Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[N:14]([C@H:17]([CH3:21])[C:18](Cl)=[O:19])[N:13]=[CH:12]2)=[CH:7][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1>ClCCl>[F:30][C:31]1[CH:32]=[C:33]([F:37])[CH:34]=[CH:35][C:36]=1[C:18](=[O:19])[C@H:17]([N:14]1[C:15](=[O:16])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:25])([F:1])[CH:22]([F:24])[F:23])=[CH:6][CH:7]=2)[CH:12]=[N:13]1)[CH3:21]
Reactant: C[C@H](C(=O)Cl)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@H](C(=O)c1ccc(F)cc1F)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 0 °C
Yield: 61 %

Procedure:
(2R)-2-[4-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]propanoyl chloride (1 g) was dissolved in 20 ml of dichloromethane, to which 2.5 ml of 1,3-difluorobenzene and 1.50 g of anhydrous aluminium chloride in a powdery form were added. The mixture was refluxed with heating for eight hours. After cooling, the reaction solution was poured into 50 ml of ice water and extracted from a mixture of 100 ml of ethyl acetate and 50 ml of diisopropyl ether. The extract was washed with 30 ml of 1N-hydrochloric acid and 30 ml of a saturated aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 60 g, eluent; hexane:ethyl acetate:acetic acid=2:1:0.03) to give 0.77 g of 2-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (yield: 61%) as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:21][CH2:20]1)[CH2:3][CH:4]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:5]([OH:7])=O.[CH3:36][N:37]1[CH2:42][CH2:41][CH:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH3:36][N:37]1[CH2:42][CH2:41][CH:40]([CH:43]2[CH2:48][CH2:47][N:46]([C:5](=[O:7])[CH:4]([CH2:8][C:9]3[CH:18]=[CH:17][C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[CH:10]=3)[CH2:3][C:2]([N:19]3[CH2:20][CH2:21][CH:22]([N:25]4[CH2:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:27][C:26]4=[O:35])[CH2:23][CH2:24]3)=[O:1])[CH2:45][CH2:44]2)[CH2:39][CH2:38]1
Reactant: O=C(O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1ccc2c(c1)CCCC2
Reactant: CN1CCC(C2CCNCC2)CC1
Product: CN1CCC(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc4c(c3)CCCC4)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from 4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butanoic acid and 1-methyl-[4,4′]bipiperidinyl.
Reaction SMILES: C([O-])(=O)C.[Na+].Br[C:7](Br)([CH3:14])[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].[F:16][C:17]1[C:30]([NH:31][NH2:32])=[CH:29][C:20]2[N:21]([CH2:26][C:27]#[CH:28])[C:22](=[O:25])[CH2:23][O:24][C:19]=2[CH:18]=1>O>[F:16][C:17]1[C:30]([NH:31][N:32]=[C:7]([CH3:14])[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:29][C:20]2[N:21]([CH2:26][C:27]#[CH:28])[C:22](=[O:25])[CH2:23][O:24][C:19]=2[CH:18]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(NN)cc21
Reactant: CC(Br)(Br)C(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(NN=C(C)C(=O)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 8.0 g (97.2 mmol) of sodium acetate and about 50 ml of water was added under ice cooling 6.9 g (24.3 mmol) of 3,3-dibromo-1,1,1-trifluoro-butanone, and the reaction was allowed to proceed at 80° C. for 30 minutes. Then, the reaction mixture was cooled to 0° C., to which 4.4 g (18.7 mmol) of 7-fluoro-6-hydrazino-4-propargyl-2H-1,4-benzoxazin-3-one was added, and the reaction mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration, washed twice with 10 ml of water, and dried, which afforded 6.1 g (17.0 mmol) of 1,1,1-trifluoro-2,3-butandione 3-(7-fluoro-3-oxo-4-propargyl-2H-1,4-benzoxazin-6-ylhydrazone).
Reaction SMILES: [OH:1][CH:2]([CH2:17][NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:3][O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10].[H][H]>CO.[Pd]>[OH:1][CH:2]([CH2:17][NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:3][O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: [H][H]
Reactant: CCCC(=O)NCCNCC(O)COc1ccccc1C=CC(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCC(=O)NCCNCC(O)COc1ccccc1CCC(=O)OC
Yield: 85.3 %

Procedure:
A solution of 3.0 g (0.008 mole) of methyl 2-[2-hydroxy-3-[N-[2-(methylpropionamido)ethyl]amino]propoxy]cinnamate in 100 ml of methanol was treated with 0.3 g of 10% Pd-C catalyst and hydrogenated at 40 psi until no further uptake of hydrogen was observed (about 48 hr.). The catalyst was removed by filtration and the filtrate concentrated under reduced pressure to a solid, which was recrystallized from methanol:ether to provide 2.5 g (83%) of product, having a melting point of 119°-120° C. The IR and NMR spectra and elemental analysis were consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][NH:7][C:6]=2[CH:13]=1.[CH3:14][N:15](C)C=O>C(N)CN.O>[C:14]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][NH:7][C:6]=2[CH:13]=1)#[N:15]
Reactant: CN(C)C=O
Reactant: CC1(C)CNc2cc(Br)ccc2O1
Solvent: NCCN
Solvent: O
Product: CC1(C)CNc2cc(C#N)ccc2O1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A mixture of 480 mg of 6-bromo-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine, 206 mg of cuprous cyanide and 5 ml of N,N-dimethylformamide was stirred at 130° C. for 4 hours and further at 150° C. for 5 hours. This reaction mixture was diluted with 0.5 ml of ethylenediamine and 10 ml of water and extracted with benzene. The organic layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel column and elution was carried out with ethyl acetate-hexane (10:1). The crude crystals from the eluate were washed with hexane and dried to give 160 mg of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine. This compound has the following physicochemical properties.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1>CS(C)=O.C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(Nc2ccc(OC)cc2)c1
Yield: 79 %

Procedure:
A solution of methyl 3-fluoro-4-nitrobenzoate (10.0 g, 54.0 mmol) and p-anisidine (13.3 g, 108 mmol) in dimethylsulfoxide (300 mL) was stirred at 70° C. for 3.5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/tetrahydrofuran to give the title compound (12.9 g, yield 79%) as red crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[N:11]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].O.NN>C1COCC1.CO>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH:10]([NH2:11])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC(N)c1cccc(Cl)c1
Temperature: 55 °C

Procedure:
To a stirred solution of [3-(3-chloro-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-carbamic acid tert-butyl ester (0.15 g, 0.36 mmol) in THF (2 mL) and methanol (2 mL) was added hydrazine hydrate (0.18 g, 3.6 mmol). The mixture was heated at 55° C. for 2 hours. Then the reaction mixture was concentrated and extracted with ethyl acetate (10 mL). The organic mixture was washed with water (3×1 mL), brine (1 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (methanol:dichloromethane, 1:100) to afford [3-amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butyl ester. (Yield 0.061 g, 60%). LC-MS: [M+H]+ 285.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[C:3]=1[O:13][CH3:14].[N+:15]([O-])([OH:17])=[O:16].C(OCC)C.CCCCCC>S(=O)(=O)(O)O>[Br:1][C:2]1[C:10]([F:11])=[C:9]([N+:15]([O-:17])=[O:16])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[C:3]=1[O:13][CH3:14]
Reactant: COc1c(F)c(C(=O)O)cc(F)c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1c(F)c(C(=O)O)c([N+](=O)[O-])c(F)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 8 ml of sulfuric acid was dissolved 2.0 g of 4-bromo-2,5-difluoro-3-methoxybenzoic acid, and 4 ml of nitric acid was dropwise added to the solution with ice-cooling, after which the resulting mixture was stirred at room temperature for one hour. The reaction mixture was added to a mixed solvent of 50 ml of diethyl ether and 50 ml of ice water, and the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. To the residue thus obtained was added n-hexane, and the resulting crystals were collected by filtration to obtain 1.9 g of pale yellow, crystalline 4-bromo-2,5-difluoro-3-methoxy-6-nitrobenzoic acid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ccc(C)nc4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccc(C)nc4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-3-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.20 g) in methylene chloride (6.0 ml) was added dropwise a solution of m-chloroperbenzoic acid (80 mg) in methylene chloride (4.0 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography and recrystallized from ethanol, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-3-pyridinyl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 253) (104 mg).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[N:16]3[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]3)=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=2)Cl)=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:45]([C:42]1[CH:43]=[CH:44][C:39]([CH:37]([C:34]2[CH:35]=[CH:36][C:31]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=2)[O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[N:16]4[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]4)=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=3)=[O:7])=[CH:25][CH:26]=2)=[CH:40][CH:41]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Reactant: CCOC(=O)CCCc1cc(C(=O)c2ccc(O)cc2)n2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCc1cc(C(=O)c2ccc(OC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)cc2)n2ccccc12
Yield: 22 %

Procedure:
A mixture of ethyl 4-[3-(4-hydroxybenzoyl]indolizin-1-yl]butyrate (400 mg), bis(4-isobutylphenyl)chloromethane (430 mg) and diisopropylethylamine (736 mg) in dichloromethane (20 ml) was refluxed for 14 hours and evaporated. The residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with n-hexane and ethyl acetate (4:1) to give ethyl 4-[3-[4-[bis(4-isobutylphenyl)methoxy]benzoyl]indolizin-1-yl]butyrate (158 mg) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)[N:3]=1.[F:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:43]=1[CH:44]=[C:45](B1OC(C)(C)C(C)(C)O1)[NH:46]2.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe].O>[F:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:43]=1[CH:44]=[C:45]([C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4]([C:15]3[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]4[O:22][C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=4[CH:34]=3)[N:3]=1)[NH:46]2
Reactant: CC1(C)OB(c2cc3c(F)cccc3[nH]2)OC1(C)C
Reactant: CCOC(=O)CCc1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 90 °C

Procedure:
To a mixture of ethyl 3-(2-chloro-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)pyridin-3-yl)propanoate (120 mg, 0.204 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (80 mg, 0.306 mmol), cesium carbonate (133 mg, 0.408 mmol) and dichloro[1,1′-bis(di-t-butylphosphino)ferrocene]palladium (II) (13.3 mg, 0.02 mmol) was added 1,4-dioxane (1.86 mL) and H2O (0.186 mL). A steady stream of N2 was bubbled through the reaction mixture for 5 minutes then the mixture was heated to 90° C. for 9 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed successively with H2O (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc/Hexanes as eluent and further purified by silica gel column chromatography using a step gradient of 0-20-80% EtOAc/CH2Cl2 as eluent. MS (M+H)+: 687.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][CH:23]2[CH2:30][CH:26]3[O:27][CH2:28][O:29][CH:25]3[CH2:24]2)[CH:3]=1.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:35]1([CH2:34][CH2:33][CH2:32][NH:31][C:19]([C:16]2[S:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[O:22][CH:23]4[CH2:24][CH:25]5[O:29][CH2:28][O:27][CH:26]5[CH2:30]4)[C:10]=3[C:17]=2[CH3:18])=[O:21])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CC4OCOC4C3)c12
Reactant: NCCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCCN2CCCC2)sc2ncnc(Nc3ccc(F)cc3OC3CC4OCOC4C3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.15 g 4-[4-fluoro-2-(tetrahydro-cyclopenta[1,3]dioxol-5-yloxy)phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid, 0.045 g 1-(3-aminopropy)pyrrolidine, 0.159 g HATU and 0.097 ml TEA in 15 ml DMF was stirred at rt for 1 hour. The reaction mixture was poured on water, extracted with DCM, dried and filtered. The filtrate was concentrated. The residue was triturated with diisopropylether.
Reaction SMILES: C[Si](C)(C)CC[S:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:17]3[CH:21]=[CH:20][O:19][CH:18]=3)=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].Cl>CN(C=O)C.C1COCC1.O>[SH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:17]3[CH:21]=[CH:20][O:19][CH:18]=3)=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)CCSc1ccc2c(-c3ccoc3)cc(=O)oc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=c1cc(-c2ccoc2)c2ccc(S)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
The coumarin from Step 1 (963 mg) was dissolved in DMF (25 mL) and to this solution there was added n-Bu4NF (1M) in THF (8.4 mL). The mixture was stirred at r.t. for 2 h, poured onto 1N aqueous HCl (50 mL), diluted with H2O (50mL) and filtered to afford the title compound (620 mg) as a tan. solid. m.p.: 167°-170° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]([OH:15])[CH:10]([CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:17]([O:15][CH:11]1[CH:12]([CH3:14])[CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH:10]1[CH3:16])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CN(Cc2ccccc2)CC(C)C1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC1C(C)CN(Cc2ccccc2)CC1C
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of N-benzyl-4-hydroxy-3,5-dimethylpiperidine (21.9 g, 0.1 mole), acetic anhydride (15.3 g), N,N-dimethyl-4-aminopyridine (0.01 g) and pyridine (100 ml) was stirred at 110° C. for 2 hr. The reaction mixture was concentrated to dryness, triturated with water (50 ml) and extracted with chloroform (2×50 ml). The extract was dried (Na2SO4) and concentrated to dryness to furnish a crude mixture of cis- and trans-4-acetoxy-1-benzyl-3,5-dimethylpiperidine. Yield 16 g (61.3%), C16H23NO2, m/z 262 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][CH2:9][CH2:10][O:11][C:3]=12.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[N:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:22].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[N:21]([CH:23]1[CH2:24][CH2:25][N:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[O:8][CH2:9][CH2:10][O:11][C:3]=23)[CH2:27][CH2:28]1)[CH3:22]
Reactant: Clc1ccnc2c1OCCO2
Reactant: CN(C1CCNCC1)C1Cc2ccccc2C1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN(C1CCN(c2ccnc3c2OCCO3)CC1)C1Cc2ccccc2C1
Temperature: 130 °C
Yield: 8.5 %

Procedure:
1.1 g (6.5 mmol) of 8-chloro-2,3-dihydro-1,4-dioxino[2,3-b]pyridine, 3 g (13 mmol) of 4[N-(indan-2-yl)-N-methylamino]piperidine and 5 ml of pyridine are placed in a reactor. The whole is heated at 130° C. for 8 hours. After cooling, the whole is taken up in toluene and concentrated. The residue is chromatographed on 130 g of silica (eluant: CH2Cl2 /CH3OH/NH4OH, 95/5/0.5) to yield the expected product which melts (MK) at 167-170° C. Yield=8.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[N:8]([C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=1)[CH2:7][CH2:6]2.Cl[Sn]Cl>C1COCC1.CC(O)=O.O>[NH2:34][C:31]1[CH:32]=[CH:33][C:28]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc2c(c1)CCN(c1ccc([N+](=O)[O-])cc1)C2Cc1ccc(OCc2ccccc2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(c1ccc(N)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 95.8 %

Procedure:
A suspension of 6-methoxy-2-(4-nitrophenyl)-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.70 g, 1.46 mmol) and SnCl2*H2O (1.35 g, 6.0 mmol) in 20 mL of THF/HOAc (1:1) and 3 mL of water was heated at 60° C. for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was quenched by the addition of saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layer was dried over MgSO4 then concentrated. The crude product was purified by flash chromatography to provide the title compound (0.63 g, 95% yield). ES-MS, (m/z) 451 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]([O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][C:33]=1[CH3:39])[CH3:27].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:26]([O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38][CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:34][C:33]=1[CH3:39])[CH3:27]
Reactant: FC(F)(F)c1ccc(-c2nc(CCc3ccccc3)c(CCl)s2)cc1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCc2ccccc2)cc1C
Temperature: 25 °C
Yield: 83.5 %

Procedure:
To a solution of 5-chloromethyl-4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazole (190 mg, 0.5 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (100 mg, 0.44 mmol) in acetonitrile (3 mL) is added Cs2CO3 (325 mg, 1 mmol). The mixture is stirred at room temperature over night, quenched by water, extracted with ethyl acetate, dried over sodium sulfate. Column chromatography on silica gel of the crude product gave 210 mg (83.5% yield) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[N:20][C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:17]=3[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:24][N:23]([CH3:25])[C:21]1[N:20]=[CH:19][C:18]2[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][NH:16][C:17]=2[CH:22]=1
Reactant: CN(C)c1cc2[nH]cc(C3CCN(C(=O)OC(C)(C)C)CC3)c2cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2[nH]cc(C3CCNCC3)c2cn1
Yield: 100.7 %

Procedure:
The 4-(6-dimethylamino-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (135 mg, 0.39 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated. The residue was dissolved in MeOH (10 mL) and neutralized with DOWEX 550A OH anion exchange resin to pH 8. The resin was then filtered off and MeOH was removed under reduced pressure to give 96 mg (100%) of a yellow solid. MS (electrospray): exact mass calculated for C14H20N4, 244.17; m/z found, 245.2 [M++H]. 1H NMR (CDCl3, 400 MHz): 9.23 (br s, 1H), 8.54 (s, 1H), 6.67 (s, 1H), 6.31 (d, J=0.98 Hz, 1H), 3.15 (d, J=2.13 Hz, 2H), 3.02 (s, 6H), 2.91-2.81 (m, 1H), 2.81-2.72 (m, 2H), 2.01 (d, J=12.52 Hz, 2H), 1.69-1.52 (m, 2H).