Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=4)[CH2:12]3)=[C:8]([C:25]([NH2:27])=[O:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH3:29][C:30]([OH:47])([CH3:46])[CH2:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.N#N>C(O)(C)(C)C.CO.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([N:13]2[CH2:14][C@H:15]([CH3:16])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:28]=[C:2]([C:35]5[CH:34]=[N:33][N:32]([CH2:31][C:30]([OH:47])([CH3:46])[CH3:29])[CH:36]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:25]([NH2:27])=[O:26])[CH2:12]2)=[N:18][CH:19]=1)#[N:24]
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H]1CN(c2ccc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: CC(C)(C)O
Solvent: O
Solvent: CO
Product: C[C@H]1CN(c2ccc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CC(C)(C)O)c3)cc12
Temperature: 110 °C
Yield: 43.1 %

Procedure:
A solution of 6-bromo-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.045 mmol, from Step 2), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (24.18 mg, 0.091 mmol, from Step 3), potassium phosphate tribasic (28.9 mg, 0.136 mmol), palladium(II) acetate (1 mg, 4.45 μmol) and dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (4.78 mg, 8.90 μmol) in tert-butanol (0.5 mL) was degassed by vacuum-N2 refill cycle twice. The sealed tube was then heated at 110° C. for 2 h. The crude material was diluted with methanol (1.3 mL) and water (0.2 mL) and filtered. The filtrate was purified by preparative RP-HPLC (50-80% solvent B in 30 min, 30 mL/min, Pursuit XRs 10 u C18 30×250 mm) to give the title compound (9.7 mg). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.31 (br. s., 1H), 8.07 (s, 1H), 7.85 (s, 1H), 7.74 (s, 2H), 7.63 (dd, J=8.9, 1.5 Hz, 1H), 6.98 (d, J=1.5 Hz, 1H), 6.49 (d, J=8.9 Hz, 1H), 4.97 (br. s., 1H), 4.10 (s, 2H), 3.99-3.75 (m, 3H), 3.46-3.36 (m, 1H), 2.84 (br. s., 1H), 1.29 (d, J=6.9 Hz, 3H), 1.20 (s, 6H); MS (ES+) m/z: 500.2 (M+H); LC retention time: 1.18 min (analytical LCMS Method I).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[C:12]([Cl:17])[C:11]=1[OH:18]>>[Cl:9][C:10]1[CH:15]=[C:14]([CH:13]=[C:12]([Cl:17])[C:11]=1[O:18][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1)[NH2:16]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: Clc1ccc(Cl)nn1
Product: Nc1cc(Cl)c(Oc2ccc(Cl)nn2)c(Cl)c1

Procedure:
In one embodiment, the process further comprises providing the compound of Formula (I) by contacting 3,6-dichloropyridazine with 2,6-dichloro-4-aminophenol to form 3,5-dichloro-4-((6-chloropyridazin-3-yl)oxy)aniline, hydrolyzing 3,5-dichloro-4-((6-chloropyridazin-3-yl)oxy)aniline and protecting the amine group of 3,5-dichloro-4-((6-chloropyridazin-3-yl)oxy)aniline either before or after the hydrolysis to form the compound of Formula (I). The contacting of 3,6-dichloropyridazine with 2,6-dichloro-4-aminophenol is performed in a polar aprotic solvent (e.g., dimethylacetamide (DMAC)) in the presence of a base (e.g., Cs2CO3) at a reaction temperature between 60 and 120° C. (e.g., about 65° C.). Further, a purification step may be included. That is, before step (a), the compound of Formula (I) is purified in an acidic solution at a temperature between 80 and 100° C.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([CH2:15][CH3:16])[CH2:9]2)[C:3](O)=[O:4].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[CH3:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([CH2:15][CH3:16])[CH2:9]2)[C:3]([Cl:19])=[O:4]
Reactant: CCC1Cc2ccc(C(C)C(=O)O)cc2C1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCC1Cc2ccc(C(C)C(=O)Cl)cc2C1

Procedure:
A solution of 57 g of 2-methyl-(2-ethylindan-5-yl)acetic acid and 40 ml of thionyl chloride in 200 ml of benzene is heated under reflux for 2 hours. The solvent and the excess thionyl chloride are then evaporated off in vacuo. The resulting oil is then distilled in vacuo. 56 g of 2-methyl-(2-ethylindan-5-yl)-acetic acid chloride are thus recovered in the form of a liquid:
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21]>>[CH2:1]([O:5][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21])[C:2]#[C:3][CH3:4]
Reactant: CC#CCO
Reactant: O=C(OCCCCCCCCCCCCBr)C1CC1
Product: CC#CCOCCCCCCCCCCCCOC(=O)C1CC1

Procedure:
In an analogous manner to that described in Example 5, from 2-butyn-1-ol and cyclopropane carboxylic acid 12-bromododecyl ester there is obtained cyclopropane carboxylic acid 12-(2-butynyloxy)dodecyl ester of melting point 38°-40° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]=1.[Li:13]CCCC>CCCCCC>[CH3:1][N:2]([CH3:12])[C:3]1([Li:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: [Li]CCCC
Reactant: CN(C)C1=CCc2ccccc21
Solvent: CCCCCC
Product: [Li]C1(N(C)C)C=Cc2ccccc21
Reaction time: 8 h
Yield: 90.7 %

Procedure:
In the drybox 3.8 g (23.9 mmol) of N,N-dimethyl-1H-inden-3-amine was combined with 100 mL of hexane. To this solution 15 mL (23.9 mmol) of n-BuLi (1.6 M) was added dropwise. Upon complete addition of the n-BuLi the solution was stirred overnight. The resulting precipitate was collected via filtration, washed with hexane and dried under reduced pressure to give 3.58 g of product. Yield 91 percent.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH2:16])=[O:15])C)C1C=CC=CC=1>C(O)C.[Pd]>[C:17]1([C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:12][CH2:11][CH2:10][NH:8][CH3:1])[C:14]([NH2:16])=[O:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reaction time: 87 h

Procedure:
A mixture of 5-(N-benzyl-N-methylamino)-2,2-diphenylpentanamide (11 g--see Example 1) and 10% palladium-on-carbon (1.1 g) in ethanol (150 ml) was hydrogenated at room temperature and 50 p.s.i. (344.7 kPa) pressure for 87 hours. The mixture was filtered and the filtrate concentrated in vacuo to give an oil. The oil was triturated with ether to give the title compound as a colourless powder, yield 4.5 g.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:31]3[CH2:30][CH2:29][CH:28]([C:25]4[C:24]5[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=5[O:27][N:26]=4)[CH2:33][CH2:32]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(C(=O)CCCCl)sc2C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Product: CC(=O)N1CCc2cc(C(=O)CCCN3CCC(c4noc5cc(F)ccc45)CC3)sc2C1
Yield: 36 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.2 g of 6-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine and 2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 1.3 g of 6-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as white crystals, m.p. 145°-147° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]=[O:28])[CH2:23][CH2:22]3)[N:18]=[C:17]([O:29][CH2:30][CH2:31][C:32]([OH:34])=O)[C:16]=2[O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:44]([C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[NH2:49])([CH3:46])[CH3:45]>>[CH:44]([C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[NH:49][C:32](=[O:34])[CH2:31][CH2:30][O:29][C:17]1[C:16]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=2)(=[O:12])=[O:13])[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]=[O:28])[CH2:25][CH2:26]2)[N:18]=1)([CH3:46])[CH3:45]
Reactant: CC(C)c1ccccc1N
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C=O)CC2)nc1OCCC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C=O)CC2)nc1OCCC(=O)Nc1ccccc1C(C)C

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-2-(4-formylpiperazinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyloxy]propionic acid and 2-isopropylaniline, to thereby obtain the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:3]=1.CC1(C)C(C)(C)[O:25][B:24](B2OC(C)(C)C(C)(C)O2)[O:23]1.C([O-])(=O)C.[K+].Cl>O1CCOCC1.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>[CH:15]1([O:14][C:4]2[CH:3]=[C:2]([B:24]([OH:25])[OH:23])[CH:7]=[CH:6][C:5]=2[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)Cc1ccc(Br)cc1OC1CCCCC1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(B(O)O)cc1OC1CCCCC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution of ethyl (4-bromo-2-cyclohexyloxyphenyl)acetate (1.23 g) in 1,4-dioxane (14.6 ml) were added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.01 g), dichlorobis(triphenyphosphine)palladium(II) (126 mg) and potassium acetate (1.06 g) at room temperature under nitrogen, and the mixture was stirred at 95° C. for 2 hours. The resulting mixture was poured into 1N hydrochloric acid and the aqueous layer was extracted with a mixture of hexane and ethyl acetate (1:1). The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, evaporated and dried in vacuo. To a suspension of the above obtained residue in a mixture of ethyl acetate (14.6 ml) and water (24.6 ml) were added ammonium acetate (1.75 g) and sodium periodate (4.86 g) at room temperature, and the mixture was stirred at the same temperature for 24 hours. The resulting mixture was poured into dilute hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2:1 to 1:1) to give [3-cyclohexyloxy-4-(ethoxycarbonylmethyl)phenyl]boronic acid (719 mg).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:13]([O:15]CC)=[O:14].[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>CN(C=O)C.O.C(OCC)(=O)C>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH:4]=[C:3]([C:13]([OH:15])=[O:14])[C:2]2=[O:1]
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1c[nH]c2c(Cl)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cccc(Cl)c32)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-oxo-8-chloro-1,4-dihydroquinoline-3-carboxylate (1.0 g), potassium iodide (0.66 g) and sodium carbonate (1.1 g) in DMF (20 mL) was added 1-(chloromethyl)-4-methoxybenzene (0.7 mL), and the mixture was stirred at 70° C. overnight. The reaction mixture was diluted with water and ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was solidified with a diisopropyl ether-ethyl acetate mixed solution. The obtained solid was dissolved in ethanol-THF (1:1, 12 mL), 1 N aqueous sodium hydroxide solution (6 mL) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with water, neutralized with 1 N hydrochloric acid (10 mL), and the precipitate was collected by filtration, washed with water, and dried to give the title compound (0.52 g).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([CH:13]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18](=[O:23])[CH:17]([O:24][SiH:25]([CH3:27])[CH3:26])[CH2:16][CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].Cl>O1CCCC1.CCOCC>[C:1]1([C:18]2([OH:23])[CH2:19][CH2:20][CH2:21][CH2:22][CH:13]([C:9]([CH3:12])([CH3:10])[CH3:11])[CH2:14][CH2:15][CH2:16][CH:17]2[O:24][SiH:25]([CH3:27])[CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[SiH](C)OC1CCCC(C(C)(C)C)CCCCC1=O
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[SiH](C)OC1CCCC(C(C)(C)C)CCCCC1(O)c1ccccc1
Temperature: 40 °C

Procedure:
21 ml of a solution (1.0 M) of phenylmagnesium bromide in tetrahydrofuran was dissolved in 50 ml of anhydrous ether, and to the solution was added 1.5 g of the above product (b). The reaction solution was stirred at 40° C. for three and a half hours. The reaction solution was poured into ice water and adjusted to pH 4 by addition of 2N HCl, and extracted with ether. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was subject to column chromatography on silica gel, and the eluate with ethyl acetate-hexane (1:20) was collected, to afford 1.1 g of the titled compound (c) as a colorless oily matter.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:12]=1[NH:20][S:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36](I)[CH3:37].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:12]=1[N:20]([CH2:36][CH3:37])[S:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:23])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCI
Reactant: CCOC(=O)CS(=O)(=O)Nc1cc(C(C)C)ccc1CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CS(=O)(=O)N(CC)c1cc(C(C)C)ccc1CCNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of 0.387 g of ethyl [[2-(2-tert-butoxycarbonylaminoethyl)-5-isopropylphenyl]sulfamoyl]acetate in 5 mL of N,N-dimethylformamide were added 0.131 g of potassium carbonate and 0.169 g of ethyl iodide at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.342 g of ethyl [[2-(2-tert-butoxycarbonylaminoethyl)-5-isopropylphenyl](ethyl)sulfamoyl]acetate.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:17])[NH:14][C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:31][Si:32]([CH2:35][CH2:36][O:37][CH2:38]Cl)([CH3:34])[CH3:33]>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:17])[N:14]([CH2:38][O:37][CH2:36][CH2:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2\NC(=O)NC2=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C2\NC(=O)N(COCC[Si](C)(C)C)C2=O)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 0.08 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[(2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.200 g, 0.524 mmol) in DMF (2 mL) is added sodium hydride (80% in oil, 0.02 g, 0.67 mmol) and the mixture stirred for 5 minutes. (Trimethylsilyl)ethoxymethyl chloride SEM-C1 (0.100 mL, 0.536 mmol) is added and the mixture allowed to stir for 16 hours. The solvents are removed in vacuo and the residue dissolved in ethyl acetate and water. After drying the organic fraction over MgSO4, the required product is isolated by chromatography, eluting with 0.5% methanol in chloroform. Crystallized from ether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[Se:27][C:26]=1[C:34]([NH2:36])=[O:35].CN(C=O)C.[OH-].[Na+]>>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:24][C:25]4[CH:29]=[C:28]([C:30]([CH3:33])([CH3:31])[CH3:32])[Se:27][C:26]=4[C:34]([NH2:36])=[O:35])=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:19][CH2:20]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(C(C)(C)C)[se]c3C(N)=O)ncnc2cc1OCCCN1CCOCC1

Procedure:
The reaction of 4-chloro-7-(3-morpholinopropoxy)-6-methoxyquinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a pale yellow color solid, mp 216-220° C. IR (KBr) vmax 3342, 3120, 2957, 2853, 1633, 1572, 1497, 1457, 1393, 1315, 1234, 1141, 1113, 1021, 903, 854, 798 cm1; 1H NMR (400 MHz, CDCl3): δ 12.06 (1H, s, exchangeable with D2O), 8.86 (1H, s), 8.71 (1H, s), 7.34 (1H, s), 7.25 (1H, s), 5.57 (2H, s, exchangeable with D2O), 4.25 (2H, t, J=6.6 Hz), 4.06 (3H, s), 3.74 (4H, t, J=4.4 Hz), 2.59 (2H, t, J=7.2 Hz), 2.51 (4H, br s), 2.10-2.16 (2H, m), 1.46 (9H, s); 13C NMR (100 MHz, CDCl3): δ 168.9, 168.6, 154.4, 154.3, 153.3, 150.1, 148.1, 147.4, 121.7, 109.6, 109.2, 108.3, 100.3, 67.3, 66.8, 56.2, 55.3, 53.7, 37.2, 32.6, 25.9; LC-MS (positive ion mode): m/z 546, 548 (M+H)+.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([Cl:16])([Cl:15])[Cl:14])[O:10][CH:9]([C:17]([Cl:20])([Cl:19])[Cl:18])[C:8]=2[CH:21]=1.[CH3:22]I>C(O)C>[CH3:22][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([Cl:14])([Cl:15])[Cl:16])[O:10][CH:9]([C:17]([Cl:20])([Cl:19])[Cl:18])[C:8]=2[CH:21]=1
Reactant: Oc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reaction time: 0.25 h

Procedure:
A solution of sodium hydroxide (0.52 g.) in ethanol (50 ml.) was added dropwise to a stirred solution of 6-hydroxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin (5 g.) in ethanol (100 ml.) and the resulting solution was stirred for 15 minutes. Methyl iodide (1.7 ml.) was then added, the reaction mixture was warmed on a steam bath for 1 hour, and evaporated to dryness under reduced pressure, and the oily residue was triturated with diethyl ether and filtered to remove sodium iodide. The filtrate was chromatographed on silica (Kieselgel 60; 200 g.) and the product was crystallised from ethanol to give 6-methoxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 105°-107° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].[C:22](OC)(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[SH:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:21])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=[O:30])[N:20]=2)[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:10])([CH3:9])[CH3:11])=[O:4]
Reactant: CC(C)(Cc1ccnc(C#N)c1)C(=O)OCC[Si](C)(C)C
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(Cc1ccnc(-c2nc(=O)c3ccccc3s2)c1)C(=O)OCC[Si](C)(C)C
Yield: 53.6 %

Procedure:
2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-(2-cyano-4-pyridyl)propionate (0.68 g, 2.2 mmol) and methyl thiosalicylate (0.60 g, 3.6 mmol) were dissolved in toluene (2.5 ml), and triethylamine (0.56 ml, 4.0 mmol) was added thereto. The reaction mixture was refluxed for 16 hrs and subjected to a silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected and concentrated to give the titled compound (0.52 g, 53%) as white crystals.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[BH4-].[Na+].[OH-].[Na+]>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:10][C:8]2[CH:7]=[CH:6][C:5]3[N:1]=[CH:2][NH:3][C:4]=3[CH:9]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CNc2ccc3nc[nH]c3c2)cc1

Procedure:
Alternatively the compound was synthesized starting from benzimidazol-5-amine (2.66 g; 20 mmol; 1 eq.), 4-methoxybenzaldehyde (3.26 g; 2.9 ml; 24 mmol; 1.2 eq.), NaBH4 (1.14 g; 30 mmol; 1.5 eq.) and 5 N NaOH (20 ml; 100 mmol; 5 eq.) according to method 2; Yield: 4.53 g (89.5%); MS m/z: 254.3 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[CH2:26]([C:28]1[O:29][CH:30]=[CH:31][C:32](=[O:35])[C:33]=1[OH:34])[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[NH:8][C:6]1[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=[C:2]([O:34][C:33]2[C:32](=[O:35])[CH:31]=[CH:30][O:29][C:28]=2[CH2:26][CH3:27])[N:7]=1
Reactant: CCc1occc(=O)c1O
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1occc(=O)c1Oc1nc(Nc2ccc(OC)c(Cl)c2)nc(NC2CCCCCC2)n1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 133 (0.3 g, 0.78 mmol), 2-ethyl-3-hydroxy-4H-pyran-4-one (0.11 g, 0.78 mmol) and K2CO3 (0.54 g, 3.91 mmol) in dimethylformamide (15 mL) was stirred at 80° C. for 6 hours under nitrogen atmosphere. After completion of the reaction the mixture was cooled to 25° C. and diluted with water (50 mL). The precipitated solid was filtered off and dried under vacuum to afford the title compound E19 as an off-white solid (0.2 g, 52%). mp 124-126° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns 50:50 [0.01 M KH2PO4 (0.1% TFA):CH3CN], 223 nm, Rt 18.47 min, 98.18% purity); MS (CI): m/z 486 (M+, 100), 382 (90).