Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:35]=1)[C:23]([N:25]=[S@@:26]([CH3:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH3:34][S@:26](=[N:25][C:23]([C:22]1[CH:35]=[C:18]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)[CH:19]=[N:20][CH:21]=1)=[O:24])(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)c1
Yield: 22.8 %

Procedure:
In a manner similar to that described in Example 449, tert-butyl 3-ethynylphenylcarbamate (0.098 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) reacted to give the title compounds as a white solid (32 mg, 23%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C@H:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].S(=O)(=O)(O)O.II.O.O.[I:26](O)(=O)(=O)=O>C(O)(=O)C.O>[F:1][C:2]([F:15])([F:16])[C:3]([NH:5][C@H:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:26])=[CH:10][CH:9]=1)=[O:4]
Reactant: C[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](Cc1ccc(I)cc1)NC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 185.4 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[(1R)-1-methyl-2-phenylethyl]acetamide (3.75 g) in acetic acid (32 ml)—water (6.5 ml)—sulfuric acid (0.97 ml) were added iodine (1.65 g) and periodic acid dihydrate (740 mg) at room temperature, and the mixture was heated to 60–80° C. for 5 hours. After being allowed to cool to room temperature, the mixture was partitioned between hexane/ethyl acetate and water. The organic layer was separated, washed successively with water, sodium sulfite solution, water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was recrystallized from diisopropyl ether (44 ml) to give 2,2,2-trifluoro-N-[(1R)-2-(4-iodophenyl)-1-methylethyl]acetamide (2.15 g) as a colorless needle.
Reaction SMILES: C(NC(C)C)(C)C.[N:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[C:15](OCC)(=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.O>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15](=[O:24])[CH2:14][C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccncc1
Reactant: CCOC(=O)c1ccc(OC)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Cc2ccncc2)cc1
Temperature: -5 °C
Yield: 66.2 %

Procedure:
A solution of diisopropylamine (33.2 mL) in anhydrous tetrahydrofuran (300 mL) was cooled to −78° C. and 1.6 M n-butyllithium-hexane solution (148 mL) was added dropwise with stirring. After completion of dropwise addition, the mixture was stirred for 10 min at the same temperature, then γ-picoline (20 g) was added dropwise. The temperature was raised to −10-0° C., and after stirring for 20 min, a solution of ethyl p-anisate (19.4 g) in anhydrous tetrahydrofuran (40 mL) was added dropwise. After completion of dropwise addition, the mixture was stirred at room temperature for 1 h, and water (100 mL) was added. The organic solvent was evaporated under reduced pressure and an oily product was extracted with ethyl acetate. The extract was washed with water, and after drying, the solvent was evaporated. the remaining crude crystals were recrystallized from ethyl acetate-isopropyl ether to give the title compound (16.2 g, yield 66%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]CO.[C:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11].C[O-].[Na+]>>[C:9](=[O:14])([O:12][CH2:13][CH2:1][O:2][CH2:3][CH2:4][O:5][CH3:6])[O:10][CH3:11]
Reactant: COCCOCCO
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COCCOCCOC(=O)OC
Temperature: 84 °C
Yield: 90 %

Procedure:
A total of 144.2 grams (1.2 mol) of 2-(2-methoxyethoxy)ethanol, 400 grams (4.4 mol) of dimethyl carbonate and 3 grams (0.05 mol) of sodium methoxide were combined in a 1-liter 3-neck round bottom flask equipped with a 14 inch distillation column, distillation head, and magnetic stirbar. The system was evacuated and purged three times with nitrogen using a Firestone valve, and left under a constant nitrogen atmosphere. After a period of 1.5 hours at reflux (kettle temperature 84° C.), methanol (boiling point 64° C.) was slowly removed overhead to drive the equilbrium. A total of 49.8 grams of methanol was removed over a period of 3 hours, after which time the stopcock was closed and the reaction mixture was allowed to reflux overnight. The mixture was then cooled to room temperature, filtered and charged (429 grams) to a 500 milliliter round bottom flask equipped with a distillation head and magnetic stirbar. Excess dimethyl carbonate (boiling point 90° C.) was removed overhead. The flask was then cooled, put under vacuum (10-11 mm Hg), and methyl 2-(2-methoxyethoxy)ethyl carbonate removed overhead (boiling point 115-125° C.). A total of 193 grams (ca. 90% yield) was obtained. Gas chromatography analysis of this material showed 97.74% purity (remainder was 2-(2-methoxyethoxy)ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2C.[CH4:12].[CH3:13][OH:14]>>[ClH:1].[CH3:12][N:6]1[C:7]2[C:3](=[C:2]([C:13]3([OH:14])[CH2:3][CH2:4][CH2:5][NH:6][CH2:7]3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: CO
Reactant: C
Reactant: Cn1ccc2c(Cl)cccc21
Product: Cl
Product: Cn1ccc2c(C3(O)CCCNC3)cccc21

Procedure:
50 g of hydrochloride of Step A in 1.5 liters of methanol was hydrogenated at 40° C. in the presence of 15 g of palladized active charcoal. The mixture was then cooled and the catalyst was filtered off. The filtrate was distilled to dryness under vacuum to obtain 37 g of 3-(1-methyl-1H-indole-4-yl)-3-piperidinol hydrochloride with an Rf=0.3 [Support: silica--Eluant: chloroform-methanol-triethylamine (6:3:1)].
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C1COCC1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH2:19][N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: c1cc2nc(N3CCN(C4CC4)CC3)sc2cc1CN1CCOCC1
Temperature: 63 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (500 mg, 1.7 mmol) in MeOH (14 mL) and THF (28 mL) was added morpholine (296 mg, 3.4 mmol), acetic acid (22 mg, 0.4 mmol) and NaCNBH3 (158 mg, 2.7 mmol). The mixture was stirred at 63° C. overnight. Then the resulting mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (15 mL). The mixture was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 306 mg (31%) of 2-(4-cyclopropylpiperazin-1-yl)-6-(morpholin-4-ylmethyl)-benzothiazole as a trifluoroacetate salt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[C:11]3=[C:27]([CH3:31])[N:28]=[C:29]([CH3:30])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:32](O)(=[O:35])[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)CCl>CN(C=O)C>[CH3:31][C:27]1[N:28]=[C:29]([CH3:30])[N:10]2[C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[N:13][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:34])[CH2:32][OH:35])=[CH:7][CH:6]=1)=[N:9]2
Reactant: COc1cc(Nc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc(-c3ccc(NC(=O)CO)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of are 50 mg (0.12 mmol) of N-[2-(4-aminophenyl)-5,7-dimethyl-imidazo[5,1-f][1,2,4]triazin-4-yl]-N-(3,4,5-trimethoxyphenyl)amine from example 3 in DMF is treated with 18 mg (0.24 mmol) of glycolic acid, 90 mg (0.24 mmol) of HATU and 46 mg (0.24 mmol) of EDC. It is stirred overnight at 20° C. The solvent is removed under reduced pressure and the residue is purified by HPLC.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=CC=1.[CH2:20]([O:27][C:28]1[N:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>C(COC)OC.O>[CH2:20]([O:27][C:28]1[C:29]([CH2:30][C:16]#[N:17])=[CH:32][CH:33]=[CH:34][N:35]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cccnc1OCc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: N#CCc1cccnc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of potassium t-butoxide (4.52 g) and dimethoxyethane (20 mL) was added a solution (20 mL) of toluenesulfonylmethylisocyanide (4.12 g) in dimethoxyethane at −78° C. Further, a solution (20 mL) of 2-(benzyloxy)nicotinaldehyde (4.12 g) in dimethoxyethane was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 1 hr. Methanol (20 mL) was added to the reaction mixture at room temperature and the mixture was heated under reflux for 30 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-(2-benzyloxy-3-pyridyl)acetonitrile as an oil from a fraction eluted with ethyl acetate-hexane (1:8, v/v).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]=[C:27]3[C:23]([N:24]=[CH:25][N:26]3[C@@H:29]3[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]3[OH:40])=[C:22]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:21]=2)[CH2:16]1)(C)(C)C.CO>Cl>[NH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]=[C:27]3[C:23]([N:24]=[CH:25][N:26]3[C@@H:29]3[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]3[OH:40])=[C:22]([NH:41][CH2:42][CH:43]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:21]=2)[CH2:16]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{(R)-1-[9-((1R,2S,3R,4S)-2,3-Dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester trifluoroacetate (3.22 g, 4.80 mmol) is dissolved in 1.25 M HCl in MeOH (60 ml, 75 mmol) and left to stir at room temperature overnight. The solvent is removed in vacuo and the crude product is dissolved in a minimal volume of EtOH/saturated sodium carbonate solution and purified by reverse phase column chromatography (Isolute™ C18, 0-100% MeOH in water) to yield the title product.
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[C:18]3[CH2:31][CH2:30][NH:29][C:19]=3[N:20]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:22]=2)[CH:14]=[CH:15][CH:16]=1)([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[S:34](Cl)([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>O>[C:6]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[C:18]3[CH2:31][CH2:30][N:29]([S:34]([C:37]4[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=4)(=[O:36])=[O:35])[C:19]=3[N:20]=[C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:22]=2)[CH:14]=[CH:15][CH:16]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCc3c(-c4cccc(OC(C)(C)C)c4)nc(N4CCOCC4)nc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a dimethylformamide solution (1 ml) of 4-(3-t-butoxyphenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (11 mg), sodium hydride (60% mineral oil dispersion, 1.5 mg, 1.2 equivalents) was added with ice cooling, followed by stirring at room temperature for 30 minutes. With ice cooling, tosyl chloride (6.6 mg, 1.1 equivalents) was added, followed by stirring at room temperature for 10 hours. To the reaction mixture, water (5 ml) was added, followed by extraction with ethyl acetate (5 ml×2). The organic layer was washed with aqueous ammonium chloride solution and brine, followed by drying over sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (n-hexane/ethyl acetate=2/1), to obtain the desired compound as a colorless powder (11 mg, 70%).
Reaction SMILES: [CH2:1](/[N:8]=[C:9](\[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1)/[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O>[CH2:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1)[C:10]([F:13])([F:11])[F:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)/C(=N/Cc1ccccc1)c1ccc(Br)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: FC(F)(F)C(NCc1ccccc1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
To a stirred solution of Benzyl-[1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-eth-(E)-ylidene]-amine (0.45 g, 1.31 mmol) in methanol (20 mL) is added sodium triacetoxy borohydride (0.55 g, 2.62 mmol) at 0° C. then stir at room temperature for 3 hours. Reaction mixture is diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting in 10% ethyl acetate in hexane to afford the title compound (0.15 g). 1H NMR (400 MHz, DMSO-d6) δ: 3.57-3.61 (m, 1H), 3.64-3.73 (m, 2H), 4.50 (m, 1H), 7.22-7.25 (m, 1H), 7.28-7.29 (m, 4H), 7.73 (d, J=8.2 Hz, 1H), 7.91-7.93 (dd, J1=8.2 Hz, J2=2.24 Hz, 1H), 8.48 (d, J=2.08 Hz, 1H). LC-MS (m/z): [M+H]=347.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH:12]([CH:14]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:15]([O-:17])=[O:16])=O.Cl.[C:27]1(C)C=CC=C[CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH:6]/[CH:12]=[C:14](/[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)\[C:15]([O:17][CH2:27][CH3:28])=[O:16]
Reactant: COc1ccc(C(C=O)C(=O)[O-])cc1
Reactant: COc1ccc(N)cc1OC
Reactant: Cc1ccccc1
Agent: Cl
Product: CCOC(=O)/C(=C\Nc1ccc(OC)c(OC)c1)c1ccc(OC)cc1
Yield: 65 %

Procedure:
A solution of 3,4-dimethoxyaniline (1.76 g, 11.49 mmol) and ethyl ∀-formyl-4-methoxyphenylacetate (2.81 g, 1.1 eq) in toluene (20 ml) is refluxed for 18 hours. After cooling, the reaction mixture is diluted with toluene (10 ml) and then acidified with 10% HCl. After extraction, the organic phase obtained is dried over MgSO4 and then evaporated under reduced pressure. The residue is purified by chromatography on silica gel (eluent: 7/3 PE/EtOAc) to give 2.67 g (65%) of compound 30 in the form of a pale yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[N:32][CH:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:43])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][OH:35])=[N:32][CH:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2ncnc2COC2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ncnc3CO)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-chloro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M55) (0.78 g, 1.22 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (370 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.COC1C=CC([SH:29]2(=S)PP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:29])[CH2:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: O=C1CCC(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: COc1ccc(P2(=S)P[SH](=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Fc1ccccc1C1CCC(=S)Nc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
30 g of 7-chloro-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are dissolved in 105 ml of hexamethylphosphoric acid triamide and treated with 22 g of 2,4-bis-(4-methoxyphenyl)-1,2,3,4-dithiadiphosphetane-2,4-disulphide. The mixture is heated to 100° for 1 hour, again cooled to room temperature and poured into 1.41 l of water. The mixture is extracted four times with ethyl acetate and the organic extracts are washed with water. The ethyl acetate solution is dried, filtered and evaporated in vacuo. After crystallization of the residue from ethanol, there is obtained 7-chloro-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1-benzazepine-2-thione of melting point 190°.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:10]([C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]=1[CH2:26][CH3:27])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(=S)=S>[CH2:10]([C:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:25][C:20]=2[O:19][C:18]=1[CH2:26][CH3:27])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCc1oc2ccccc2c1Cc1ccccc1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc2c(Cc3ccccc3)c(CC)oc2c1
Yield: 4.2 %

Procedure:
Propionyl chloride (7.3 mL; 0.784 mol) was added dropwise to the mixture of Aluminum chloride (10.5 g; 0.784 mol), and 3-benzyl-2-ethyl-benzofuran (18.5 g; 0.784 mol) in carbon disulfide (50 mL) while stirring and cooling in an ice bath. The reaction mixture was then stirred at room temperature for 30 minutes then heated at reflux for 2 hours. The solvent was then evaporated and the residue was diluted with ether then poured into water. The organic phase was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was crystallized from ethyl acetate/hexane mixture to give the title compound (9.6 g) as a solid, mp: 86-87° C. Mass spectrum (ESI, [M+] m/z 292. 1HNMR (400 MHz, DMSO-d6): δ 1.08 (t, 3H, J=7.26 Hz), 1.24 (t, 3H, J=7.47 Hz), 2.88 (q, 2H, J=7.47 Hz), 2.04 (q, 2H, J=7.26 Hz), 4.02 (s, 2H), 7.16-7.19 (m,1H), 7.23-7.29 (m, 5H), 7.47 (d, 1H, J=8.09 Hz), 7.78 (dd, 1H, J=8.09, 1.45 Hz), 8.07 (d, 1H, J=1.45 Hz). Elemental Analysis for C20H20O2: Calculated: C, 82.16; H, 6.90 Found: C, 82.22; H, 7.01.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][CH:46]=[C:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[N:48]=1>C(Cl)(Cl)Cl.O>[C:49]([C:47]1[N:48]=[C:44]([NH:43][C:35]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[F:23])=[O:41])[S:45][CH:46]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)c1csc(N)n1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nc(C(C)(C)C)cs4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (3 ml) to prepare a solution. Triethylamine (0.3 ml) and a solution of triphosgene (27 mg) in chloroform (0.2 ml) were then added to the solution, and the mixture was stirred at room temperature for 30 min. Next, a solution of 2-amino-4-t-butylthiazole (64 mg) in chloroform (0.6 ml) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The extract was washed with saturated brine and was dried over anhydrous sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 26 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.BrC1C=C2C(=CC=1[Cl:24])C(Cl)=NC=C2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:24])[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: Clc1cc2c(Cl)nccc2cc1Br
Product: O=c1[nH]ccc2cc(Br)c(Cl)cc12

Procedure:
The title compound was prepared by the method, described for 6-Bromo-2H-isoquinolin-1-one (6), starting from 6-Bromo-1,7-dichloro-isoquinoline (11). Rt=1.26 min (Method C). Detected mass: 258.2/260.2 (M+H+).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH2:20][S:21][C:22]2[N:23]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:24]([C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH3:38])[CH:31]=3)([CH3:29])[CH3:28])=[CH:25][N:26]=2)=[C:15]([Cl:46])[CH:14]=1)(=[O:12])=[O:11])(=[O:4])=[O:3].[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CC#N>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[Cl:46][C:15]1[CH:14]=[C:13]([S:10]([NH:9][CH2:8][CH2:7][CH2:6][N+:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)(=[O:11])=[O:12])[CH:18]=[C:17]([F:19])[C:16]=1[CH2:20][S:21][C:22]1[N:23]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)[C:24]([C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH3:38])[CH:31]=2)([CH3:28])[CH3:29])=[CH:25][N:26]=1
Reactant: c1ccncc1
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCCOS(C)(=O)=O)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Solvent: CC#N
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCC[n+]4ccccc4)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Product: CS(=O)(=O)[O-]
Yield: 70.5 %

Procedure:
A mixture of 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenylsulfonamido)propyl methanesulfonate (50 mg, 0.064 mmol) and pyridine (0.1 mL, 12.8 mmol) in CH3CN was refluxed in sealed tube 3 h. After cooling and evaporation of volatiles, the residue was purified by column chromatography (DCM/MeOH=5:1) to give the title compound (36 mg, 80% yield). 1H NMR (400 MHz, CD3OD) δ 9.21 (d, J=5.71 Hz, 2H), 8.40 (t, J=7.79 Hz, 1H), 8.07-7.98 (m, 2H), 7.49 (s, 1H), 7.29 (dd, J=8.90, 1.32 Hz, 1H), 7.17 (s, 1H), 6.86 (dd, J=11.02, 8.48 Hz, 1H), 6.80 (dd, J=11.65, 5.39 Hz, 2H), 6.55 (dd, J=8.10, 2.16 Hz, 1H), 6.47 (ddd, J=8.34, 4.11, 2.22 Hz, 1H), 6.44-6.38 (m, 2H), 4.99 (t, J=6.27 Hz, 2H), 4.07 (s, 2H), 2.92-2.82 (m, 2H), 2.63 (s, 3H), 2.25-2.12 (m, 2H), 3.75 (s, 3H), 1.49 (s, 7H); MS (EI) m/z 701 (M+).