Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH:15]([CH3:23])[C:16]([O:18]C(C)(C)C)=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[O:1][CH:15]([CH3:23])[C:16]([OH:18])=[O:17]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C(=O)O)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Methyl 4-hydroxy-3-methoxybenzoate (1.09 g, 5.98 mmol) and tert-butyl 2-bromopropanoate (1.25 g, 0.97 mL, 5.98 mmol) and cesium carbonate (1.95 g, 5.98 mmol) were added into DMF (10 mL) in a 20 mL microwave vial equipped with a stir bar and sealed. The mixture was heated in Biotage microwave synthesizer for 1 hour at 100° C. The solvent was removed and the remained sticky oil was dissolved in DCM (7 mL) and TFA (7 mL). The mixture was stirred overnight. The reaction mixture was neutralized with sodium bicarbonate and organic layer was separated from the mixture. The aqueous layer was washed with DCM (2×10 mL), combined organics and acidified to around pH5 with 2N HCl. Aqueous was extracted with DCM and then with ethyl acetate, dried with sodium sulfate and concentrated to an oil. The crude product was dissolved in DCM (4 mL) and a pure product (0.530 g) precipitate out from the solution by adding diethyl ether (4 mL).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11](CC=C)[C:10]([C:18]#[N:19])=[N:9][C:8]=2[N:7]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]>C1COCC1.CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:18]#[N:19])=[N:9][C:8]=2[N:7]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C#N)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCn1c(=O)c2[nH]c(C#N)nc2n(CCCC)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
A solution of 1,3-dibutyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carbonitrile (140 mg, 0.43 mmol) in anhydrous THF (4 ml) and anhydrous DMSO (0.4 ml) was treated with Pd(PPh3)4 (74 mg, 0.064 mmol). The mixture was degassed under gentle vacuum, morpholine (371 uL) added, and left to stir at rt under nitrogen for 4 hours. The yellow solution was partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down and amino-propyl SPE (5 g), eluting with MeOH followed by 5%→50% AcOH/MeOH. The product eluted with a small impurity which was washed out, after concentrating, with cyclohexane to afford the title compound as an off-white solid (30 mg, 24%). NMR δH (400 MHz, d6-DMSO) 0.89 (app. td, 6H, J=7 and 3 Hz), 1.25-1.35 (m, 4H), 12.48-1.55 (m, 2H), 1.58-1.69 (m, 2H), 3.87 (t, 2H, J=7 Hz), 3.95 (t, 2H, J=7 Hz), NH not observed to δH 15; m/z 290.3[MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:16][CH2:17][CH:18]=C.CN(C)P(=O)(N(C)C)N(C)C>C1COCC1.CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:18][CH:17]=[CH2:16])[CH:6]=[CH:5]2
Reactant: C=CCCBr
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCOc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
A solution of 10.00 g (45 mmol, Aldrich) of 6-bromo-2-naphthol and 2.16 g (49.0 mmol, 1.1 eq. 60% in oil, Aldrich) of NaH dispersion in 100 ml of dry THF was stirred at 0° C., until gas evolution ceased. A solution of 4.60 ml (45.0 mmol, Aldrich) of 4-bromo-1-butene in 25 ml of DMF was added dropwise and the solution was warmed to room temperature, then stirred at 70° C. overnight. To this solution was added 2.28 ml (22.5 mmol, 0.5 eq., Aldrich) of 4-bromo-1-butene and 6 ml of hexamethylphosphoric triamide (HMPA). Then 1.00 g (20.8 mmol, 60% in oil, Aldrich) of NaH dispersion in 10 ml of dry THF was added, stirred at 70° C. for 8 hours and finally heated to 90° C. for 12 hours. The mixture was cooled, water was added, this was extracted with EtOAc, dried (MgSO4) and concentrated in vacuo. Purification was achieved via flash chromatography (silica gel, 1:8 EtOAc/petroleum ether) to yield 4.31 g (35%) of title compound as a bright yellow solid, m.p. 35°-37° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 50.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (79.1 mg, 0.131 mmol) prepared in Example 20b, triethylsilane (0.05 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (30.0 mg, 51%) as a colorless solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[BrH:12].BrBr>C(O)(=O)C>[Br:12][CH2:10][C:9]([C:6]1[CH:7]=[N:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: Br
Reactant: CNc1ccc(C(C)=O)cn1
Agent: BrBr
Solvent: CC(=O)O
Product: CNc1ccc(C(=O)CBr)cn1
Yield: 63.8 %

Procedure:
380 mg (2.53 mmol) of 1-(6-methylaminopyrid-3-yl)ethanone, 416 μl (2.53 mmol) of hydrobromic acid, 130 μl (2.53 mmol) of bromine and 5 mL of glacial acetic acid were used in the reaction. After precipitation with ethyl ether and filtration, the precipitate is taken up in water. The solution is basified with saturated NaHCO3 solution. The precipitate formed is filtered off, washed with water and then dried under vacuum. 370 mg of 2-bromo-1-(6-methylaminopyrid-3-yl)ethanone are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:64]([N:66]1[CH2:72][CH2:71][CH2:70][N:69]([CH:73]2[CH2:78][CH2:77][CH:76]([NH2:79])[CH2:75][CH2:74]2)[CH2:68][CH2:67]1)[CH3:65]>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:79][CH:76]5[CH2:75][CH2:74][CH:73]([N:69]6[CH2:70][CH2:71][CH2:72][N:66]([CH2:64][CH3:65])[CH2:67][CH2:68]6)[CH2:78][CH2:77]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN1CCCN(C2CCC(N)CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCCN(C2CCC(NC(=O)c3ccc(Nc4ncc5c(n4)N(C4CCCC4)CC4(CC4)C(=O)N5C)c(OC)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (44 mg, 0.1 mmol, 1 eq), DIPEA (35 μl, 0.2 mmol, 2 eq) and TBTU (36 mg, 0.12 mmol, 1.2 eq) were added to 1 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-(4-ethyl-1,4-diazepan-1-yl)cyclohexanamine (Intermediate 15) as the trihydrochloride salt (32 mg, 0.1 mmol, 1 eq) and DIPEA (53 μL, 0.3 mmol, 3 eq). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-(4-(4-ethyl-1,4-diazepan-1-yl)cyclohexyl)-3-methoxybenzamide as a mixture cis and trans isomers (white solid, 10 mg, 16%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Br:19])[C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Br:19])[C:12]2[S:16][C:15]([NH:17][C:23]([NH:22][CH2:20][CH3:21])=[O:24])=[N:14][C:13]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 91.8 %

Procedure:
To a solution of 5-benzyloxy-7-bromo-benzothiazol-2-ylamine (1.35 g, 4.02 mmol) in dioxane (50.0 mL) was added ethyl isocyanate (1.90 mL, 24.22 mmol) and the resulting reaction mixture was heated to 80° C. for 15 h. The solvent was then evaporated and the residue was stirred in water at 85° C. for 5-6 h. The solution was then filtered and the solid thus obtained was washed with hot water and hexane to get the desired product (1.50 g, 92%) as an off-white solid. M.P. 294.2° C.
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3].[CH3:18][NH:19][CH3:20]>C(Cl)Cl>[CH3:18][N:19]([CH3:20])[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3]
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Reactant: CNC
Solvent: ClCCl
Product: C[C@@H](CS(=O)(=O)N(C)C)C(=O)OCc1ccccc1
Temperature: -78 °C

Procedure:
A 100 mL round bottomed flask equipped with magnetic stir bar was charged with 1.7 g benzyl 3-chlorosulfonyl-2(R)-methylpropionate from Example 3 in 25 mL CH2Cl2. The solution was cooled to -78° C. and 15 mL of anhydrous dimethylamine was slowly added. After 30 minutes the reaction was concentrated in vacuo and the residue was partioned between EA/H2O. The organic phase was dried, concentrated in vacuo to yield 1.4 g of benzyl 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionate as a clear amber oil which was used directly in the next step.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)=[C:8]([C:25](=[O:27])[NH2:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH2:29]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)[CH3:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:25]([C:8]1[CH:7]=[N:6][N:5]2[CH:28]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH2:29][CH3:30])[CH:35]=3)[N:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:12]1)(=[O:27])[NH2:26]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CC)c3)nc12
Temperature: 100 °C

Procedure:
A solution of (3S,4S)-tert-butyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-ethylpyrrolidine-1-carboxylate (200 mg, 0.441 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (147 mg, 0.662 mmol) in 2M aq K3PO4 (0.662 ml, 1.324 mmol) and dioxane (2 ml) was purged with N2 for 2 min, followed by addition of PdCl2(dppf) CH2Cl2 Adduct (1:1) (36.3 mg, 0.044 mmol). The reaction mixture was purged with nitrogen for 2 min, sealed and heated at 100° C. for 120 min. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, filtered through CELITE®, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (ISCO 12 g column, 20-80% EtOAc/hexane over 15 min) to afford (3S,4S)-tert-butyl 3-((7-carbamoyl-2-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-4-ethylpyrrolidine-1-carboxylate as an off-white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(N(CC)CC)C.[C:21]1([S:27]([Cl:30])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O.CCOC(C)=O.O1CCOCC1.C(Cl)Cl>[ClH:30].[C:21]1([S:27]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N1CCNCC1
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
A 500 ml, round-bottomed flask was charged with 1-Boc-piperazine (18.55 g, 100 mmol, Sigma-Aldrich, St. Louis, Mo.), triethylamine (18.05 mL, 129 mmol), and 200 mL of CH2Cl2. To this was added benzenesulfonyl chloride (16.05 mL, 124 mmol, Sigma-Aldrich, St. Louis, Mo.). After 15 min, the mixture was diluted with water (150 mL) and the layers were separated. The organics were dried (MgSO4) and concentrated to give a white solid. This solid was dissolved in EtOAc (300 mL) and 150 mL of 4N HCl in dioxane. After 3 h at 65° C., the white precipitate was filtered to give 1-(phenylsulfonyl)piperazine hydrochloride (21.0 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (220 mg, 1.16 mmol) in THF (2 mL) was added sodium hydride (55% dispersion in mineral oil, 996 mg, 22.8 mmol). After stirring for 0.5 h at ambient temperature 6-chloronicotinonitrile (161 mg, 1.16 mmol) was added and the reaction mixture was stirred for 5 h at ambient temperature. It was diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL). After drying over sodium sulfate and concentration purification by chromatography (SiO2, heptane:ethyl acetate=90:10 to 60:40) afforded the title compound (307 mg, 91%) as a white solid. MS: m/e=292.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[N:9]=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.Br[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20].[Si](Cl)(C)(C)C.[NH4+].[Cl-]>[Zn].CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:19]([CH3:21])([CH3:20])[CH:18]=[CH2:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=N\c1ccc(OC)cc1
Reactant: CC(C)=CCBr
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CC(C)(C)C(Nc1ccc(OC)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 20.7 %

Procedure:
To a round bottom flask was added (Z)-ethyl 2-(4-methoxyphenylimino)acetate (4000 mg, 19.30 mmol) and DMF (30 mL). The reaction was cooled to 0° C. Then, 1-bromo-3-methylbut-2-ene (3740 mg, 25.09 mmol) was added to the reaction followed by zinc (1641 mg, 25.09 mmol) and a drop of TMS-Cl (0.247 mL, 1.93 mmol). The reaction mixture was slowly warmed up to rt over 45 min and then stirred at rt for 20 min. The reaction mixture was cooled to 0° C. and aqueous 5% NH4Cl (10 mL) was added to the reaction. The reaction was extracted with ether (3×50 mL). The combined ether layer was washed with water (100 mL) and saturated aqueous NaCl (100 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-60% EtOAc/Hex to give ethyl 2-(4-methoxyphenylamino)-3,3-dimethylpent-4-enoate (1.1 g, 4.0 mmol, 21% yield) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 6.76 (d, J=9.35 Hz, 2H), 6.60 (d, J=8.80 Hz, 2H), 5.96 (dd, J=17.32, 10.72 Hz, 1H), 5.19-5.08 (m, 2H), 4.15 (q, 2H), 3.85 (s, 1H), 3.77-3.71 (m, 4H), 1.23 (t, J=7.15 Hz, 3H), 1.21 (s, 3H), 1.17 (s, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 173.09, 152.71, 143.47, 141.42, 115.30, 114.79, 113.92, 66.02, 60.54, 55.69, 40.06, 24.89, 23.70, 14.27.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:14]([O-])=O)[CH:4]=1.[BH4-].[Na+]>S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:14])[CH:4]=1
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Product: COc1cc(N)c(C(N)=O)cc1OC

Procedure:
Specifically, 4,5-dimethoxy-2-nitrobenzoic acid (compound 1) was treated with thionyl chloride to form acid chloride, followed by reacting with ammonia to yield 4,5-dimethoxy-2-nitrobenzamide (compound 2). Compound 2 was reduced with sodium borohydride in the presence of catalytic amounts of copper sulphate to give 4,5-dimethoxy-2-aminobenzamide (compound 3), which was directly refluxed with formic acid to yield 6,7-dimethoxyquinazoline-4(3H)-one (compound 4). Compound 4 was refluxed with phosphorus oxytrichloride to give 4-chloro-6,7-dimethoxyquinazoline (compound 5) in good yield.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][C:10]([CH3:14])([CH3:13])[C:11]#[CH:12].O>C(N(CC)CC)C.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.[Cu]I>[CH3:9][C:10]([CH3:14])([CH3:13])[C:11]#[C:12][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5]
Reactant: C#CC(C)(C)C
Reactant: Nc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1cccc(N)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
1.05 g (1.5 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.26 g (1.5 mmol) of copper(I) iodide are added to a solution consisting of 5.47 g (25 mmol) of 3-iodoaniline in 40 ml of triethylamine. With ice-cooling, 3.08 g (37.5 mmol) of 3,3-dimethyl-1-butyne are added dropwise such that the temperature remains at 20° C. After the addition has ended, the mixture is stirred at 20° C. for 20 hours. The reaction solution is concentrated under reduced pressure and the residue formed is stirred into 1 l of water. The mixture is then extracted three times with diethyl ether. The combined organic phases are once more washed with water, dried with sodium sulphate and concentrated under reduced pressure. The crude product obtained is purified by silica gel chromatography (mobile phase methylene chloride). This gives 2.70 g (60% of theory) of 3-(3,3-dimethylbut-1-yn-1-yl)aniline having a content of 97% according to HPLC. log P=2.71.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([NH:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH3:22])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[CH3:23][S:24]([NH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:25].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:20][CH2:21][CH3:22])[N:15]([NH:16][CH:17]([CH3:19])[CH3:18])[C:6]=2[C:5]2[CH:4]=[CH:3][C:2]([C:32]3[CH:33]=[C:28]([NH:27][S:24]([CH3:23])(=[O:25])=[O:26])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1NC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: CCCc1nc2c(N)nc3cc(-c4cccc(NS(C)(=O)=O)c4)ccc3c2n1NC(C)C
Temperature: 100 °C
Reaction time: 17 h
Yield: 56 %

Procedure:
A suspension of 7-bromo-N1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.00 g, 2.76 mmol) in 20 mL of 1-propanol was treated with 3-(methanesulfonylamino)phenylboronic acid (0.653 g, 3.04 mmol). The headspace of the reaction flask was purged and back-filled with nitrogen (3×). The reaction mixture was then treated with triphenylphosphine (11 mg, 0.041 mmol), sodium carbonate (1.66 mL, 3.31 mmol, 2 M solution in H2O), H2O (2 mL) and palladium (II) acetate (3.1 mg, 0.014 mmol). Again the headspace of the reaction flask was purged and back-filled with nitrogen (3×). The reaction was heated to 100° C. After 17 h, the reaction was cooled to ambient temperature and concentrated under reduced pressure to yield a brown solid. The solid was partitioned between 15 mL of H2O and 15 mL of CHCl3 and then separated. The aqueous portion was extracted with CHCl3 (2×15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a tan foam. The material was purified by chromatography (SiO2, 50% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) and then dissolved in boiling CHCl3 and slowly cooled to yield N-{3-[4-amino-1-(isopropylamino)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}methanesulfonamide (0.700 g) as a white solid. mp 217–227° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.54 (d, J=8.5 Hz, 1H), 7.79 (d, J=1.4 Hz, 1H), 7.60 (s, 1H), 7.52–7.42 (m, 3H), 7.22 (d, J=7.8 Hz, 1H), 7.01 (s, 1H), 6.55 (s, 2H), 3.55–3.51 (m, 1H), 3.06 (s, 3H), 2.92 (bs, 2H), 1.91–1.84 (m, 2H), 1.05–1.01 (m, 9H); 13C NMR (125 MHz, DMSO-d6) δ 155.4, 152.9, 145.8, 142.4, 139.9, 138.6, 133.1, 130.8, 124.9, 124.2, 123.1, 122.5, 120.2, 119.5, 118.7, 114.9, 51.8, 28.7, 21.6, 21.1, 14.8; MS (APCI) m/z 453 (M+H)+; Anal. Calcd for C23H28N6O2S: C, 61.04; H, 6.24; N, 18.57; Found: C, 60.66; H, 60.40; N, 18.47.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: ClCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=Cc2cc(OCc3ccccc3Cl)ccc2S(=O)(=O)CC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 2-chlorobenzyl chloride (0.25 ml), potassium carbonate (309 mg) and DMF (10 ml) was stirred at 60° C. for 5 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:2) to obtain methyl 7-[(2-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (413 mg) as colorless crystals.