Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>N1C=CC=CC=1>[C:11]([C:10]1[C:4]2[S:3][C:2]([NH:1][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[O:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=2)[CH:17]=[CH:18][CH:19]=1)#[N:12]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3C#N)c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
To a solution of N-{3-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.33 mmol) in pyridine (2 mL) was added cyclopropanecarbonyl chloride (59 μL, 0.66 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was suspended in ethyl acetate (50 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), successively, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (119 mg, 69%) as a white powder.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[C:3]([O:5]C)=[O:4].C(=O)([O-])[O-:18].[Na+].[Na+].Cl.[Cl-].[Na+]>O>[OH:18][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)CCCCCCC(Br)C(=O)OC
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCCCCC(O)C(=O)O

Procedure:
A stirred mixture of 295 g. of dimethyl 2bromononanedioate, [Acta. Chim. Acad. Sci. Hung., 46, 85 (1965)], 371 g. of anhydrous sodium carbonate, and 3 liters of water is heated at reflux for 22 hours. The solution which forms is cooled and acidified with 600 ml. of 12 N hydrochloric acid. The mixture is saturated with sodium chloride and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give 184 g. of white solid, m.p. 86°-92° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[C:5]([NH:13]C(=O)C(F)(F)F)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[N:35][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>CCOC(C)=O.O.ClCCl.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:13][C:5]1[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)=[CH:7][C:2]([C:31]2[CH:32]=[N:33][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[N:35][CH:36]=2)=[CH:3][C:4]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(C)(O)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1c(C2CCCO2)cc(Br)cc1[N+](=O)[O-])C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)c1ncc(-c2cc(C3CCCO3)c(N)c([N+](=O)[O-])c2)cn1

Procedure:
N-(4-Bromo-2-nitro-6-tetrahydrofuran-2-yl-phenyl)-2,2,2-trifluoro-acetamide (6) (19.00 g, 49.59 mmol), 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (7) (14.41 g, 54.55 mmol), aqueous 2.7 M sodium carbonate (73.48 mL, 198.4 mmol), and 1,4-dioxane (190 mL, Sigma-Aldrich 360481) were mixed. A stream of nitrogen was bubbled through the stirring mixture for 40 minutes, followed by addition of 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium dichloromethane adduct (2.025 g, 2.480 mmol, Strem 460450). The reaction mixture was stirred at reflux under N2 for 7 hrs, added another 50 mL of saturated aqueous sodium carbonate, and refluxed for another 16 hrs. The reaction mixture was allowed to cool, then diluted with EtOAc (500 mL) and water (200 mL). The layers were separated and the aqueous phase extracted with EtOAc (200 mL). The combined organic phase was washed with water (500 mL), brine (500 mL), dried over Na2SO4, filtered through a Florisil® plug, and concentrated on a rotary evaporator to give crude (8) as an orange oil. Purified by ISCO silica gel chromatography eluting with 20-90% EtOAc/hexane to give (8) as an orange solid (15.00 g, 81-88% purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 345.35 (2.68 min). 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 2H), 8.36 (d, J=2.2 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.09 (s, 2H), 4.92 (t, J=7.2 Hz, 1H), 4.62 (s, 1H), 4.20-4.11 (m, 1H), 4.03-3.94 (m, 1H), 2.39-2.26 (m, 1H), 2.23-2.08 (m, 3H), 1.64 (s, 6H) ppm.
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:25]=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[C:11]([CH2:36][CH2:37][CH2:38][CH3:39])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:36]([C:11]1[CH:10]=[C:9]([OH:8])[CH:35]=[CH:34][C:12]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:23]=[C:24]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:25]=[CH:26][CH:27]=2)[O:19][C:20]=1[CH3:21])[CH2:37][CH2:38][CH3:39]
Reactant: [H][H]
Reactant: CCCCc1cc(OCc2ccccc2)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Agent: [Pd]
Solvent: CCO
Product: CCCCc1cc(O)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C

Procedure:
A solution of 4-[2-(4-benzyloxy-2-butylphenoxy)ethyl]-5-methyl-2-biphenyl-3-yl-oxazole (3.16 mmol) in ethanol (100 mL) was treated with 5% Pd/C (160 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give 3-butyl-4-[2-(5-methyl-2-biphenyl-3-yl-oxazole-4-yl)ethoxy]phenol as a tan solid.
Reaction SMILES: C[C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.C(N)(CC)C>>[NH2:20][C:8]([NH:4][CH:5]([CH2:6][CH3:2])[CH3:7])=[N:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Agent: CCC(C)N
Agent: CS(=O)(=O)O
Product: CCC(C)NC(N)=NS(=O)(=O)c1ccc(C)cc1

Procedure:
The compound of Example 15 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of s-butylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 269.36; found mol. wt. (M+H) 270.2; 539.1 (Dimer)
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[OH:21][C@H:22]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]([N:28]2[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C@H:22]([OH:21])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:30][CH2:29]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2c(Cl)nc(Cl)nc2c1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3)nc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 183 %

Procedure:
To a solution of 2,4-dichloro-7-methylquinazoline (2.09 g, 9.83 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (2.74 mL, 19.66 mmol), followed by the addition of (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one (1.97 g, 9.83 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then quenched with water and extracted twice with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated to obtain (R)-1-(4-(2-chloro-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one (6.78 g, 95%). LC/MS: m/z 377.5 (M+H)+ at 2.61 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:12]([C@H:13]1[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]1)=[O:11]
Reactant: COC(=O)[C@H]1CC[C@H](CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C=O)CC1
Reaction time: 1 h

Procedure:
To a solution of oxalyl chloride (4.48 mL) in methylene chloride (50 mL) is added dropwise dimethylsulfoxide (4.55 g) in methylene chloride (5 mL) at −60° C. over a period of 15 minutes. To the mixture is added dropwise a solution of methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate (compound obtained in Reference Example 238; 5.9 g) in methylene chloride (30 mL) over a period of 30 minutes. The mixture is stirred at the same temperature for 1 hour and thereto is added dropwise triethylamine (16.7 mL) at −60° C. The mixture is stirred at the same temperature for 30 minutes and at 0° C. for 1 hour. The reaction mixture is diluted with chloroform, and washed successively with water, 5% citric acid solution, water, and saturated brine. The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give methyl trans-4-formylcyclohexanecarboxylate (5.32 g, yield; 91%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCOc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.3 %

Procedure:
To a solution of [2-(4-bromophenoxy)ethanol (10.0 g, 46 mmol) in 150 mL dry dimethylformamide (30 mL) was added t-butyldimethylsilyl chloride (8.34 g, 55 mmol) and imidazole (7.82 g, 115 mmol). Additional dimethylformamide (20 mL) was used to wash these materials into the reaction flask. The resulting solution was stirred overnight at rt with a Newman tube. It was poured onto water (200 mL) and extracted with ether (3×75 mL). The combined extracts were washed with 0.5N HCl (200 mL), sat. NaHCO3 (200 mL), water (4∴150 mL), and sat. NaCl (200 mL), dried over MgSO4, and filtered. The solvent was removed under reduced pressure on a rotary evaporator to give the crude product (16.5 g; >100%). 1H NMR (CDCl3) δ7.34 (2H, d, J=8.9), 6.78 (2H, d, J=8.9), 4.00-3.93 (4H, m), 0.89 (9H, s), 0.08 (6H, s). 13C NMR (CDCl3) δ158.1, 132.2, 116.4, 112.8, 69.6, 61.9, 25.9, 18.4. FDMS (m/e) 330 (M+, 79Br). It was used as 100% without purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]4[O:33][N:32]=[C:31]([CH3:34])[CH:30]=4)[CH:24]=3)[CH2:20][C:19](=[O:35])[NH:18][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)ccn2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)ccn2)on1

Procedure:
The title compound was prepared from (4-chloro-5-dimethylamino-2-{3-[2-(3-methyl-isoxazol-5-yl)-pyridin-4-yl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example M10) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (111 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O1C=CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C=C.C([C:30]1([N:37]([CH3:39])[CH3:38])[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1)#N.[Cl-].[NH4+].Cl.N>O1CCCC1.C(OCC)C.C(Cl)(Cl)Cl.CO.C1C=CC=CC=1>[OH:8][C:4]1[CH:3]=[C:2]([C:30]2([N:37]([CH3:39])[CH3:38])[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C1(C#N)CCC(=O)CC1
Reactant: Oc1cccc(Br)c1
Agent: C1=COCCC1
Agent: C=C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN(C)C1(c2cccc(O)c2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A reaction solution consisting of 5.0 gm. (0.029 mole) m-bromophenol, 5.0 gm. dihydropyran, 0.30 gm. p-toluenesulfonic acid, and 80 ml. anhydrous diethyl ether is stirred at 25° C. for four (4) hours. The mixture is washed successively with 25 ml. portions of 1 N aqueous sodium hydroxide, with water, and with brine. The thus washed organic layer is taken to dryness by removing the solvent by evaporation under reduced pressure. There is thus obtained 7.42 gm. of m-(tetrahydropyranyl-2-oxy)bromobenzene which is converted to the corresponding Grignard reagent by dissolving in 60 ml of tetrahydrofuran and adding the solution to 0.70 magnesium. To this Grignard is added 1.50 gm. (0.0071 mole) of 4-cyano-4-dimethylaminocyclohexanone ethylene metal (prepared in Example 41, Part B, above) dissolved in 30 ml tetrahydrofuran. This reaction mixture is heated at the reflux temperature for 22 hours. After cooling, the mixture is treated with 10 ml. saturated ammonium chloride is benzene. The organic solvent portion is initially washed with water and then with brine. The organic solvent is then removed by evaporation under reduced pressure. The residue thus obtained is dissolved in diethyl ether and treated with 4 N ethereal hydrogen chloride until precipitation of the hydrochloride salt is complete. The salt is collected on a filter and then suspended in 25 ml. water containing 1 ml. 2.5 N hydrochloric acid. The acidified mixture is stirred at 25° C. for one hour, when sodium bicarbonate (solid) is added until the pH is 8. This slightly basic mixture is extracted thoroughly with diethyl ether. The ether extracts are combined and the ether removed by evaporation under reduced pressure. The residue thus obtained is transferred to a column of the grade silica gel 1" is cross section by 48" is length. The chromatogram is developed with a solvent medium consisting of 0.5% ammonia and 7.6% methanol in chloroform, and 20-ml. fractions are collected. Those fractions which contain product (as determined by tlc analysis) are combined. The solvent is removed by evaporation under reduced pressure to give 0.96 gm. (44% yield) of crude 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone, ethylene ketal having a melting point at 169° to 175° C. An analytical sample is obtained by recrystallization from a mixture of ethyl acetate and cyclohexane. The melting point is 175° to 177° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:40]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:40])=[O:31])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Yield: 88.2 %

Procedure:
A solution of (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.20 g, 0.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.8 mmol) and 1-hydroxybenzotriazole ammonium salt (0.12 g, 0.8 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-n-hexane to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.18 g, 90.0%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)c(-c2ccc(F)cc2Cl)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(O)cc2)c(-c2ccc(F)cc2Cl)s1

Procedure:
The compound obtained in stage 16D) is added to 100 ml of CH2Cl2, cooling is carried out to −50° C. and 40 ml of a 1M solution of BBr3 in CH2Cl2 are added. The temperature is allowed to return to 20° C. and then 20 ml of methanol are added. The mixture is concentrated to dryness and the residue is taken up in CH2Cl2, washed with water, MgSO4 and concentrated to dryness. After purifying by chromatography on silica (heptane up to heptane/AcOEt 75/25), 4.8 g of the expected compound are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C([Sn](CCCC)(CCCC)[C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(O)=O.[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:16])=[O:15]
Reactant: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCOCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: NC(=O)c1[nH]c2ccc(-c3ccco3)cc2c1S(=O)(=O)N1CCOCC1
Temperature: 90 °C

Procedure:
5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (50 mg, 0.13 mmol, 1.0 equiv), 2-(tributylstannyl)furan (48 μL, 0.15 mmol, 1.2 equiv), tri-o-tolylphosphine (7.8 mg, 0.03 mmol, 0.2 equiv) and palladium(II)acetate (2.9 mg, 0.015 mmol, 0.1 equiv) were dissolved in 5 mL of dry DMF and heated to 90° C. for 1 hour. The mixture was cooled to ambient temperature, poured into aqueous saturated NaHCO3 and the aqueous layer was extracted 3 times with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography through silica gel (0-5% MeOH with 10% NH4OH/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 376.1 [M+H]+.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCC[CH2:2]1.[CH3:16][C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1.C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[CH3:16][C:17]1[S:21][C:20]([C:22]([O:24][CH2:1][CH3:2])=[O:23])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(C)s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 15.9 g (77.4 mmol) of 1,3-dicyclohexylcarbodiimide in 40 mL dichloromethane was added 10 g (70.3 mmol) of 5-methyl-2-thiophenecarboxylic acid and 4.85 g (105.5 mmol) of anhydrous ethanol. 0.86 g of dimethylaminopyridine was then added and the suspension stirred at room temperature for 20 hours. The resulting white precipitate was removed by filtration. The filtrate was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by bulb-to-bulb distillation (bp=95° C., 3 mm Hg) to give the title compound as a clear, pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH3:11])=[CH:6][CH:5]=1)([O-])=O.S1C=CC=C1.N.[H][H]>CO.[Pt]>[N:12]1([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH3:11])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CC(c1ccc([N+](=O)[O-])cc1)n1ccnc1
Reactant: [H][H]
Agent: [Pt]
Agent: N
Solvent: c1ccsc1
Solvent: CO
Product: CC(c1ccc(N)cc1)n1ccnc1
Yield: 91.3 %

Procedure:
(a-3) A mixture of 34.4 parts of 1-[1-(4-nitrophenyl)ethyl]-1H-imidazole, 2 parts of a solution of thiophene in methanol 4%, 200 parts of methanol and 200 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with 4 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The oily residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane (2:1 by volume). The product was filtered off and dried, yielding 27 parts (91.3%) of 4-[1-(1H-imidazol-1-yl)ethyl]benzenamine; mp. 130° C. (int. 114).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-])=O.CN(C=O)C>[Pd].C(O)C>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1
Reactant: O=C1NCCOc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ccc2c(c1)OCCNC2=O
Yield: 35.1 %

Procedure:
A solution of 8-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.23 g, 0.00096 mol), 10% palladium on carbon (0.02 g), DMF (10 mL), and ethanol (30 mL) was hydrogenated for 3 days. Filtration and evaporation gave an oil which was chromatographed on Al2O3 to give 8-amino-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.06 g, 35%) as a tan solid. MP: 151-2° C.; 1H-NMR (DMSO-d6) δ 7.77 (s, 1H), 7.54-6 (d, 1H), 6.25-7 (d, 1H), 6.05 (s, 1H), 5.63 (s, 2H), 4.17-9 (m, 2H), 3.25-8 (m, 2H); LC/MS (ESI+): 179 (M+H).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: C1CCNCC1
Product: CCC(CC)N1CCN(C(=O)c2ccc(CN3CCCCC3)cc2)CC1

Procedure:
Prepared from the product of Example 12 and piperidine.