Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4].[OH-:16].[K+].Cl>O>[OH:16][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4]
Reactant: CCCCCCCCCCC(Cl)C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCC(O)C(=O)O

Procedure:
0.1 Mole of alpha-chlorolauric acid prepared in the foregoing manner was admixed with 500 mls. water and 0.4 moles of KOH in a suitable reaction vessel and stirred overnight at a temperature of 98°-100° C. The reaction mixture was poured into a separatory funnel, to which was added hydrochloric acid (40 ml. conc. HCl in 200 ml. H2O). The mixture was extracted with chloroform. The chloroform layer was removed and the CHCl3 evaporated to yield alpha-hydroxylauric acid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1)=[CH2:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:5][CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[N:8]=1)[CH3:2]
Reactant: C=Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-{[3-ethenyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (460 mg, 1.24 mmol) in methanol (12 ml) was added palladium on carbon (10% wt, 50% wet) (131 mg, 0.124 mmol) and the resulting mixture was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”). To this was then added further palladium on carbon (10% wt, 50% wet) (131 mg, 0.124 mmol) and the resulting mixture was stirred under a balloon of hydrogen gas for 72 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.CO>[Pd].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(C=CC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of (E)-tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (27 mg, 0.06 mmol) in 4:1 MeOH:DCM (2.5 mL) was added palladium on carbon (10% wt., 0.59 mg, 5.53 μmol). The reaction was stirred at room temperature under a hydrogen balloon for 12 h after which the reaction was purged with nitrogen and filtered through Celite™. The remaining palladium was washed with DCM (30 mL) and the resulting solution was concentrated in vacuo to afford tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)propenoate (27 mg, 0.06 mmol, 100% yield) which was used without further purification. LC/MS (m/z, MH+): 491.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([NH:49][CH2:48][C:47]3[CH:50]=[CH:51][C:44]([F:43])=[CH:45][CH:46]=3)=[O:21])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: NCc1ccc(F)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NCc3ccc(F)cc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-fluorobenzylamine (13.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-4-fluorobenzylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (38.3 mg).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:19][O:18][C:16](=[O:17])[CH2:15][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]1=[O:13]
Reactant: COC(=O)CBr
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)n1c(=O)n(CC(=O)OC)c2ccccc21
Yield: 99 %

Procedure:
N-isopropenyl-2-benzimidazolone (15.0 g, 86.10 mmol), methyl bromoacetate (13.2 g, 86.1 mmol) and potassium carbonate (14.25 g, 103.26 mmol) were stirred in acetonitrile (300 ml) at room temperature overnight. The next day the reaction mixture was filtered and concentrated to give 21.0 g (99% yield) of (3-isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid methyl ester as a clear oil:
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[C:4](=[O:7])[O:3][C:2]2=[O:8].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]2=[O:22])=[CH:12][C:11]=1[F:23]>C1COCC1>[F:23][C:11]1[CH:12]=[C:13]([N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]2=[O:22])[CH:14]=[CH:15][C:10]=1[NH:9][C:4]([CH:5]1[CH2:6][CH:1]1[C:2]([OH:3])=[O:8])=[O:7]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: O=C1OC(=O)C2CC12
Solvent: C1CCOC1
Product: O=C(O)C1CC1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Yield: 31.9 %

Procedure:
A solution of 3-oxabicyclo[3.1.0]hexane-2,4-dione (160 mg) in THF (5 ml) was treated with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (321 mg; CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912). The suspension was stirred over night at r.t. The solid was collected by filtration, triturated with 1N HCl (5 ml), again collected by filtration, washed with 1N HCl, H2O, then cyclohexane and dried to give (1RS,2SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic acid (144 mg) as off-white solid. MS: 315.3 ([M−H]−)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:17]=[C:18]([C:19]([O:21]C)=[O:20])[C:13]=3[N:12]=[C:11]2[CH3:29])[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Li+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:13]=3[N:12]=[C:11]2[CH3:29])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1ccc(C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(Cn2c(C)nc3c(C(=O)O)cc(N4CCOCC4)cc32)cc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
To a mixture of methyl 1-[(3,4-dimethylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylate (0.24 g, 0.61 mmol) in Tetrahydrofuran (THF) (10 mL) was added in lithium hydroxide (5.99 mL, 11.99 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature. The organic solvent was removed in-vacuo. The precipitate was collected by filtration. Water (20 mL) was added in. The mixture was acidified with 1 N HCl. The resulting solid was filtered and washed with water and dried to give the product (0.16 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (s, 6H), 2.58-2.75 (s, 3H), 3.06-3.22 (m, 4H), 3.71-3.82 (m, 4H), 5.55 (s, 2H), 6.94 (m, 1H), 7.04 (s, 1H), 7.11 (d, 1H, J=7.83 Hz), 7.52 (m, 2H). MS (ES+) m/e 380.2[M+H]+
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]([F:11])([F:10])[F:9])([CH3:6])[C:3](=[O:5])[CH3:4].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:4][C:3](=[O:5])[C:2]([CH3:1])([S:7][C:8]([F:10])([F:11])[F:9])[CH3:6]
Reactant: CC(=O)C(C)(C)SC(F)(F)F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(SC(F)(F)F)C(=O)CBr
Temperature: 40 °C
Yield: 85 %

Procedure:
3-Methyl-3-trifluoromethylthio-butan-2-one was dissolved in chloroform and bromine was added dropwise at 20° C. at such a rate that decolorization occurred continuously. Addition was stopped when the color persisted, the reaction mixture was further stirred at 40° C. 1-Bromo-3-methyl-3-trifluoromethylthio-butan-2-one of boiling point 56° C./0.4 mbar was obtained in a yield of 85%. ##STR13##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([Br:11])[CH:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[C:6]([Br:11])[CH:5]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCN(C)CC2)c(Br)c1
Temperature: 80 °C

Procedure:
The crude 3-bromo-4-fluorobenzoic acid methyl ester is dissolved in 120 mL of N,N-dimethylformamide, 4.32 g (43.1 mmol, 2 eq.) of N-methylpiperazine and 4.46 g (32.3 mmol, 1.5 eq.) of potassium carbonate were added and the reaction mixture heated at 80° C. for 8 hours. The mixture was poured into 300 mL of water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH:18]([NH2:20])[CH3:19])=[C:8]([N:11]3[CH2:17][C:13]4([CH2:16][O:15][CH2:14]4)[CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24](Cl)[N:23]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24]([NH:20][CH:18]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:17][C:13]3([CH2:16][O:15][CH2:14]3)[CH2:12]2)[CH3:19])[N:23]=1
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CC2(COC2)C1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CC2(COC2)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a 10 mL vial were added 1-(1-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (81 mg, 0.30 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (50.4 mg, 0.297 mmol) and Et3N (0.083 mL, 0.60 mmol) in DMF (2 mL). The resulting yellow solution was heated to 90° C. and stirred for 5 hours. The reaction mixture was diluted with EtOAc and washed with saturated NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The desired compound was precipitated with ether, filtered, and purified by silica gel column chromatography, eluting with 1:1 EtOAc/hexane to 100% EtOAc to 9:1 EtOAc/MeOH gradient. The resulting yellow foam was further purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium bicarbonate). The fractions containing the product were combined and lyophilized to give the title compounds (racemate) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28-1.40 (m, 3 H), 3.71-3.82 (m, 3 H), 3.96-4.07 (m, 2 H), 4.14-4.25 (m, 2 H), 4.72-4.85 (m, 4 H), 5.44-5.58 (m, 1 H), 6.37-6.45 (m, 1 H), 6.45-6.55 (m, 2H), 6.55-6.66 (m, 2 H), 6.68-6.79 (m, 1 H), 7.08-7.16 (m, 1 H), 7.37-7.45 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H23N9O, 406.2; found 406.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([NH:42][CH:43]1[CH2:45][CH2:44]1)=O>>[CH:43]1([NH:42][CH2:40][CH2:39][O:37][C:36]2[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:3][C:2]=2[F:1])[CH2:45][CH2:44]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: O=C(CCl)NC1CC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCNC3CC3)c(F)c2)c1
Yield: 6.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (37 mg) and 2-chloro-N-cyclopropylacetamide (19 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (2.2 mg) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[N:26]=[N:27][NH:28][N:29]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:36]>O1CCCC1.C(OCC)(=O)C>[ClH:36].[NH2:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[N:26]=[N:27][NH:28][N:29]=1)=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nn[nH]n3)ccc2c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(-c3nn[nH]n3)ccc2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 97 %

Procedure:
Tert-butyl[2-isobutyl-1-oxo-4-phenyl-6-(2H-tetrazol-5-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.15 g, 0.32 mmol) was dissolved in tetrahydrofuran (4 mL) and a solution (4 mL) of 4N hydrogen chloride in ethyl acetate was added thereto. This mixture was stirred at room temperature for 17 h, and the precipitated crystals were collected by filtration to give the title compound (0.13 g, 97%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:3]=1.O[CH2:16][CH2:17][O:18][C:19](=[O:22])[CH:20]=[CH2:21]>CN(C)C=O>[C:19]([O:18][CH2:17][CH2:16][O:13][C:12]([CH2:11][C:4]1[CH:3]=[C:2]([OH:1])[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=1)=[O:14])(=[O:22])[CH:20]=[CH2:21]
Reactant: O=C(O)Cc1cc(O)n2ncnc2n1
Reactant: C=CC(=O)OCCO
Solvent: CN(C)C=O
Product: C=CC(=O)OCCOC(=O)Cc1cc(O)n2ncnc2n1
Reaction time: 8 h

Procedure:
19.4 g of 7-hydroxy-5-carboxymethyl-1,2,4-triazolo[1,5-a]pyrimidine and 12 g of hydroxyethylacrylate were dissolved in 150 ml of dimethylformamide (DMF) and thereto, a solution of 20.6 g of N,N-dicyclohexylcarbodiimide in 30 ml of DMF was added dropwise at a room temperature for 10 minutes. Thereafter, stirring was continued at a room temperature for 8 hours, and the precipitate produced was removed by filtration. The filtrate was condensed under a reduced pressure and low temperature. The thus obtained residue was chromatographed through silica gel put in a column in order to separate it into components and purify. The intended compound was obtained in a form of crystal. It was recrystallized from ethyl acetate. Thus, 6 g of white crystal having a melting point of 108° to 109° C. (intended compound) was obtained.
Reaction SMILES: CC[CH2:3][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][C:18]([OH:20])=[O:19].CCCCCCCC/C=C\CCCCCCCC(O)=O>>[CH3:3][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][C:18]([OH:20])=[O:19]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)O

Procedure:
c16:1 5.8%; c18:0 4.8%; c18:1 22.2%.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15]>C(#N)C>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH:15][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCc1ccccc1F
Reactant: O=C(O)c1ccncc1F
Solvent: CC#N
Product: O=C(O)c1ccncc1NCc1ccccc1F
Temperature: 158 °C
Reaction time: 1 h
Yield: 10.3 %

Procedure:
3-Fluoroisonicotinic acid (100 mg, 0.71 mmol) and 2-fluorobenzylamine (308 μL, 2.84 mmol) were combined in ACN (3 mL) and the solution was stirred at 158° C. in a microwave for 1 h. The solution was concentrated in vacuo and purified by silica gel chromatography (10% to 20% MeOH/DCM). The semi-pure fractions were concentrated and then taken up in water to give a white precipitate, which was collected by filtration and dried under vacuum to give 18 mg (10%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.99 (br s, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.31-7.41 (m, 2H), 7.15-7.23 (m, 2H), 4.62 (s, 2H). [M+H] calc'd for C13H11FN2O2, 247. Found 247.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH2:30][C@H:31]3[CH2:35][CH2:34][CH2:33][N:32]3[C:36](OC(C)(C)C)=O)[CH:28]=2)[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].CCOCC>C1COCC1.O>[CH2:7]([O:14][CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH2:30][C@H:31]3[CH2:35][CH2:34][CH2:33][N:32]3[CH3:36])[CH:28]=2)[CH2:21][CH2:22]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(N2CCC(CCOCc3ccccc3)CC2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN1CCC[C@@H]1COc1cncc(N2CCC(CCOCc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 111.9 %

Procedure:
To a suspension of lithium aluminum hydride (46.4 mg, 1.22 mmol, 5 equiv.) in THF (2 mL) was added a solution of 3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(R)-pyrrolidinyl]methoxy]pyridine (121 mg, 0.24 mmol) in THF (0.5 mL). The resulting mixture was refluxed for 1.5 h, then cooled to room temperature. To a flask containing 4-5 g of Na2SO4 was added with stirring 40-50 mL of Et2O followed by the cooled reaction mixture. Water was subsequently added dropwise to quench the reaction. When no more gas was generated, the mixture was filtered, and the solid phase was washed with CH2Cl2/MeOH 4:1 (100-150 mL). Solvent removal furnished crude 3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[(1-methyl-2(R)-pyrrolidinyl)methoxy]pyridine (110 mg), which could be used in the following step without purification.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:28]([NH:30][C:31](=[N:39][CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH:45]=1)OC1C=CC=CC=1)#[N:29]>>[C:28]([NH:30][C:31]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:25])=[N:39][CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:51]2[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]2)[CH:45]=1)#[N:29]
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCCCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCCCCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.48 g (1.3 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,7-heptanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Chromatographic working-up analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=671 ([M+H]+, 3), 229 (100); IR (KBr): 2164 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanol/ether; m.p.: 96°-98° C. (isopropanol/ether).
Reaction SMILES: [H-].[Na+].O[C:4](C(F)(F)F)=O.[C:10]1([C:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CI.O>CN(C=O)C>[CH3:4][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:20]=2)[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:17]1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1ccc2c(-c3ccccc3)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(-c3ccccc3)cn(C)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
NaH (60% dispersion in mineral oil, 4.52 mmol, 186 mg) was added portion-wise to a solution of methyl 3-phenyl-1H-indole-6-carboxylate TFA salt 62c (2.07 mmol, 757 mg) in DMF at 0° C. and the mixture was stirred for 20 min. Methyl iodide (2.28 mmol, 0.14 mL) was added and the reaction mixture was maintained at 0° C. for 1 h. Water was then added and the reaction was extracted with EtOAc. The organics were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give 62d.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=O)[CH3:9])[CH:3]=1.[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])([CH3:14])([CH3:13])[CH3:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH:8]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)[CH3:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CC(=O)c1cc(C)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnc(C(C)NCCCCNC(=O)OC(C)(C)C)c1

Procedure:
Using General Procedure B: To a stirred solution of 1-(4-methyl-pyridin-2-yl)-ethanone (Sundberg, R J et al. J. Am. Chem. Soc. 1969, 91, 658-668) and (4-amino-butyl)-carbamic acid tert-butyl ester in CH2Cl2 was added NaBH(OAc)3 to give {4-[1-(4-methyl-pyridin-2-yl)-ethylamino]-butyl}-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.35 (d, 3H, J=6.6 Hz), 1.42 (s, 9H), 1.46-1.49 (m, 4H), 1.80 (br, 1H), 2.34 (s, 3H), 2.40-2.51 (m, 2H), 3.06-3.09 (m, 2H), 3.78 (q, 1H, J=6.6 Hz), 4.89 (br, 1H), 6.96 (d, 1H, J=5.1 Hz), 7.08 (s, 1H), 8.39 (d, 1H, J=5.1 Hz).
Reaction SMILES: C([O:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].C(O)(=O)C.[ClH:29]>C(O)C.O>[ClH:29].[OH:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:16][CH:17]=[CH:18][CH2:19][CH2:20]2)=[CH:12][CH:11]=1
Reactant: O=C(Oc1ccc(CN2CC=CCC2)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Oc1ccc(CN2CC=CCC2)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 1-(4-benzoyloxybenzyl)-1,2,3,6-tetrahydropyridine (1.0 g.) in ethanol (15 ml.) and water (5 ml.) containing sodium hydroxide (0.245 g.) was stirred for 2.5 hours. Ice-water (35 ml.) was added followed by acetic acid to pH7. The solid which formed was collected by filtration, washed with water, dried and dissolved in acetone (10 ml.). The solution obtained was acidified with concentrated hydrochloric acid to pH3 to give 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine hydrochloride (0.6 g.), m.p. 232°-4° C.