Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.[NH3:21]>C(O)C>[F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:21])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1
Reactant: N
Reactant: N#CCCCCn1ccc(NC(=S)NCC(F)(F)F)n1
Solvent: CCO
Product: N#CCCCCn1ccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
The above thiourea (12.5 g.) was dissolved in 8M ammonia in ethanol (120 ml.). Mercuric oxide (12.8 g.) was added and the mixture was stirred at 20° for 30 minutes. The resulting mixture was filtered and the filtrate was evaporated in vacuo to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeronitrile as an oil. A sample of the oil was dissolved in acetone and 5 molecular equivalents of maleic acid were added. Ether was added to the resulting clear solution to produce the crystalline maleate, m.p. 123°-125°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CN(C)C=O>[C:7]1([C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CNCCN1
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
Piperazine (1.00 g, 11.6 mmol) (Wako Pure Chemical Industries, Ltd.) was dissolved in N,N-dimethylformamide (25 mL) (Wako Pure Chemical Industries, Ltd.), and triphenylchloromethane (0.65 g, 2.33 mmol) (Wako Pure Chemical Industries, Ltd.) was added little by little, and the mixture was stirred at room temperature overnight. Water was poured into the reaction solution, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):methanol (Wako Pure Chemical Industries, Ltd.)=9:1 as an eluent). The residue was dissolved in ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.), and the mixture was shaken, followed by separation of the organic layer. The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and then the solvent was distilled off under reduced pressure, to thereby obtain the title compound (0.76 g, 99% yield).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]([C:19]1[N:20]=[C:21]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[S:22][C:23]=1[C:24]([OH:26])=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[ClH:18].[NH2:8][CH2:9][CH2:10][CH:11]([C:19]1[N:20]=[C:21]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[S:22][C:23]=1[C:24]([OH:26])=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCC(c1ccc(Cl)cc1)c1nc(N2CCOCC2)sc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCC(c1ccc(Cl)cc1)c1nc(N2CCOCC2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 215.2 %

Procedure:
To a solution of 4-{3-[(tert-butoxycarbonyl)amino]-1-(4-chlorophenyl)propyl}-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylic acid (0.304 g, 0.631 mmol) in DCM (5.9 mL) was added a solution of hydrogen chloride in dioxane (4 M, 3.1 mL, 12 mmol) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was then azeotroped with toluene and dried under vacuum to give the product (0.284 g, 108%) which was used directly in the next step. LCMS: (AA) ES+ 382, 384.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.[CH3:9][NH2:10]>>[CH3:9][NH:10][CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1
Reactant: CN
Reactant: Nc1nc(CCl)cs1
Product: CNCc1csc(N)n1

Procedure:
4-(Chloromethyl)-1,3-thiazol-2-amine (490 mg, 2.65 mmol) was stirred in 40% aqueous methylamine (25 ml) overnight. The reaction mixture was evaporated. The residue was diluted with 95:5 dichloromethane/methanol (25 ml), was dried over sodium sulfate, was filtered and was evaporated to provide 4-[(methylamino)methyl]-1,3-thiazol-2-amine that was used without purification. LCMS: (M+H)+: 144.0.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[C:10]([CH3:17])[CH:9]=1.[F:18][C:19]([F:37])([F:36])[C:20]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:22]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:7][C:8]1[C:13]([C:14]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([N:22]3[C:23]([C:25]([F:26])([F:27])[F:28])=[CH:24][C:20]([C:19]([F:37])([F:36])[F:18])=[N:21]3)=[CH:35][CH:34]=2)=[O:16])=[CH:12][N:11]=[C:10]([CH3:17])[CH:9]=1
Reactant: Cc1cc(C)c(C(=O)O)cn1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(C)c(C(=O)Nc2ccc(-n3nc(C(F)(F)F)cc3C(F)(F)F)cc2)cn1
Temperature: 17.5 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Oxalyl chloride (8.7 ml) was added to a mixture of 4,6-dimethylnicotinic acid (15.1 g) and dichloromethane (150 ml) under ice cooling, followed by stirring at 15 to 20° C. for one hour. A mixture of 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]aniline (23.59 g) and dichloromethane (300 ml) was added to the resulting reaction solution, followed by stirring at room temperature for 18 hours. An aqueous 20% potassium carbonate solution (about 200 ml) was added to the reaction solution, from which the organic layer was separated. Subsequently, the aqueous layer was extracted with dichloromethane (about 50 ml). The organic layer and the extract solution were combined together and subsequently concentrated under reduced pressure. The resulting residue was recrystallized from a mixed solvent (270 ml) of ethanol and water (2:1, respectively), to obtain 4,6-dimethyl-4′-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]nicotinanilide (26.70 g) as bluish white solid.
Reaction SMILES: [NH2:1]/[C:2](/[N:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([CH:35]3[CH2:37][CH2:36]3)[O:33][CH:34]=2)=[CH:26][CH:25]=1)[CH2:6][CH2:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)=[N:3]\[OH:4].C(N(CC)CC)C.[F:45][C:46]([F:57])([F:56])[C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50](Cl)=O>C1(C)C=CC=CC=1>[CH:35]1([C:32]2[O:33][CH:34]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([CH2:23][N:5]([C:2]4[N:1]=[C:50]([C:49]5[CH:53]=[CH:54][CH:55]=[C:47]([C:46]([F:45])([F:56])[F:57])[CH:48]=5)[O:4][N:3]=4)[CH2:6][CH2:7][C:8]4[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=4)=[CH:29][CH:28]=3)[N:31]=2)[CH2:36][CH2:37]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(-c3coc(C4CC4)n3)cc2)/C(N)=N/O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(-c3coc(C4CC4)n3)cc2)c2noc(-c3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
To a cooled solution of ethyl 2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (0.108 g, 0.21 mmol) in toluene (2 ml) was added triethylamine (0.028 mL, 0.20 mmol) dropwise. After 5 min, 3-(trifluoromethyl)benzoyl chloride (0.031 ml, 0.20 mmol) in toluene (0.1 ml) was added dropwise. The mixture was allowed to warm to rt over 2 h and then heated to 110C for 2 hr. Upon cooling, the mixture was filtered, and the solid was washed with EtOAc. The filtrate was concentrated in vacuo, and the resulting residue was partitioned between EtOAc and a solution of 0.5N aqueous HCl. The organic phase was washed with 0.5N aqueous HCl (1×), 0.5N aqueous NaOH (2×), and brine (1×), dried with Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc/hexanes, 10:90 to 20:80) to yield ethyl 2-{4-[2-([4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoate (76 mg, 58%).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13].[CH:20]1([CH3:32])[CH2:25][CH2:24][CH:23]([CH:26]([CH3:28])[CH3:27])[CH:22]([C:29](Cl)=[O:30])[CH2:21]1.Cl>C(Cl)Cl>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:29]([CH:22]1[CH2:21][CH:20]([CH3:32])[CH2:25][CH2:24][CH:23]1[CH:26]([CH3:28])[CH3:27])=[O:30]
Reactant: NCC(O)c1ccccc1
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CCC(C(C)C)C(C(=O)NCC(O)c2ccccc2)C1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
A 500 mL round bottom flask equipped with stir bar was charged with CH2Cl2 (200 mL), DIEA (28 g, 0.219 mol), and 2-Amino-1-phenyl-ethanol (10 g, 0.073 mol) and cooled to 0° C. Menthoyl chloride (14.8 g, 0.073 mol) was added drop wise over a 15 min period. Once the addition was complete the reaction was allowed to warm to ambient temperature and stirred 2 h. CH2Cl2 (100 mL) and 1N HCl (100 mL) was added to the reaction mixture and stirred for an additional 20 min. The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with CH2Cl2 (2×100 mL). The organic phases were combined and washed with 1N HCl (8×100 mL), H2O (1×100 mL), 1N NaOH (2×100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was eluted through a plug of silica gel (50% ethyl acetate/hexane for elution) provided the title compounds as colorless solid (18.8 g, 85%).
Reaction SMILES: [CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:10][C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:30]Br>C(O)(=O)C>[CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[C:10]([Br:30])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2cccc(Cl)c2)cc(=O)n1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(OCc2cccc(Cl)c2)c(Br)c(=O)n1Cc1ccccc1
Reaction time: 1 h

Procedure:
The product of example 38 (SC-83316), 1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.91 mmol, 310 Mg), acetic acid (20 mL), and sodium acetate (0.91 mmol, 80 Mg) were stirred at room temperature when bromine (0.91 mmol, 145 Mg) was added. After stirring for one hour, the mixture was concentrated, dissolved in ethyl acetate, and washed successively with saturated aqueous sodium bicarbonate solution, brine, and water. After drying over magnesium sulfate and concentrating, the product was recrystallized from tetrahydrofuran/hexanes to yield a white solid. (240 Mg, 63%): 1H NMR (DMSO-d6/300 MHz) 7.6-7.0 (m, 10H), 6.5 (s, 1H), 5.33 (s, 2H), 5.33 (s, 2H), 2.3 (s, 3H). ES HRMS m/z 420.019 (M+H, C20H17NO2BrCl requires 420.019).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:12][CH:13]1[O:17][CH2:16][CH2:15][O:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[CH2:12][NH:5][C:4]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cccc(C)c1N
Reactant: ClCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(C)c1NCC1OCCO1

Procedure:
2-Ethyl-6-methylaniline (70 grams), 2-chloromethyl-1,3-dioxolane (30 grams), potassium carbonate (38 grams) and dimethylformamide (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux for a period of about 24 hours. After this time the mixture was filtered and distilled to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-2-ethyl-6-methylaniline.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-].[K+].[OH:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[C:6]1([CH2:5][C:4]#[C:3][CH2:2][O:14][N:15]2[C:16](=[O:25])[C:17]3=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]3[C:19]2=[O:20])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCC#CCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1OCC#CCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
51.3 g (0.23 mol) of the 1-bromo-4-phenyl-2-butyne obtained above were added dropwise in the course of 30 minutes to a mixture consisting of 230 ml of N-methylpyrrolid-2-one, 3 g of potassium iodide, 37 g (0.23 mol) of N-hydroxyphthalimide and 20.6 g (0.15 mol) of potassium carbonate. Stirring was carried out for a further 5 hours at 60° C. and then overnight at room temperature, the mixture was poured into 800 ml of ice water and the precipitated crystals were filtered off under suction and washed thoroughly with water and isopropanol.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:21]3[S:22][C:23]4[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[CH:26][C:24]=4[CH:25]=3)[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:37]O.C[O-].[Na+]>ClCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:21]3[S:22][C:23]4[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[CH:26][C:24]=4[CH:25]=3)[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[C:10]([CH2:11][O:12][CH3:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CO)n4ncnc(N)c34)sc12
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCc1c(CN2CCNC(=O)C2)c(-c2cc3cc(C)cc(OC)c3s2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 21 %

Procedure:
A suspension of Example 125 (88 mg, 194 μmol) in dichloromethane (5 ml) was treated with thionyl chloride (29 μl, 389 μmol), and the mixture was stirred at rt for 65 min. Another portion of thionyl chloride (29 μl, 389 μmol) was added, and stirring was continued for 1.5 h. An excess of methanol was then added, followed by dropwise addition of a 5.4 M solution of sodium methylate in methanol (84 mg, 1.56 mmol) until pH 8 was reached. After stirring for 3 days, the volatiles were evaporated under reduced pressure, and the residue was separated by preparative RP-HPLC (Reprosil C18, gradient 20-40% acetonitrile/0.2% aq. trifluoroacetic acid). The product fractions were evaporated to yield 19 mg of the title compound (21% of th.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Br)c(-c2ccncc2)c1
Temperature: 120 °C
Yield: 41.4 %

Procedure:
A solution of pd(ph3p)4 (1.410 g, 1.220 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (3.94 ml, 24.41 mmol), pyridin-4-ylboronic acid (3.00 g, 24.41 mmol), and potassium carbonate (13.49 g, 98 mmol) in 32 mL dioxane and 6 mL water was heated to 120° C. overnight. Additional portions of pyridin-4-ylboronic acid (3.00 g, 24.41 mmol) and potassium carbonate (13.49 g, 98 mmol) were added and the reaction mixture was heated to 120° C. for 3 hours. The reaction mixture was then poured into water and was extracted with DCM. The organics were then concentrated. Purification of the crude residue by silica gel column chromatography (0-100% EtOAc/heptane) gave 4-(2-bromo-5-(trifluoromethyl)phenyl)pyridine (3.054 g, 10.11 mmol, 41.4% yield) as a white solid. [M+H]+=303.9
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([CH:19]([OH:21])[CH3:20])[C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:22]=C)[C:3]=1[C:24]#[N:25].[O:26]=[O+][O-].CSC>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[C:17]([CH:19]([OH:21])[CH3:20])[C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[C:4]([CH:22]=[O:26])[C:3]=1[C:24]#[N:25]
Reactant: C=Cc1c(C#N)c(Cl)cc(C(C)O)c1OCCNC(=O)OC(C)(C)C
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: CC(O)c1cc(Cl)c(C#N)c(C=O)c1OCCNC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
Tert-butyl {2-[4-chloro-3-cyano-6-(1-hydroxyethyl)-2-vinylphenoxy]ethyl}carbamate (1.6 g, 4.4 mmol) was dissolved in methylene chloride (1.2 mL) cooled in a dry ice acetone bath and ozone/oxygen was bubbled through the solution until a persistent blue color remained. The reaction was purged with oxygen and nitrogen to remove excess ozone and dimethyl sulfide (0.80 mL, 11 mmol) was added to reduce the ozonide. After stirring for 1 h, the reaction was complete. This was concentrated in vacuo to give a residue give tert-butyl {2-[4-chloro-3-cyano-2-formyl-6-(1-hydroxyethyl)phenoxy]ethyl}carbamate. LCMS calculated for C17H21ClN2O5Na (M+Na)+: m/z=391.1; found: 391.1.
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[CH3:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][NH2:22]>C(O)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:17])[C:6](=[O:18])[C:5]=2[NH:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:19])=[CH:14][CH:13]=1
Reactant: CC(CN)c1ccccc1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CCO
Product: COc1ccc(-c2c(NCC(C)c3ccccc3)c(=O)c2=O)cc1
Yield: 66.4 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 2-methyl-2-phenyl-ethylamine (0.165 g, 1.22 mmol) in ethanol (2 mL) were converted to the title compound (0.130 g, 66%) m.p.: 215.4-216.2° C.; 1H NMR (DMSO-d6) δ 9.07(br t,1H), 7.95(ABq,2H), 7.30-7.18(m,5H), 7.08(ABq,2H), 3.90-3.72(m,2H), 3.82(s,3H), 3.09(m,1H), 1.26(d,3H); IR (KBr) 3160, 2960, 1775, 1730, 1560, 1430, 1300, 1250, 1170, 1100, 1020, 840 cm−1; MS (m/z) 322 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=O)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:30]([C:32]1[N:36]=[C:35]([CH2:37][N:38]2[C:43]3[CH:44]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:46][C:42]=3[C:41](=[O:53])[N:40]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[C:39]2=[O:60])[O:34][N:33]=1)[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([C:19]([N:57]4[CH2:58][CH2:59][CH:54]([N:40]5[C:41](=[O:53])[C:42]6[S:46][C:45]([C:47]7[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:35]6[O:34][N:33]=[C:32]([CH2:30][CH3:31])[N:36]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[O:21])[CH:22]=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CC)no5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
The title compound is prepared analogously as described for example 1 using 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C8), 1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-phenyl-3-piperidin-4-ylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B32), HBTU (167 mg), DIPEA (0.28 ml) and DCM (3 ml). The crude product is purified by flash column chromatography (amino phase silica gel, eluent gradient: EtOAc/methanol, 98/2 to 95/5 (v/v)) and afterwards by preparative TLC [silica gel, eluent: EtOAc/MeOH/triethylamine, 92.5/5/2.5 (v/v/v)] to yield the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:8]([O:21][CH3:22])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:23]N(C=NC=[N+](C)C)C.[Cl-].C(O)(=O)C.C([O-])(=O)C.[Na+]>O1CCOCC1>[CH3:22][O:21][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:1]=[CH:23][NH:6][C:4]2=[O:5]
Reactant: COc1cc(C(N)=O)c(N)cc1OCCCN1CCOCC1
Reactant: CN(C)C=NC=[N+](C)C
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A mixture of 2-amino-5-methoxy4-(3-morpholinopropoxy)benzamide (4.57 g, 12.25 mmol) and Gold's reagent (2.6 g, 15.89 mmol) in dioxane (35 ml) was heated at reflux for 5 hours. Acetic acid (0.55 ml) and sodium acetate (1.0 g) were added to the reaction mixture which was heated for a further 3 hours. The mixture was cooled to ambient temperature and the volatiles removed by evaporation. The residue was adjusted to pH7 with 2 M sodium hydroxide and then purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with methanol (gradient of 0 to 60%) in water. Concentration of the fractions by evaporation gave a precipitate which was collected by filtration and dried under vacuum over phosphorus pentoxide to give 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (3.04 g, 78%) as a white solid.
Reaction SMILES: S1C(C2C3C=C(OCC)C(OCC)=CC=3CC(=O)NN=2)=CC2C=CC=C[C:2]1=2.[S:28]1[C:32]([C:33]2[C:39]3[CH:40]=[C:41]([O:47][CH2:48][CH3:49])[C:42]([O:44][CH2:45][CH3:46])=[CH:43][C:38]=3[CH:37]([CH2:50][CH2:51][CH3:52])[C:36](=[O:53])[NH:35][N:34]=2)=[CH:31][C:30]2[CH:54]=[CH:55][CH:56]=[CH:57][C:29]1=2>>[S:28]1[C:32]([C:33]2[C:39]3[CH:40]=[C:41]([O:47][CH2:48][CH3:49])[C:42]([O:44][CH2:45][CH3:46])=[CH:43][C:38]=3[CH:37]([CH2:50][CH2:51][CH3:52])[C:36](=[O:53])[N:35]([CH3:2])[N:34]=2)=[CH:31][C:30]2[CH:54]=[CH:55][CH:56]=[CH:57][C:29]1=2
Reactant: CCCC1C(=O)NN=C(c2cc3ccccc3s2)c2cc(OCC)c(OCC)cc21
Reactant: CCOc1cc2c(cc1OCC)C(c1cc3ccccc3s1)=NNC(=O)C2
Product: CCCC1C(=O)N(C)N=C(c2cc3ccccc3s2)c2cc(OCC)c(OCC)cc21
Yield: 34 %

Procedure:
By replacing 1-(2-benzo[b]thienyl)-7,8-diethoxy-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIab in example IIIba by 1-(2-benzo[b]thienyl)-7,8-diethoxy-5-n-propyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIac and proceeding in the same manner, the abovenamed product is obtained. Yield: 34%. M: 61–63° C. 1H-NMR (200 MHz, CDCl3): d 1.01 (t, J=7.34, 3H, (CH2)2CH3), 1.39–4.55 (m, 8H, CH2CH2CH3+2×OCH2CH3), 1.75–2.42 (m, 2H, CH2CH2CH3), 3.04–3.11 (m, 1H, 5-H), 3.45 (s, 3H, 3-CH3), 3.99–4.23 (m, 4H, 2×OCH2CH3), 6.83 (s, 1H Ar), 7.12 (s, 1H Ar), 7.35–7.44 (m, 3H Ar), 7.72–7.89 (m, 2H Ar).