Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)[C:13]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:8][CH:7]=1.O>CS(C)=O>[N:1]([CH2:19][CH2:18][CH2:17][N:14]1[CH:15]=[CH:16][C:12]([C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=2)=[C:13]1[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)OCCCn2ccc(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCCn1ccc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
0.38 g (5.90 mmol) of sodium azide were added to a solution of 1.33 g (2.95 mmol) of 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1-[3-(p-toluenesulfonyloxy)propyl]-1H-pyrrole [prepared as described in step 22(iii) above] in 13 ml of dimethylsulfoxide. The resulting mixture was stirred at 70° C. for 1 hour. At the end of this time water was added to the reaction mixture and then this was extracted with dichloromethane. The organic extract was washed with water and then concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethylacetate as the eluant to afford 100 mg (yield 11%) of the title compound as a pale brown powder.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([CH2:16][CH2:17][NH2:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:8]([NH:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: NCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CCNCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of phenylacetaldehyde (6.0 g, 50 mmol) and 2-phenylethylamine in THF (200 mL) is added sodium triacetoxy-borohydride drop wise. The solution is stirred under nitrogen overnight at room temperature. The solution is quenched with aq. saturated sodium bicarbonate (200 mL), and extracted with EtOAc (4×100 mL). The organic extracts are combined, dried and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; EtOAc/MeOH 9:1) to provide 1.25 g (11%) of the compound D as a clear oil. M+H+=226.10.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.C(N(CC)CC)C>C(O)(C)C>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][CH2:11][C:9]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]3[CH:19]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=3[N:10]=2)[N:24]=[CH:23][N:22]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: NCc1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: N#Cc1c(N)ncnc1NCc1nc2ccc(F)cc2n1-c1ccccc1
Yield: 48.7 %

Procedure:
(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)methylamine hydrochloride (0.113 g, 0.4 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.123 g, 0.8 mmol), triethylamine (0.28 mL, 2 mmol) in isopropanol (2 mL) was heated to 80° C. in a sealed tube for 2 h. After cooling the pink solid was removed by filtration and washed with isopropanol (0.5 mL). This material was purified by column chromatography (Si—PCC, gradient 0-4% MeOH in DCM). Product containing fractions were evaporated to a white solid. This was triturated with diethyl ether and dried to give 371 as a white solid, (70 mg, 69%). LCMS (Method C): RT 3.54 min [M+H]+ 360.02. 1H NMR δ (ppm) (DMSO-d): 7.87 (1H, s), 7.69 (1H, t, J=5.2 Hz), 7.65 (1H, dd, J=8.80, 4.87 Hz), 7.64-7.46 (5H, m), 7.22 (2H, s), 7.06 (1H, ddd, J=9.86, 8.79, 2.53 Hz), 6.87 (1H, dd, J=8.97, 2.51 Hz), 4.62 (2H, d, J=5.37 Hz)
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=2[OH:13])[CH:8]=[O:9])[CH2:3][CH2:2]1.I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=2[O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]=[O:9])[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(O)c(OC2CC2)c1
Reactant: CCCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCCCCCCCOc1ccc(C=O)cc1OC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
To a solution of 1.78 g (10.0 mmol) of 3-(cyclopropyloxy)-4-hydroxybenzaldehyde and 2.54 g (10.0 mmol) of 1-iodononane in 20 mL acetonitrile was added 3.58 g (11.0 mmol) of Cs2CO3. The slurry was stirred at rt for 12 h. The reaction was quenched with 30 mL of water and extracted with ethyl acetate (50 mL×2). The combined extractions were washed with water, dried with sodium sulfate and concentrated to a solid. Flash chromatography on a Biotage 40M cartridge using 10% ethyl acetate/hexanes afforded 2.9 g (95%) of the title compound as a white solid. 1H NMR (500 Mhz) δ 0.87-0.91 (m, 7H), 1.30-1.90 (m, 14H), 3.85 (m, 1H), 4.10 (t, J=6.9, 2H), 6.98 (d, J=8.2, 1H), 7.48 (dd, J=8.5, 1.8, 1H), 7.77 (d, J=1.8, 1H), 9.89 (s, 1H); LC-1: 4.6 min; ESI-MS 305 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH2:26])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[NH:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1
Reactant: CN1CCN(CCN)CC1
Reactant: Clc1ccc2c(Cl)c3ccccc3nc2c1
Product: CN1CCN(CCNc2c3ccccc3nc3cc(Cl)ccc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 3,9-dichloroacridine (J. Med. Chem. 1985, 28. 940-944) and 2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained; MS (Found M+1=355).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>CN(C)C=O>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[N:14]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC5(CC4)OCCO5)cc3c2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC4(CC2)OCCO4)n3CC(F)(F)F)CC1
Yield: 78 %

Procedure:
The title compound was synthesized in analogy to example 51, from (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 196), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a colorless foam (78%).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14][C@H:13]1[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14][C@H:13]1[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27]
Reactant: [H][H]
Reactant: CO[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CNC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CC[C@H](N)[C@H](CNC(=O)OC(C)(C)C)C1

Procedure:
A sample of the product from Step 5 was dissolved in MeOH (100 ml). Palladium on carbon (0.185 g, 1.743 mmol) was added to the solution and the reaction mixture was stirred under 50 psi hydrogen for 2 h. The reaction mixture was filtered through Celite with EtOAc. The resulting solution was concentrated in vacuo to yield tert-butyl ((1S,2S,5R)-2-amino-5-methoxycyclohexyl)methylcarbamate as a clear oil which was used without any further purification. A quantitative yield was assumed. LC/MS found [M+H]+=259.41.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[C:11]3[O:19]C(C)(C)[O:21][CH2:22][C:10]=23)=[O:7])=[CH:4][CH:3]=1>C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:10]([CH2:22][OH:21])=[C:11]([OH:19])[C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=2)=[O:7])=[CH:25][CH:26]=1
Reactant: COC(=O)c1ncc(NC(=O)c2ccc(F)cc2)c2c1OC(C)(C)OC2
Solvent: O=CO
Product: COC(=O)c1ncc(NC(=O)c2ccc(F)cc2)c(CO)c1O

Procedure:
Methyl 5-(4-fluorobenzamido)-3-hydroxy-4-(hydroxymethyl)picolinate (23e) was synthesized from methyl 5-(4-fluorobenzamido)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate (Compound 23d) and formic acid as described above. MS-ESI m/z 361 [MH]+.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:16][CH:15]=1>>[CH2:1]([N:5]([CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCOc1ccc(/C=C/c2nc3ccccc3s2)cc1
Reactant: CCCCNCCCC
Product: CCCCN(CCCC)CCOc1ccc(/C=C/c2nc3ccccc3s2)cc1
Yield: 36 %

Procedure:
Reaction of this product (2.0 g, 6.3 mmol) with dibutylamine produced 1.1 g (36% yield) of the named compound as the HCl salt, mp 172°-173° C. IR(KBr): 3400, 1600 cm-1. MS: 409(MH+). 1H NMR (CDCl3): δ 8.37-6.79 (m, 10H), 4.67 (t, J=5.4 Hz, 2H), 3.55 (t, J=5.4 Hz, 2H), 3.12 (m, 4H), 1.99-0.79 (m, 14H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=O.[CH3:14][N:15]([CH3:19])[C:16]([NH2:18])=[S:17]>C(O)(C)C.CCOC(C)=O>[CH3:14][N:15]([CH3:19])[C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[N:18]=1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C(N)=S
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CN(C)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Yield: 64.7 %

Procedure:
A solution of 2-bromo-4′-nitroacetophenone (4.42 g, 18.1 mmol), N,N,-dimethylthiourea (3.77 g, 36.2 mmol) in isopropanol (60 mL) was heated at reflux for 45 min. The cooled reaction mixture was diluted with EtOAc. The solution was washed with saturated aqueous NaHCO3, H2O and brine, dried (MgSO4) and concentrated under reduced pressure to give N,N-dimethyl-4-(4-nitrophenyl)-2-thiazolamine (2.92 g, 65% yield) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ8.24 (d, J=8.8 Hz, 2H), 8.11 (d, J=8.8 Hz, 2H), 7.56 (s, 1H), 3.11 (s, 6H); MS (FAB) m/z 250 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13].C([Sn](CCCC)(CCCC)[C:40]([O:42]CC)=[CH2:41])CCC.Cl.C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:40]([C:2]1[CH:3]=[N:4][N:5]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13])(=[O:42])[CH3:41]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(-c2c(Br)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1cnn(-c2ccc(C#N)cc2)c1-c1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-bromo-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 93) (54.6 mg) in 1,4-dioxane (1.0 ml) were added tetrakis(triphenylphosphine)palladium (23.8 mg) and tributyl(1-ethoxyvinyl)tin (103.4 μl) and the resulting mixture was stirred for one hour with heating in microwave instrument (120° C.). To the reaction mixture were then added 1M hydrochloric acid (1 mL) and ethyl acetate (2 ml) and the resulting mixture was stirred at room temperature for one hour. To the reaction mixture was ethyl acetate (50 ml) and the mixture was washed with 10% aqueous potassium carbonate solution (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(4-acetyl-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (19.0 mg) as white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])C.[Li+].[OH-]>CO.O>[Cl:11][C:10]1[N:9]([CH:12]2[CH2:13][CH2:14][CH2:15]2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(C2CCC2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(C2CCC2)c1Cl
Yield: 93.4 %

Procedure:
To a solution of 5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ester (182 mg, 0.79 mmol) in methanol (8 mL) and water (8 mL) was added LiOH (23 mg, 0.96 mmol). The reaction mixture was stirred at reflux for 4 hours and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water, acidified to pH 2 with concentrated HCl and extracted with ethyl acetate. The organic layer was evaporated in vacuo to give 5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid (148 mg, 94%) which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C:23]3=[O:31])[CH2:18][CH2:17]2)=[O:15])=[CH:5]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:14]([N:16]3[CH2:17][CH2:18][CH:19]([N:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][C:23]4=[O:31])[CH2:20][CH2:21]3)=[O:15])=[CH:5][N:4]2[CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:8][CH:9]=1
Reactant: NCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21

Procedure:
A solution of 1-{1-[1-(2-amino-ethyl)-6-chloro-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one (1 eq) in dry CH2Cl2 was treated with methanesulfonyl chloride (1.1 eq) and triethylamine at RT for 15 h. Quenching with H2O and extraction into CH2Cl2 followed by concentration and purification by prep HPLC gave the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:13][CH:14]=[CH:15][CH2:16][C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=2)[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:25]([C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][C:7]2[CH:8]=[C:9]([CH3:12])[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[CH:22]=[C:21]([CH3:23])[C:20]=1[OH:24])([CH3:26])([CH3:28])[CH3:27]
Reactant: [H][H]
Reactant: Cc1cc(CC=CCc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(CCCCc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
8.55 g (22.5 mmol) of 1,4-bis(3'-tert-butyl-5'-methyl-4'-hydroxyphenyl)but-2-ene in 100 ml of ethyl acetate are hydrogenated over 1 g of Pd/C (5%) at room temperature under atmospheric pressure. After 30 minutes, the uptake of hydrogen has ended. The reaction mixture is filtered over Celite and the resulting filtrate is concentrated. Crystallization of the crude product from acetonitrile gives 6.6 g (77% of theory) of 1,4-bis(3'-tert-butyl-5'-methyl-4'-hydroxyphenyl)butane of melting point 106°-107° C.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]2[C:8](=[O:28])[N:9]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:10]3[C:15]([C:6]=2[CH:5]=1)=[CH:14][N:13]=[C:12]1[CH:16]=[C:17]2[O:22][CH2:21][O:20][C:18]2=[CH:19][C:11]=31)([O-])=O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]2[C:8](=[O:28])[N:9]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:10]3[C:15]([C:6]=2[CH:5]=1)=[CH:14][N:13]=[C:12]1[CH:16]=[C:17]2[O:22][CH2:21][O:20][C:18]2=[CH:19][C:11]=31
Reactant: CN(C)CCn1c(=O)c2ccc([N+](=O)[O-])cc2c2cnc3cc4c(cc3c21)OCO4
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)CCn1c(=O)c2ccc(N)cc2c2cnc3cc4c(cc3c21)OCO4
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
To a solution of compound 5a (40 mg, 0.1 mmol) in ethanol (10 mL), Ra—Ni (˜50 mg) and then hydrazine hydrate (0.2 mL) were added and the reaction stirred at room temperature for 3 h. The catalyst was filtered through Celite and filtrate was concentrated in vacuo to provide 23 mg of a solid (61.1% yield); mp 300–301° C.; 1H NMR (CDCl3) δ 2.36 (s, 6H), 3.01 (t, 2H, J=6.6), 4.33 (s, 2H), 4.63 (t, 2H, J=7), 6.18 (s, 2H), 6.91(dd, 1H, J=2.2, 8.8), 7.46 (s, 1H), 7.45 (d, 1H, J=2.2), 7.83 (s, 1H), 8.30 (d, 1H, J=8.8), 9.35 (s, 1H); HRMS m/z calcd for C21H20N4O3H: 377.1614. found 377.1606.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[B:11](OC)([O:14]C)[O:12]C>CCOCC>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([B:11]([OH:14])[OH:12])=[CH:3][CH:4]=1)[CH3:9]
Reactant: COB(OC)OC
Reactant: CCc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: CCc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
A solution of 1-bromo-4-ethyl benzene (2.0 g, 11 mmol) in dry ether (5 ml) was added to magnesium turnings (311 mg, 13 mmol), which had been suspended in dry ether, by dropwise addition. After addition was complete, the suspension was refluxed for a period of 15 min, by which time nearly all of the magnesium had reacted. The solution was then added to trimethy borate (1.12 g, 11 mmol), previously dissolved in ether (5 ml) at -78° C., warmed to room temperature and stirred for 90 min. The reaction was quenched by the addition of 10% aqueous HCl (2 ml) and the solution was extracted with ether. The combined ether extract was extracted with 1M NaOH (2×20 ml), the aqueous extracts were acidified with dilute HCl to pH 2 and extracted with ether (2×25 ml). The resulting combined ether extract was washed once with water (10 ml), dried and evaporated to produce a white solid (676 mg, 38% yield), m.p. 138°-140° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C(O[N:21]1N=N[C:23]2C=CC=C[C:22]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N)C>C1COCC1.CN(C=O)C>[CH2:22]([NH:21][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:12])[CH3:23]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C(=O)O)c1ccc(O)cc1
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)C(C)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 4.00 g (24.1 mmol) 2-(4-hydroxyphenyl)propionic acid in 50 mL THF and 5 ml DMF are added 6.76 g (66.1 mmol) TEA and 8.50 g TBTU. The reaction mixture is stirred at r.t. for 5 min, then 36.1 ml (2 mold solution; 72.2 mmol) ethylamine are added. The reaction mixture is stirred at r.t. 5 h. The solvent is removed in vacuo and the crude product is purified by prep. HPLC-MS (ACN/H2O/NH4OH).
Reaction SMILES: [Br:1][CH2:2][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][NH:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([O:25][CH:26]=[CH:27]C(OCC)=O)=[O:24])=[CH:21][CH:20]=1.[H][H]>[Pd].O1CCCC1>[Br:1][CH2:2][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][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:33][CH:34]=1
Reactant: CCOC(=O)C=COC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
A solution of 4 g. 2-(ethoxycarbonyl)vinyl 4-(16-bromohexadecylamino)benzoate and 400 mg. 10% palladium-on-carbon in 100 ml. tetrahydrofuran is hydrogenated at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetonitrile to yield 2-ethoxycarbonyl)ethyl 4-(16-bromohexadecylamino)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[CH:6]=[CH:7][CH2:8]Cl.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:8][CH:7]=[CH:6][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: COc1cc(C=CCCl)cc(OC)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(C=CCN2CCc3nc(N)sc3CC2)cc(OC)c1
Yield: 21 %

Procedure:
Prepared from 3,5-dimethoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield 21% of theory, Melting point: 114°-19° C. (petroleum ether).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][O:10][C:11](=[O:28])[C:12]1[C:13](=[C:18]([NH:22]CCCCC)[CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH3:17])=[O:15]>C(OCC)C>[CH3:9][O:10][C:11](=[O:28])[C:12]1[C:13](=[C:18]([NH:22][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=Cc1cccnc1
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Solvent: CCOCC
Product: COC(=O)c1cccc(NCc2cccnc2)c1C(=O)OC
Yield: 61 %

Procedure:
3-Pyridinecarboxaldehyde (0.94 ml, 10 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. After removal of pyridine the residue was dissolved in methylene chloride (100 ml) and washed with water (2×100 ml), saturated NaHCO3 (2×100 ml), brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give an oil. The oil was dissolved in diethyl ether (100 ml) and extracted with 0.1 N HCl (2×100 ml). The combined aqueous HCl extracts were washed with diethyl ether (2×100 ml) and the pH adjusted to 10 by dropwise addition of saturated Na2CO3. The product was extracted with diethyl ether (3×100 ml). The combined ether extracts were washed with brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give 0.91 g (61%) of product as a light yellow oil which was used without further purification: 1H NMR CDCl3) δ8.61 (d, J=2.0 Hz, 1H), 8.53 (dd, J=1.1 Hz and 4.8 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.31-7.21 (m, 3H), 6.85 (d, J=7.3 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 4.45 (d, J=5.7 Hz, H), 3.87 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [N:1]1[C:2]([CH2:14][OH:15])=[CH:3][N:4]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[N:1]1[C:2]([CH:14]=[O:15])=[CH:3][N:4]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12
Reactant: OCc1cn2c(n1)-c1ccccc1CC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1cn2c(n1)-c1ccccc1CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5,6-dihydroimidazo[2,1-a]isoquinolin-2-yl)-methanol (177 mg, 0.88 mmol) in DCM (10 mL) under an atmosphere of argon was added Dess-Martin periodinane (41 mg, 0.97 mmol) and the solution stirred at room temperature for 2 h.