(=O)=[O:3].[I-].[K+].C(=O)(O)[O-].[Na+].Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH2:34][OH:35])[CH2:28][CH2:27]1.Cl>CN(C)C=O.C1(C)C=CC=CC=1.O>[OH2:3].[OH:35][CH2:34][CH2:33][CH2:32][CH:29]1[CH2:30][CH2:31][N:26]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)OCCCOc1ccc(C#N)cc1
Reactant: OCCCC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OCCCN2CCC(CCCO)CC2)cc1
Temperature: 70 °C
Reaction time: 7 h
Yield: 83.3 %

Procedure:
Into a solution of 50.0 g of 3-(4-cyanophenoxy)propyl methanesulfonate in 250 mL of N,N-dimethylformamide, 32.5 g of potassium iodide, 32.9 g of sodium bicarbonate and 37.0 g of 3-(4-piperidinyl)-1-propanol hydrochloride were added at room temperature, which was then stirred at 70° C. for 7 hours. To the reaction mixture, after being cooled down to room temperature, 250 mL of water and 150 mL of toluene were added, and then hydrochloric acid was added to adjust the pH to 1.0. The aqueous layer was separated, adjusted to pH 10.0 with a 20% sodium hydroxide aqueous solution, and stirred at room temperature for 15 min and under cooling on ice for 30 min. The solid matter was collected by filtration and washed twice with 50 mL of water and twice with 50 mL of toluene to obtain 52.3 g of 4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzonitrile monohydrate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[F:29]C1C(O)=NC=CC=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I.CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:29])[C:23]4=[O:28])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2)nn1)c1ccc(Cl)s1
Reactant: Oc1ncccc1F
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: O=C(NCc1cn(-c2ccc(-n3cccc(F)c3=O)cc2)nn1)c1ccc(Cl)s1
Temperature: 120 °C

Procedure:
Aryl iodide 35 (Example 290, 50 mg, 0.11 mmol) and 3-fluoro-2-hydroxypyridine (38 mg, 0.33 mmol) were dissolved in 1.0 mL dry dioxane and 0.3 mL dry DMSO in a sealed tube. To it were added N,N′-dimethylethylenediamine (8 μL, 0.066 mmol), CuI (11 mg, 0.055 mmol) and K3PO4 (48 mg, 0.22 mmol) in order. The mixture was stirred and heated in 120° C. bath for overnight. The mixture was filtered and directly subjected to reverse phase preparative HPLC to isolate the title compound as a white powder after lyophilization. MS found for C19H13ClFN5O2S as (M+H)+ 430.0, 432.0.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:17][C:16](=[O:18])[CH2:15][C@H:10]1[C:11]([O:13][CH3:14])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:17][C:16](=[O:18])[CH2:15][C@H:10]1[C:11]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)CCSC(C)=O
Agent: N
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)CCS

Procedure:
The product from Example 28 is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to yield 1-(3-mercapto-1-oxopropyl)-4-oxo-L-proline, methyl ester.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:7].Br[CH2:26][C:27]([CH3:29])=[CH2:28]>CN(C=O)C>[Br:3][C:4]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:5]=1[C:6]([N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH2:28][C:27]([CH3:29])=[CH2:26])=[O:7]
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2Br)cc1
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CN(Cc1ccc(OC)cc1)C(=O)c1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of NaH (1.22 g) in DMF (130 mL) was added 2-bromo-N-(4-methoxy-benzyl)-5-nitro-benzamide (6.2 g) in DMF (60 mL) at −78° C. The mixture was warmed to 0° C., 3-bromo-2-methyl-propene (4.57 g) was added and the mixture was stirred for 2 h at 0° C. The reaction was poured into ice water, extracted with EtOAc (2×400 mL), dried over MgSO4, filtered and concentrated to a DMF solution which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH:18]=1)([O-])=O.[H][H]>C(O)C.Cl.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Yield: 147.1 %

Procedure:
To a solution of 38.2 gm (145 mMol) 5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 1.9 L ethanol and 30 mL 5N HCl were added 10.0 gm 5% palladium on carbon. The reaction mixture was hydrogenated at ambient for 18 hours with an initial hydrogen pressure of 60 p.s.i. The reaction mixture was filtered and then concentrated under reduced pressure. The residue was dissolved in methanol and the solution filtered. This filtrate was concentrated under reduced pressure and the residue redissolved in ethanol. The solution was concentrated to about 500 mL and product allowed to crystallize. The crystals were filtered to give 48.9 gm (95%) of the title compound as its dihydrochloride salt, ethanol solvate.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+]>CO>[S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCNCc2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCNCc2sccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
A solution of 2.1 g of 5,6,7,8-tetrahydrothieno-[2,3-c]azepin-4-one prepared in the step 5 in 20 mL of methanol was cooled with ice, 0.28 g of sodium borohydride was slowly added thereto and the mixture was stirred for 3 hours at room temperature. The reaction solution was slowly added to ice water so that an excess of sodium borohydride was decomposed and, after that, the reaction solution was subjected to extraction with diethyl ether. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo to give 1.37 g of the objective compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:17]#[N:18])=[CH:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:19]([Mg]Br)[CH2:20][CH:21]=[CH2:22].[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH2:1]([O:3][P:4]([CH:9]([C:17]#[N:18])[CH:10]([CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[CH2:22][CH2:21][CH:20]=[CH2:19])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(C#N)=CC1CCOCC1
Reactant: C=CCC[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(C1CCOCC1)C(C#N)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the oil isolated in Step A (51.26 g, 188 mmol) and CuI (1.00 g) in THF (200 mL) at −30° C., 3-butenylmagnesium bromide in THF (0.5 M, 394 mL, 197 mmol) was added slowly. The reaction mixture was stirred at room temperature overnight. Aqueous saturated ammonium chloride solution (300 mL) was then added. The reaction mixture was stirred 30 min at room temperature and then was extracted with ethyl acetate (400 mL) once. The organic solution was washed with saturated ammonium chloride solution three times, with brine one time and then was dried over magnesium sulfate. The reaction mixture was then filtered and concentrated to yield a residue. The residue was purified by Kugelrohr distillation to yield [1-cyano-2-(tetrahydro-pyran-4-yl)-hex-5-enyl]-phosphonic acid diethyl ester as a colorless oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1.[C:14]([O:18][C:19](=O)[O:20]C(C)(C)C)([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1>[C:14]([O:18][C:19]([NH:3][CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]([OH:13])=[O:12])[CH2:9][CH2:10]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reaction time: 20 h

Procedure:
63.6 ml of an N aqueous NaOH solution and 1.28 g of MgO are introduced, at 0° C., into 50 ml of dioxane containing 5 g of trans-4-(aminomethyl)cyclohexylcarboxylic acid, followed, slowly, by 6.94 g of di(t-butyl)carbonate in solution in 20 ml of dioxane. After 20 hours at room temperature, the mixture is filtered, the solvent is removed and the residue is taken up in 100 ml of H2O and the aqueous phase is washed with (C2H5)2O before acidifying it up to pH 2 by addition of KHSO)4 ; it is then extracted in CH3COOC2 H5 to yield 7.3 g of trans-N-(t-butoxycarbonyl)-4-(aminomethyl)cyclohexylcarboxylic acid which melts at 125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([S:26]([CH3:28])=[O:27])[CH:12]=3)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([S:26]([CH3:28])(=[O:39])=[O:27])[CH:12]=3)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(S(C)=O)cc21
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To 439 mg of ethyl 9-p-chlorobenzyl-6-methylsulfinyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetate from Example 24, in 10 cc of methylene chloride was added 353 mg of m-chloro perbenzoic acid. The resulting mixture was stirred for 18 hours at room temperature. The reaction mixture was diluted with ether and washed consecutively with a solution of sodium bicarbonate, water and brine. The crude product obtained after evaporation of the organic layer was purified on silica gel by flash chromatography eluting with 30% hexane/ethyl acetate and yielded 200 mg (42%) of the pure title compound.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]=1[OH:21])(=O)[CH3:2].B(F)(F)F.CCOCC.C([BH3-])#N.[Na+].C([SiH](CC)CC)C>C1COCC1>[CH2:1]([C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:11][CH2:12][C:6]=2[C:5]=1[OH:21])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
Under nitrogen dissolve 7-acetyl-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 3.32 mmol) in anhydrous THF (100 mL). Cool the solution to 0° C., add boron trifluoride diethyl etherate (3.4 mL, 26.6 mmol) and sodium cyanoborohydride (836 mg, 13.3 mmol). Remove the ice bath and stir for 5 h at ambient temperature. Dilute with EtOAc and wash with 0.1N aqueous HCl. Separate the organic layer, dry over Na2SO4, filter and concentrate in vacuo. MS (ES−) m/z: 302 (M−H)−. Mix the residue with trifluoroacetic acid (40 mL) and anhydrous DCM (50 mL) under nitrogen. Cool to 0° C. in an ice bath and add triethyl silane (3.5 mL, 21.9 mmol). After 15 min, remove the ice bath and stir at ambient temperature for 16 h. Concentrate in vacuo and purify by chromatography on silica gel eluting with EtOAc/hexane (1:9) to obtain the desired intermediate (698 mg, 73%). MS (ES−) m/z: 286 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:13][CH2:12]2)[CH:3]=1.[NH3:31]>CO>[NH2:31][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:13][CH2:12]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)C1CCC(c2cc(Cl)n3nccc3n2)CN1C(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCC(c2cc(N)n3nccc3n2)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Di-tert-butyl 5-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1,2-dicarboxylate was dissolved in 30 mL ˜7N ammonia in methanol in a sealed vessel. The reaction mixture was heated at 80° C. for 16 hours. After 16 hours, the reaction mixture is cooled to room temperature and concentrated in vacuo to yield a brown solid. LC-MS: 418 [M+H]. The title compound was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][C:20](=[O:24])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[C:20](=[O:24])[CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)C(=O)C1
Temperature: 120 °C
Yield: 76.9 %

Procedure:
A mixture of 5-bromo-2-nitropyridine (200 mg, 1 mmol), 1-Boc-3-oxopiperazine (240 mg, 1.2 mmol), Xantphos (43 mg, 0.075 mmol), cesium carbonate (326 mg, 1 mmol), palladium(II) acetate (11 mg, 0.049 mmol) in dioxane (5.5 mL) is heated to 120° C. in a Personal Chemistry microwave apparatus for 0.5 h. TLC and LCMS analysis indicates completion of the reaction. The reaction mixture is filtered through Celite, evaporated in vacuo, and the residue is partitioned between water and ethyl acetate. The organic layer is washed with brine, dried (Na2SO4) and evaporated in vacuo. Purification by flash chromatography on silica (ethyl acetate) provides 4-(6-Nitropyridin-3-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester as a pale brown solid (248 mg, 77%). MS (ESI) m/z 323 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:43]4[CH2:42][CH2:41][N:40]([C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:46])([F:47])[F:32])[CH:35]=5)[CH2:45][CH2:44]4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-[3-(trifluoromethyl)phenyl]piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=659.99 (M+H+); retention time=1.08 minutes.