Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4]1.[H-].[Na+].[C:16]1([C:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][CH2:30]Br)[CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>CN(C)C=O.C(Cl)Cl.C(C(C)=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[CH3:1][N:2]([CH3:13])[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:30][CH2:29][CH2:28][N:25]1[CH2:24][CH:23]=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:27][CH2:26]1
Reactant: BrCCCN1CC=C(c2ccccc2)CC1
Reactant: CN(C)C1NC(=O)c2ccccc21
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 3-dimethylamino-1-isoindolinone (11.7 g) in anhydrous dimethylformamide (300 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (3.5 g) in anhydrous dimethylformamide (150 cc) at a temperature close to 20° C. in the course of 30 minutes, and agitation is continued for 1 hour. Then, a solution of 3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-1-bromopropane (20.5 g) in dimethylformamide (150 cc) is added in the course of 15 minutes, and agitation is continued for a further 20 hours. The solution obtained is evaporated to dryness under reduced pressure (1 mm mercury; 0.1 kPa). The residue obtained is dissolved in methylene chloride (350 cc) and washed with distilled water (3×150 cc). The organic extract is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (50 cc) and poured onto silica (1000 g) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (95-5 by volume). The first 2300 cc are eliminated and the eluate corresponding to the next 1500 cc is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is dissolved in methyl ethyl ketone (80 cc). A solution of oxalic acid (1.9 g) in methyl ethyl ketone (20 cc) is added and agitation is continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 7.6 g of 3-dimethylamino-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 159° C.
Reaction SMILES: [Br:1][C:2]([CH3:29])([CH3:28])[C:3]([NH:5][C:6]1[S:7][C:8]2[C:14]3[CH:15]=[N:16][N:17](C(=O)C(Br)(C)C)[C:13]=3[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[C:9]=2[N:10]=1)=[O:4].O1CCCC1.C(O)CO.C(N(CC)CC)C>C(OCC)(=O)C.O>[Br:1][C:2]([CH3:29])([CH3:28])[C:3]([NH:5][C:6]1[S:7][C:8]2[C:14]3[CH:15]=[N:16][NH:17][C:13]=3[CH:12]=[C:11]([C:24]([F:25])([F:26])[F:27])[C:9]=2[N:10]=1)=[O:4]
Reactant: CC(C)(Br)C(=O)Nc1nc2c(C(F)(F)F)cc3c(cnn3C(=O)C(C)(C)Br)c2s1
Solvent: OCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)Nc1nc2c(C(F)(F)F)cc3[nH]ncc3c2s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.7 %

Procedure:
A mixture of 4.32 g of 2-bromo-N-[6-(2-bromo-2-methyl-propionyl)-4-trifluoromethyl-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-yl]-2-methyl-propionamide, 25 ml of tetrahydrofuran, 10 ml of ethyleneglycol and 1.30 ml of triethylamine was stirred at room temperature for 14 hours. After the completion of the reaction was confirmed by HPLC, water and ethyl acetate were added and then portioned. The ethyl acetate layer was washed with 1M hydrochoric acid, water and brine and dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. Hexane was added to the residue and the solid was collected by filtration to give 2.87 g (yield: 91%) of 2-bromo-2-methyl-N-(4-trifluoromethyl-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-yl)-propionamide as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH2:12])=[CH:5]2.[CH3:13]OC(OC)N(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][CH3:13])=[CH:5]2
Reactant: COC(OC)N(C)C
Reactant: Nc1cc2cc(Br)ccc2cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc2cc(Br)ccc2cn1
Temperature: 110 °C
Yield: 43 %

Procedure:
To a solution of 6-bromoisoquinolin-3-amine (50.0 mg, 2.6 mmol) in N,N-dimethylformamide (10 mL) was added N,N-dimethylformamide dimethylacetal (2 mL). The reaction vessel was sealed and heated in a Biotage Smith Synthesizer microwave to 110° C. for 20 minutes. Sodium triacetoxyborohydride (59 mg, 0.28 mmol) was then added to the reaction mixture. The vial was resealed and heated again to 110° C. on a Biotage Smith Synthesizer microwave for 10 minutes. The reaction was concentrated. The residue was dissolved in ethyl acetate (50 mL) and washed with brine (2×20 mL). The organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave the title compound (23 mg, 43%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.76 (s, 1H), 7.74 (s, 1H), 7.61 (d, 1H), 7.28 (d, 1H), 6.40 (s, 1H), 5.09-5.07 (m, 1H), 2.97 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[CH:33]=O>ClCCl>[Br:21][C:20]([Br:24])=[CH:33][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:27]=1[O:26][CH3:25]
Reactant: COc1ccncc1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccncc1C=C(Br)Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask is charged with triphenylphosphine (21.4 g, 81.6 mmol), carbon tetrabromide (13.5 g, 40.8 mmol) and dichloromethane (300 mL). 4-Methoxy-pyridine-3-carbaldehyde (2.8 g, 20.4 mmol) in dichloromethane (300 mL) is added at 0° C. The mixture is stirred at 0° C. for 1 h. The mixture is extracted with saturated aqueous ammonium chloride and the aqueous phase is neutralized with NaHCO3 and extracted with dichloromethane. The organic phase is dried over Na2SO4, concentrated and purified by silica gel chromatography eluting with a 0 to 10% methanol-dichloromethane gradient to give 3-(2,2-dibromo-vinyl)-4-methoxy-pyridine. 1H NMR (400 MHz, CDCl3) δ ppm 3.90 (s, 3H), 6.81 (d, J=5.8 Hz, 1H), 7.48 (s, 1H), 8.48 (d, J=5.8 Hz, 1H), 8.76 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Product: CN1c2cc(OCc3ccc(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[NH:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[O:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)CC(=O)c2ccc3ccccc3c2NCC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)CC(=O)c2ccc3ccccc3c2NCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
To a solution of 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][(1,1-dimethylethoxycarbonyl)methyl]aminonaphthalene (147 mg, 0.30 mmol) in CH2Cl2 (2.0 mL) was added TFA (3.0 mL). The resulting reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo to afford an oil, which was diluted with water (15 mL), adjusted to pH 4.5 by saturated NaHCO3, then extracted by ethyl acetate (3×15 mL). The organic layer was evaporated in vacuo to afford 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][carboxymethyl]aminonaphthalene (90 mg) as a solid; NMR (CDCl3) 1.26 (t, 3), 3.24–3.30 (m, 2), 3.35–3.42 (m, 6), 3.57 (m, 2), 4.14 (q, 2), 4.52 (s, 2), 7.48 (d, 1), 7.58 (m, 2), 7.84–7.94 (m, 4) ppm.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])=[O:8])([CH3:4])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O.C(C1C=C(O)C(=CC=1)O)(C)(C)C.II>[C:1]([O:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:13]([C:11]([CH3:13])=[CH:10][C:9]([CH3:15])([CH3:7])[NH:12]2)=[CH:14][CH:15]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ONC(=O)c1cccc(N)c1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: II
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)=O
Product: CC1=CC(C)(C)Nc2cc(C(=O)NOC(C)(C)C)ccc21
Temperature: 25 °C
Yield: 165.3 %

Procedure:
To an oven-dried 1 L r.b. flask containing 3-tert-butyloxycarbamoylaniline (17.4 g, 83.5 mmol), MgSO4 (50 g, 5 equivuiv), and 4-tert-butylcatechol (420 mg, 3 mol %) in 120 mL acetone (approx 0.75 M in the analine) was added iodine (1.07 g, 5 mol %), and the mixture was heated to reflux for 8 h. The crude reaction mixture was then cooled to rt, filtered through a bed of Celite™ on a fritted-glass funnel, rinsing with ethyl acetate, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded 19.9 g (82%) of 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2,4-trimethylquinoline as a white solid, which was further purified by recrystallization from acetonitrile to give white needles. Data for 7-tert-butyloxycarbamoyl-1,2-dihydro-1,2-dihydro-2,2,4-trimethylquinoline: 1H NMR (400 MHz, CDCl3) 6.93 (d, J=8.3, 1H, 5-H), 6.81 (br, s, 1H, HNBoc), 6.34 (m, 2H, 6,8-H), 5.21 (d, J=0.9, 1H, 3-H), 3.71 (br, s, 1H, NH), 1.94 (d, J=1.0, 3H, 4-CH3), 1.50 [s, 9H, (CH3)3CO)], 1.24 [s, 6H, 2(--CH3)2 ].
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:19][CH2:20][N:15]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16][CH2:17]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Product: CC(C)(C)OC(=O)NN1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 63.9 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (29.8 g, 137 mmol) and tert-butyl piperazin-1-ylcarbamate (28.9 g, 144 mmol) gave tert-butyl (S)-{4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-yl}carbamate (36.68 g, yield 64%) as a white powder in the same manner as in Example 496.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:9]2[CH2:10][C@H:11]3[CH2:23][C@H:12]3[C:13]=2[N:14]([C:16]2[CH:21]=[C:20](Br)[CH:19]=[CH:18][N:17]=2)[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-:24].[Li+]>CC(N(C)C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([NH:5][C:6]([C:8]1[C:9]2[CH2:10][C@H:11]3[CH2:23][C@H:12]3[C:13]=2[N:14]([C:16]2[CH:21]=[C:20]([Cl:24])[CH:19]=[CH:18][N:17]=2)[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Reactant: [Cl-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 180 °C
Yield: 51.5 %

Procedure:
A mixture of (1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid tert-butylamide (0.010 g, 0.027 mmol) and lithium chloride (5.65 mg, 0.133 mmol) in DMA (1 mL) was heated in a heavy-walled sealed tube under microwave irradiation at 160 for 1 hour. Lithium chloride (20 mg) and tetrabutylammonium bromide (5 mg) were added. The reaction was heated in a heavy-walled sealed tube under microwave irradiation at 180° C. for 10 h. The mixture was purified by preparative HPLC to give the title compound as a white solid (4.6 mg). LCMS m/z=331.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[BH4-].[Na+].O.Cl>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1ccc(C(=O)O)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(O)c1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To 159 mg of product from Example 11 suspended in 10 ml of ethyl alcohol at 0° C. was added 13 mg of sodium borohydride. An additional 10 ml of ethyl alcohol was added and the reaction stirred overnight while allowed to warm to room temperature. An additional 40 mg of sodium borohydride was added followed in about 20 hours by 50 ml of ethanol and 100 mg of sodium borohydride. Stirring was continued for 20 hours whereupon 25 ml of water was added, followed by 20 ml of 10% hydrochloric acid. The organic solvent was removed using a rotary evaporator and the aqueous residue extracted with two 50 ml portions of ethyl ether. The organic extracts were combined, washed with water, dried over sodium sulfate, and filtered. The solvent was removed using a rotary evaporator to give a white solid (150 mg). Recrystallization of the solid from methanol/hexane gave 139 mg of product identical with that disclosed in Example 14 of U.S. Pat. No. 4,469,885.
Reaction SMILES: C([O:8][N:9]([CH3:37])[C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[NH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11])C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[OH:8][N:9]([CH3:37])[C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[NH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11]
Reactant: CN(OCc1ccccc1)C(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(O)C(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reaction time: 1.17 h
Yield: 83 %

Procedure:
A suspension of 10% Pd/C (0.20 g) and N-benzyloxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperdine-2-(R)-carboxamide (0.40 g, 0.75 mmol) [prepared as described in Step 4 above] in 80% ethanol/tetrahydrofuran (6 ml) was stirred under a hydrogen atmosphere (1 atm) for 70 min. The reaction was degassed with nitrogen, filtered through Celite and the filtrate was concentrated in vacuo. The residue was chromatographed (PTLC, SiO2, 10% methanol/methylene chloride) to give N-hydroxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (83%) as a white solid.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=O.[N:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([C:21]([F:24])([F:23])[F:22])[CH:13]=1)=[C:10]=[O:11]>>[OH:7][CH2:6][C:2]1([CH3:8])[NH:1][C:10](=[O:11])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([C:21]([F:22])([F:23])[F:24])[CH:13]=2)[C:3]1=[O:5]
Reactant: O=C=Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CC(N)(CO)C(=O)O
Product: CC1(CO)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O

Procedure:
Follow the procedure in Example 12, using 2-amino-3-hydroxy-2-methyl-propionic acid and 4-isocyanato-1-nitro-2-trifluoromethyl-benzene, known from the literature as starting material to yield the title compounds as a yellow solid.
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccc(F)cc2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperizine was reacted with 4-fluorobenzyl chloride to form 1-(4-fluorobenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine, mp 242° C. (dec).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:16]([CH:18]2[CH2:20][CH2:19]2)[OH:17])=[C:6](F)[CH:5]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[CH:16]([CH:18]3[CH2:20][CH2:19]3)[O:17][C:6]=2[CH:5]=1
Reactant: OC(c1cnccc1-c1ccc(Cl)cc1F)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)OC(C1CC1)c1cnccc1-2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
To a suspension of NaH (389 mg, 9.72 mmol) in THF (9 mL) cooled to 0° C., was added (4-(4-chloro-2-fluorophenyl)pyridin-3-yl)(cyclopropyl)methanol (900 mg, 3.24 mmol) in THF (9 mL) dropwise over a period of 10 min. The reaction mixture was stirred at 0° C. for 15 min and then warmed to room temperature and stirred for 15 h. The reaction mixture was quenched by addition of cold water (10 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine (1×25 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified via silica gel column chromatography (ethyl acetate/hexanes) to give 8-chloro-5-cyclopropyl-5H-chromeno[3,4-c]pyridine (630 mg, 2.45 mmol, 75% yield). LCMS (ESI) m/e 258.0 [(M+H)+, calcd for C15H13ClNO 258.1]; LC/MS retention time (Method C): tR=2.08 min.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([OH:3])=O.[CH3:15][C:16]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].CC(C)=O.CO>C(Cl)Cl>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:6]2[C:5]=1[CH2:4][C:1](=[O:3])[N:19]([CH2:18][C:17]1[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:16]=1[CH3:15])[C:7]2=[O:9]
Reactant: Cc1ccc(CN)c(C)c1
Reactant: O=C(O)Cc1c(Cl)cccc1C(=O)O
Solvent: CC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(CN2C(=O)Cc3c(Cl)cccc3C2=O)c(C)c1
Temperature: 180 °C
Yield: 72.7 %

Procedure:
A mixture of 2-carboxymethyl-3-chlorobenzoic acid (1.91 g, 8.9 mmol) and 2,4-dimethylbenzylamine (1.35 mL, 9.6 mmol) was placed in a vented vial and heated in an oil bath maintained at 180° C. After heating for 64 hours the reaction was allowed to cool to ambient temperature, then taken up in a mixture of CH2Cl2, acetone, and methanol. The solution was mixed with silica gel and then concentrated under reduced pressure to afford a free flowing solid. This solid was loaded onto the top of a silica gel column and eluted with a gradient from 0% to 14% ethyl acetate/hexane to afford 5-chloro-2-(2,4-dimethylbenzyl)-4H-isoquinoline-1,3-dione (2.03 g, 73% yield) as a yellow solid: 1H-NMR (400 MHz, CDCl3): δ 8.17 (1H, dd, J=7.8, 1.3 Hz), 7.65 (1H, dd, J=7.8, 1.3 Hz), 7.42 (1H, app. t, J=7.8 Hz), 6.98 (1H, br s), 6.96-6.92 (1H, m), 6.91-6.87 (1H, m), 5.16 (2H, s), 4.09 (2H, s), 2.44 (3H, s), 2.26 (3H, s) ppm.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1.Cl.[OH-].[NH4+]>C1COCC1.C(Cl)(Cl)Cl.C(O)(C)C>[F:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([OH:12])[CH3:1])=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(F)nc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Add methyl magnesium bromide (3 M in ether, 12 mL, 36 mmol) at 0° C. under nitrogen to a solution of 6-fluoro-pyridine-3-carbaldehyde (3 g, 24 mmol) in THF (20 mL). Continue to stir the mixture for overnight at room temperature. Hydrolyze the mixture with 1 N HCl and follow the basification with diluted ammonium hydroxide to ˜pH 9. Abstract the product with chloroform/isopropyl alcohol (3/1). Dry over sodium sulfate. Concentrate the solution in vacuo to yellow oil. Purify by column chromatography (10% methanol in dichloromethane) to give the product as a colorless oil (2.3 g, 68%). MS (ES) m/z 142 [M+1]+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[CH:16]=1>>[N:18]1([CH2:17][C:15]2[CH:16]=[C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:13][CH:14]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ncc(Cn2ccnc2)cc1Br
Product: c1ccc(-c2cc(Cn3ccnc3)cnc2-c2ccccc2)cc1

Procedure:
Synthesized using phenylboronic acid (134 mg, 1.10 mmol) and 6 (150 mg, 0.55 mmol) according to Method C. Yellow solid. Yield: 79 mg, 0.25 mmol, 46%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.27 (s, 2H), 7.00 (brs, 1H), 7.11-7.13 (m, 2H), 7.16 (brs, 1H), 7.21-7.28 (m, 6H), 7.32-7.34 (m, 2H), 7.49 (d, J=2.1 Hz, 1H), 8.60 (d, J=2.1 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.3, 119.2, 127.6, 128.0, 128.1, 128.4, 129.2, 129.4, 129.8, 136.4, 137.1, 137.5, 139.0, 139.3, 147.1, 147.1, 157.6; MS (ESI): m/z=312.10 [M+H]+.
Reaction SMILES: CC(=[N:4][OH:5])C.CC(C)([O-])C.[K+].Cl[C:13]1[C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=O)=[CH:17][CH:16]=[CH:15][N:14]=1>CN(C)C=O>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([C:19]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[O:5][N:4]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(C(=O)c2cccnc2Cl)c1
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2noc3ncccc23)c1
Reaction time: 1 h
Yield: 67.7 %

Procedure:
Combine acetone oxime (3.1 g, 42.4 mmol) in dimethylformamide (15 mL) and add potassium t-butoxide (4.76 g, 42.4 mmol) and stir for 1 hour. Add (2-chloro-pyridin-3-yl)-(3-methoxy-phenyl)-methanone (8.40 g, 34 mmol) dissolved in dimethylformamide (10 mL) and stir at room temperature, overnight. Separate the product between water and ether and evaporate. Purify by column (silica) chromatography (10% ethyl acetate/dichloromethane) and then reflux in a mixture of 1:1 ethanol:5% aqueous hydrochloric acid. Work-up with 5% aqueous sodium hydroxide and ether and purify by flash chromatography (5% ethyl acetate in dichloromethane) to give the title compound (5.21 g, 68% Yield).