Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([N+:36]([O-])=O)=[C:31]([F:39])[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[Sn](Cl)Cl>CCOC(C)=O.C(O)C.O>[NH2:36][C:32]1[C:31]([F:39])=[CH:30][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:34][C:33]=1[F:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c([N+](=O)[O-])c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(N)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 55.4 %

Procedure:
A solution of 5-cyclopropyl-6-(N-(3,5-difluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.65 g, 1.16 mmol) and tin (II) chloride (0.66 g, 3.49 mmol) in EtOAc (10 mL) and ethanol (10 mL) was heated under reflux for 2 h. The reaction mixture was diluted with EtOAc and water and the suspension was filtered through celite. The organic layer was dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (0.34 g, 55%) as a white solid. LCMS (m/z, ES+)=530.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.C(O)(=O)C.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[S:3][C:4]([CH2:7][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][N:6]=1
Reactant: C1CCNCC1
Reactant: O=Cc1cnc(Br)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1ncc(CN2CCCCC2)s1
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
2-Bromo-5-formylthiazole (198 mg, 1.034 mmol, available from Fluorochem) was mixed with acetic acid (0.148 mL, 2.58 mmol) and Piperidine (0.128 mL, 1.292 mmol), dissolved in Dichloromethane (DCM) (9.5 mL) and stirred under nitrogen for 30 minutes. sodium triacetoxyborohydride (411 mg, 1.938 mmol) was added and the reaction was allowed to stir under nitrogen for 45 minutes. A second sample of sodium triacetoxyborohydride (411 mg, 1.938 mmol) was added and the reaction was left to stir under nitrogen for 4.5 days. The reaction was loaded onto a 5 g SCX-column, eluting with MeOH (40 mL) followed by 2M MeOH/NH3 (40 mL). Product-containing fractions were evaporated to dryness to give a yellow solid. This was partitioned between sodium bicarbonate (20 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (70 mL) and the organic fractions were combined, washed (brine (50 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a yellow solid (214 mg). This was purified on a 25+S Biotage silica column, eluting with DCM:2M MeOH/NH3 (1:0 to 49:1, 22 CV). Product-containing fractions were evaporated to dryness to give a dark yellow solid (134 mg)
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 3-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (600 mg, 2.0 mmol), as prepared in the preceding step, N-tert-butoxycarbonyl-4-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step (b) of Example 1, and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (20 mL) at 0° C. The mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (1:3 ethyl acetate/hexane) to give the title compound as a colorless liquid (800 mg, 81%). 1H-NMR (300 MHz, CDCl3) δ 1.24 (m, 2 H), 1.47 (s, 9 H), 1.75 (m, 2 H), 1.90 (m, 1 H), 2.25 (s, 3 H), 2.73 (t, 2 H, J=12.5 Hz), 3.68 (d, 2 H, J=3.1 Hz), 4.13 (m, 2 H), 6.34 (t, 1H, J=2.2 Hz), 6.39 (s, 1 H), 6.61 (s, 1 H), 7.49 (t, 1 H, J=7.8 Hz),7.63 (d, 1H, J=0.7 Hz),7.75 (d, 1 H,J=3.9 Hz), and 7.86 (t, 1 H, J=1.8 Hz).
Reaction SMILES: [CH2:1]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:26][C:27]([O-:29])=[O:28])([C:16]2[C:24](O)=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:8]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([C:16]3[CH:17]=[C:18]4[O:22][CH2:21][O:20][C:19]4=[CH:23][C:24]=3[O:29][C:27](=[O:28])[CH2:26]2)[C:8]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C(CC(=O)[O-])(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN1C(=O)C2(CC(=O)Oc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
To a solution of 2-(1-hexyl-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-2-oxoindolin-3-yl)acetate (0.19 g, 0.43 mmol) in THF:H2O (2:1) was added lithium hydroxide (0.04 g, 0.86 mmol). The mixture was stirred at ambient temperature for 4 hrs. The organic solvent was removed in vacuo and the pH of the aqueous residue was adjusted to 2 followd by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography eluting with 25% ethyl acetate/hexane to yield the title compound (0.09 g, 53%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.33 (dt, 1H), 7.14-7.03 (m, 2H), 6.93 (d, 1H), 6.66 (s, 1H), 6.06 (s, 1H), 5.88 (dd, 2H), 3.76-3.63 (m, 2H), 2.94 (q, 2H), 1.69-1.62 (m, 2H) 1.34-1.22 (m, 6H), 0.83 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 175.9, 165.8, 148.3, 147.2, 144.6, 142.6, 129.9, 129.6, 123.8, 123.4, 114.7, 109.2, 105.1, 101.9, 99.8, 49.6, 40.3, 37.2, 31.2, 27.2, 26.4, 22.4, 13.9; MS (ES+) m/z 394.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)COc1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To (2,4-dichloro-phenoxy)-acetic acid (110.6 mg, 0.5 mmol), 2-aminobenzoic acid methyl ester (151.2 mg, 1.0 mmol), and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (pybop) (520.3 g, 1.0 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.17 mL, 1.0 mmol). The mixture was stirred overnight and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (118.0 mg, 66.6% yield).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]([O:11][CH2:12][C:13]#[CH:14])(=[O:10])[CH3:9].[I-].CO>CCN(CC)CC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1](=[O:6])[C:14]#[C:13][CH2:12][O:11][C:8](=[O:10])[CH3:9]
Reactant: C#CCOC(C)=O
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)OCC#CC(=O)C(C)(C)C

Procedure:
Pivaloyl chloride (612 μl), propargyl acetate (644 μl), cupper iodide (12 mg) and bis-(triphenylphosphine) palladium(II)-dichloride (9.1 mg) in NEt3 (10 ml) were stirred at RT for 24 h. MeOH was added and the mixture was evaporated off. The residue was taken up in Et2O and the resulting suspension filtered off. The solution was washed with a 1M HCl solution, water, dried (Na2SO4) and evaporated off. Column chromatography (EA/Hept 1/3) afforded 343 mg of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][C:11](=C)[CH2:10][C@H:9]2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:22]CC1.I([O-])(=O)(=O)=O.[Na+].C(OCC)(=O)C>CC(C)=O.O.O1CCCC1.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][C:11](=[O:22])[CH2:10][C@H:9]2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](c2ccc(Cl)cc2)C1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H]1CC(=O)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 50 mL round bottom flask equipped with a magnetic stir bar was charged with 1.20 g (4.8 mmol) of the product of Step B dissolved in 8.6 mL acetone. To the reaction mixture was added 0.673 g (5.74 mmol) of 4-methylmorpholine N-oxide dissolved in 2 mL water followed by 1.52 mL (0.20 mmol) of an osmium tetroxide solution (4 wt % in water). The reaction mixture was stirred 1 h at room temperature at which point TLC analysis indicated complete consumption of the starting material. The reaction mixture was quenched with excess 10% aqueous sodium bisulfite, then partitioned between water and ethyl acetate in a separatory funnel. The organic layer was washed with water, separated, dried (MgSO4), filtered and evaporated in vacuo. The residual oil was redissolved in 5.5 mL tetrahydrofuran in a 25 mL round bottom flask and 5.5 mL water was added. To this solution was added 1.228 g (5.74 mmol) of sodium periodate. After stirring for approximately 10 min at room temperature, a precipitate formed and the suspension was diluted with 5 mL tetrahydrofuran. Stirring was continued for 1 h, at which point TLC analysis revealed a new less polar product spot. The mixture was suspended between ethyl acetate and water and extracted. The organic layer was separated, dried (MgSO4), filtered and evaporated in vacuo. The residual clear oil was used in the next step without further purification.
Reaction SMILES: [BrH:1].[CH:2]1([NH:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[C:14]=3[OH:18])[C:9]2=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3]1>[Pd].O>[BrH:1].[CH:2]1([NH:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[C:14]=3[OH:18])[CH:9]2[OH:20])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2ccc(O)c(O)c2CCC1NC1CCCC1
Agent: [Pd]
Agent: Br
Solvent: O
Product: Oc1ccc2c(c1O)CCC(NC1CCCC1)C2O

Procedure:
Using 2 parts of 5% palladium-on-carbon, 2parts of 2-cyclopentylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide in 50 volume parts of water is subjected to catalytic reduction at ordinary temperature and pressure. After a stoichiometric amount of hydrogen has been absorbed, the reaction is terminated and the catalyst is filtered off. The filtrate is freeze-dried and the residue is recrystallized from a mixture of ethanol and ethyl acetate. The procedure yields 1.54 parts of 2-cyclopentylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide as colorless crystals melting at 210°-218° C (decomposition).
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[OH:6][OH:7].[Si]=[Ti:9]=[Si].O.[NH3:12]>>[S:2](=[O:3])(=[O:1])([OH:5])[OH:4].[OH:6][OH:7].[N:12]#[Ti:9]
Reactant: N
Reactant: [Si]=[Ti]=[Si]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: N#[Ti]

Procedure:
In this embodiment, the first wet etching is performed using a mixed solution of the composition of H2SO4 :H2O2 =5:1 at an etchant temperature of 140° C. for 20 minutes. The amount of the titanium disilicide film of the C49 structure etched off during the first etching by this mixed solution is extremely less than the amount of the titanium disilicide film of the C49 structure etched off during the first etching by the mixed solution of ammonia water and hydrogen peroxide (under this condition, about 1 nm of the film is etched off) (FIG. 5). During the first etching by the mixed solution of sulfuric acid and hydrogen peroxide, the titanium nitride film formed during the first rapid thermal annealing is removed in about 10 minutes. In this embodiment, therefore, the first wet etching is performed for 20 minutes including margin. Since the first wet etching is performed at 140° C., the maintenance of the composition of the mixed solution is required. During the first wet etching, the titanium-excess titanium silicide (Ti5 Si3) film is only little removed. In this embodiment, therefore, the second wet etching is performed using the mixed solution having a composition of NH4OH:H2O2 :H2O=1:1:5 at room temperature for 30 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18]CN(C(C)C)C(C)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(tert-Butoxycarbonyl)azepane-4-carboxylic acid (1.0 g; 4.11 mmol) in DCM (20 ml) and treated with DIPEA (1.5 ml, 8.22 mmol) followed by trimethyloxonium tetrafluoroborate (790 mg, 5.34 mmol) in DCM (5 ml). The mixture was stirred at RT for 3 hours and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic portion was separated and the aqueous was further extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: C([Li])(CC)C.[Si:6]([O:23][CH2:24][C:25]1[C:30]([N:31]2[CH2:36][C@H:35]([CH3:37])[O:34][C@H:33]([CH3:38])[CH2:32]2)=[C:29]([F:39])[C:28]([F:40])=[CH:27][CH:26]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CON(C)[C:44]([C:46]1[N:47]=[C:48]([CH3:51])[O:49][CH:50]=1)=[O:45]>C1COCC1>[Si:6]([O:23][CH2:24][C:25]1[C:30]([N:31]2[CH2:36][C@H:35]([CH3:37])[O:34][C@H:33]([CH3:38])[CH2:32]2)=[C:29]([F:39])[C:28]([F:40])=[C:27]([C:44]([C:46]2[N:47]=[C:48]([CH3:51])[O:49][CH:50]=2)=[O:45])[CH:26]=1)([C:19]([CH3:21])([CH3:22])[CH3:20])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CON(C)C(=O)c1coc(C)n1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cc1nc(C(=O)c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(F)c2F)co1
Reaction time: 2 h

Procedure:
sec-Butyl lithium (1.4 M in cyclohexane, 3.2 eq) was added to a stirred solution of (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3, 1.0 g, 2.02 mmol) in anhydrous THF (10 mL) at −78° C., and the mixture was stirred for 2 h. N-methoxy-N,2-dimethyl-1,3-oxazole-4-carboxamide (1.0 g, 6.46 mmol) in THF (5 mL) was added dropwise and stirring was continued for an additional 1 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was removed under vacuum and the residue was purified by silica gel chromatography using ethyl lacetate-pet. ether gradient to obtain product. Yield: 600 mg, (50%)
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[CH:6][C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15].[CH3:19][N:20]=[C:21]=[O:22].C(N(CC)CC)C>C(Cl)Cl>[F:18][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[CH:6][C:5]=1[S:14]([NH:17][C:21]([NH:20][CH3:19])=[O:22])(=[O:16])=[O:15]
Reactant: CN=C=O
Reactant: NS(=O)(=O)c1cc(OC(F)F)ccc1OC(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)NS(=O)(=O)c1cc(OC(F)F)ccc1OC(F)F
Temperature: 25 °C

Procedure:
14.5 g of 2.5-bis(difluoromethoxy)phenylsulfonamide are suspended in 50 ml of absolute methylene chloride. Then 3.5 g of methyl isocyanate are added and 6.3 g of triethylamine are subsequently added dropwise over 10 minutes to form a clear solution. The solution is stirred at room temperature for a further hour, evaporated to dryness, and the residue is dissolved in 5% sodium carbonate solution. N-[2,5-bis(difluoromethoxy)phenylsulfonyl]-N'-methylurea with a melting point of 162°-165° C., is precipitated from the solution by acidification with 10% hydrochloric acid. Yield: 15.0 g.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.[Cl:34][C:35]1[CH:43]=[C:42]([C:44]#[C:45][CH2:46][O:47][CH3:48])[C:38]2[O:39][CH2:40][O:41][C:37]=2[C:36]=1[NH2:49]>CC(N(C)C)=O>[Cl:34][C:35]1[CH:43]=[C:42]([C:44]#[C:45][CH2:46][O:47][CH3:48])[C:38]2[O:39][CH2:40][O:41][C:37]=2[C:36]=1[NH:49][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CC(=O)N(C)C
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Temperature: 0 °C
Yield: 72.2 %

Procedure:
Sodium hexamethyldisilazane (1M solution in THF; 1.0 ml) was added to a mixture of 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (0.16 g) and 5-chloro-7-(3-methoxyprop-1-ynyl)-1,3-benzodioxol-4-amine (0.12 g) in DMA (5 ml) that was cooled to 0° C. The resultant mixture was stirred and allowed to warm to ambient temperature for 2 hours. The reaction mixture was reduced in vacuo and partitioned between ethylacetate and water. The organic layers were washed with water and brine and the product was purified column chromatography on silica using a gradient of 0-10% methanol/methylene chloride as eluent. The resultant yellow gum was dissolved in minimal methylene chloride, diluted with diethyl ether and precipitated as an HCl salt by the addition of 1.0M ethereal HCl. The resultant solid was centrifuged and washed with diethyl ether (3 times) and dried to give the title compound as a yellow solid (185 mg); NMR Spectrum: (DMSOd6+CD3CO2D at 100° C.) 2.33-2.40 (m, 2H), 3.30-3.40 (m, 9H), 3.93-3.98 (m, 4H), 4.03 (s, 3H), 4.38-4.41 (m, 4H), 6.19 (s, 2H), 7.15 (s, 1H), 7.41 (s, 1H), 8.16 (s, 1H), 8.66 (s, 1H); Mass Spectrum: M+H+ 541.5.
Reaction SMILES: Br.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]=[C:8]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3Br)[CH:9]=[CH:10][C:3]1=2.C([Mg]Cl)C.CN(C)[CH:26]=[O:27]>O1CCCC1>[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]=[C:8]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3[CH:26]=[O:27])[CH:9]=[CH:10][C:3]1=2
Reactant: CN(C)C=O
Reactant: BrC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Agent: Br
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: O=CC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Reaction time: 0.33 h

Procedure:
3-(Benzo[b]thiophen-5-yl)-2-bromo-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (1.9 g) was added in portions under nitrogen at 0-5° C. to a stirred solution of ethylmagnesium chloride (2M solution in ether; 6.8 ml) in tetrahydrofuran (30 ml), then the mixture was stirred at this temperature for 20 minutes. Dimethylformamide (1.5 ml) was added at <15° C., the mixture was stirred at <15° C. for 20 minutes and at ambient temperature for 1 hour, then it was quenched by the addition of saturated aqueous ammonium chloride solution (10 ml) and water (5 ml). Ethyl acetate (30 ml) was added, the mixture was stirred at ambient temperature for 18 hours, then the organic layer was separated and further product was isolated from the aqueous layer by extraction into ethyl acetate (2×15 ml). The combined ethyl acetate solutions were washed with water (2×30 ml) and saturated aqueous sodium chloride solution (35 ml), then they were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 9:1 mixture of ethyl acetate and methanol as eluant. Appropriate fractions were combined and the solvents were removed in vacuo to give 3-(benzo[b]thiophen-5-yl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxaldehyde (0.7 g) as a yellow solid, m.p. 146° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]([F:12])[F:11])=[C:6]([OH:8])[CH:7]=1.CCCCCCC=CCCC.[CH3:24][C:25](O)([C:27]#[CH:28])[CH3:26].C1CCN2C(=NCCC2)CC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O.C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]([F:11])[F:12])=[C:6]([O:8][C:25]([CH3:26])([CH3:24])[C:27]#[CH:28])[CH:7]=1
Reactant: C#CC(C)(C)O
Reactant: Oc1cc(Br)ccc1OC(F)F
Agent: CCCC=CCCCCCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C#CC(C)(C)Oc1cc(Br)ccc1OC(F)F
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To 30 ml of acetonitrile solution containing 7.31 g (30.6 mmol) of 5-bromo-2-difluoromethoxyphenol obtained in Reference example 11-(a) were added 6.4 mg of cuprous chloride and 6.43 ml of 1,8-diazabicyclo[5TO 5.4.0]-7-undecene at −10° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dropwise 30 ml of acetonitrile solution containing 6.18 g (73.5 mmol) of 2-methyl-3-butyn-2-ol which further contains 7.34 ml of 1,8-diazabicyclo[5.4.0]-7-undecene and 5.05 ml of trifluoroacetic anhydride at −10° C. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1.5 hours, and further at 0° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and extracted with toluene. The organic layer after separation was washed successively with 2N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 4.88 g of the title compound as a colorless oil. (Yield: 52%)