Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:9]2([CH3:19])[CH2:14][CH2:13][S:12][C:11]([NH:15][C:16](=[O:18])[CH3:17])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[C:26]([Sn](CCCC)(CCCC)CCCC)=[N:25][CH:24]=[CH:23][N:22]=1.[Cl-].[Li+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C@:9]2([CH3:19])[CH2:14][CH2:13][S:12][C:11]([NH:15][C:16](=[O:18])[CH3:17])=[N:10]2)=[CH:3][C:2]=1[C:26]1[C:21]([F:20])=[N:22][CH:23]=[CH:24][N:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccnc1F
Reactant: CC(=O)NC1=N[C@](C)(c2ccc(F)c(Br)c2)CCS1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CC(=O)NC1=N[C@](C)(c2ccc(F)c(-c3nccnc3F)c2)CCS1
Reaction time: 3 h
Yield: 31 %

Procedure:
To solution of (S)-N-(4-(3-bromo-4-fluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-yl)acetamide (500 mg, 1.5 mmoles, 1 equiv), 2-fluoro-3-(tributylstannyl)pyrazine (1.7 g, 4.3 mmoles, 3.0 equiv) in toluene (15 mL) is added bis(triphenylphosphine)palladium(II) chloride (51 mg, 72 μmoles, 0.05 equiv) and lithium chloride (92 mg, 2.2 mmoles, 1.5 equiv). The reaction is irradiated in a laboratory-grade microwave to a temperature of 130° C. and held for 3 h. The solvent is removed under reduced pressure and the residue is purified by silica gel chromatography eluting with a linear gradient of hexane to hexane:ethyl acetate (1:1) ramp 20 min to give the title compound (31% yield): MS (m/z): 363 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(CC)CC>C1(C)C=CC=CC=1>[CH:12]([N:13]1[CH2:16][CH:15]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14]1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 41.3 %

Procedure:
Methane sulphonyl chloride (0.5 mL, 6.43 mmol) was added to a solution of 1-(diphenylmethyl)-3-hydroxyazetidine (1.38 g, 5.77 mmol) and Et3N (0.9 mL, 6.46 mmol) in toluene (10 mL) at 0° C. The reaction mixture was stirred and warmed to room temperature overnight. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL). The organic layer was dried over MgSO4 and concentrated to give pale yellow oil (756 mg, 41%) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH3:19])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[C:29](ON1C(=O)C2C=CC=CC=2N=N1)(=[O:33])[CH:30]([CH3:32])[CH3:31].C(O)(=O)C(C)C>>[F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([CH:12]=[C:13]([CH2:16][N:17]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[O:18][CH3:19])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CC(C)C(=O)On1nnc2ccccc2c1=O
Solvent: CC(C)C(=O)O
Product: CON(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)C(=O)C(C)C
Yield: 77 %

Procedure:
The title compound was prepared by a procedure similar to that in Example 41. Namely, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-benzamide obtained in Example 15 was reacted with 4-oxo-4H-benzo[d][1,2,3]triazin-3-yl isobutyrate prepared from isobutyric acid to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isobutyryl-methoxy-amino)-methyl]-benzamide (88.9 mg, 77%).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][CH:12]([NH:20][C:21](=[O:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57]([NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][C:67]([OH:69])=[O:68])=[O:58].CCN(C(C)C)C(C)C>C(O)C>[C:43]([O:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21](=[O:47])[NH:20][C@H:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:9](=[O:8])[NH:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57](=[O:58])[NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][C:67]([OH:69])=[O:68])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Reactant: NCCOCCOCC(=O)NCCOCCOCC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2-(19-tert-Butoxycarbonylnonadecanoylamino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl) ester (2.50 g) and [2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetic acid (alternative name: H-OEG-OEG-OH)(1.47 g) in ethanol (40 ml) was added DIPEA (1.26 ml). The mixture was stirred at room temperature overnight and then concentrated in vacuo. To the residue was added aqueous 0.1 N HCl (150 ml) and ethyl acetate (200 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with water and brine, dried (magnesium sulphate) and concentrated in vacuo to give an oil, which crystallised on standing. Yield 96% (3.1 g). LCMS: Theoretical mass: 874.2. Found: 874.49.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:7]2.[H-].[Na+].I[CH2:36][CH3:37]>CN(C)C=O>[CH2:36]([N:20]([C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[CH:26]=1)[C:4]1[C:3]2[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=2[F:1])[N:7]=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:5]=1[CH3:19])[CH3:37]
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1cncc(N2CCOCC2)c1)c1c(C)c(-c2ccccn2)nc2cc(F)cc(F)c12
Reaction time: 2 h

Procedure:
To a stirred solution of 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(pyridin-2-yl)quinolin-4-amine (0.06 g, 0.14 mmol) in N,N-dimethylformamide (1.4 mL) was added sodium hydride (0.011 g, 0.28 mmol) followed by iodoethane (0.043 g, 0.28 mmol). Stirring continued at 60° C. for 2 h. After which the reaction was quenched with water (25 mL). The mixture was extracted with EtOAc (2×10 mL) and DCM (1×10 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% EtOAc in hexane) to give the desired product N-ethyl-5,7-difluoro-3-methyl-N-(5-(4-morpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (1H, d, J=4.7 Hz), 7.83-7.96 (2H, m), 7.74 (2H, m), 7.34-7.50 (2H, m), 7.26 (1H, br. s), 6.93-7.04 (1H, m), 6.31 (1H, br s), 3.77-3.94 (5H, m), 3.70 (1H, m), 3.10 (4H, br. s), 2.33-2.40 (3H, s), 1.29 (3H, t, J=7.2 Hz). Mass Spectrum (ESI) m/e=462.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[CH3:26][N:27]([CH3:32])[S:28](Cl)(=[O:30])=[O:29]>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9](=[O:10])[NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][S:28]([N:27]([CH3:32])[CH3:26])(=[O:30])=[O:29])[N:4]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: CN(C)S(=O)(=O)Cl
Product: Cc1ccc(NC(=O)Nc2nc(CNS(=O)(=O)N(C)C)cs2)c(C(=O)C2CCCC2)c1
Yield: 89.3 %

Procedure:
N-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl)-N′,N′-dimethylsulfamide (104 mg, 89%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and dimethylsulfamoyl chloride (0.06 mL, 0.5 mmol) following the general procedure T.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6](/[C:19](/[C:27]2[NH:32][C:31](=[O:33])[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16].O>CO.[Cl-].[Na+].O>[Cl:3][C:4]1[CH:5]=[C:6](/[C:19](/[C:27]2[NH:32][C:31](=[O:33])[C:30]([C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][CH3:16])[CH2:17][CH3:18]
Reactant: CCN(CC)CCCOc1ccc(/C(=C\[C@H]2CCC(=O)C2)c2ccc(C(F)(F)F)c(=O)[nH]2)cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CC)CCCOc1ccc(/C(=C\[C@H]2CCC(O)C2)c2ccc(C(F)(F)F)c(=O)[nH]2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
Sodium borohydride (4.4 mg) was added to a solution of 6-{(E)-1-{3-chloro-4-[3-(diethylamino)propoxy]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-one obtained in Example 1-83 (30 mg) in methanol (0.15 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water and brine were added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether to give the title compound (10 mg, 34%) as a pale yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:45]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>CN(C)C=O>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([C:51]([CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:52])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1ccc(N(Cc2cnn(C(=O)C3CCCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) in dimethylformamide (5 mL) were added triethylamine (0.23 mL) and cyclohexanecarbonyl chloride (0.22 mL), and the mixture was stirred at room temperature for one day. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 5-benzyloxy-N-{[1-(cyclohexylcarbonyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g). By the reaction and treatment of this compound in the same manner as in Example 139, N-{[1-(cyclohexanecarbonyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.23 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:13]P(=O)(OCC)OCC.[H-].[Na+].[CH3:24][O:25][CH2:26][O:27][C:28]1[C:32]([CH:33]=O)=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1.O>O1CCCC1>[CH3:24][O:25][CH2:26][O:27][C:28]1[C:32](/[CH:33]=[CH:13]/[C:3]2[N:4]=[C:5]([N:7]3[CH2:8][CH2:9][O:10][CH2:11][CH2:12]3)[S:6][C:2]=2[CH3:1])=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1
Reactant: CCOP(=O)(Cc1nc(N2CCOCC2)sc1C)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1nc(N2CCOCC2)sc1C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a solution of diethyl {[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}phosphonate (1.56 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 0.22 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.14 g) was added to the reaction mixture, and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5, v/v) to give 4-(4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazol-2-yl)morpholine as pale-yellow crystals (1.05 g, yield 54%). melting point: 162-164° C.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1C=CC(S(O)(=O)=O)=CC=1.[C:17]1([C:23]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:6]([O:30][C:29]([C:23]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1)=[O:31])[CH3:7]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)C1(c2ccccc2)CCNCC1

Procedure:
To a stirred solution of H2SO4 (1.62 g, 16.56 mmol) in EtOH (200 mL), 4-phenyl-4-piperidinecarboxylic acid 4-methylbenzenesulfonate (25 g, 66.23 mmol) was added and the mixture was stirred and refluxed for 12 h. Excess ethanol was evaporated at reduced pressure and the residue was poured into a mixture of ice and 6N NaOH. The pH was adjusted to 10-11 by adding more 6N NaOH and extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 extracts were dried (MgSO4) and the solvent evaporated to leave the desired product as a colorless viscous oil, the 1H-NMR showed it to be pure (14.68 g, 95%) and was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2.[Cl-].C[Al+]C.[CH3:23][CH:24]1[CH2:29][C:28](=[O:30])[O:27][C:26](=[O:31])[CH2:25]1>C(Cl)Cl.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:5]2[C:28](=[O:30])[CH2:29][CH:24]([CH3:23])[CH2:25][C:26]([OH:31])=[O:27]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CCCCCCCc1cc2cc(Cl)ccc2n1C
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCCc1c(C(=O)CC(C)CC(=O)O)c2cc(Cl)ccc2n1C
Reaction time: 0.5 h

Procedure:
To the solution of 5-chloro-2-heptyl-1-methyl-1H-indole in methylene chloride at 0° C. was added dimethyl aluminum chloride solution in hexane. The reaction mixture was stirred for 30 minutes. To this solution 4-methyl-dihydro-pyran-2,6-dione was added at 0° C. and the reaction mixture was stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [C:1](=[S:3])=S.CP(=[N:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1)(C)C>C1COCC1>[N:8]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16]1)=[C:1]=[S:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N=P(C)(C)C)C1
Reactant: S=C=S
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N=C=S)C1
Reaction time: 0.25 h

Procedure:
tert-butyl ((3S)-1-(3-isothiocyanato-4-pyridinyl)-3-piperidinyl)carbamate. A dry, 3 neck, 100 mL Morton flask was configured as follows: opening 1: septa/Ar inlet; opening 2 (center): septa/PTFE addition needle; opening 3: septa. The flask was charged with tert-butyl ((3S)-1-(3-azido-4-pyridinyl)-3-piperidinyl)carbamate (3.25 g, 10.22 mmol), a stirbar, and dry THF (10 mL). The slurry was stirred for 10 min, and immersed into an ice-water bath. A syringe charged with 1.0 M PMe3 in THF (10.73 mL, 10.73 mmol, Aldrich) was fitted to the PTFE addition needle and added over a 15 min period via a syringe pump. The reaction was stirred for 15 min. The solution was charged to a dry 50 mL glass syringe via the PTFE addition needle to afford (S)-tert-butyl (1-(3-((trimethylphosphoranylidene)amino)pyridin-4-yl)piperidin-3-yl)carbamate. A dry, 250 mL, one neck round bottom flask was charged with dry THF (16 mL), carbon disulfide (6.17 mL, 102 mmol) and a stirbar. The flask was fitted with a septa/Ar inlet, and immersed into an ice-water bath. The solution was stirred for 15 min. The septa was pierced with the PTFE addition needle fitted to the 50 mL glass syringe containing the solution of (S)-tert-butyl (1-(3-((trimethylphosphoranylidene)amino)pyridin-4-yl)piperidin-3-yl)carbamate and the solution (19 mL) was added via syringe pump over a 1 h period. The reaction was stirred an additional 10 min and the solvent was removed in vacuo. The residue was further dried at <1 mm Hg at RT to afford tert-butyl ((3S)-1-(3-isothiocyanato-4-pyridinyl)-3-piperidinyl)carbamate. MS (ESI, pos. ion) m/z: 335.0 [M+H].
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[SH:31])([CH3:24])[CH3:23].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:22]([CH3:24])[CH3:23]
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: CC(C)c1ccccc1S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)c1ccccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.05 mmol of 2-isopropylbenzenethiol, and 1.05 mmol of piperidine in 20 mL of dichloromethane. The product was triturated with ether to afford a solid (m.p. 216°-217° C.). 1H NMR (DMSO-d6) δ 1.17 (d, J=6.8 Hz, 6 H), 3.20 (m, 1 H), 3.77 (bs, 2 H), 5.64 (d, 1 H), 6.45 (t, 1 H), 6.92 (t, 1 H), 7.12 (d, 1 H), 7.32 -7.48 (m, 10 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1cccc(F)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-fluorophenoxy)benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.17 (1H, d, J=2.8 Hz), 7.93 (2H, d, J=8.4 Hz), 7.65 (1H, d, J=7.4 Hz), 7.42–7.26 (4H, m), 6.94–6.88 (2H, m), 6.74–6.65 (2H, m), 5.28 (1H, dq, J=7.4, 7.3 Hz), 3.90 (3H, s), 1.48 (3H, d, J=7.3 Hz).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O(CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:29]1C=CC=C[CH:30]=1.Cl.OC(COC1C=CC(OC)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:29][CH3:30])[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: CCc1ccccc1OCC(O)CNC(C)(C)Cc1ccc(OC)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 342 (M−15,1), 237 (16), 236 (100), 163 (5), 121 (17), 114 (7), 91 (6), 77 (7).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[CH3:12][N:13]([CH3:29])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[S:27][C:26]2[C:21](=[N:22][CH:23]=[CH:24][C:25]=2Cl)[CH:20]=1)=[O:18]>>[CH3:12][N:13]([CH3:29])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[S:27][C:26]2[C:21](=[N:22][CH:23]=[CH:24][C:25]=2[NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)[CH:20]=1)=[O:18]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CN(C)CCNC(=O)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCCN(C)C)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (2-dimethylamino-ethyl)-amide by a procedure analogous to Example 1C. MS: 394 (MH+), HPLC Rf: 3.43; HPLC purity: 98%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([OH:7])=[C:5]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15].O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([S:36](Cl)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35]>CC(C)=O>[CH3:1][C:2]1[C:6]([O:7][S:36]([CH2:32][CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])=[C:5]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1O
Reactant: CCCCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CCCCS(=O)(=O)Oc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1C

Procedure:
A mixture of 2.3 g (8 mmol) of di-isopropyl 3-methyl-4-hydroxy-2,5-thiophene-dicarboxylate, 30 ml of dioxane, 60 ml of acetone, 1.6 g (120 mmol) of anhydrous potassium carbonate and 1.6 g (10 mmol) of butane-sulfonyl chloride was refluxed for about 10 hours. The mixture was then freed from dioxane and acetone by distillation in vacuo and then added with ethylether, washed with water, and dried with anhydrous magnessium sulfate. The solvent was removed by distillation and then recrystallization was effected from methanol to give 2.8 g (86%) of the desired white crystalline compound. m.p. 59°-61° C.