Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[CH:17]=[C:16]([OH:23])[N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:31])C(=O)C1>C(O)(=O)C>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[C:17]([Cl:31])=[C:16]([OH:23])[N:15]=2)=[CH:12][CH:13]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(O)cc(C3CC3)n2)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(O)c(Cl)c(C3CC3)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A mixture of N-tert-butyl-5-(4-cyclopropyl-6-hydroxypyrimidin-2-yl)thiophene-2-sulfonamide (353 mg, 1.0 mmol) and NCS (139 mg, 1.05 mmol, 1.0 equiv.) in acetic acid (5 mL) was stirred at rt for 1 h. The reaction was extracted with EA, the organic layer was washed with (brine), dried (Na2SO4) and concentrated to provide N-tert-butyl-5-(5-chloro-4-cyclopropyl-6-hydroxypyrimidin-2-yl)thiophene-2-sulfonamide (341 mg, 88%). LC-MS (m/z)=388.1 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.0 g of 4-hydroxybenzaldehyde are dissolved in 400 ml of abs. THF under a protective-gas atmosphere, 55.1 g of dihydropyran and 13.7 g of pyridinium p-toluenesulfonate are added, and the mixture is stirred overnight at room temperature. The solvent is removed in a rotary evaporator, and the residue is subjected to conventional work-up, giving 4-(tetrahydropyran-2-yloxy)benzaldehyde (“BA”) as a colourless oil.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:18][CH3:19])[C:8]2[C:13]([C:14]#N)=[CH:12][CH:11]=[C:10]([CH2:16][CH3:17])[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.[OH-:30].[Na+]>ClCCl>[CH:1]1([CH2:6][N:7]([CH2:18][CH3:19])[C:8]2[N:9]=[C:10]([CH2:16][CH3:17])[CH:11]=[CH:12][C:13]=2[CH:14]=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(C#N)c(N(CC)CC2CCCC2)n1
Reactant: [OH-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc(C=O)c(N(CC)CC2CCCC2)n1
Reaction time: 4 h
Yield: 48 %

Procedure:
A solution of 2-[(cyclopentylmethyl)(ethyl)amino]-6-ethylpyridine-3-carbonitrile (484 mg, 1.87 mmol) in dichloromethane (5 mL) was added with diisobutylaluminum hydride (0.99 M solution in toluene, 1.99 mL, 1.97 mmol) at −78° C., and the mixture was stirred at the same temperature for 4 hours. The mixture was further added with diisobutylaluminum hydride (0.99 M solution in toluene, 0.2 mL, 0.198 mmol) at the same temperature, and the mixture was stirred at the same temperature for 45 minutes. Then, the mixture was added with 2 M aqueous sodium hydroxide, stirred at room temperature for 30 minutes, and extracted with chloroform. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to obtain 2-[(cyclopentylmethyl)(ethyl)amino]-6-ethylnicotinaldehyde (233 mg, 48%) as yellow oil.
Reaction SMILES: [OH-].[Na+].[CH2:3](Br)[CH2:4][CH2:5][CH3:6].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:25])([CH2:23][SH:24])[CH2:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[ClH:26]>CO.C(OCC)C>[CH2:3]([S:24][CH2:23][C@:16]([C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[Cl:8])([OH:25])[CH2:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)[CH2:4][CH2:5][CH3:6].[ClH:26]
Reactant: O[C@@](CS)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: CCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CCCCSC[C@](O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reaction time: 5 h

Procedure:
To a solution of sodium hydroxide (2 g) in methanol (100 ml) were added n-butylbromide (2 g) and (R)-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-3-mercapto-2-propanol (II) obtained in Example 2 at a temperature of 20°-25° C. in nitrogen atmosphere. The mixture was stirred at 25°-30° C. for 5 hours and then concentrated under reduced pressure. The residue was treated with water (50 ml) and extracted with dichloromethane (50 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to give an oil. The oil was dissolved in diethyl ether (20 ml), and hydrogen chloride gas was introduced thereto. Precipitated crystals were collected by filtration and dried to give (R)-3-(n-butylthio)-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2-propanol (I: n=3) hydrochloride (3.4 g). Yield, 86.8%. M.P., 168°-169° C. [α]D20 -89.7° (c=1, methanol). The optical purity of the product was not less than 99% determined by high performance liquid chromatography.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl>[Pd].C(O)C>[NH:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: C1=C(c2c[nH]c3ncccc23)CCNC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1cnc2[nH]cc(C3CCNCC3)c2c1

Procedure:
Preparation took place by hydrogenation of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine with palladium on carbon in ethanol with the addition of hydrochloric acid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].Cl[CH2:9][C:10]1[CH:44]=[CH:43][C:13]([C:14]([NH:16][C:17]2[C:18]3[CH:31]=[C:30]([C:32]([NH:34][N:35]([CH3:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[S:29][C:19]=3[N:20](C(OC(C)(C)C)=O)[N:21]=2)=[O:15])=[CH:12][CH:11]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][C:17]2[C:18]3[CH:31]=[C:30]([C:32]([NH:34][N:35]([CH3:42])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:33])[S:29][C:19]=3[NH:20][N:21]=2)=[O:15])=[CH:43][CH:44]=1)[CH3:6]
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Reactant: CNCCN(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(C)CCN(C)Cc1ccc(C(=O)Nc2n[nH]c3sc(C(=O)NN(C)c4ccccc4)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide and then 144 μL (1.11 mmol) of N,N,N′-trimethylethylenediamine are added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours and then poured onto ice. It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 4 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 40 mg of 4-{[(2-dimethylaminoethyl)methylamino]methyl}-N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]benzamide are thus obtained in the form of a yellow powder. LC-MS-DAD-ELSD: 506(+)=(M+H)(+).
Reaction SMILES: [CH3:1][C:2]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H][H]>[Rh]>[CH3:1][C:2]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1
Reactant: CCCCCCC1=CC(C)(CCCCCC)Nc2ccccc21
Reactant: [H][H]
Agent: [Rh]
Product: CCCCCCC1CC(C)(CCCCCC)NC2CCCCC12
Reaction time: 2.5 h

Procedure:
Following the procedure given in the preceding example, 65 grams of 2-methyl-2,4-dihexyl-1,2-dihydroquinoline was reacted with hydrogen in the presence of 2 grams of rhodium at 5% by weight on charcoal, at a temperature of 200° C. and a pressure of 1000 psig for 2.5 hours, to yield 2-methyl-2,4-dihexyldecahydroquinoline of 94% purity (as determined by vapor pressure chromotography). The product has a boiling point of 170° C. at 1 mm of Hg and has an NMR spectra consistent with the desired structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]([F:25])([F:24])[CH2:22][NH2:23].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.O>[F:20][C:21]([F:25])([F:24])[CH2:22][NH:23][C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)NCC(F)(F)F
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A mixture of (2S)-2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acid (2.98 g, 11 mmol), 2,2,2-trifluoroethylamine (1.35 g, 10 mmol), EDC (2.87 g, 15 mmol), HOBt (2.03 g, 15 mmol) and NMM (5.05 g, 50 mmol) in 100 mL of CH2Cl2 was stirred overnight. The mixture was poured into water (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and evaporated to give the residue. The residue was purified by silica chromatography to give tert-butyl (S)-1-(2,2,2-trifluoroethylcarbamoyl)-2-cyclohexylethylcarbamate (2.8 g, 80%). 1H NMR (CDCl3, 400 MHZ) δ 0.90 (m, 2 H), 1.25 (m, 4 H), 1.44 (s, 9 H), 1.68 (m, 7 H), 3.89 (m, 1 H), 4.16 (brs, 1 H), 4.82 (brs, 1 H), 6.78 (brs, 1 H).
Reaction SMILES: Cl[C:2]1[C:3]([Cl:26])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:27][N:28](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CCOC(C)=O>[Cl:26][C:3]1[C:2]([C:27]#[N:28])=[CH:7][N:6]=[C:5]2[NH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)=[N:10][C:4]=12
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Temperature: 120 °C
Yield: 24 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.063 g, 0.16 mmol), Zn(CN)2 (0.018 g, 0.153 mmol), Pd2(dba)3 (0.036 g, 0.039 mmol) and dppf (0.036 g, 0.065 mmol) were mixed in a vial. DMF (6 ml) was added and the reaction mixture was heated to 120° C. under argon for 3 h. EtOAc (50 ml) was added and the solution was washed with water. Drying (Na2SO4) and evaporation delivered crude material which was purified by HPLC-C18, giving the title product (0.015 g, 24%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][C:25]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:25]=3[Br:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: Cc1cccc(C(=O)O)c1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2ccc(NC(=O)c3cccc(C)c3Br)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg) with 2-bromo-3-methylbenzoic acid (19 mg) under the agency of HATU (68 mg) and N,N-diisopropylethylamine (32 l) in dichloromethane (4 ml) was performed according to the method described in example 11.
Reaction SMILES: ClS([N:5]=C=O)(=O)=O.[C@@H:8]1([C:14]([O:16][CH3:17])=[O:15])[CH2:10][C@@H:9]1[C:11](O)=O.CN(C=O)C.O>C1C=CC=CC=1>[C:11]([C@H:9]1[CH2:10][C@H:8]1[C:14]([O:16][CH3:17])=[O:15])#[N:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H]1C(=O)O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H]1C#N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
In 25 ml of benzene was dissolved 13.77 g (97 mmol) of chlorosulfonyl isocyanate, and to the solution was added 12.7 g (88 mmol) of cis-methyl hydrogen cyclopropane-1,2-dicarboxylate which had been synthesized by the process of Journal of Organic Chemistry, Vol. 36, pp. 3356-3361 (1971). The mixture was stirred on an oil bath at 60° C. for 30 minutes. After cooling, 13.6 ml (176 mmol) of DMF was added thereto, followed by stirring for 30 minutes. Water was added thereto, and the reaction mixture was extracted with benzene. The organic layer was washed successively with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was distilled under reduced pressure to obtain 6.14 g (55.7%) of methyl cis-2-cyanocyclopropanecarboxylate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:13][CH:12]([OH:14])[CH2:11][CH:10]1[CH:15]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:16][CH:17]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:8].N1C=CC=CC=1.O=C1CCC(=O)N1[O:53][C:54](=O)[O:55][CH:56]1[CH2:72][CH:71]2[C:59]([CH3:99])([CH:60]3[CH:68]([CH2:69][CH2:70]2)[CH:67]2[C:63]([CH3:98])([CH:64]([CH:73]([CH3:97])[CH2:74][CH2:75][C:76](=[O:96])[NH:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH3:95])[CH2:65][CH2:66]2)[CH2:62][CH2:61]3)[CH2:58][CH2:57]1.CCOC(C)=O>ClCCl>[CH3:99][C:59]12[CH2:58][CH2:57][CH:56]([O:55][C:54](=[O:53])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]3[CH2:13][CH:12]([OH:14])[CH2:11][CH:10]3[CH:15]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:16][CH:17]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:8])[CH2:72][CH:71]1[CH2:70][CH2:69][CH:68]1[CH:60]2[CH2:61][CH2:62][C:63]2([CH3:98])[CH:67]1[CH2:66][CH2:65][CH:64]2[CH:73]([CH3:97])[CH2:74][CH2:75][C:76](=[O:96])[NH:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH3:95]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(OC(=O)ON5C(=O)CCC5=O)CCC4(C)C3CCC12C
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(OC(=O)NCCCCCC(=O)N5CC(O)CC5C(OC(c5ccc(OC)cc5)c5ccc(OC)cc5)c5ccccc5)CCC4(C)C3CCC12C
Temperature: 0 °C

Procedure:
Amine 5 (4.22 g, 7.9 mmol) is dissolved in anhydrous dichloromethane (25 mL) and cooled to 0° C. To the solution are added pyridine (10 mL) and compound 89 (9.3 g, 7.9 mmol) successively. The reaction temperature was brought to ambient temperature and stirred further. The completion of the reaction is ascertained by TLC (EtOAc). The reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water followed by brine. The organic layer is dried over sodium sulfate, filtered and concentrated under vacuum to afford the crude product. Compound 90 is obtained as a white solid after column chromatography over silica gel.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CON(C)[C:8]([C:10]1[S:14][C:13]2[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[CH:18][C:12]=2[CH:11]=1)=[O:9]>O1CCCC1>[CH3:20][O:19][C:15]1[C:13]2[S:14][C:10]([C:8](=[O:9])[CH2:1][CH3:2])=[CH:11][C:12]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CC[Mg]Br
Reactant: COc1cccc2cc(C(=O)N(C)OC)sc12
Solvent: C1CCOC1
Product: CCC(=O)c1cc2cccc(OC)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethylmagnesium bromide (1M solution in tetrahydrofuran; 6.4 ml) was added to a solution of N,7-dimethoxy-N-methylbenzo[b]thiophene-2-carboxamide (1.5 g) in tetrahydrofuran, then the mixture was stirred at ambient temperature for 1 hour and at reflux temperature for 1 hour. Further ethylmagnesium bromide (1M solution in tetrahydrofuran; 6.4 ml) was added, the mixture was stirred at ambient temperature for 1 hour and at reflux temperature for 2.5 hour, then it was cooled to ambient temperature and quenched by the addition of 5M hydrochloric acid (10 ml) and water (150 ml). The product was extracted into dichloromethane (3×60 ml), then the combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using dichloromethane followed by a 99:1 mixture of dichloromethane and methanol as eluants. Appropriate fractions were combined, and the solvents were removed in vacuo to give 1-(7-methoxybenzo[b]thiophen-2-yl)propan-1-one (0.7 g) as an oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]([C:10](=O)[CH2:11][CH2:12][C:13]([C:15]2[NH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:19]=2)=O)=[CH:7][CH:6]=1)=[O:4].C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]([C:10]2[S:41][C:13]([C:15]3[NH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:19]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc(C(=O)OC)[nH]2)[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(-c3ccc(C(=O)OC)[nH]3)s2)[nH]1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A mixture of compound 4 (1.73 g, 5.2 mmol), dry toluene (75 mL), and Lawesson's reagent (1.50 g, 3.7 mmol) was refluxed under an argon atmosphere for 12 hours. The solution was cooled to room temperature and concentrated to one-third its original volume in vacuo. Methanol was added slowly to the toluene until a precipitate appeared. Column chromatography was performed using pure CH2Cl2 (silica gel; 230-400 mesh) as the initial eluant to remove impurities. Conversion to a 50:50 hexanes:EtOAc eluant system yielded 0.86 g (2.6 mmol, 50%) of a yellow solid. 1H-NMR (CDCl3): δ 7.70 (s, 1H), 6.96 (dd, 1H), 6.52 (dd, 1H), 3.93 (s, 3H). 13C-NMR: δ 161.8, 134.0, 132.4, 125.7, 124.0, 117.8, 109.2, 52.2.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C@@H:13]([CH2:18][OH:19])[CH2:14][CH:15]([CH3:17])[CH3:16].O>C1COCC1>[OH:19][CH2:18][C@H:13]([N:12]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)C[C@@H](N)CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](CO)N1C(=O)c2ccccc2C1=O
Temperature: 85 °C
Yield: 47.1 %

Procedure:
Phthalic anhydride (10.30 g, 69.55 mmol) and D-Leucinol (8.15 g, 69.55 mmol) were mixed in THF (100 mL), the reaction mixture was heated at 85° C. and refluxed for 18 hours. After cooling to room temperature, water was added and the solution was extracted with EtOAC, the extracts were washed with 1 N HCl, water, aq. NaHCO3, water and brine, dried over MgSO4, filtered and evaporated to give 8.1 g of (R)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (47%). 1H NMR (500 MHz, CDCl3): δ 0.94 (m, 6H); 1.54 (m, 2H); 1.99 (m, 1H); 3.86 (m, 1H); 4.04 (m, 1H); 4.47 (m, 1H); 7.72 (m, 2H); 7.83 (m, 2H).
Reaction SMILES: O=[C:2]1[C:14]2[C:13]3[C:12]([C:15]([O:17]C)=O)=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(O)(=O)C.O.[NH2:24][NH2:25]>CO>[CH2:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]4[C:15](=[O:17])[NH:24][N:25]=[C:2]([C:14]=2[C:13]=34)[CH2:3][CH2:4]1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: NN
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C1NN=C2CCCc3[nH]c4cccc1c4c32
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A solution of compound methyl 4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate (73 mg, 0.3 mmol), acetic acid (0.15 mL, 2.6 mmol), and hydrazine hydrate (0.86 mL, 1.5 mmol) in methanol (4 mL) was heated at reflux. After 8 h, the solid was collected by hot filtration and washed with water, EtOAc, and dichloromethane, to give the target compound (42 mg, 62%). 1H NMR (DMSO-d6) δ 11.70 (s, 1H), 9.79 (s, 1H), 7.36-7.38 (m, 2H), 7.05 (t, 1H, J=7.8 Hz), 2.77-2.79 (m, 2H), 2.35-2.37 (m, 2H), and 1.92-1.93 (m, 2H). MS (ESI) m/e [M+1]+ 226.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[CH3:39][NH:40][CH2:41][CH2:42][OH:43]>>[OH:43][CH2:42][CH2:41][N:40]([CH3:39])[CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: CNCCO
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN(C)CCO)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 2-methylaminoethanol were converted to the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17](/[CH:21]=[CH:22]/[CH2:23][OH:24])[CH:18]=[CH:19][CH:20]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH:21]=[CH:22][CH:23]=[O:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(/C=C/CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(C=CC=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
Activated manganese dioxide (25.0 g) was added to a solution of (E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-phenyl]-2-propenol (11.0 g) in dichloromethane (200 ml), and the mixture was stirred at room temperature for 2 hours. The insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure to give 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamaldehyde (10.5 g, 96%). This product was recrystallized from ethyl acetate-hexane. Colorless columns, mp: 103-104° C.