Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])COC)(=[O:13])=[O:12])=[C:7]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:13])=[O:12])=[C:7]([CH:27]=[CH:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1C=Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1C=Cc1ccccc1
Temperature: 75 °C
Yield: 49.5 %

Procedure:
To a solution of 25 (134.0 mg; 0.27 mmol) in tetrahydrofuran (8 mL) was added aqueous hydrochloric acid (8.0 mL; 16.0 mmol; 2N). The reaction mixture was heated at 75° C. for 4 hours, and then additional aqueous hydrochloric acid (3.0 mL; 6N) was added and the reaction mixture further heated at reflux for 4-5 hours. The reaction mixture was allowed to cool to room temperature and then extracted with ethyl acetate (15 mL). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield an orange oil residue which was purified by automated silica gel chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 30% v/v over 400 mL gradient elution) to yield the title product as a white solid (60.9 mg).
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[N:8][C:9]=2[C:13]1[CH:14]=[N:15][C:16]([NH2:19])=[N:17][CH:18]=1)([CH3:3])[CH3:2].C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)Cl>[Br:33][C:12]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2[C:10]([N:11]=1)=[C:9]([C:13]1[CH:14]=[N:15][C:16]([NH2:19])=[N:17][CH:18]=1)[N:8]=[C:7]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:6]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)n1cnc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Solvent: ClC(Cl)Cl
Product: CC(C)n1c(Br)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 5-(9-isopropyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine, (1.03 g, 3.03 mmol) in 15 ml of chloroform, was added slowly NBS (594 mg, 3.34 mmol) at a temperature of 5° C. The reaction was continued for 2 h at this temperature. After simple work-up, the product 5-(8-bromo-9-isopropyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine was purified by flash column (solvent system: 50% ethyl acetate in hexane) to deliver 5-(8-bromo-9-isopropyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine in a yield of 52% (660 mg). 1H NMR, MeOD: 9.67 (s, 2H), 4.90 (m, 1H), 3.89 (m, 4H), 3.82 (s, 4H), 1.72 (d, 6H). m/z: 419.31, 421.07 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19][CH2:18]3)=[O:16])[C:9]2=[O:33])=[CH:4][CH:3]=1>O1CCCC1>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15](=[O:16])[N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9]2=[O:33])=[CH:35][CH:36]=1
Reactant: O=C(CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Product: O=C(CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCNCC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A 50 mL pressure bottle was charged with tetrahydrofuran (10 mL), the product of Example 23E (0.500 g, 0.913 mmol) and 20% Pd(OH)2—C, wet (0.100 g, 0.712 mmol). The reaction mixture was stirred at 50° C. under an atmosphere of 30 psi H2 for 15 minutes. The mixture was filtered through a nylon membrane and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix Intelliflash 280; 2N NH4OH in CH3OH/CH2Cl2, 2:98, eluant) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.30-7.21 (m, 4H), 7.15-7.05 (m, 4H), 4.17 (s, 2H), 3.45-3.24 (m, 7H), 2.66 (d, J=3.6, 4H), 2.55-2.46 (m, 2H), 1.74-1.60 (m, 2H); MS (DCI+) m/z 414 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:37])=[C:12]([C:29]2[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=2)[O:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)=[CH:7][C:6]=1[C:38]([F:41])([F:40])[F:39])(=[O:4])=[O:3].[ClH:42].B(Br)(Br)Br.[CH3:47]O>C(OCC)(=O)C.C(OCC)C.O.ClCCl>[ClH:42].[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:13][C:14]3[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:27][CH:28]=3)=[C:29]3[C:34](=[CH:47][CH:37]=2)[CH:33]=[C:32]([OH:35])[CH:31]=[CH:30]3)=[CH:7][C:6]=1[C:38]([F:40])([F:41])[F:39])(=[O:4])=[O:3]
Reactant: COc1ccc(C(Oc2ccc(OCCN3CCCCC3)cc2)=C(C)c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)cc1
Reactant: CO
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1C(F)(F)F
Temperature: 0 °C
Yield: 53 %

Procedure:
Dissolve the product of Example 31 in ethyl acetate (10 mL) and diethyl ether (5 mL). Add 2M HCl in diethyl ether (0.1 mL, 0.2 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with external ice bath. Add BBr3 (0.1 mL, 1.1 mmol) and stir for 1 hour. Dilute with water (1.0 mL) and dichloromethane (10 mL). Separate the layers and wash the organic layer with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). Dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting the 6-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol/dichloromethane (O to 5%). Dissolve the free base in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and add 2M HCl in diethyl ether (0.1 mL, 0.2 mmol). Collect the precipitate on filter paper, rinse with diethyl ether and dry in vacuo (<2 mm of Hg) at 65° C. for 48 hours to give 34 mg of the title compound (53%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:7])[CH:5]=[CH2:6])O.C1(C=CC(O)=CC=1)O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O>[N:16]1([CH2:1][NH:3][C:4](=[O:7])[CH:5]=[CH2:6])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C=CC(=O)NCO
Reactant: C1COCCN1
Agent: Oc1ccc(O)cc1
Solvent: O
Product: C=CC(=O)NCN1CCOCC1

Procedure:
In a 300 cc capacity round bottom flask equipped with a stirrer were put 50.5 g (0.5 mole) of N-methylolacrylamide and 50 cc of water and, as a polymerization-inhibitor, 500 mg of hydroquinone. On the other hand, 43 g (0.5 mole) of morpholine were gradually added thereto while stirring. Afterwards, the entire contents were stirred for 1 hour at 50° to 60°C. The reaction product was concentrated and then recrystallized from ethyl acetate. m.p.; 91°-92°C. In addition, the resulting product was further distilled under reduced pressure to obtain 34.5 g of fraction of 140°-160°C/0.01 mmHg (45.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:26])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]=[O:23])=[C:16]([CH3:24])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:25]=2)=[C:4]([CH3:27])[CH:3]=1.[CH:28]([Mg]Br)=[CH2:29]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:26])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]([OH:23])[CH:28]=[CH2:29])=[C:16]([CH3:24])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:25]=2)=[C:4]([CH3:27])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=O)[nH]c(=O)c3c2n1C
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a 1 L 3-neck round-bottom flask equipped with a magnetic stir-bar was added 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (7.96 g, 21.9 mmole) and THF (260 mL). The resulting slurry was cooled to −78° C., and vinylmagnesium bromide (175 mL, 1.0 M in THF) was added dropwise over 30 minutes. The mixture was stirred at −78° C. for 2 hours, then warmed to −10° C. over 30 minutes and maintained at −10° C. for an additional 2 hours. The reaction was then quenched by addition of saturated aqueous ammonium chloride (200 mL), and extracted into EtOAc (2×200 mL). The organic layers were collected, washed with brine (2×100 mL), dried over sodium sulfate, and concentrated in vacuo to provide 2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (7.8 g, 91%) as an orange-yellow solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.52 (br s, 1H), 10.38 (br s, 1H), 7.71 (app s, 2H), 7.55 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.24 (td, 1H, J1=9.1 Hz, J2=11.7 Hz), 6.02 (ddd, 1H, J1=5.9 Hz, J2=10.6 Hz, J3=17.2 Hz), 5.41 (app d, 1H, J=5.5 Hz), 5.33 (dt, 1H, J1=1.6 Hz, J2=17.2 Hz), 5.17 (dt, 1H, J1=1.2 Hz, J2=10.2 Hz), 4.19 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H); ESMS (m/z): 393 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH2:22][CH3:23])[CH3:21])[CH3:3].Cl[CH2:25][CH:26]([OH:32])[CH2:27][S:28]([O-:31])(=[O:30])=[O:29].[Na+].[OH-].[Na+]>O.C(O)(C)C>[CH3:3][N+:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH2:22][CH3:23])[CH3:21])([CH2:25][CH:26]([OH:32])[CH2:27][S:28]([O-:31])(=[O:30])=[O:29])[CH3:1]
Reactant: O=S(=O)([O-])CC(O)CCl
Reactant: CCC(C)CCCCCCCCCCCCCCCCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCC(C)CCCCCCCCCCCCCCCC[N+](C)(C)CC(O)CS(=O)(=O)[O-]
Reaction time: 56 h

Procedure:
A 1-L round bottom flask (equipped with a magnetic stirrer and reflux condenser) was charged with 20 g (61 mmol) of N,N-dimethyl-(2-butyl)hexadecylamine, 20 g (100 mmol) of sodium 3-chloro-2-hydroxy-1-propanesulfonate, 140 mL isopropanol, 50 mL of water, and 0.6 g (8 mmol) of 50% sodium hydroxide. The mixture was stirred at reflux. The progress of the reaction was followed using a Waters Associates C-18 μ-Bondapak reverse-phase column, 1.5 mL/min of a 10:1 isopropanol:water as solvent and a refractive index detector. Total reflux time was 56 hours. The reaction mixture was extracted with chloroform (200 mL). The organic layer was concentrated in vacuum to give a white solid which was taken up in 600 mL of a 1:1 isopropanol:water mixture and washed with petroleum ether (2 times using 200 mL of petroleum ether).
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:10](Br)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cu](C#N)[C:16]#[N:17]>CN(C)C(=O)C>[NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:10]([C:16]#[N:17])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: N#C[Cu]C#N
Reactant: CCOC(=O)c1cc(Br)cc(C)c1N
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(C#N)cc(C)c1N
Yield: 83.2 %

Procedure:
The above-described method (Example 2) was repeated to react ethyl 2-amino-5-bromo-3-methylbenzoate (2.00 g, 7.65 mmol) with copper cyanide (0.70 g, 7.80 mmol) in N,N-dimethylacetamide at 160° C. for 8 hours. Following working up similar to Example 2, ethyl 2-amino-5-cyano-3-methylbenzoate (1.30 g, 80.2% of theory, 96.3 area % LC) was obtained as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)([O-:3])=[O:2].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-]>CN(C)C=O>[F:12][C:13]1[CH:14]=[C:15]([NH:16][C:9]([C:7]2[NH:6][N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=2)=[O:11])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Reactant: Nc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(F)c1)c1cc([N+](=O)[O-])n[nH]1
Yield: 42 %

Procedure:
3-nitro-1H-pyrazole-5-carboxylic acid (1 g, 6.36 mmol) in dimethylformamide (10 ml) was reacted with 3-fluoroaniline (673 μl, 7 mmol) in the presence of 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) and 2-hydroxy-pyridin-1-oxide (778 mg, 7 mmol) at 40° C. for 1.5 hour. The solvent was evaporated, and the residue purified by chromatography on silica gel. Elution with dichloromethane:methanol (99:1) then (97:3) yielded N-(3-fluorophenyl)-3-nitro-1H-pyrazole-5-carboxamide (668 mg, 42% yield):
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.[CH3:18][O:19][N:20]=[C:21]([C:29]1[O:30][CH2:31][CH2:32][N:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28].[OH-].[Na+]>CN(C)C=O>[CH3:18][O:19][N:20]=[C:21]([C:29]1[O:30][CH2:31][CH2:32][N:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: CON=C(C1=NCCO1)c1ccccc1O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON=C(C1=NCCO1)c1ccccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 52 %

Procedure:
N,N-Dimethylformamide (2.2 ml), potassium carbonate (210 mg, 1.5 mmol) and 2-chloro-5-trifluoromethylpyridine (220 mg, 1.2 mmol) were added to 2-hydroxyphenyl 2-oxazolin-2-yl ketone O-methyloxime (220 mg, 1.0 mmol), and the mixture was stirred at 100° C. for 2.5 hours. After completion of the reaction, aqueous 1N sodiumhydroxide solution NaOH (100 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(5-trifluoromethyl-2-pyridyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime (190 mg, 52.1%) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([OH:11])[CH2:13]1)([O-:10])=[O:9]
Reactant: OC1CCCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnccc1N1CCCC(O)C1

Procedure:
Method 1 of Example 1 was followed using 1 equivalent each of 4-chloro-3-nitropyridine, (+/−)-3-hydroxypiperidine and triethylamine in DMF yielding (+/−)-1-(3-nitropyridin-4-yl)piperidin-3-ol, LCMS (m/z): 224.1 (MH+); LC Rt=1.06 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([OH:9])=O.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[NH:32][NH2:33]>ClCCl>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH:33][NH:32][C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:9]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cn1ccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cn1ccnc1C(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-methyl-1H-imidazole-2-carboxylic acid (500 mg, 3.57 mmol, commercially available from e.g. Sigma-Aldrich), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (554 mg, 3.57 mmol) and 1-H-1,2,3-benzotriazol-1-ol (54.6 mg, 0.357 mmol) in dichloromethane (20 ml) pre-stirred for 30 mins under argon at room temp was added solid t-butyl carbazate (722 mg, 5.35 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mixture was partitioned between dichloromethane (˜50 ml) and saturated sodium bicarbonate solution (˜50 ml). The aqueous phase was extracted with dichloromethane (2×25 ml) and the combined organic extracts washed with saturated sodium bicarbonate solution (˜25 ml), dried over magnesium sulphate and evaporated in vacuo to give the crude product as a yellow oil.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2>>[C:1]1([S:7][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2cc(OCCCl)ccc2N1
Reactant: Sc1ccccc1
Product: O=C1CCc2cc(OCCSc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from thiophenol and 6-(2-chloro-ethoxy)-3,4-dihydro-carbostyril (m.p. 152.5° to 153.5° C.).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:24])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8]([C:25]([O:27]C)=[O:26])=[CH:7][C@H:6]1[OH:29])(=[O:3])[CH3:2].C(N(CC)CC)C>C(N(CC)CC)C.O>[C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:24])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8]([C:25]([OH:27])=[O:26])=[CH:7][C@H:6]1[OH:29])(=[O:3])[CH3:2]
Reactant: COC(=O)C1=C[C@@H](O)[C@@H](NC(C)=O)[C@H](C(=O)NCCCCCc2ccccc2)O1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N[C@@H]1[C@H](O)C=C(C(=O)O)O[C@H]1C(=O)NCCCCCc1ccccc1
Yield: 53.5 %

Procedure:
(4R,5R,6R)-5-Acetylamino-4-hydroxy-6-(phenethylpropylcarbamoyl)-5,6-dihydro-4-H-pyran-2-carboxylic acid, methyl ester (300 mg) in triethylamine/water (1:2, 1.5 ml) was heated at 50° C. for 2 hours. Further triethylamine (1 ml) was added and the reaction heated for 2 hours. The reaction mixture was evaporated to dryness and co-evaporated with toluene (5 ml, ×3) and ether and dried to give the title compound (155 mg). 1H NMR (250MHz, D6 -DMSO, rotamers) 7.7 (1H, 2×d, J=9Hz), 7.2--7.4 (5H, m), 5.8 (1H, 2×d, J=5Hz), 4.8 (1H, 2×d, J=8Hz)), 4.2 (1H, m), 4.1 (1H, m), 3.0-3.8 (5H, m), 2.7--2.9 (2H, m) 1.8 (3H, two s) 1.4-1.6 (2H, m) 0.8 (3H, m). Mass Spec. (Low resolution): MH+ =391. Mass Analysis: C20H26N2O6.0.8 C6H5N, 1.0 H2O Requires: C, 60.9; H,8.2; N, 8.0. Found: C, 60.9; H, 8.0; N, 8.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[C:31]2[CH2:30][CH2:29][O:28][C:27]=2[CH:26]=[CH:25][CH:24]=1>CO>[O:28]1[CH2:29][CH2:30][C:31]2[C:23]([O:22][CH2:21][C@@H:19]([OH:18])[CH2:20][N:15]3[CH2:14][CH2:13][CH:12]([C:7]4[CH:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[CH:8]=4)[CH2:17][CH2:16]3)=[CH:24][CH:25]=[CH:26][C:27]1=2
Reactant: c1cc2c(c(OC[C@@H]3CO3)c1)CCO2
Reactant: Fc1ccc2cc(C3CCNCC3)ccc2c1
Solvent: CO
Product: O[C@H](COc1cccc2c1CCO2)CN1CCC(c2ccc3cc(F)ccc3c2)CC1
Yield: 26.1 %

Procedure:
A solution 4-(6-fluoronaphth-2-yl)piperidine (0.075 g, 0.327 mmol) and (S)-(+)-4-(oxiranylmethoxy)-2,3-dihydrobenzo[b]furan (0.063 g, 0.327 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient elution) to give the title compound as a white amorphous solid (0.036 g, 26%). FDMS m/e=422 (M++1). [α]D=21.65 (c 0.508, methanol). C26H28FNO3.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:24][NH:25][O:26][CH3:27].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:27][O:26][N:25]([CH3:24])[C:6]([C:3]1([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]1)=[O:7]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a mixture of 1-(trifluoromethyl)cyclopropanecarboxylic acid (150 mg, 0.974 mmol), 1-hydroxybenzotrizole monohydrate (224 mg, 1.46 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (280 mg, 1.46 mmol) and N,O-dimethylhydroxylamine hydrochloride (142 mg, 1.46 mmol) in DMF (5 mL) was added DIPEA (0.50 mL, 2.92 mmol) and the mixture was stirred at room temperature for overnight. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc. The collected organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to provide compound A103-1 (164 mg, 85%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:6][CH:7]=1.Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=3)[CH2:24][CH2:23]2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: N#Cc1cc(Cl)ccn1
Product: COC(=O)c1ccc(NCC2CCN(c3ccnc(C#N)c3)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Yield: 96.3 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-5-methoxycarbonyl-2-[(4-piperidinylmethyl)amino]benzamide (0.30 g, 0.74 mmol) and 4-chloro-2-cyanopyridine (0.21 g, 1.5 mmol) afforded 360 mg (96%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl.C(N(CC)CC)C>[CH2:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A 2-L round-bottom flask was charged with 25.832 g isonipecotic acid, 30.5 mL benzaldehyde, 41.8 mL triethylamine, and 500 mL 1,2-dichloroethane to which was added 63.6 g sodium triacetoxyborohydride in portions over 20 minutes with stirring. After 24 hours, 4 mL benzaldehyde was added along with 21.2 g sodium triacetoxyborohydride in portions with 400 mL 1,2-dichloroethane. After an additional 8 hours, 4 mL of benzaldehyde was added along with 8.8 g sodium triacetoxyborohydride in portions. After stirring for additional 20 hours, the reaction mixture was poured into a separatory funnel, 300 mL each of ice water and concentrated HCl was added, the layers were separated, and the organic layer was washed with 4×75 mL 0.5M HCl. The combined aqueous layer was washed with 2×200 mL ether and was then concentrated under reduced pressure to constant weight to give 142 g of crude 1-benzyl-piperidine-4-carboxylic acid. To this material was added 39.02 g of N,O-dimethyl hydroxylamine hydrochloride, 81.08 g 1-hydroxybenzotriazole hydrate and 750 mL DMF with stirring. Next was added 174 mL diisopropylethylamine with stirring followed by 76.68 g 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide in several portions over 5 minutes with stirring. After stirring for 72 hr, the cloudy reaction mixture was poured into 2 L ice water containing 100 mL 5N NaOH. The mixture was extracted with 500 and 4×250 mL ether, and the combined ether was washed with water (3×300 mL) and saturated brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 51.13 g of a yellow liquid. Flash chromatography on silica gel eluting with 40˜100% ethyl acetate in hexanes with 1% (v/v) Et3N gave 47.32 g title compound as a yellowish oil. RF: 0.16 (25% EtOAc in hexanes with 1% (v/v) Et3N). 1H NMR (500 MHz, CDCl3): δ7.31˜7.36 (m, 4H), 7.24˜7.28 (m, 1H), 3.71 (s, 3H), 3.53 (s, 2H), 3.20 (s, 3H), 2.94˜2.98 (m, 2H), 2.63˜2.70 (m, 1H), 2.01˜2.07 (m, 2H), 1.82˜1.90 (m, 2H), 1.70˜1.74 (m, 2H).