Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[CH:36][CH:35]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[CH:36][CH:35]=3)[N:24]=2)[CH:20]=[CH:21][CH:22]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(=O)Nc1ccc(CCN)cc1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CC(=O)Nc1ccc(CCNc2nccc(-c3cccc(CN(CCCN)S(C)(=O)=O)c3)n2)cc1

Procedure:
Intermediate 4 from above was coupled with N-[4-(2-Amino-ethyl)-phenyl]-acetamide by procedure F and the resulting product deprotected by procedure G to give 3. LC-MS showed the product had the expected M+H+ of 497. 1H NMR (Varian 300 MHz, CDCl3-CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 8.0 (m, 1H) 7.6 (m, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.3 (m, 1H) 7.2 (d, 2H) 4.4 (s, 2H) 3.9 (m, 2H) 3.3 (m, 2H) 2.9 (m, 2H) 2.8 (s, 3H) 2.7 (m, 2H) 2.1 (s, 3H) 1.8 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:22])([F:21])[C:15]([F:20])([F:19])C([O-])=O.[Na+]>CN1CCCC1=O.[Cu]I>[F:19][C:15]([F:20])([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[C:14]([F:22])([F:21])[F:13]
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C1CCCc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of 10 g (0.044 mol) of 7-bromo-1,2,3,4-tetrahydronaphthalenone in 300 mL of N-methylpyrrolidone was added 32.23 g (0.17 mol) of CuI and 31.59 g (0.17 mol) of sodium pentafluoropropanoate and the mixture was heated for 3 h at reflux under an argon atmosphere. After cooling to room temperature, the resulting suspension was poured into a mixture of H2O--Et2O (1:1) and filtered over celite. The layers were separated and the organic phase was washed with H2O and dried over MgSO4. The solvent was removed, to afford a residue that was chromatographed on silica gel (hexane-AcOEt), to give the desired product as a colourless oil (8.75 g, yield: 80%).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:15]1([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH2:25])[CH:19]=[CH:18][N:17]=[CH:16]1.CN1CCOCC1.CN(C=O)C>C(Cl)Cl>[N:15]1([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][C:12](=[O:14])[CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: Nc1ccsc1-n1ccnc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1cccc2ccccc12)Nc1ccsc1-n1ccnc1
Reaction time: 8 h
Yield: 33 %

Procedure:
To a mixture of 1-naphthyl acetic acid and 2-(1H-imidazol-1-yl)thiophen-3-amine in anhydrous CH2Cl2 was added O-(7-azabenzotriazol-1-yl)-N,N,N,N,-tetramethyl uronium hexafluorophosphate and 4-methymorpholine. A small amount of DMF was added to help starting material reagents go into solution. The reaction mixture was stirred overnight under N2 (g) inlet and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica, 10:90 methanol/methylene chloride) to afford N-(2-(1H-imidazol-1-yl)thiophen-3-yl)2-(naphthalen-1-yl)acetamide (209 mg, 33%). The desired product was purified by preparative HPLC. Method [8] m/z 334.1 (M+H); retention time=4.885. 1H-NMR (CD3OD) δ 8.83 (s, 1H), 7.89-7.80 (m, 2H), 7.77 (d, J=7.8 Hz, 1H), 7.51 (d, J=6.3 Hz, 2H), 7.48-7.32 (m, 5H), 7.17 (d, J=6.3 Hz, 2H), 4.08 (s, 2H).
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[CH:8]=[C:9]([CH2:23][CH2:24][NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:10]=[C:11]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[C:12]=1[Cl:13].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOCC>[Cl:6][C:7]1[CH:8]=[C:9]([CH2:23][CH2:24][NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:10]=[C:11]([CH2:14][OH:15])[C:12]=1[Cl:13]
Reactant: CCC(=O)NCCc1cc(Cl)c(Cl)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)NCCc1cc(Cl)c(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a THF (0.12 M) solution of N-{2-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]ethyl}propanamide (1 eq.) from the previous step was added TBAF (1.0 M THF solution, 1.1 eq.). The resulting solution was stirred at RT for 2 h. The now orange solution was diluted with ether and quenched with 1 N aq. NaOH. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a pale yellow oil.
Reaction SMILES: C([NH:4][C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([Cl:14])[N:6]=1)(=O)C.C([O:18][C@@H:19]1[C@H:23]([O:24]C(=O)C)[C@@H:22]([CH2:28][O:29]C(=O)C)[O:21][CH:20]1N1C2C(N=CN=2)=CN=C1)(=O)C.N>Cl[Hg]>[NH2:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:20]2[O:21][C@H:22]([CH2:28][OH:29])[C@H:23]([OH:24])[C@H:19]2[OH:18])=[C:7]([Cl:14])[N:6]=1
Reactant: CC(=O)OC[C@H]1OC(n2cncc3ncnc2-3)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)Nc1nc(Cl)c2[nH]cnc2n1
Agent: Cl[Hg]
Agent: N
Product: Nc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@H](O)[C@H]3O)c2n1

Procedure:
The chloromercury derivative of 2-acetamido-6-chloropurine is condensed with 2,3,5-tri-O-acetyl-3-D-ribofuranosylpurine utilizing the method of Lee et. al. (1971), J. Med. Chem., 14:819. The condensation product was treated with ammonia to yield 2-amino-6-chloro-9-(β-D-xylofuranosyl)purine. Further treatment with sodium hydroxyethylmercaptide gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:33]2=[O:35])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NCCNc2cccc(Cl)c2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCN(c3cccc(Cl)c3)C2=O)C1
Reaction time: 1 h
Yield: 106 %

Procedure:
In ice bath and under N2 atmosphere, to a stirred solution of (R)-tert-butyl 3-(2-(3-chlorophenylamino)ethylamino)piperidine-1-carboxylate (398) (10.1 g, 28.37 mmol) and Et3N (3.01 g, 29.8 mmol) in anhydrous DCM (300 mL) was added a solution of triphosgene (2.95 g, 9.93 mmol) in DCM (100 mL) dropwise. The resulting mixture was stirred in ice bath for 1 hour, and quenched with NaHCO3 (aq.) (1M, 50 mL). The mixture was extracted with DCM (100 mL×3). The combined organic layer was washed with brine, dried, concentrated and subjected to silica flash column chromatography using 0 to 5% MeOH in DCM to isolate (R)-tert-butyl 3-(3-(3-chlorophenyl)-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (399) (4 g, 37%) as a white solid. It was treated with 40 mL commercial 4N HCl in dioxane to give (R)-1-(3-chlorophenyl)-3-(piperidin-3-yl)imidazolidin-2-one hydrochloride (400) (3.3 g, quant.) as a white solid. Proton NMR (DMSO-d6): δ 9.26 (1H, s), 8.93 (1H, s), 7.77 (1H, t, J=2.0 Hz), 7.47-7.40 (1H, m), 7.35 (1H, t, J=8.1 Hz), 7.06 (1H, dd, J=7.9, 1.1 Hz), 4.10-3.94 (1H, m), 3.89-3.76 (2H, m), 3.48 (2H, t, J=8.5 Hz), 3.25-3.14 (2H, m), 3.06-2.97 (1H, m), 2.82-2.72 (1H, m), 1.95-1.86 (1H, m), 1.83-1.68 (3H, m) ppm.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-])[CH:3]=1.[C-]#N.[Na+].[CH2:14]([N:16](CC)CC)C.C[Si](Cl)(C)C>CN(C=O)C>[C:14]([C:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:10])=[O:9])=[CH:3][N:4]=1)#[N:16]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc[n+]([O-])c1
Agent: C[Si](C)(C)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)O)cn1
Temperature: 110 °C
Reaction time: 10 h
Yield: 21.9 %

Procedure:
To a solution of the nicotinic acid N-oxide (51 g, 0.37 mol) in 1.2 L of DMF, NaCN (54 g, 1.1 mol) was added, followed by triethylamine (255 mL, 1.83 mol) and TMSCl (185 mL). The reaction mixture was stirred at 110° C. for 10 h, filtered. and the filtrate was concentrated. The residue was dissolved in 100 mL of 2N HCl and extracted with methylene chloride. The organic layers were combined, concentrated and recrystallised from water to yield 12 g (22%) of the product.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[OH-].[Li+].O1CCCC1.CO>O>[CH3:1][CH:2]([CH3:21])[CH:3]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(C(Oc2ccccc2)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(Oc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of methyl 4-(2-methyl-1-phenoxypropyl)benzoate (240 mg, 0.84 mmol), lithium hydroxide monohydrate (178 mg, 4.2 mmol), tetrahydrofuran (12 mL), methanol (4 mL) and water (4 mL) was stirred at 20° C. for 4 hours. The reaction mixture was concentrated, acidified with concentrated hydrochloric acid to pH=1, extracted with ethyl acetate (20 mL×3). The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 4-(2-methyl-1-phenoxypropyl)benzoic acid as a white solid (227 mg, 100%). LRMS (M+H)− m/z: calcd 268.15. found 268.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]([N:19]=[C:20](OCC)[CH3:21])#[N:18]>N1C=CC=CC=1>[C:17]([N:19]=[C:20]([NH:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])[CH3:21])#[N:18]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CCOC(C)=NC#N
Solvent: c1ccncc1
Product: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of trans-4-amino-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (15.28 g) and ethyl N-cyanoacetimidate (9.42 g) in pyridine (70 ml) was refluxed under nitrogen atmosphere for 9 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 ml), washed with 5% hydrochloric acid (100 ml), water (100 ml), and brine (100 ml), successively. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give trans-4-[N-[1-(cyanoimino)ethyl]amino]-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (12.68 g).
Reaction SMILES: [CH:1](=[O:17])[CH:2]=[CH: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][CH3:16].[CH:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O>C1(C)C=CC=CC=1>[CH:1](=[O:17])/[CH:2]=[CH: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][CH2:18][CH3:20]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCC=CC=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCC/C=C/C=O

Procedure:
12 g (50 mmol) of hexadecenal and 15.2 g (50 mmol) of formylmethylenetriphenylphosphorane in 250 ml of anhydrous toluene are boiled under reflux for 8 hours. The mixture is evaporated to dryness. The residue is extracted five times with 100 ml of ether. The extract is evaporated to dryness and chromatographed on silica gel using toluene. Yield: 8.2 g (62%). Melting point: 35° C.; RF =0.8, toluene/ethyl acetate 8:2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:15][CH:16]1[CH2:21][CH2:20][S:19](=[O:23])(=[O:22])[CH2:18][CH2:17]1.[Li+].[OH-]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:15][CH:16]1[CH2:17][CH2:18][S:19](=[O:22])(=[O:23])[CH2:20][CH2:21]1
Reactant: COC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Br)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of methyl 5-bromo-3-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]-1H-indole-7-carboxylate (1.3 g, 3.26 mmol) in MeOH (50 mL) was added a solution of 3 N LiOH (3.5 mL, 9.77 mmol). The mixture was stirred for 2 hours at reflux. The reaction was concentrated, and the residue was dissolved in 1N NaOH and extracted with DCM. The combined organic layers were dried (MgSO4) and concentrated, giving 1.2 g (96%) of the title compound.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([O-:15])=[O:14])=O)(C)(C)C.[CH2:21]1COC[CH2:22]1>>[ClH:1].[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([O:15][CH2:21][CH3:22])=[O:14]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1C(=O)[O-]
Agent: Cl
Product: CCOC(=O)c1cc(F)ccc1CN
Temperature: 50 °C

Procedure:
Concentrated HCl (37%; 16 ml) was added dropwise to a solution of thyl 2-((tert-butoxycarbonylamino)methyl)-5-fluorobenzoate (Example 3; 15.9 g; 53.6 mmol) in THF (96 ml). The mixture was heated at 50° C. for 2 hours. The mixture was concentrated to dryness. The residue was taken up in ethanol (200 ml) and concentrated again. The solid was triturated from ether (100 ml). The precipitate was filtered off and washed with diethyl ether (2×50 ml).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15].C(N(C(C)C)CC)(C)C.O1CCOCC1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[OH:5][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O[C@H](CCCl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 34.2 %

Procedure:
Into a 25-mL RB-flask was added (R)-(+)-3-chloro-1-phenyl-1-propanol (0.426 g, 2.50 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.565 g, 2.00 mmol), diisopropylethylamine (1.29 g, 10.0 mmol), dioxane (5.0 mL) and catalytic amount of tetrabutylammonium iodide at room temperature. After stirring at 90° C. for 72 hrs, the reaction mixture was poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC plates (1:5:100=isopropylamine:methanol:ethyl acetate) to afford the desired product (0.260 g, 34.2% yield) as light-yellow solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH:3][O:2][CH3:1])=[CH:10][CH:9]=1
Reactant: CON=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
In an alternative procedure a solution of 4-fluorobenzaldehyde O-methyloxime (0.82 g, 5.35 mmol) in acetic acid (8 ml) was treated at 10° C. with sodium cyanoborohydride (0.67 g, 10.7 mmol) added in small portions over 10 min and the resulting solution was stirred at 25° C. for 18 h. The solvent was evaporated under reduce pressure (co-evaporation with toluene twice) and the residue was slurried with water and the pH was adjusted to 9 with 2 N aqueous sodium hydroxide. The aqueous phase was extracted twice with ether and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residual oil was chromatographed on silica gel (elution hexane-ethyl acetate, 8:2) and distilled in vacuo to give 0.62 g (75% yield) of the title amine as a clear oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:29](=[O:31])=[O:30].O>C1COCC1.CCCCCC>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:29]([OH:31])=[O:30])=[C:11]([F:16])[CH:10]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Fc1cc(F)cc(N(Cc2ccccc2)Cc2ccccc2)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1c(F)cc(N(Cc2ccccc2)Cc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
At −78° C., 10.0 g (32.3 mmol) of N,N-dibenzyl-3,5-difluoroaniline (Florvall, Lennart; Fagervall, Ingrid; Larsson, Lars-Gunnar; Ross, Svante B.; Eur. J. Med. Chem. Chim. Ther. 1999, 34, 137-152.) are initially charged in 90 ml of THF. 12.9 ml (32.3 mmol) of a 2.5 M solution of n-butyl-lithium in hexane are added dropwise, and the mixture is stirred at this temperature for 45 min. Excess dry ice is then added. The mixture is stirred at this temperature for another hour and then allowed to warm slowly to RT. Water is added to the reaction solution, which is then extracted twice with tert-butyl methyl ether. The aqueous phase is acidified with 10 ml of 4N hydrochloric acid, resulting in the formation of a precipitate. The mixture is extracted twice with dichloromethane, the combined phases are dried over sodium sulfate and the solvent is removed under reduced pressure.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:4][CH2:3]1.Br[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][CH2:8][C:5]3([CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH2:12][CH2:11]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN1CCC2(CCNCC2)CC1
Reactant: Clc1ccc(Br)cc1Cl
Product: CN1CCC2(CC1)CCN(c1ccc(Cl)c(Cl)c1)CC2

Procedure:
Was prepared according to method A from 3-methyl-3,9-diaza-spiro[5.5]undecane and 1-bromo-3,4-dichlorobenzene as a yellow oil. LC-ESI−HRMS of [M+H]+ shows 313.1238 Da. Calc. 313.123829 Da, dev. −0.1 ppm.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@@H:11]([CH3:13])[NH:10][CH2:9][C@@H:8]2[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([C:33](Cl)=[O:34])=[CH:30][C:29]=2[CH:36]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([C:33]([N:10]3[CH2:9][C@@H:8]([CH3:14])[N:7]([CH2:6][C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:12][C@@H:11]3[CH3:13])=[O:34])=[CH:30][C:29]=2[CH:36]=1
Reactant: O=C(Cl)c1cc2cc(Cl)ccc2o1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)c2cc3cc(Cl)ccc3o2)[C@@H](C)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
To an ice cold solution of (trans)-1-(4-fluorobenzyl)-2,5-dimethylpiperazine (712 mg, 3.2 mmol) and triethylamine (506 mg, 5 mmol) in CH2Cl2 (5 mL) a solution of the 5-chloro-1-benzofuran-2-carbonyl chloride (4.2 mmol) in CH2Cl2 (2 mL) was dropwise added. The reaction mixture was stirred at room temperature over night and washed with 0.5 M aqueous NaOH. The organic layer was dried, concentrated and submitted to flash column chromatography (CHCl3/MeOH; 1:0→10:1) to yield 1.05 g (82%) of the title compound.
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].Cl.[NH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[CH:15]=[CH:14][N:13]=1.C([O-])(O)=O.[Na+]>O.O1CCOCC1.CO>[N:11]1[CH:1]=[CH:2][N:13]2[CH:14]=[CH:15][C:16]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:12]=12
Reactant: CCOC(CBr)OCC
Reactant: Nc1cc(-c2ccc(C=O)cc2)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: O=Cc1ccc(-c2ccn3ccnc3c2)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A mixture of bromoacetaldehyde diethyl acetal (0.49 mL, 23.3 mmol, 2.0 equiv) and concentrated HCl (0.05 mL, 0.4 equiv) in water (10 mL) was stirred at 23° C. for 2 h, then heated at 80° C. for 30 min. The mixture was allowed to cool to 23° C., and 4-(2-aminopyridin-4-yl)benzaldehyde (2-2, 323 mg, 1.63 mmol, 1 equiv) and NaHCO3 (324 mg, 3.91 mmol, 2.40 equiv) were added. The resulting mixture was then heated to 50° C. where MeOH (2 mL) and dioxane (3 mL) were added to increase solubility. The reaction mixture was stirred at 50° C. for 18 h, then concentrated. The residue was partitioned between EtOAc (200 mL) and brine (200 mL). The organic layer was concentrated to provide 4-imidazo[1,2-a]pyridin-7-ylbenzaldehyde (2-3) as a brown solid. LRMS m/z (M+H) Calcd: 223.2, found 223.0.
Reaction SMILES: [CH3:1][C@H:2]([N:11]1[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC2C=CC=CC=2)[C:12]1=[O:27])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]>[Pd].C(O)C>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@@H:2]([CH3:1])[C:3]([N:5]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[O:4])[C:12]1=[O:27]
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N)C1=O
Reaction time: 16 h
Yield: 95.7 %

Procedure:
A mixture of benzyl (3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-ylcarbamate (20 g), 10% palladium on carbon (2 g) and ethanol (1.3 l) was stirred under an atmosphere of hydrogen for 16 h. The reaction mixture was filtered through Celite™ and the filtrate was concentrated under reduced pressure to give the title compound (12.3 g) as a pale white oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CC1C=CC(S(O[C:21]2[C:30]3[C:25](=[C:26]([O:33][CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[O:24][C:23](=[O:39])[CH:22]=2)(=O)=O)=CC=1>>[CH:34]1([O:33][C:26]2[C:27]([O:31][CH3:32])=[CH:28][CH:29]=[C:30]3[C:25]=2[O:24][C:23](=[O:39])[CH:22]=[C:21]3[CH2:8][C:7]2[C:6]([Cl:9])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: COc1ccc2c(OS(=O)(=O)c3ccc(C)cc3)cc(=O)oc2c1OC1CCCC1
Reactant: Cc1c(Cl)cncc1Cl
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)cc(=O)oc2c1OC1CCCC1

Procedure:
The title compound was prepared from 3,5-dichloro-4-methylpyridine and 8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-yl 4-methylbenzenesulfonate following the procedure outlined in Example 1, Step 4. 1H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 2H), 7.77 (d, 1H), 7.19 (d, 1H), 5.32 (s, 1H), 4.83 (m, 1H), 4.45 (s, 2H), 3.92 (s, 3H), 1.80-1.00 (m, 8H); MS (ESI): 419.9.