Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[Li+].[CH3:14]CC[CH2-].IC>O1CCCC1>[CH3:14][C:3]1[C:4]2[O:5][CH2:6][O:7][C:8]=2[CH:9]=[CH:10][C:2]=1[C:1]([OH:12])=[O:11]
Reactant: [CH2-]CCC
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc2c1OCO2
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a round bottom flask equipped with an overhead stirrer and a nitrogen inlet was added piperonylic acid (50.0 g, 301 mmol) and tetrahydrofuran (753 mL). This was cooled to −75° C. in a dry ice-acetone bath. N-Butyllithium (1.6 M in hexanes) (414 mL, 662 mmol) was added dropwise maintaining the temperature of the reaction at or below −65° C. When the addition was complete the cooling bath was removed and the reaction was allowed to warm to −20° C. The reaction was returned to the bath and cooled to at least −60° C. at which time iodomethane (37.5 mL, 602 mmol) was added dropwise. Cooling was removed and the reaction allowed to warm to 10° C. at which time the reaction was placed in an ice bath and stirred at 0° C. for 30 minutes. The reaction was quenched by addition of 1N HCl and the tetrahydrofuran removed by evaporation. The residue was slurried in 1N HCl and filtered. The filtrate was washed with water, and dried at 50-60° C. in vacuo to give a pale yellow solid, 4-methyl-benzo[1.3]dioxole-5-carboxylic acid (52.8 g, 293 mmol) in 97% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.44 (s, 3H), 6.10 (s, 2H), 6.77 (d, 1H), 7.64 (d, 1H). TLC Rf=0.54 (1:1 ethyl acetate/hexane, piperonylic acid=0.41).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22](O)(=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1>>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:2]2([CH3:1])[CH2:6][C:5]3[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=3[O:3]2)[CH2:17][CH2:18]1)=[O:31]
Reactant: COc1cccc(C(=O)O)c1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Product: COc1cccc(C(=O)N2CCN(CC3(C)Cc4c(C)c(N)c(C)c(C)c4O3)CC2)c1
Yield: 73 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and m-anisic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 73%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH3:26])[C:18]2=[C:27]3[C:32](=[N:33][C:17]=12)[CH:31]=[CH:30][CH:29]=[CH:28]3)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:34][N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH3:26])[C:18]2=[C:27]3[C:32](=[N:33][C:17]=12)[CH:31]=[CH:30][CH:29]=[CH:28]3)[CH2:10][CH2:9][CH2:8][NH2:7]
Reactant: CN(CCCNC(=O)OC(C)(C)C)CCCNc1c2nc3ccccc3c-2n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCCN)CCCNc1c2nc3ccccc3c-2n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
To a solution of [3-[methyl-[3-(5-methyl-5H-indolo[3,2-b]quinolin-11-ylamino)-propyl]amino]propyl)-carbamic acid tert-butyl ester (49 mg, 0.1 mmol) in CH2Cl2 (10 ml), was added trifluoroacetic acid (12_l). This mixture was stirred at room temperature for 16 h, at which point the reaction was completed by TLC. All solvents were removed under reduced pressure to give N1-methyl-N1-[3-(5-methyl-5H-indolo[3,2-b]quinolin-11-ylamino)propyl]propane-1,3-diamine (38 mg, 92%) as an oil, which was used directly. 1H-NMR [MeOD,_, ppm]: 8.52 (d, J=8.5 Hz, 1H), 8.35-7.73 (m, 4H), 7.63-7.60 (m, 2H), 7.31 (m, 1H), 4.45 (s, 3H, NCH3), 3.60 (m, 2H, CH2NO), 3.02 (m, 2H, CH2N(CH3)), 2.92 (s, 3H, N(CH3)), 2.36 (m, 4H, 2CH2CN(CH3)), 2.14 (m, 2H, CH2N(CH3)), 1.90 (m, 2H, CH2CN(CH3)).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:32]([NH2:35])[CH2:33][CH3:34]>O1CCCC1>[CH2:32]([NH:35][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:33][CH3:34]
Reactant: CCCN
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCNC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Temperature: -30 °C

Procedure:
to a solution of 44.64 parts of benzyloxycarbonyl-D-alanine in 276 parts of tetrahydrofuran is added 2.02 parts of N-methylmorpholine. The resulting solution is cooled to about -30° C. and 25.4 parts of isobutyl chloroformate is added with stirring. After stirring for about 5 minutes, 13.0 parts of n-propylamine is added and the mixture stirred for a further 10 minutes. The mixture is cooled overnight and then concentrated under reduced pressure to a syrup. This residue is dissolved in methylene chloride and washed successively with 2 M potassium carbonate, water, twice with 1 M hydrochloric acid and finally, twice with water. After drying over anhydrous magnesium sulfate the solution is concentrated under reduced pressure. The residue is diluted with 180 parts of ethyl ether and cooled to 5° C. The resulting crystals are filtered, washed with ether and dried to give benzyloxycarbonyl-D-alanine n-propylamide, melting at about 116.5°-120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>CN(C)C(=O)C>[C:16]([NH:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:25]([CH:22]4[CH2:24][CH2:23]4)=[O:26])[CH:21]=[CH:20][CH:19]=3)=[N:11][N:10]2[CH:12]=1)(=[O:18])[CH3:17]
Reactant: O=C(Cl)C1CC1
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)C4CC4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 51.2 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (17 mg, 0.06 mmol), cyclopropanecarbonyl chloride (9.5 mg, 0.09 mmol) and N,N-dimethylacetamide (0.5 mL) was stirred at room temperature for 14 hr. The reaction mixture was purified by preparative HPLC to give the title compound (10.8 mg, 51%).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].C1([C:14]([PH3+])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=CC=CC=2)C=CC=CC=1.C1(C([N:37]2[CH:41]=[C:40]([C:42]3[C:43]4[CH:50]=[CH:49][N:48]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:44]=4[N:45]=[CH:46][N:47]=3)[CH:39]=[N:38]2)CC=O)CCCC1>C1COCC1>[CH:26]1([CH:21]([N:37]2[CH:41]=[C:40]([C:42]3[C:43]4[CH:50]=[CH:49][N:48]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:44]=4[N:45]=[CH:46][N:47]=3)[CH:39]=[N:38]2)[CH2:14][CH:15]=[CH2:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)C4CCCC4)c3)ncnc21
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC(C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To a solution of 1.0 M potassium tert-butoxide in THF (0.207 mL) in THF (2.0 mL) at 0° C. was added triphenylmethylphosphonium bromide (77.8 mg, 0.218 mmol). The resulting mixture was warmed to room temperature and allowed to stir for 30 minutes. A solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal (0.100 g, 0.228 mmol) in THF (2.0 mL) was added. After 30 minutes, the mixture was quenched by the addition of saturated ammonium chloride solution and the product was then extracted with ether. The ether extract was dried over sodium sulfate and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient of 0-40% ethyl acetate in hexanes) afforded the product (40 mg, 44%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](=O)(OCC)[O:20]CC.C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH:15]([CH2:16][OH:17])[O:18][C:19]3=[O:20])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCC(O)CNc1ccc(C2CCCCC2)cc1
Reactant: CCOC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1OC(CO)CN1c1ccc(C2CCCCC2)cc1
Reaction time: 8 h
Yield: 52.9 %

Procedure:
2.4 g (9.62 mmol) of (RS)-3-(4-cyclohexyl-phenylamino)-propane-1,2-diol were dissolved in 50 ml of toluene, treated with 1.25 g (10.6 mmol) of diethyl carbonate and 0.4 ml of a 1 molar sodium methylate solution in methanol and stirred overnight at an oil bath temperature of 110°. The solvent was distilled off in a water-jet vacuum and the residue was treated with water and 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and the solvent was distilled off. 1.4 g of product in the form of yellowish crystals were obtained from ethyl acetate/hexane. A further 0.9 g of pure product was obtained from the mother liquor. M.p.: 167°-167.5°.
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[CH:6][C:7](=[O:9])[N:8]=1.[Cl:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=2)=[CH:13][C:12]=1[C:27]([F:30])([F:29])[F:28]>N1C=CC=CC=1>[Cl:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:3]3[NH:4][CH:5]=[CH:6][C:7](=[O:9])[N:8]=3)=[CH:18][CH:17]=2)=[CH:13][C:12]=1[C:27]([F:28])([F:29])[F:30]
Reactant: CSc1nc(=O)cc[nH]1
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: c1ccncc1
Product: O=c1cc[nH]c(NCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)n1
Yield: 77.8 %

Procedure:
2-Methylsulfanyl-1H-pyrimidin-4-one (70 mg, 0.492 mmol, 1.41 eq) and 2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (110 mg, 0.348 mmol, 1 eq) were heated in a sealed vial at 150° C. in 400 μl of dry pyridine for 16 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 10 g normal phase silica SNAP column and DCM/30% MEOH in DCM solvent system (gradient 2-20% of 30% MeOH in DCM in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the resulting crude was triturated with diisopropyl ether and cyclohexane to afford 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-1H-pyrimidin-4-one (111 mg, yield=73.8%, purity=95%) as a white powder. MS: [M+H]+=410.33 1H NMR (300 MHz; CDCl3) δ/ppm 2.92 (t, J=6.95 Hz, 2H), 3.61-3.72 (m, 2H), 5.59 (d, J=6.38 Hz, 1H), 6.18 (br.s, 1H), 6.95 (d, J=8.51 Hz, 2H), 7.03 (dd, J=9.07 Hz, J=2.69 Hz, 1H), 7.24 (d, J=8.51 Hz, 1H), 7.30 (d, J=2.69 Hz, 1H), 7.41 (d, J=8.80 Hz, 1H), 7.77 (d, J=6.38 Hz, 1H), 11.77 (br.s, 1H)
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[C:12]([CH3:21])=[CH:13][C:14]2[O:18][C:17](=[O:19])[CH2:16][C:15]=2[CH:20]=1>CN(C)C=O>[CH2:1]([NH:9][C:17](=[O:19])[CH2:16][C:15]1[CH:20]=[C:11]([OH:10])[C:12]([CH3:21])=[CH:13][C:14]=1[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: Cc1cc2c(cc1O)CC(=O)O2
Solvent: CN(C)C=O
Product: CCCCCCCCNC(=O)Cc1cc(O)c(C)cc1O
Reaction time: 0.25 h

Procedure:
A solution of 7.75 g of n-octylamine dissolved in 15 ml of dimethylformamide is placed in a solution of 10 g of 5-hydroxy-6-methyl-3H-benzofuran-2-one dissolved in 15 ml of dimethylformamide. After 15 minutes at 100° C., the mixture is evaporated to dryness at reduced pressure. It is treated with 100 ml of ethyl acetate, rinsed with water, dried, then evaporated, yielding a white solid which is recrystallized from isopropyl acetate.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)Oc1ccc(N)cc1
Product: CC(=O)Oc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 80.5 %

Procedure:
Using general procedure A, 1-Boc-4-piperidone (2.52 g, 12.66 mmol) and acetic acid 4-amino-phenyl ester (Bargota, Rakesh S.; et al., Bioorg. Med. Chem. Lett., 13, 10, 2003, 1623-1626) (2.95 g, 19.52 mmol) afforded 4-(4-acetoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (3.41 g, 76%).
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:13]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:12]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[O:13])=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CO)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(COC(=O)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a solution of 4-isopropylbenzyl alcohol (4.51 g, 30.02 mmol) in 50 mL toluene was added 1,1′-carbonyldiimidazole (4.87 g, 30.02 mmol). This solution was stirred 18 h at ambient temperature. White precipitate was filtered off and the filtrate was concentrated under reduced pressure. The resultant oil was flash chromatographed with 15% ethyl acetate/hexanes to yield 6.41 g (87%) of imidazole-1-carboxylic acid-(4-isopropyl)benzyl ester, a clear oil.
Reaction SMILES: C([CH2:5][CH2:6][C@@:7](O[SiH](C)C)([N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[CH:10]1)[CH3:8])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.C([O:46]C(C)C)(C)C>O1CCCC1.C(O)C>[OH:46][CH2:5][CH2:6][C@H:7]([N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[CH:10]1)[CH3:8]
Reactant: CC(C)OC(C)C
Reactant: C[SiH](C)O[C@](C)(CCC(C)(C)C)n1cnc(-c2cccnc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](CCO)n1cnc(-c2cccnc2)c1
Reaction time: 0.17 h

Procedure:
To a solution of 3-[1-[(1R)-3-tertbutyldimethylsiloxy-1-methylpropyl]-1H-imidazol-4-yl]-pyridine (30) (1.12 g, 3.24 mmol) in 4 mL tetrahydrofuran was added 4 mL of 1M tetrabutylammonium flouride, and the reaction was stirred for 10 min. Hydrochloric acid in ethanol was added, followed by isopropyl ether. The solids were collected by filtration and recrystallized from acetonitrile to provide 0.51 g of product.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc(C(=O)c3ccccc3)cc2)cc1
Yield: 98 %

Procedure:
Reaction of 4-aminobenzophenone (98 mg, 0.51 mmol) in THF (6 mL) with p-anisoyl chloride (90 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-benzoyl-phenyl)-4-methoxy-benzamide (165 mg, 0.50 mmol, 98% yield) as a white powder after purification by washing the crude product with ethyl acetate and hexane.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.[CH:24](OCCCC)=[O:25]>>[F:23][C:19]1[CH:18]=[C:17]([S:14]([NH:13][C:7]2[CH:6]=[CH:5][C:4]3[CH:3]([CH2:2][NH:1][CH:24]=[O:25])[CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: CCCCOC=O
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Product: O=CNCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21

Procedure:
A solution of 0.28 grams (0.837 mmoles) N-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-fluoro-benzenesulfonamide in 6 mL n-butyl formate was heated under reflux for 1.5 hours. The solution was concentrated under reduced pressure. 3-Fluoro-N-(5-formylaminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide was obtained by recrystallization of the residue from 2-propanol/ethyl ether to provide 0.27 grams (89%) of 3-fluoro-N-(5-formylaminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide, m.p. 143-144° C., M+H=363
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH:6]=1)=[O:4].CO[CH2:20][N:21]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:22][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:27]([N:21]1[CH2:22][C@@:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:9][C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C@H:6]2[CH2:20]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)C1=CC[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@]12C[C@H](NC(=O)OC(C)(C)C)C[C@H]1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step B (5.51 g, 20 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (6.4 mL, 24 mmol, Aldrich) in DCM (40 mL) was added 1M TFA in DCM (2.4 mL, 2.4 mmol) slowly. The resulting mixture was stirred at rt overnight and quenched by the addition of saturated aqueous NaHCO3 solution. The organic phase was washed with brine, dried over Na2SO4. Evaporation and purification by column chromatography (eluent: 10% EtOAc in hexanes to 20%) gave the desired isomer as a colorless gel. 1H-NMR (400 MHz, CDCl3) of the desired isomer: δ 1.38 (s, 9H), 1.66-1.86 (m, 2H), 1.86-1.96 (m, 1H), 1.96-2.08 (m, 1H), 2.29-2.63 (m, 3H), 2.71-2.93 (m, 2H), 3.43-3.56 (m, 2H), 3.58-3.74 (s, 3H), 4.08-4.29 (m, 1H), 4.78 (d, J=6.6 Hz, 1H), 7.11-7.31 (m, 5H). LC/MS: C24H28N2O4: m/z 375.2 (M+H).
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=O)=[CH:16][CH:15]=2)[N:11]=1)(=[O:5])=[O:4])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[NH:37][NH2:38].O>O1CCCC1>[CH2:1]([S:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH:38][NH:37][C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:23])=[CH:18][CH:19]=2)[N:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCS(=O)(=O)Nc1nc(CCc2ccc(CC(=O)O)cc2)cs1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)Nc1nc(CCc2ccc(CC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 42.5 °C
Reaction time: 1 h

Procedure:
To a suspension of [4-(2-{2-[(ethylsulfonyl)amino]-1,3-thiazol-4-yl}ethyl)phenyl]acetic acid (700 mg, 1.98 mmol) in anhydrous tetrahydrofuran (5 ml) was added 1,1′-carbonyldiimidazole (480 mg, 2.96 mmol), and the mixture was stirred at 40-45° C. for 1 hr. After cooling to 0° C., tert-butyl carbazate (914 mg, 6.91 mmol) was added, and the mixture was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The combined organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give tert-butyl 2-{[4-(2-{2-[(ethylsulfonyl)amino]-1,3-thiazol-4-yl}ethyl)phenyl]acetyl}hydrazinecarboxylate (989 mg, quantitatively) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH:34]([CH3:36])[CH3:35])([C:30](OC)=O)[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:27][CH3:28])=[C:21]([O:25][CH3:26])[CH:22]=3)[CH2:17][N:16]2[CH3:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C(C)=CC=CC=1.[Al]([NH2:48])(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH:34]([CH3:35])[CH3:36])([C:30]#[N:48])[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:27][CH3:28])=[C:21]([O:25][CH3:26])[CH:22]=3)[CH2:17][N:16]2[CH3:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C(CCCC1Cc2cc(OC)c(OC)cc2CN1C)(c1ccc(OC)c(OC)c1)C(C)C
Reactant: C[Al](C)N
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: COc1ccc(C(C#N)(CCCC2Cc3cc(OC)c(OC)cc3CN2C)C(C)C)cc1OC

Procedure:
Alternatively, one may convert the ester group of compound 11.1 directly to the cyano group by treatment with 2 equivalents of dimethylaluminum amide (S. Weinreb, et al., Tetrahedron Lett., 4907 (1979), incorporated herein by reference). This reaction is performed in a suitable aprotic hydrocarbon solvent, preferably a high-boiling solvent such as xylene. Two equivalents of Me2AlNH2 in CH2Cl2 is added to a solution of the ester of formula 11.1 in the appropriate solvent and heated at 80°-170° C., preferably in refluxing xylene, for about 30 minutes to about 20 hours. The reaction is followed by TLC. For example, 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-(carbomethoxy)butyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (11.1) is heated in refluxing xylene with Me2AlNH2 for about 15 hours to yield 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31]OS(C)(=O)=O)[C:6]=2[CH:37]=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.[K]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][N:42]3[C:38](=[O:48])[C:39]4=[CH:47][CH:46]=[CH:45][CH:44]=[C:40]4[C:41]3=[O:43])[C:6]=2[CH:37]=1
Reactant: CS(=O)(=O)OCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2CCCC(CCN3C(=O)c4ccccc4C3=O)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Temperature: 110 °C
Reaction time: 3 h
Yield: 103.1 %

Procedure:
To a solution of 7-chloro-5-(2-methanesulfonyloxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.6 g) in dimethylformamide (30 ml) is added potassium phthalimide (0.58 g), and the mixture is stirred at 110° C. for 3 hours. The mixture is poured into ice-water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-phthalimidoethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.8 g) as colorless amorphous.
Reaction SMILES: C(OC(N1C[CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)C1)=O)(C)(C)C.[N:33]1([C:39]([CH3:44])([CH3:43])[C:40]([NH2:42])=[O:41])CCNCC1>>[Cl:31][C:22]1[N:23]=[C:24]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:19]2[S:18][C:17]([CH2:16][N:12]3[CH2:11][CH2:10][N:33]([C:39]([CH3:44])([CH3:43])[C:40]([NH2:42])=[O:41])[CH2:14][CH2:13]3)=[N:32][C:20]=2[N:21]=1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Product: CC(C)(C(N)=O)N1CCN(Cc2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
The title compounds was prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2-piperazin-1-yl-isobutyramide in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as an off-white solid (71 mg, 36%).