Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([NH2:22])[CH3:21])[O:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>O1CCCC1>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([NH:22][C:34](=[O:36])[CH3:35])[CH3:21])[O:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3noc(C(C)N)n3)s2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(C)c1nc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)no1
Yield: 51.5 %

Procedure:
To a solution of Example 40D (265 mg, 0.76 mmol) in tetrahydrofuran (5 mL) at room temperature, was added diisopropylethyl amine (400 uL) followed by acetic anhydride (150 μL, 1.59 mmol). After an hour the reaction was quenched with methanol and stirred for additional hour. The solvent was removed under vacuum and the product was purified via silica-gel column chromatography using a gradient of 25 to 75% ethyl acetate in hexane to provide the title compound (152 mg). 1H NMR (300 MHz, CDCl3) δ ppm 7.90 (s, 1H) 7.17-7.25 (m, 2H) 6.89-6.99 (m, 2H) 6.09 (d, J=7.72 Hz, 1H) 5.33-5.53 (m, 1H) 4.54 (heptet, J=6.0 Hz, 1H) 2.08 (s, 3H) 1.62 (d, J=7.0 Hz, 3H) 1.36 (d, J=6.0 Hz, 6.0H).). MS (DCI): m/z 389 (M+H).
Reaction SMILES: FC1C=CC(C2C=C(CN3CCN(C)CC3)C(=O)N(CC(C)C)N=2)=CC=1C.[C:28]([C:31]1[C:32](=[O:49])[N:33]([CH2:45][CH:46]([CH3:48])[CH3:47])[N:34]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[CH:38]=2)[CH:36]=1)(O)=[O:29]>>[F:44][C:39]1[CH:38]=[C:37]([C:35]2[CH:36]=[C:31]([CH2:28][OH:29])[C:32](=[O:49])[N:33]([CH2:45][CH:46]([CH3:47])[CH3:48])[N:34]=2)[CH:42]=[CH:41][C:40]=1[F:43]
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(C(=O)O)c1=O
Agent: Cc1cc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)ccc1F
Product: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(CO)c1=O
Yield: 25 %

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one was reacted to yield the title compound as colorless fine-needles (yield: 25.0%).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.C(Cl)Cl.[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24](Cl)=[O:25]>C(N(CC)CC)C>[N:10]1([C:4]2[N:3]=[C:2]([NH:1][C:24]([O:23][CH2:22][CH2:21][O:20][CH3:19])=[O:25])[N+:7]([O-:8])=[C:6]([NH:9][C:24]([O:23][CH2:22][CH2:21][O:20][CH3:19])=[O:25])[CH:5]=2)[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1
Reactant: COCCOC(=O)Cl
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OCCOC)[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide are stirred at 5° C. in 150 ml. of methylene chloride and 30 ml. of triethylamine and treated with 20 ml. of chloroformic acid 2-methoxyethyl ester. The mixture is stirred at room temperature for 4 hours, then washed with water and extracted with methylene chloride. The organic phases are evaporated under reduced pressure and the residue is recrystallized from diethyl ether, there being obtained bis(2-methoxyethyl) 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 126°-128° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC)=O)=N\C(OCC)=O.[Cl:32][C:33]1[C:34]([OH:40])=[CH:35][C:36](=[O:39])[NH:37][CH:38]=1.[Cl:41][C:42]1[CH:43]=[N:44][C:45]([N:48]2[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]2)=[N:46][CH:47]=1>CCCCCC.CCOCC.CN(C=O)C>[Cl:32][C:33]1[C:34]([O:40][CH:51]2[CH2:50][CH2:49][N:48]([C:45]3[N:46]=[CH:47][C:42]([Cl:41])=[CH:43][N:44]=3)[CH2:53][CH2:52]2)=[CH:35][C:36](=[O:39])[NH:37][CH:38]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: OC1CCN(c2ncc(Cl)cn2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=c1cc(OC2CCN(c3ncc(Cl)cn3)CC2)c(Cl)c[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
To a 200 mL recovery flask was added triphenylphosphine (7.34 g, 28.0 mmol) and DMF (40 mL) to produce a nearly complete solution with 2-3 minutes of stirring. To this mixture was added (E)-diethyl diazene-1,2-dicarboxylate (3.80 mL, 24.00 mmol). After stirring at room temperature for 5 minutes, 5-chloro-4-hydroxypyridin-2(1H)-one (Gimeracil) (5.82 g, 40.0 mmol) was added. After stirring at room temperature for 5 minutes, 1-(5-chloropyrimidin-2-yl)piperidin-4-ol (4.27 g, 20 mmol) was added. The reaction mixture was placed under a nitrogen line with a vent and placed in a 100° C. oil bath for 115 minutes. After cooling to room temperature, the clear brown reaction mixture was added to 1000 mL of ether with stirring which resulted in the formation of a tan-pink oily precipitate. To this mixture was added 500 mL of hexane. The mixture was stirred for 5 minutes and then allowed to settle for 10 minutes. The mixture was poured through a medium porosity funnel. The tan-pink solids that were retained were washed with 100 mL of ether/hexane (1/2 ratio) and dried in vacuo to provide 5.06 g of tan-pink solids. The clear, nearly colorless filtrate was concentrated to 54 g of a clear pale amber liquid. This material was dissolved in 500 mL of ethyl acetate and washed with 3×50 mL of water. The ethyl acetate solution was dried with magnesium sulfate, filtered, and concentrated to 20.3 g of tan solids. This was combined with the 5.06 g of tan-pink solids from above and purified on a 60 mm id×160 mm silica gel column eluting as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:29](=[O:31])[NH2:30])[CH2:15][CH2:16][C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[O:18])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32](O)(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:29](=[O:31])[NH2:30])[CH2:15][CH2:16][C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:18])=[O:12])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)N[C@@H](CCCCN)C(=O)O)C(N)=O
Reactant: CCCCCC(=O)O
Product: CCCCCC(=O)NCCCC[C@H](NC(=O)CC[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(N)=O)C(=O)O

Procedure:
In the same manner as described in Example 1-(2), 1.10 g of Nα -(t-butyloxycarbonyl-alanyl-D-isoglutaminyl)lysine and 0.69 g of an N-hydroxy-5-norbornene-2,3-dicarboxyimide active ester of hexanoic acid were reacted to obtain 1.17 g of Nα -(t-butyloxycarbonyl-alanyl-D-isoglutaminyl)-Nε -hexanoyl-lysine; melting point: 116° to 118° C. (decomp.); [α]D25 -12.1° (c 1.1, methanol).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH:8][CH:9]1[CH:17]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10]1)(=[O:7])=[O:6])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>O1CCOCC1.O>[CH3:1][C:2]([S:5]([NH:8][CH:9]1[CH2:10][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:16][CH:17]1[N:18]([C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:34](=[O:35])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:6])=[O:7])([CH3:3])[CH3:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H](NC1CC2(CC1NS(=O)(=O)C(C)(C)C)OCCO2)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](c1ccccc1)N(C(=O)OCc1ccccc1)C1CC2(CC1NS(=O)(=O)C(C)(C)C)OCCO2
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-N-(8-{[(1R)-1-phenylethyl]amino}-1,4-dioxaspiro[4.4]nonan-7-yl)propane-2-sulfonamide (274 mg, 0.72 mmol) and sodium carbonate (114 mg, 1.074 mmol) in 1,4-dioxane (2 ml) and water (0.4 ml) at 0° C. was added drop wise benzyl chloroformate (CAS number 501-53-1; 0.13 ml, 0.90 mmol). The reaction mixture was allowed to warm to room temperature for 2 hours then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-70% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[CH2:12]1C[O:15][CH2:14][CH2:13]1>>[CH2:14]([O:15][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:13]=[CH2:12]
Reactant: C1CCOC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=CCOCc1ccccc1
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of isomer A product from Step 1 (1.62 g, 4.23 mmol) in THF (50 mL) was added NaH 60% (540 mg, 13.4 mmol) followed by benzylbromide (1.5 mL, 13.4 mmol) and the reaction was stirred at 55 C overnight. The cooled mixture was poured into water, extracted with EtOAc, dried over Na2SO4 and concentrated. The residue was purified by flash-chromatography over silica gel (eluted with Hexanes/AcOEt 99:1 to 50:50) to afford 1.07 g (53%) of allylbenzylether isomer A.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl.[C:11]1([C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[C:11]1([C:17]2[CH2:22][CH2:21][N:20]([C:6]3[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([Cl:1])[N:7]=3)[CH2:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CC=C(c3ccccc3)CC2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
In 4 ml of ethanol was dissolved 415 mg of 2,4-dichloro-6-methylpyrimidine, and the solution was cooled with ice-water. To the solution were added 503 mg of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and 664 mg of diisopropylethylamine, followed by stirring overnight under cooling with ice. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=10/1 to 3/1) to give 491 mg of 4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-2-chloro-6-methylpyrimidine as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](Cl)=[O:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:20])[CH:3]=1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Br)cc2[nH]ncc12)c1ccccn1

Procedure:
6-Bromo-1H-indazol-4-amine (100 mg, 0.47 mmol), 2-pyridinecarbonyl chloride hydrochloride (100 mg, 0.56 mmol) and DIPEA (0.164 ml, 0.94 mmol) were stirred in DCM (10 ml) at RT overnight. The reaction was concentrated in vacuo. The residue was purified by MDAP (Method B) and appropriate fractions were evaporated to give the title compound, 38 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[C:21]([C:23]2[N:27]([CH2:28]C)[CH:26]=[C:25]([C:30]([OH:32])=O)[CH:24]=2)[CH:20]=[CH:19][N:18]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:64]([C:66]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[C:67]=1[NH2:68])[CH3:65]>CN(C)C=O.C(OCC)(=O)C>[CH2:64]([C:66]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[C:67]=1[NH:68][C:30]([C:25]1[CH:24]=[C:23]([C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:4]3[CH:5]=[CH:6][C:7]([N:9]4[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]4)=[CH:8][C:3]=3[O:2][CH3:1])[N:22]=2)[N:27]([CH3:28])[CH:26]=1)=[O:32])[CH3:65]
Reactant: CCn1cc(C(=O)O)cc1-c1ccnc(Nc2ccc(N3CCN(C)CC3)cc2OC)n1
Reactant: CCc1cccc(CC)c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1NC(=O)c1cc(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)n(C)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
A suspension of 5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-ethyl-1H-pyrrole-3-carboxylic acid (75 mg, 0.178 mmol) in anhydrous dimethylformamide (5 mL) was treated with N-ethyl-N,N-diisopropylamine (0.3 mL, 1.775 mmol) and TBTU (91 mg, 0.284 mmol). The mixture was then treated with 2,6-diethylaniline (0.3 mL, 1.775 mmol). The resulting mixture was stirred at 80° C. for 4 hours under argon. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL), washed with a saturated aqueous solution of sodium hydrogen carbonate (20 mL), brine, dried over anhydrous Na2SO4 and concentrated. Purification by flash chromatography on silica gel (eluant: dichloromethane/methanol 95/5) afforded 23 mg (23%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([N:33]3[C:45](=[O:46])[C:44]4[N:36]([C:37]5[C@H:38]6[CH2:47][C@@H:41]([C:42]=5[CH:43]=4)[CH2:40][CH2:39]6)[CH2:35][CH2:34]3)[C:28]=2[CH:48]=[O:49])=[CH:3]1.[BH4-].[Na+]>CO>[OH:49][CH2:48][C:28]1[C:29]([N:33]2[C:45](=[O:46])[C:44]3[N:36]([C:37]4[C@H:38]5[CH2:47][C@@H:41]([C:42]=4[CH:43]=3)[CH2:40][CH2:39]5)[CH2:35][CH2:34]2)=[N:30][CH:31]=[CH:32][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:23][O:24][CH2:25]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5[C@@H]5CC[C@H]6C5)C4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5[C@@H]5CC[C@H]6C5)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.6 %

Procedure:
A mixture of 174a (150 mg, 0.23 mmol), NaBH4 (34 mg, 0.90), and methanol (10 mL) was stirred at room temperature for 1 h. The mixture was quenched with water (30 ml) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 174 (42 mg, 28%). MS-ESI: [M+H]+ 663.3. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=3.0 Hz, 1H), 8.48 (d, J=6.0 Hz, 1H), 7.96 (d, J=2.5 Hz, 1H), 7.85-7.84 (m, 2H), 7.36 (d, J=6.5 Hz, 1H), 7.32 (dd, J=3.5, 11.0 Hz, 1H), 6.82-6.80 (m, 2H), 5.16-5.06 (m, 1H), 4.72-4.61 (m, 5H), 4.08-4.05 (m, 1H), 4.32-4.21 (m, 3H), 3.88-3.85 (m, 1H), 3.71 (s, 3H), 3.54-3.50 (m, 2H), 3.38-3.37 (m, 2H), 3.08-3.06 (m, 2H), 2.57-2.54 (m, 1H), 2.48-2.45 (m, 2H), 2.21-2.17 (m, 1H), 1.93-1.91 (m, 3H), 1.66-1.64 (m, 1H), 1.14-1.08 (m, 2H), 0.98 (d, J=8.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].C([NH+:22]([CH2:29][CH:30]1[CH2:32][CH:31]1[CH3:33])[CH2:23][CH2:24][CH2:25][NH+:26]([CH3:28])[CH3:27])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[CH3:28][NH+:26]([CH3:27])[CH2:25][CH2:24][CH2:23][NH2+:22][CH2:29][CH:30]1[CH2:32][CH:31]1[CH3:33]
Reactant: CC1CC1C[NH+](CCC[NH+](C)C)Cc1ccccc1
Agent: [Pd+2]
Agent: O=C([O-])C(F)(F)F
Agent: [OH-]
Solvent: CCO
Product: CC1CC1C[NH2+]CCC[NH+](C)C
Reaction time: 1 h

Procedure:
A solution of N1-benzyl-N3,N3-dimethyl-N1-[(2-methylcyclopropyl)methyl]propane-1,3-diaminium bis(trifluoroacetate) (0.42 g, 0.86 mmol) in ethanol (50 mL) was degassed with nitrogen and treated with palladium hydroxide (75 mg). The reaction was placed under a hydrogen atmosphere and stirred vigorously for 1 hour. The reaction was filtered through celite, washed with methanol and concentrated in vacuo to give N,N-dimethyl-N′-[(2-methylcyclopropyl)methyl]propane-1,3-diaminium bis(trifluoroacetate) as a pale yellow oil.
Reaction SMILES: C1([C@H]2[CH2:12][C@@H:11]([OH:13])[CH2:10][CH2:9]N2)C=CC=CC=1.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(C(C)=O)=C>>[CH3:12][C:11]([CH2:10][CH2:9][NH:22][O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13]
Reactant: NOCc1ccccc1
Reactant: O[C@H]1CCN[C@@H](c2ccccc2)C1
Agent: C=CC(C)=O
Product: CC(=O)CCNOCc1ccccc1

Procedure:
Other chiral γ-aminoalcohols include cis-2-phenyl-4-hydroxypiperidine (which may be prepared by the Michael addition of O-benzylhydroxylamine to methyl vinyl ketone to yield 2-(benzyloxyamino)ethyl methyl ketone, followed by an intramolecular Mannich reaction with benzaldehyde to yield 1-benzyloxy-4-oxo-2-phenylpiperidine, reduction with sodium borohydride to the corresponding 4-hydroxy compound, removal of the N-benzyloxy group with hydrogen and palladium catalyst, and resolution of the resulting 4-hydroxy-2-phenylpiperidine with the use of an optionally active acid, such as mandelic acid) and the like.
Reaction SMILES: Cl.[F:2][C:3]([F:33])([F:32])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:25]=[CH:24][C:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:17]=4[CH:16]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48]>CN(C=O)C>[F:33][C:3]([F:2])([F:32])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:25]=[CH:24][C:18]4[CH2:19][CH2:20][N:21]([CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:22][CH2:23][C:17]=4[CH:16]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CCCBr
Reactant: FC(F)(F)c1cc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)ccc1-c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)cc2CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 107.1 %

Procedure:
7-{5-[2-(Trifluoromethyl)-4-biphenylyl]-1,2,4-oxadiazol-3-yl}-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 20) (200 mg, 0.424 mmol), DIPEA (0.281 ml, 1.608 mmol) and ethyl 4-bromobutanoate (0.131 ml, 0.919 mmol) were stirred at RT in DMF (10 ml) for 5 hours. The reaction mixture was then heated to 60° C. for 5 hrs, and then allowed to stand overnight at room temperature. Further ethyl 4-bromobutanoate (0.066 ml, 0.459 mmol) was added and the reaction mixture heated at 60° C. for 6 hours. The reaction mixture was partitioned between EtOAc (˜30 ml) and water (˜30 ml) and the aqueous layer extracted once more with EtOAc (˜40 ml). The combined organics were concentrated in vacuo to yield the title compound (277 mg, 0.454 mmol) as an orange solid. MS (ES): C31H30F3N3O3 requires 549; found 550 [M+H]+.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[NH:5])#[N:2].[ClH:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(O)(C)C>[ClH:10].[NH:5]=[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)[NH:3][C:1]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[NH:2]
Reactant: N#CNC(=N)NC1CC1
Reactant: C1COCCN1
Agent: Cl
Solvent: CC(C)O
Product: N=C(NC(=N)N1CCOCC1)NC1CC1
Temperature: 160 °C
Yield: 85 %

Procedure:
A mixture of 4.0 g (32.3 mmoles) of N-cyano-N'-cyclopropylguanidine and 3.98 g (32.3 mmoles) of morpholine hydrochloride is heated at 160° C. under a nitrogen atmosphere for 2 and a half hours. The solid mass obtained is dissolved in 200 ml of boiling isopropyl alcohol. The mixture is filtered hot and the filtrate is concentrated until a solid suspension appears. The mixture is then cooled to room temperature and 200 ml of diethyl ether are added. The reaction product crystallizes. It is filtered, washed with diethyl ether and dried. 6.8 g of N-[imino(cyclopropylamino)methyl]-4-morpholinecarboximidamide hydrochloride are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:24][CH3:25])=[N:10][CH:11]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.BrCC1C=C(C2C=CC=C(Cl)C=2)[C:31]([O:34]C)=[N:32]C=1.[N+](C1C=CC(B(O)O)=CC=1)([O-])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:31]([NH2:32])=[O:34])=[CH:17][CH:16]=3)[CH:11]=[N:10][C:9]=2[O:24][CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(Cc2ccc([N+](=O)[O-])cc2)cc1-c1cccc(Cl)c1
Reactant: COc1ncc(CBr)cc1-c1cccc(Cl)c1
Agent: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: COc1ncc(Cc2ccc(NC(N)=O)cc2)cc1-c1cccc(Cl)c1

Procedure:
3-(3-Chlorophenyl)-2-methoxy-5-(4-nitrobenzyl)pyridine. The title compound was prepared in a manner analogous to Example 1, from Intermediate 2 and 4-nitrophenyl boronic acid to afford a tan solid. [M+H]=355.07.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17](=[S:19])[NH2:18])=[CH:15][N:16]=2)[CH2:8][CH2:7]1.Cl[CH2:27][C:28](=O)[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CO.O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]3[S:19][CH:27]=[C:28]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[N:18]=3)=[CH:15][N:16]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)CC(=O)CCl
Reactant: NC(=S)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Solvent: CO
Solvent: O
Product: COC(=O)Cc1csc(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)s2)n1
Temperature: 82.5 °C

Procedure:
A mixture of 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carbothioamide (240 mg, 0.62 mmol) and methyl 4-chloroacetoacetate (73 μL, 0.62 mmol) in methanol (3 mL) was heated in a sealed tube at 80-85° C. overnight. After cooling, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed twice with water, dried (Na2SO4) and concentrated. The crude material was purified by column chromatography on silica gel (eluting with 30-60% EtOAc/hexanes) to give the title compound as a pale yellow gum.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH2:16][C:17]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29]C)([CH3:21])[CH3:20])[N:6]=1)=[O:4].B(Br)(Br)Br>>[CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH2:16][C:17]([OH:35])([C:31]([F:32])([F:33])[F:34])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[OH:29])([CH3:21])[CH3:20])[N:6]=1)=[O:4]
Reactant: CNC(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: BrB(Br)Br
Product: CNC(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3O)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 38, 97 mg (0.197 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylic acid methylamide is reacted with 8.0 ml (8.0 mmol) of a 1 M boron tribromide solution. After working-up and purification on silica gel with hexane-ethyl acetate (0–70%), 18 mg (18% of theory) of the product is obtained.