Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].Cl.[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>O>[N+:15]([C:10]1[C:9]([O:12][CH3:13])=[CH:8][C:4]([CH2:5][CH2:6][NH2:7])=[C:3]([O:2][CH3:1])[CH:11]=1)([O-:17])=[O:16]
Reactant: COc1ccc(OC)c(CCN)c1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc([N+](=O)[O-])c(OC)cc1CCN
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
45.5 g (250 mmol) 2,5-dimethoxyphenethylamine J1 was mixed with 40 ml water and cooled to 0° C. while 30 ml conc. HCl was added slowly. The resultant milky emulsion was cooled to 0 to 5° C., and 65 ml conc. HNO3 was added slowly and carefully within about 2 hours, keeping the temperature below 10° C. The mixture solidified when about half of the HNO3 had been added. 50 ml icy water was added to render the mixture stirrable. Then the rest of the HNO3 was added. The mixture was warmed up to room temperature and stirred at room temperature for 3 hours, was basified with 40% NaOH to pH>12 and then extracted with 2×11 CHCl3. The CHCl3 extraction was back washed with 3×110.5 M NaOH and dried over 15 g K2CO3. The solvent was evaporated to afford 49.8 g orange oil (yield: 88%), which crystallized when cooled.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>C(#N)C>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COc1ccc(N2CCNCC2)cc1
Solvent: CC#N
Product: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
To a suspension containing 0.16 g of 1,2-difluoro-4-nitrobenzene (2) and 0.28 mL of N-diisopropyl ethylamine (DIPEA) in 4 mL acetonitrile, 0.19 of 1-(4-methoxyphenyl)piperazine (1) was added. The reaction mixture was stirred at room temperature for over night (12 h). The reaction mixture was filtered to get the yellowish solid. Then the collected solid was washed with hexane to get nitro compound 3 (0.25 g, 75%). 1H NMR (400 MHz, CDCl3, δH): 8.01 (dd, J=8.8, 2.4 Hz, 1H), 7.93 (dd, J=12.8, 2.4 Hz, 1H), 6.99-6.97 (m, 3H), 6.89-6.87 (m, 2H), 3.79 (s, 3H), 3.47 (bs, 4H), 3.26 (d, J=4.8 Hz, 4H). 13C NMR (100 MHz, CDCl3, δC): 154.4, 151.9, 121.0, 118.9, 117.3, 114.6, 112.8, 112.5, 55.6, 51.0, 49.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]Cl.[I-:25].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][I:25]
Reactant: Cc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nnc(CI)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 7, 2',5-dichloro-2-[3-(chloromethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is treated with potassium iodide in acetone to give 2',5-dichloro-2-[3-(iodomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone of melting point 185°-195° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[I:14]I.OS([O-])=O.[Na+]>C(Cl)Cl.O>[I:14][C:4]1[CH:3]=[C:2]([CH3:1])[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: Cc1ccc(N)cc1
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a solution of 4-methylaniline (53.5 g, 500 mmol) in DCM (200 mL) was added a solution of NaHCO3 (50.4 g) in water (500 mL), and then I2(127 g) was added. The mixture was stirred at rt overnight. The mixture was treated with aqueous NaHSO3 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated in vacuo to afford the product as brown oil (110 g, yield 95%). 1H NMR (300 MHz, CDCl3): δ 7.48 (dd, J=1.8 & 0.6 Hz, 1H), 6.96 (dd, J=8.1 & 1.8 Hz, 1H), 6.67 (d, J=8.1 Hz, 1H), 3.98 (bs, 2H), 2.22 (s, 3H) ppm.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)C(OCC)=O)(=[O:3])[CH3:2].Cl>C1COCC1>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:4][C:1](=[O:3])[CH3:2])=[CH:17][CH:16]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)C(CCc1ccc([N+](=O)[O-])cc1)C(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)CCCc1ccc([N+](=O)[O-])cc1
Yield: 40.3 %

Procedure:
A mixture of 22.3 g (0.080 mol) of α-acetyl-4-nitrobenzenebutanoic acid, ethyl ester in 500 ml of THF was charged with 250 ml of 6N hydrochloric acid and refluxed overnight. The reaction mixture was cooled and evaporated to dryness under reduced pressure. The residue was diluted with water and extracted three times with diethyl ether. The organic extracts were separated, washed twice with 1N sodium hydroxide, three times with water and once with a saturated sodium chloride solution. The organic solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was distilled to remove the 4-chlorobutanol. The residue of this distillate was then further distilled through a 6 inch jacketed vigreaux column and fraction 2 therefrom afforded 6.681 g of 5-(4-nitrophenyl)-2-pentanone.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])N(OC)C.[CH:26]1([Mg]Br)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(OCC)C.[Cl-].[NH4+]>C1COCC1>[CH:26]1([C:11]([C:10]2[S:9][C:8]([NH:17][C:18]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[O:19])=[N:7][C:6]=2[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:16])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Br[Mg]C1CCCC1
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCCC2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 7 %

Procedure:
Compound 98 (74.0 mg, 0.207 mmol) was dissolved in THF (1.5 mL), and a 2 mol/L solution of cyclopentylmagnesium bromide in diethyl ether (0.500 mL, 1.00 mmol) was added thereto under ice-cooling, followed by stirring at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 431 (5.60 mg, 7%) as a pale brown solid.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH3:11]>>[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][Br:1]
Reactant: Cc1ccc(Cl)cc1Br
Reactant: BrBr
Product: Clc1ccc(CBr)c(Br)c1
Temperature: 25 °C

Procedure:
In a three-necked round-bottom 500 ml flask equipped with a reflux condenser, thermometer, dropping funnel with pressure-equalizing, and magnetic stirring bar, 41.3 ml (128 g, 0.80 mmol) of bromine were added dropwise to 164 g (0.80 mol) of 2-bromo-4-chlorotoluene under exposure to 500 W lamp for 3 h at 190° C. The resulting mixture was cooled to room temperature. Fractional distillation gave a colorless liquid, b.p. 111-115° C./7 mm Hg. Yield 182 g (80%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([NH:13][NH2:14])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: CCO
Solvent: O
Product: NNc1ncccc1C(F)(F)F

Procedure:
A solution of 200 g of 2-chloro-3-trifluoromethylpyridine in 500 ml of ethanol and 300 ml of hydrazine hydrate is heated under reflux for 6 hours. The solution is then concentrated in vacuo and, after cooling, the crystalline residue is then taken up with water, filtered off, washed with water and dried to give 145 g of 3-trifluoromethyl-2-hydrazinopyridine in the form of crystals melting at 72° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][N:16]=[N+]=[N-])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pt]=O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][NH2:16])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN=[N+]=[N-])CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN)CC1

Procedure:
trans-(4-Azidomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (24 g) in ethyl acetate (1 liter) is hydrogenated over platinumoxide (2.4 g) at ambient temperature under atmospheric pressure of hydrogen. The catalyst is filtered-off and the filtrate concentrated to yield trans-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester as an oil. Rf(C2) 0.41.
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[C-:21]#[N:22].[Na+]>CN(C)C=O.O>[C:21]([C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1)#[N:22]
Reactant: Cc1cc2c(cc1Br)C(c1ccccn1)=NC(C)(C)O2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1C#N)C(c1ccccn1)=NC(C)(C)O2
Reaction time: 0.25 h
Yield: 20.9 %

Procedure:
Cuprous cyanide (1.1 g) was added to a solution of Compound 46 (2.0 g) in dimethylformamide (5 ml) and the mixture was heated under reflux for 23 hours. The reaction mixture was air-cooled. The mixture was then added to a solution of sodium cyanide (2.2 g) in water (6.5 ml), and the mixture was stirred for 15 minutes. The mixture was extracted with ethyl acetate, successively washed with aqueous 5% sodium cyanide solution and saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off. The resulting crude product was washed with ether/isopropyl ether to obtain 6-cyano-2,2,7-trimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.35 g) (Compound 64).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:27]=[O:28])C.Cl>C1COCC1>[CH3:11][C:8]1([CH3:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:27]=[O:28])[CH:10]=2)[CH2:6][O:7]1
Reactant: CN(C)C=O
Reactant: CC1(C)OCc2ccc(Br)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)OCc2ccc(C=O)cc21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-1,1-dimethyl-1,3-dihydro-isobenzofuran (1.41 g, 6.3 mmol) in anhydrous THF (10 mL) was added under Argon at −78° C. 2.5 M nBuLi in hexane (2.7 mL, 6.6 mmol) and after stirring for 0.5 h at −78° C. DMF (0.98 mL, 12.5 mmol) was added. After stirring for 2 h at −78° C. the reaction mixture was added to 0.5 N cold aq. HCl and extracted with Et2O. Combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The title compound was obtained after chromatographic purification (Combi-Flash, 40 g silicagel, hexane-EtOAc 95:5 to 50:50) as a light yellow oil: TLC (hexane-EtOAc 1:1) Rf=0.50; HPLC RtA=1.43 min; 1H NMR (400 MHz, CDCl3): δ10.02 (s, 1H), 7.78 (d, 1H), 7.65 (s, 1H), 7.36 (d, 1H), 5.11 (s, 2H), 1.53 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1)#[N:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(C#N)cn3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ccc(C#N)cn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(5-cyanopyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (12 mL, 1:1) was added aqueous NaOH solution (250 mg in 3 mL water). After stirring at room temperature for two hours, the reaction mixture was evaporated, acidified to pH 3 with 1 N HCl and then concentrated. HPLC purification gave product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.25 (dd, J=8.8, 2.4 Hz, 1H), 7.19 (m, 2H), 7.04 (s, 1H), 5.47 (dd, J=9.6, 2.4 Hz, 1H), 3.03 (dd, J=15.6, 2.4 Hz, 1H), 2.24 (s, 3H), 2.12 (dd, J=15.6, 9.6 Hz, 1H). 2 protons assumed to be exchanged with solvents. MS (ESI) m/z=323 [M−H]+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.[CH3:31][C:32]([CH3:34])=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:14][C:11]1[C:12]([F:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH:32]([CH3:34])[CH3:31])[CH2:6]2)[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: CC(C)=O
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (49 mg, 0.10 mmol), acetone (8.28 μL, 0.113 mmol), and triethylamine (44.3 μL, 0.318 mmol) in dichloromethane (0.67 mL) was added sodium triacetoxyborohydride resin (89 mg, 0.20 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was filtered and concentrated and then purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/min) to give the racemic product. LCMS: found m/z=447.2 (M+H)+. The racemic mixture was separated by chiral HPLC (column IA, eluting with 5% ethanol/95% hexanes, at flow rate 18 mL/min) to give two peaks (isomer 1:9.5 mg, 21%; isomer 2: 9.2 mg, 20%).
Reaction SMILES: [CH:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([OH:10])=O)[C:4]=1[CH3:11])=[O:2].[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][C@@H:15]([CH3:19])[NH:14]1>>[CH3:12][C@H:13]1[NH:14][C@@H:15]([CH3:19])[CH2:16][N:17]([C:8]([C:5]2[C:4]([CH3:11])=[C:3]([CH:1]=[O:2])[NH:7][CH:6]=2)=[O:10])[CH2:18]1
Reactant: Cc1c(C(=O)O)c[nH]c1C=O
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Yield: 87.7 %

Procedure:
5-Formyl-4-methyl-1H-pyrrole-3-carboxylic acid (1.00 g, 6.54 mmol) reacted with cis-2,6-dimethylpiperazine (822 mg, 7.19 mmol) to give 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (1.43 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH:14]2[CH2:16][CH2:15]2)=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=O.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[NH:18][NH2:19].C(N=C=NCCCN(C)C)C>ClCCl>[C:22]([O:21][C:17]([N:18]([C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:12])[C:10]([F:11])=[C:2]([Cl:1])[C:3]=1[NH:13][CH:14]1[CH2:16][CH2:15]1)[NH2:19])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1NC1CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(N)C(=O)c1cc(F)c(F)c(Cl)c1NC1CC1
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 3-chloro-2-cyclopropylamino-4,5-difluorobenzoic acid (Example 5d, 2.09 g, 8.45 mmol) in dichloromethane (30 mL) is added tert-butyl carbazate (1.67 g, 12.7 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (2.43 g, 12.7 mmol). After 16 hours, the reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under vacuum and purified via flash column chromatography (1:2 ethyl acetate/hexanes) to afford the title compound (1.93 g). MS EI: m/z 360 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH:48]3[CH2:50][CH2:49]3)=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH:48]3[CH2:49][CH2:50]3)=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K33) (264 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (353 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:30](=O)[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH2:10][CH2:9]1.Cl.[NH2:34][OH:35].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:30](=[N:34][OH:35])[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:27])[CH3:28])[CH2:10][CH2:9]1
Reactant: NO
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.12 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone was dissolved in 1 ml of a 1:1 mixture of ethanol and water. 0.8 mmol of hydroxylamine hydrochloride was added, followed by 8.4 mmol of sodium acetate. The resulting mixture was stirred overnight at room temperature, diluted with water, filtered, washed and dried to yield the title compound as a colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][CH2:24][C:10]2([N:13]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH2:11]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([N:13]1[C:10]2([CH2:24][CH2:25][CH2:26][NH:8][CH2:9]2)[CH2:11][CH2:12]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN2C(=O)OCc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCC12CCCNC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
To a solution of an optically-active compound of 1,6-diazaspiro[3,5]-nonane-1,6-dicarboxylic acid 1-benzyl ester 6-tert-butyl ester (5.35 g) in chloroform (134 ml) cooled to 0° C. was added trifluoroacetic acid (27 ml), and the mixture was stirred for 30 minutes, warmed to room temperature and stirred for additional 30 minutes. The reaction mixture was cooled to 0° C., and thereto was added 4M aqueous sodium hydroxide solution (91 ml). The aqueous layer was extracted with chloroform (100 ml, 50 ml) twice, and the combined organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 4/1) to give the titled compound (2.37 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH:10](O)=O.C=O.[ClH:15]>>[ClH:15].[ClH:15].[CH3:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: O=CO
Reactant: OCCN1CCNCC1
Agent: C=O
Agent: Cl
Product: CN1CCN(CCO)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
A total of 100 g (0.77 mol) of 1-(2-hydroxyethyl)piperazine was added dropwise to a stirred solution of 78.6 g (1.54 mol) of 90% formic acid at 0° C. To the resulting solution, 63.2 g (0.77 mol) of 37% formaldehyde was added dropwise. The solution was stirred at 0° C. for 15 minutes and heated on a steam bath for 3 hours. The solution was acidified with 150 ml of concentrated hydrochloric acid. The water was removed and the resulting residue dissolved in 200 ml of 25% NaOH, and extracted with chloroform. The organic layer was dried over MgSO4, filtered, and the solvent removed. The resulting residue was distilled to give 84.7 g (76%) (b.p. 96-97° C./3 Torr) of the alcohol as a colorless liquid. The dihydrochloride salt was prepared by acidifying the free base to a pH of 1 and removing the water.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:23]2C(=O)C3=CC=CC=C3C2=O)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1CCOCCOCCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCOCCOCCOCCOCCOCCN
Temperature: 100 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
A solution containing 60 g of 1,17-diphthalimido-3,6,9,12,15-pentaoxaheptadecane (0.118 mol), 14.8 g of hydrazine hydrate (0.296 mol), and 500 ml of ethanol were heated with mechanical stirring in a 100° C. oil bath for three hours. The mixture was then cooled and filtered. The resultant filter cake was washed four times with 300 ml portions of ethanol. The combined filtrates were concentrated to yield 32.35 g of a yellow opaque glassy oil. The evaporative distillation at 150°-200° C. (0.01 mm) gave 22.82 g of a light yellow oil (69% yield). lit. b.p. 175°-177° C. (0.07 mm).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[I-].C([N+]1(C)[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([N:5]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N1CCC(=O)CC1
Temperature: 78 °C
Yield: 60.9 %

Procedure:
To a solution of t-butylamine (78.2 ml, 0.74 mol) in toluene (400 ml) was added a solution of 1-ethyl-1-methyl-4-oxopiperidinium iodide (40 g, 0.148 mol) and sodium bicarbonate (1.245 g, 0.014 mol) in water (60 ml). The reaction mixture was heated at 78° C. for 6 hours and then allowed to cool to ambient temperature. The layers were separated and the aqueous layer was washed with EtOAc. The organics were combined and washed with brine, dried (MgSO4), filtered and reduced in vacuo to yield 1-tert-butyl-4-oxopiperidine (14 g) (LC/MS: Rt 0.39, [M+H]+ 156).