Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][S:11]([CH2:14][CH2:15][N:16]2[CH2:23][CH:22]3[O:24][CH:18]([CH2:19][NH:20][CH2:21]3)[CH2:17]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][S:11]([CH2:14][CH2:15][N:16]2[CH2:23][CH:22]3[O:24][CH:18]([CH2:19][N:20]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)[CH2:21]3)[CH2:17]2)(=[O:13])=[O:12])=[CH:25][CH:26]=1)#[N:4]
Reactant: N#Cc1ccc(CNS(=O)(=O)CCN2CC3CNCC(C2)O3)cc1
Reactant: Fc1cccc(CCBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(CNS(=O)(=O)CCN2CC3CN(CCc4cccc(F)c4)CC(C2)O3)cc1
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 30.3 %

Procedure:
To 2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethanesulfonic acid 4-cyano-benzylamide dihydrochloride (0.127 g, 0.30 mmol; prep P above), 1-(2-bromo-ethyl)-3-fluoro-benzene (0.064 g, 0.315 mmol) and potassium carbonate (0.145 g, 1.05 mmol) was added acetonitrile (4 mL) and water (0.1 mL). The mixture was stirred for 20 minutes before it was heated by microwave irradiation (10 minutes, 160° C.) and was then filtered and evaporated. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 43 mg (30.3%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:15])[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[CH3:15][N:4]([CH2:3][CH2:2][NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13]
Reactant: O=C(O)c1cccnc1
Reactant: CN(CCN)CCNC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(CCNC(=O)OC(C)(C)C)CCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
tert-Butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (400 mg, 1.84 mmol) was taken up in CH3CN (10 mL) along with nicotinic acid (227 mg, 1.84 mmol) and EDCI (353 mg, 2.02 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (5% MeOH—CH2Cl2) to afford tert-butyl 2-(methyl(2-(nicotinamido)ethyl)amino)ethylcarbamate (180 mg, 30%). MS calculated for C16H26N4O3: 322.2. found: [M+H]+ 323.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]#[N:13].O.[OH-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]#[N:13]
Reactant: COC(=O)c1ccc(Cl)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the product from step (i) (1.5 g) and lithium hydroxide hydrate (0.84 g) in a mixture of (1:1)water and tetrahydrofuran (40 ml) was stirred at room temperature for 2 h. The tetrahydrofuran was removed under reduced pressure and the residue partitioned between diethyl ether and water. The aqueous layer was acidified with 2M hydrochloric acid then extracted with ethyl acetate. The organic layer was dried and evaporated under reduced pressure. Yield 1.3 g.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:40]1[CH:45]=[CH:44][C:43]([C:46](=[O:51])NCCC)=[CH:42][CH:41]=1)=O)C2>>[C:46]([N:5]1[CH2:6][CH2:7][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[CH2:9][CH2:10]1)(=[O:51])[C:43]1[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(NCCCCC1CCNCC1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(NCCCCC1CCN(C(=O)c2ccccc2)CC1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-[4-(piperidin-4-yl)butyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.39-7.47 (m, 3H) 7.22-7.40 (m, 6H) 6.27 (t, J=5.43 Hz, 1H) 4.56 (s, 4H) 4.36-4.52 (br s, 1H) 3.52 (br s, 1H) 3.00-3.15 (m, 2H) 2.93 (br s, 1H) 0.93-1.86 (series of br m, 12H); MS (ESI(+)) m/e 406 (M+H)+.
Reaction SMILES: [Sn](Cl)Cl.[N:4]([C:7]1[C:8]([C:14]#[N:15])=[C:9]([Cl:13])[CH:10]=[N:11][CH:12]=1)=[N+]=[N-]>C(O)C.O>[NH2:4][C:7]1[C:8]([C:14]#[N:15])=[C:9]([Cl:13])[CH:10]=[N:11][CH:12]=1
Reactant: N#Cc1c(Cl)cncc1N=[N+]=[N-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: N#Cc1c(N)cncc1Cl
Reaction time: 1 h

Procedure:
Tin (II) chloride (1.42 g, 7.5 mmol) was added to a solution of 5-azido-3-chloro-4-cyanopyridine (0.9 g, 5 mmol) in ethanol (20 ml) and water (0.3 ml). Bubbling ensued. The mixture was stirred for 1 h. and then extracted twice with ethyl acetate. The extracts were washed twice with saturated aqueous sodium bicarbonate and dried over sodium sulphate. Evaporation of the solvent gave the product as an oil, which was purified by flash column chromatography on silica gel, eluting with dichloromethane/metahnol (10:1) to afford the product. MS (+CI) m/z 152 [M−H]+; 1H NMR (d6-DMSO) 8.15 (1H, s), 7.87 (1H, s), 6.88 (2H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:29])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH2:33][C:3]1=2.Cl>CO.CCOCC>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:29])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:30][NH:31][CH2:32][CH2:33][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)nc31)CNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
tert-Butyl 9-methyl-2-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.43 g, 0.77 mmol) was treated with 1.25 M HCl in MeOH (15 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was diluted with Et2O (50 mL). The resulting solids were collected by filtration, dissolved in 10:3 CH2Cl2/MeOH (50 mL), and washed with saturated NaHCO3 solution (50 mL). The aqueous layer was extracted with CH2Cl2 (8×25 mL), and the organic extracts were combined. The remaining solids in the aqueous solution were separated by filtration and washed with MeOH (100 mL). The resulting filtrate was extracted with CH2Cl2 (3×50 mL). All the organic extracts were combined and concentrated to dryness under reduced pressure. The resulting residue was diluted in CH2Cl2, washed with brine (2×20 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure to provide the title compound (0.27 g, 76%) as an off-white powder: 1H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J=1.5 Hz, 1H), 8.19 (dd, J=8.0, 1.5 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.19 (dd, J=7.5, 2.5 Hz, 1H), 6.03 (s, J=3.0 Hz, 1H), 5.36 (s, 2H), 3.87 (s, 2H), 3.65 (s, 3H), 3.08 (t, J=5.5 Hz, 2H), 2.74 (t, J=5.5 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=[C:3]([C:2]([F:26])([F:1])[F:25])[CH:4]=1)=[N:38][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=1[Cl:34])#[N:24]
Reactant: NCc1ccccc1Cl
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Solvent: CCN(CC)CC
Product: N#CNC(=NCc1ccccc1Cl)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 72 %

Procedure:
By following a procedure analogous to the one described above in Example 1b, N-(3,5-bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea (0.300 g, 0.8 mmol) was treated with triethylamine (0.123 ml, 0.88 mmol) and 2-chlorobenzylamine (0.107 ml, 0.88 mmol) to give the title compound as a syrup. Yield 72% (0.234 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=O)=O)=[CH:15][CH:14]=1>C(O)(=O)C.CO>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:21]([C:23]3[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=3)=[N:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[N:8]=2)=[CH:17][CH:18]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2nc(-c3ccc(Br)cc3)c(-c3ccc(Br)cc3)nc12
Reaction time: 30 h

Procedure:
1.53 g (10 mmol) of 2,3-diaminonitrobenzene and 3.68 g (10 mmol) of 4,4′-dibromobenzil were dissolved in 80 g of a 1:1 mixed solvent of acetic acid/methanol, and reaction was allowed at 70° C. for 30 hr. After the reaction was over, the solvent was removed, and the reaction product was extracted on a silica gel column.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>[Pd].C(OCC)(=O)C>[CH2:19]([NH:20][CH2:6][C:2]1[NH:3][CH:4]=[CH:5][N:1]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: O=Cc1ncc[nH]1
Reactant: CCCCCCCCCCCCN
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNCc1ncc[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
In a 500-ml autoclave were placed 2-imidazolecarboxaldehyde (6.9 g (70 mmol), product of Aldrich), n-laurylamine (12.8 g (69 mmol)), 5% Pd-C (2 g), and ethyl acetate (200 ml). The contents of the flask were stirred for 24 hours at room temperature under hydrogen (20 kg/cm2). The catalyst was removed, and the solvent was concentrated. Purification via silica gel column chromatography (n-hexane:ethyl acetate=2:1) afforded 11.0 g of N-lauryl-2-imidazole methyl amine as white crystals (yield: 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:24])([CH3:23])[CH2:11][C:12]([OH:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH:13]=O.[NH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][C:30](=[O:36])[NH:31]2>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:22][C:12]1([C:15]([F:20])([F:21])[C:16]([F:18])([F:19])[F:17])[CH2:11][C:10]([CH3:23])([CH3:24])[C:4]2[C:5](=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[O:2][CH3:1])[CH:13]1[NH:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][C:30](=[O:36])[NH:31]2
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)C(F)(F)F
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)cc2c1C(C)(C)CC(O)(C(F)(F)C(F)(F)F)C2Nc1cccc2[nH]c(=O)ccc12
Yield: 0.7 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal and 93 mg of 5-aminoquinolin-2(1H)one. 2 mg of the title compound is obtained by reaction of 80 mg of the imine with 1.6 ml of titanium tetrachloride solution (1 M in dichloromethane) in 5 ml of dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)=[N:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][C:3]=1[O:30][CH3:31].B(F)(F)F.CCOCC.[CH2:41]([Mg]Cl)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:9][S@@:10]([C:12]([CH3:13])([CH3:14])[CH3:15])=[O:11])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:4][C:3]=1[O:30][CH3:31]
Reactant: COc1cc(C(=N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: Cl[Mg]Cc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(C(Cc2ccccc2)(N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reaction time: 0.17 h

Procedure:
To a solution of (R)-N-((4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide (4.4 g, 9.42 mmol) in CH2Cl2 (190 mL, 0.05 M) at −71° C. was added BF3.Et2O (2.37 mL, 18.8 mmol). The reaction mixture was stirred for 10 min and BnMgCl (25 mL, 1N in Et2O, 26 mmol) was added. The reaction mixture was stirred at −75° C. for an additional 5 min, and quenched by the addition of saturated NH4Cl. The organic portion was separated, washed by H2O, dried over Na2SO4 and filtered. The solvent was then removed under reduced pressure and the residue was purified by ISCO chromatography using hexanes/EtOAc (0-80%) to give (R)-N-(1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide as a mixture of two diastereomers. The mixture (1 to 4 ratio) was then separated by chiral AD column using 20% IPA/hep/0.15 DEA as mobile phase to afford (R)-N-((S)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (0.79 g, 15% yield). LCMS: RT=2.09 min, [M+H] 560.2 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[CH2:22]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:9]3([CH2:8][NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)[CH3:23]
Reactant: CCN1CCC(O)CC1
Reactant: Oc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1CCC(Oc2ccc(C3(CNc4ccccn4)CCOCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 2.6 %

Procedure:
To a solution of 4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (250 mg, 0.881 mmol), 1-ethylpiperidin-4-ol (103 mg, 0.8 mmol) and triphenylphosphine (231 mg, 0.881 mmol) in THF (5 ml) at 0° C. under nitrogen was added dropwise diisopropyl azodicarboxylate (95% solution, 183 μl, 0.881 mmol). Reaction was stirred for 10 minutes then warmed to room temperature for 72 hours until complete. THF was removed in vacuo and the residue partitioned between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml). The organic layer was separated, dried over sodium sulphate, filtered and concentrated in vacuo. Crude product was purified by flash chromatography eluting with dichloromethane:methanol:ammonia (100:0:0 to 96:4:0.4 by volume) to give the title compound (8.2 mg, 23%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.05 (t, 3H), 1.80-1.98 (m, 4H), 2.00-2.18 (m, 4H), 2.28-2.42 (m, 2H), 2.44-2.54 (q, 2H), 2.72-2.86 (m, 2H), 3.50 (d, 2H), 3.55-3.62 (m, 2H), 3.78-3.88 (m, 2H), 4.00-4.08 (m, 1H), 4.30-4.39 (m, 1H), 6.22 (d, 1H), 6.50 (t, 1H), 6.90 (d, 2H), 7.23 (d, 2H), 7.30 (t, 1H), 8.01 (d, 1H). LRMS APCI+ m/z 396 [MH]+. HRMS ESI+ m/z 396.2641 [MH]+.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:5]1)([OH:3])=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1>CCOCC>[C:25]1([NH:24][C:1]([CH:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)=[O:11])[CH2:5]2)=[O:3])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)C1CCCN(C(=O)C2CCN(c3ccncc3)CC2)C1
Reactant: Nc1ccccc1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: O=C(Nc1ccccc1)C1CCCN(C(=O)C2CCN(c3ccncc3)CC2)C1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Dicyclocarbodiimide (620 mg) was added to a stirred mixture of the crude 3-carboxy-1-[4-pyridylpiperidin-4-ylcarbonyl]piperidine product from step (b) (1 g), aniline (0.17 ml), hydroxybenztriazole, (236 mg), N-methylmorpholine (0.29 ml) under an atmosphere of argon with cooling to 0 to 5° C. The mixture was stirred at 0° C. for 30 minutes and then allowed to warm to ambient temperature and stirred overnight. The mixture was quenched with water and the solvent removed by evaporation. The residue was partitioned between dichloromethane and water. The aqueous phase was seperated and washed with dichloromethane. The aqueous phase was evaporated and the residue purified by flash chromatography on silica gel using 15% MeOH/CHCl2 as eluent to give a crude product which was further purified by flash chromatography on silica gel using a gradient of 4 to 10% MeOH/CH2Cl2 as eluent to give an oil. Ether was added and then evaporated to yield 3-(phenylaminocarbonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperidine as a foam (200 mg; 80% pure);
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[Br:24]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:24])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ncc2cccc(Oc3ccc(F)cc3)c2c1O
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)c1nc(Br)c2cccc(Oc3ccc(F)cc3)c2c1O

Procedure:
The title compound was synthesized from 5-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester and N-bromosuccinimide in analogy to example 18e; MS-(+)-ion: M+1, 79Br/81Br=392.4 and 394.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:14]([C:15](O)=[O:16])[CH2:13][CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[OH:16][CH2:15][C@@H:14]1[CH2:13][CH2:12][CH:11]2[CH:9]([CH2:10]2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1C2CC2CC[C@H]1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CC2CC[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of D6 (8 g, 45.6 mmol) in THF (250 mL) cooled at 0° C., BH3 1M in THF (66 mL, 66 mmol) was added and the mixture was stirred at room temperature for 2 hours. Methanol was added, the solution was concentrated in vacuum and co-evaporated twice from methanol to give the title compound as 1/1 diasteroisomeric mixture. Yield (7.6 g, 100%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[Si]([C:13]#[N:14])(C)C.C(N(CC)CC)C>C(#N)C>[C:13]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:14]
Reactant: [O-][n+]1cccc(F)c1
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncccc1F
Yield: 69.5 %

Procedure:
3-Fluoropyridine-1-oxide (10.0g, 88.4 mmol), trimethylsilylcyanide (26.32g, 265.3 mmol), and triethylamine (17.89g, 177 mmol) were reacted in 90 mL of acetonitrile utilizing the procedure described in example 762B. Purification of the crude by silica gel chomatography using CH2Cl2 as eluent gives compound 771B (7.5g, 70%) as a light yellow solid.
Reaction SMILES: C(=O)([O-])OC(C)(C)C[N:5](C(OC(C)(C)C)=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[ClH:26].[O:27]1CCOCC1>>[ClH:26].[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:5][OH:27])=[CH:8][CH:9]=1
Reactant: C1COCCO1
Reactant: COc1ccc(CN(CC(C)(C)OC(=O)[O-])C(=O)OC(C)(C)C)cc1
Agent: Cl
Product: COc1ccc(CNO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[tert-Butoxycarbonyl-[(4-methoxyphenyl)methyl]amino]tert-butyl carbonate (1.125 Kg, 3.1 mol) is dissolved in 1,4-dioxane (2.8 L) and a hydrogen chloride solution (4 M in dioxane, 3.15 L, 12.4 mol) is added drop wise over 1 hour 30 minutes. The solution is stirred at room temperature overnight. The title product is collected by filtration as white solid (488.0 g, 81%). 1H NMR (d6-DMSO) δ 11.71 (s, 2H), 10.94 (s, 1H), 7.44 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.22 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[C:8]([C:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[O:12][C:11]=1[NH:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:9]>C(O)=O>[CH3:15][C:14]1[C:10]2[C:8](=[O:3])[NH:9][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:17][C:11]=2[O:12][C:13]=1[CH3:16]
Reactant: CCOC(=O)C(=O)Nc1oc(C)c(C)c1C#N
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)c1nc2oc(C)c(C)c2c(=O)[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of the compound obtained in the above step (1) (13.6 g) in methylene chloride (200 mL) is added piperidine (18.9 g) and thereto is added dropwise a solution of ethyl chlorooxoacetate (16.3 g) in methylene chlorode (200 mL) under ice-cooling. The mixture is stirred at 0° C. for 1.5 hours. The reaction mixture is diluted with chloroform (100 mL) and thereto is added water (300 mL). After stirring, the organic layer is separated and the aqueous layer is extracted with chloroform. The organic layers are combined and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and the residue is purified by column chromatography on silica gel (Solvent; chloroform:ethyl acetate=9:1) to give ethyl [(3-cyano-4,5-dimethylfuran-2-yl)amino](oxo)acetate (17 g, yield; 72%) as a colorless powder. A mixture of formic acid (30 mL) and acetic anhydride (30 mL) is stirred at 60° C. under argon gas atmosphere for 2 hours and thereto is added ethyl [(3-cyano-4,5-dimethylfuran-2-yl)amino](oxo)acetate (7.07 g). The mixture is refluxed for 14 hours. The reaction mixture is concentrated and the residue is purified by column chromatography on silica gel (Solvent; chloroform:ethyl acetate=9:1→chloroform:methanol=19:1) to give ethyl 5,6-dimethyl-4-oxo-3,4-dihydrofuro[2,3-d]pyrimidine-2-carboxylate (4.30 g, yield; 61%) as a colorless powder. M.p. 180-182° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([O:14][Na])([CH3:13])[CH3:12]>CC(O)C>[O:14]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)O[Na]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CC(C)O
Product: CC(C)Oc1ccc([N+](=O)[O-])cn1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A freshly oven dried 500 mL round-bottom flask was charged with 2-chloro-5-nitropyridine (5.0 g, 31.6 mmol) and anhydrous iPrOH (50 mL). The resultant solution was cooled in an ice bath and iPrONa (50 mmol) in iPrOH (250 mL) added slowly, followed by stirring at the same temperature for 30 min and then at room temperature for 14 h. The reaction was quenched with H2O (5 mL), filtered through celite, and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified through automated normal-phase chromatography to afford 2-isopropoxyl-5-nitropyridine (4.6 g, 79%) which was used directly for the next step: 1H NMR (400 MHz, CDCl3) δ 9.02 (d, 1H), 8.30 (dt, 1H), 6.75 (d, 1H), 5.40 (sep, 1H), 1.38 (d, 6H); MS (ES) (M++H) expect 183.1, found 183.1.