Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[CH3:13][C:12]1[C:11]2[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[CH:15][CH:16]=[CH:17][C:10]=2[O:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3cccc([N+](=O)[O-])c3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)oc2cccc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.9 %

Procedure:
To 300 mg of 3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carboxylic acid tert-butyl ester was added 4 mL of TFA/dichloromethane (1:1). The solution was stirred at room temperature for 5 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 232 mg (92% yield) of 3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carboxylic acid as white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.CN(C=O)C.CS(O[CH2:19][C:20]1[C:21]2[CH:29]=[C:28]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[S:27][C:22]=2[N:23]=[C:24]([CH3:26])[N:25]=1)(=O)=O>O>[CH:30]1([C:28]2[S:27][C:22]3[N:23]=[C:24]([CH3:26])[N:25]=[C:20]([CH2:19][N:1]4[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]4)[C:21]=3[CH:29]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCCCC3)sc2n1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(CN2CCS(=O)(=O)CC2)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.7 %

Procedure:
To a mixture of thiomorpholine-1,1-dioxide (65 mg) and DMF (4 mL) were added (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl methanesulfonate (110 mg) and TEA (150 μL), followed by stirring at room temperature for 24 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain 6-cyclohexyl-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (94 mg).
Reaction SMILES: CC(Cl)CC1C=CC=CC=1.C(#N)CC.[CH2:15]([CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH:19]([CH3:27])[NH:18]1)[CH3:16].C1C2C(=CC=CC=2)C=CN=1.[OH-].[Na+].[Cl:40][CH:41]([Cl:45])[C:42](Cl)=[O:43]>O.C(Cl)Cl>[Cl:40][CH:41]([Cl:45])[C:42]([N:18]1[CH:19]([CH3:27])[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]1[CH2:15][CH3:16])=[O:43]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCC1NC(C)Cc2ccccc21
Agent: CC(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2cnccc2c1
Solvent: CCC#N
Solvent: O
Product: CCC1c2ccccc2CC(C)N1C(=O)C(Cl)Cl

Procedure:
By procedures described in Example 1, α-methylphenethylchloride and propionitrile were converted to 1-ethyl-3-methyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 4 g of this isoquinoline compound, 10 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 1.1 equivalents dichloro-acetyl chloride was added dropwise to the mixture. The mixture was stirred for 15 minutes, then water was added. The organic extract was dried with magnesium aulfate, and stripped of solvent, and subjected to Kugelrohr distillation (150° C. @0.25 mm Hg) to provide 4.5 g of a yellow oil product having the following elemental analysis:
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH2:18]([NH:22][S:1]([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
One equivalent of dansyl chloride (7) was added to a solution containing 2 equivalents of both butylamine and potassium carbonate in 1:1 acetonitrile:water. Solution was stirred at room temperature for 1.5 hrs. Acetonitrile was then removed and water residue extracted with ethyl acetate. The organic solution washed with 5% sodium bicarbonate, 2M citric acid and brine. Solution was dried over magnesium sulfate, filtered and solvent removed by flash evaporation. Crude was dissolved in minimal amount of ethyl acetate and hexane was added until cloudiness. Solution was stored in the refrigerator for 2 hrs. The precipitate was collected by suction filtration, washed with hexane and dried on the pump. ESI-MS and 1H-NMR were consistent with structure 8, which is (n-butyl dansylamide; BDA): 1H-NMR (CDCl3, =ppm): 8.55 (1H, d); 8.30 (2H, dd); 7.55 (2H, m); 7.20 (1H, d); 4.80 (1H, t); 2.90 (8H, m); 1.35 (2H, m). 1.20 (2H, m); 0.70 (3H, t). ESI-MS: Calc. m/z=306.4. Found m/z+H+=307.4.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1>>[O:19]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Oc3ccccc3)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and [(4-phenoxy)benzene]sulfonyl chloride as described in the synthetic METHOD B to give a white solid (33.5 mg) with purity >90%. MS (pos) m/z 419.3.
Reaction SMILES: [BH4-].[Na+].[CH:3](=[C:10]1[C:26](=[O:27])[C:25]2([CH3:28])[CH:12]([CH:13]3[CH:22]([CH2:23][CH2:24]2)[C:21]2[CH:20]=[CH:19][C:18]([O:29][S:30](=[O:33])(=[O:32])[NH2:31])=[CH:17][C:16]=2[CH2:15][CH2:14]3)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C.O>C1COCC1.C(O)C>[CH:3](=[C:10]1[CH:26]([OH:27])[C:25]2([CH3:28])[CH:12]([CH:13]3[CH:22]([CH2:23][CH2:24]2)[C:21]2[CH:20]=[CH:19][C:18]([O:29][S:30](=[O:33])(=[O:32])[NH2:31])=[CH:17][C:16]=2[CH2:15][CH2:14]3)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC12CCC3c4ccc(OS(N)(=O)=O)cc4CCC3C1CC(=Cc1ccccc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC12CCC3c4ccc(OS(N)(=O)=O)cc4CCC3C1CC(=Cc1ccccc1)C2O

Procedure:
Sodium borohydride (100 mg, 2.64 mmol) was added to a solution of sulfamic acid 16-benzylidene-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl ester (438 mg, 1.0 mmol, CAB01148) in THF (20 ml) and ethanol (20 ml) at 0° C. The mixture was stirred for 1 h at this temperature (TLC-control) and ethyl acetate (100 ml) and water (50 ml) were added. The organic layer was separated and washed with water (50 ml) and brine (50 ml), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in a small amount of ethyl acetate and precipitated by addition of diethyl ether. Yield: 440 mg (quant.) white powder. 1H-NMR (CDCl3, 400 MHz), δ: 0.67 (s, 3H), 1.36-1.62 (m, 6H), 2.00-2.10 (m, 2H), 2.22-2.41 (m, 3H), 2.78 (dd, J=17.4, 7.2 Hz, 1H), 2.90-2.96 (m, 2H), 4.15 (d, J=9.4 Hz, 1H, H-17), 4.86 (s, 2H, —NH2), 6.55 (d, J=2.3 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 7.10 (dd, J=8.2, 2.3 Hz, 1H), 7.19-7.42 (m, 6H). LRMS (FAB+): 439.2 (100, [M]+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:37][CH2:36][C:35]1[N:31]([C:27]2[CH:26]=[C:25]([C:24]3[CH2:23][C:22](=[O:45])[NH:21][C:9]4[CH:10]=[C:11]([CH3:20])[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[N:32]=[N:33][CH:34]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3nncc3CO)c1)CC(=O)N2

Procedure:
The title compound was prepared from (RS)-[5-(isobutyl-methyl-amino)-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M108) (0.33 g, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale brown solid (188 mg, 79%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][CH:16]1[CH2:18][CH2:17]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:16]1([CH2:15][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CC2CC2)CC1
Reaction time: 12 h
Yield: 62.4 %

Procedure:
Tert-butyl piperazine-1-carboxylate 7a (6.14 g, 33 mmol), bromomethyl-cyclopropane (4.05 g, 30 mmol) and triethylamine (6.06 g, 60 mmol) were dissolved in 70 mL of dichloromethane. The reaction solution was stirred for 12 hours. The resulting solution was added with 50 mL of aqeuous saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate 31a (4.50 g, yield: 62.5%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[F:17][C:18]1([F:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>>[F:17][C:18]1([F:24])[CH2:23][CH2:22][CH2:21][N:20]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:19]1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: FC1(F)CCCNC1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC(F)(F)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3,3-difluoropiperidine hydrochloride (9.5 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.4 mg). Calcd for C16H16F2N2O2: 306.1180, found 306.1177.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([N:18]([CH:26]=[O:27])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.C1COCC1.O.[Na+].[Cl-].C([O-])(O)=O.[Na+]>C(O)(=O)C>[OH:8][CH2:9][CH:10]([N:18]([CH:26]=[O:27])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N(C=O)C(CO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C=O)C(CO)Cc1ccccc1
Yield: 98.4 %

Procedure:
tertbutyl 3-(tert-butyldimethylsilyloxy)-1-oxo-1-phenylpropan-2-lmethylcarbamate (36) (640 mg, 1.6 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by a 1:1 mixture of THF/H2O (8 mL). The mixture was stirred and glacial acetic acid (12 mL) was added to the reaction flask. The reaction stirred for 20 h at rt. The reaction was transferred to a 250 mL separatory funnel with sat. NaCl (50 mL) and sat. NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (3×70 mL) and the combined organic layers were dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 550 mg of crude material. The residue was purified by flash column chromatography (50% EtOAc/hexanes) to give 440 mg (97%) of 37 as a colorless oil. Rf=0.33 (50% EtOAc/hexanes); IR (film) 3451, 2975, 1681, 1149 cm−1; 1H NMR (500 MHz, CDCl3) δ Major rotamer: 7.96 (d, J=7.5 Hz, 1H, Ph-H), 7.90 (d, J=7.5 Hz, 1H, Ph-H), 7.58 (t, J=6.5 Hz, 1H, Ph-H), 7.46 (m, 2H, Ph-H), 5.45 (t, J=6.0 Hz, 1H, Boc-N—CH), 4.24 (m, 1H, CH—CH2), 4.14 (m, 1H, CH—CH2), 2.72 (s, 3H, Boc-N—CH3), 2.50 (m, 1H, CH2—OH), 1.43 (s, 9H, Boc-t-butyl-CH3). Minor rotamer: 4.89 (t, J=6.0 Hz, 1H, Boc-N—CH), 3.94 (m, 1H, CH—CH2), 3.81 (m, 1H, CH—CH2), 2.90 (s, 3H, Boc-N—CH3), 1.38 (s, 9H, Boc-t-butyl-CH3); 13C NMR (125 MHz, CDCl3) δ 199.9, 199.2, 156.1, 154.6, 135.7, 133.8, 128.9, 128.8, 128.5, 128.3, 81.7, 80.9, 63.5, 61.0, 60.8, 60.7, 33.3, 32.1, 28.4, 28.3; LRMS (ESI-MS m/z): Mass calcd for C15H21NO4Na [M+Na+], 302.32. Found 302.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)[CH:10]=[CH:11][CH:12]([CH:14]1[C:18](=[O:19])[C:17]([S:20][CH3:21])=[CH:16][C:15]1([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:22][Si](C)(C)C)[OH:13])(C(C)(C)C)(C)C.N1C=CC=CC=1.N1C=CC=CC=1.F.C(=O)([O-])O.[Na+]>C(#N)C>[OH:13][CH:12]([CH:14]1[C:18](=[O:19])[C:17]([S:20][CH3:21])=[CH:16][C:15]1([OH:22])[CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH:11]=[CH:10][CH:9]([OH:8])[CH2:38][CH2:39][CH2:40][OH:41]
Reactant: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)C(C(O)C=CC(CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C1=O
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: CSC1=CC(O)(CCCCOc2ccccc2)C(C(O)C=CC(O)CCCO)C1=O
Yield: 71.3 %

Procedure:
To a solution of 270 mg of 5-[4,7-bis(t-butyldimethylsilyloxy)-1-hydroxy-2-heptenyl]-2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 559 dissolved in 15 ml of acetonitrile, 2 ml of pyridine was added. While stirring the mixture under ice-cooling, 1 ml of a hydrogen fluoride-pyridine solution was added and the mixture was stirred at 0° C.--room temperature for 16 hours. The mixture was poured onto saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtration and concentration, the concentrate was subjected to silica gel chromatography to give 114 mg (yield 71%) of 5-(1,4,7-trihydroxy-2-heptenyl)-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: [N:1]1[C:10]2[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17](=[O:25])[N:18]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH3:19])([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:12]([O:16][C:17](=[O:25])[N:18]([CH3:19])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Reactant: O=C1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCCCNC1CCCc2cccnc21)C(=O)OC(C)(C)C

Procedure:
Using General Procedure B: Reaction of 6,7-dihydro-5H-quinolin-8-one, (4-amino-butyl)-methyl-carbamic acid tert-butyl ester and NaBH(OAc)3 in CH2Cl2 gave methyl-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-carbamic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.50-1.60 (m, 4H), 1.72-1.81 (m, 2H), 1.95-2.20 (m, 4H), 2.67-2.78 (m, 4H), 2.83 (s, 3H), 3.17-3.24 (m, 2H), 3.75-3.79 (m, 1H), 7.06 (dd, 1H, J=7.6, 4.7 Hz), 7.36 (d, 1H, J=7.7 Hz), 8.38 (d, 1H, J=4.5 Hz).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH2:21])[O:14][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[CH:8]2.[H][H]>O.[Pd]>[CH3:2][C:3]1[CH:4]=[C:5]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:23])[NH2:21])[O:14][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)C(C)(C)N)C2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNC(=O)C(C)(C)N)C2
Yield: 82 %

Procedure:
A hydrochloric acid salt of 5-methyl-2-(α-methylalanyl)aminomethyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1.15 g, 3.27 mmol) was dissolved in water (30 ml). To the obtained solution, 10% palladium-on-carbon (1.15 g) was added, followed by stirring at 80° C. for 3.5 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was subjected to a recrystallization procedure using methanol--ether to obtain 851 mg of the title compound as colorless powdery crystals (73.5%).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.S(=O)(=O)(O)O.[CH:28](O)([CH3:30])[CH3:29]>>[CH:28]([O:11][C:10]([C:7]1([C:4]2[CH:5]=[CH:6][C:1]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:2][CH:3]=2)[CH2:9][CH2:8]1)=[O:12])([CH3:30])[CH3:29]
Reactant: CC(C)O
Reactant: O=C(O)C1(c2ccc(-c3ccccc3)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)C1(c2ccc(-c3ccccc3)cc2)CC1
Temperature: 65 °C

Procedure:
1-(Biphenyl-4-yl)cyclopropanecarboxylic acid (10 g, 42 mmol), isopropanol (100 mL), thionyl chloride (6.8 mL, 92 mmol) were heated to 65° C. for 4 hours. Sulfuric acid (20 mL) was added and heated at 65° C. overnight. The product is extracted with CH2Cl2 and water (2×) dried and evaporated to yield 10.8 g of the title compound.
Reaction SMILES: C([Mg]Br)C.[I:5][C:6]1[N:7]=[C:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:13]=3[O:12][CH2:11][CH2:10][N:9]2[C:23]=1I.[NH4+].[Cl-]>C(OCC)C.C1COCC1>[I:5][C:6]1[N:7]=[C:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:13]=3[O:12][CH2:11][CH2:10][N:9]2[CH:23]=1
Reactant: COC(=O)c1ccc2c(c1)OCCn1c-2nc(I)c1I
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Reaction time: 1 h
Yield: 86 %

Procedure:
Fresh ethyl magnesium bromide in ethyl ether (3.0 M 1.1 mL) was added dropwise to a suspension of methyl 2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (1.1 g, 2.2 mmol) in THF at −15° C. The mixture was stirred and monitored using LC/MS. After 1 hour, there was no remaining starting material and the reaction was poured into sat. NH4Cl and extracted with EtOAc. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. At the end of this process, 0.7 g (80%) of methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate was obtained.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]([NH2:7])=[CH:5][CH:6]=1.[CH2:10]=[CH:11][C:12](=[CH2:14])[CH3:13]>CCCCC>[CH3:14][C:12]([CH3:13])=[CH:11][CH2:10][C:5]1[CH:6]=[C:1]([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]=1[NH2:7]
Reactant: C=CC(=C)C
Reactant: Cc1ccc(N)cc1N
Solvent: CCCCC
Product: CC(C)=CCc1cc(C)c(N)cc1N

Procedure:
A 200g (1.64 mol) portion of 2,4-toluenediamine, 167g (2.45 mol) of isoprene, 200g (2.78 mol) pentane, and 20g of catalyst comprised of 13% alumina and 87% silica were reacted at 200° C. in a similar fashion as indicated in Example 5. Isolation of catalyst free sample was accomplished by hot filtration. Selective removal of all residual low boiling hydrocarbons by vacuum distillation afforded the following product mixture:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[NH2:10][C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=1>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:10][C:11]1[C:16]([O:17][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=2[CH3:9])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Cc1cccc(Br)c1C
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1COc1cccnc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of a -bromo-o-xylene (89.6 g, 0.48 mol) and 2-amino-3-hydroxypyridine (48 g, 0.436 mol) in 40% aqueous sodium hydroxide solution (250 ml) and dichloromethane (250 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. The aqueous layer was extracted with dichloromethane and the combined organic layers washed with water, dried and evaporated. Chromatography (silica gel, chloroform) gave the product as an oil which later solidified (45.4 g, 49%), m.p. 96°-98° C.
Reaction SMILES: FC1C=CC(C[N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18]C2CCNCC2)=CC=1.C(O)(=O)C.CC1N=C2C=CC=CN2C=1.[OH-].[Na+]>O>[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:18]
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Agent: *CO*
Agent: Cc1cn2ccccc2n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred and cooled (0° C.) mixture of 3.8 parts of poly(oxymethylene) 37%, 15.5 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine and 7 parts of glacial acetic acid were added 6.5 parts of 2-methylimidazo[1,2-a]pyridine under nitrogen atmosphere. The whole was heated slowly to 50° C. and stirring was continued at 50° C. for 2 hours. After stirring was continued overnight at room temperature, the reaction mixture was poured into water and the whole was made alkaline with sodium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 6.7 parts (30%) of 1-[(4-fluorophenyl)methyl]-N-[(2-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 198.1° C. (compound 106).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.[OH-].[Na+]>[C:26]([O:11][C:10]1[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]([CH2:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:8][C:9]=1[C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:28])[CH3:27]
Reactant: CC(C)(C)c1cc(CCCOC2CCCCO2)cc(C(C)(C)C)c1O
Reactant: CC(=O)OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1c(C(C)(C)C)cc(CCCOC2CCCCO2)cc1C(C)(C)C
Yield: 93.4 %

Procedure:
A vigourously stirred mixture of 40.74 g (0.117 mol) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(tetrahydropyran-2-yloxy)propane and 5.85 g (16.7 mmol) of tetrabutylammonium hydrogen sulphate in 250 ml of dichloromethane and 250 ml of 50% aqueous sodium hydroxide is treated at 0° C. dropwise with 14.32 g (0.140 mol) of acetic anhydride, dissolved in 100 ml of dichloromethane, under a nitrogen atmosphere. After addition is complete, the mixture is reacted for an additional 4--hour period at ambient temperature. Following usual extradtive work-up, 42.69 g (93%) of 3-(4-acetoxy-3,5-di-tert-butylphenyl)-l-(tetrahydropyran-2-yloxy)propane is obtained as a brown viscous liquid, which is used for the following deprotection step without further purification. (C24H38O4 ; F.W. 390.6).