Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH3:15])=[CH:7][C:6]=1[Si:16]([CH3:19])([CH3:18])Cl)[CH:2]=[CH2:3].[CH3:20][N:21]([CH3:30])[C:22]1([Li])[CH:26]=[C:25]([CH3:27])[C:24]([CH3:28])=[CH:23]1>C1(C)C=CC=CC=1.O1CCCC1>[CH3:20][N:21]([CH3:30])[C:22]1[CH:26]([Si:16]([C:6]2[CH:7]=[C:8]([CH3:15])[CH:9]=[C:10]([C:11]([CH3:13])([CH3:14])[CH3:12])[C:5]=2[O:4][CH2:1][CH:2]=[CH2:3])([CH3:19])[CH3:18])[C:25]([CH3:27])=[C:24]([CH3:28])[CH:23]=1
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Reactant: [Li]C1(N(C)C)C=C(C)C(C)=C1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)C1C(N(C)C)=CC(C)=C1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.7 %

Procedure:
A solution of (2-allyloxy-3-tert-butyl-5-methylphenyl)dimethylchlorosilane (7.0 mmol) in toluene (12.1 mL) was added dropwise to a solution of 1-dimethylamino-3,4-dimethylcyclopentadienyllithium (7.0 mmol) in tetrahydrofuran (10.5 mL) and the mixture was stirred at room temperature for 6 hours. After the solvent was distilled off under reduced pressure, dehydrated pentane was added and a precipitated solid was filtered off. The filtrate was concentrated to obtain the title compound (2.86 g, 100%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[N:14]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[C:15](=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]([OH:46])[CH:43]=[CH:44][CH:45]=2)O1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(O)C.O.CCO.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[N:14]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[C:15](=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:9]=[C:10]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=3)[C:3]=12
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: Cc1ccccc1-n1c(Cn2nc(I)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1c(Cn2nc(-c3cccc(O)c3)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
3-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1611) (13 g, 24.9 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1612) (6.6 g, 30 mmol) were dissolved in DMF-EtOH—H2O (120 mL, 40 mL, 40 mL). Pd(OAc)2 (1.684 g, 7.5 mmol), PPh3 (3.935 g 15 mmol) and Na2CO3 (13.25 g 125 mmol) were added sequentially. The resulting mixture was degassed and back-filled with argon three times and then stirred at 100° C. for 1 h. The mixture was allowed to cool to RT, filtered through silica gel (10 g) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-20% MeOH/DCM) to afford the product (1613) (9 g, 76% yield) as a slight yellow solid. Then above product was suspended in EtOH (100 mL) and heated to reflux for 30 min. The mixture was allowed to cool to RT, and the solid was collected by filtration. The solid was then suspended in EA (100 mL) and stirred overnight. The precipitate was collected by filtration and further dried in vacuo to afford the desired product, 3-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1613) (8.4 g, 69% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2](C=O)C.I[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1>O.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:1]#[N:2])=[N:8]1
Reactant: CN(C)C=O
Reactant: Ic1n[nH]c2ncccc12
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1n[nH]c2ncccc12
Temperature: 120 °C

Procedure:
A DMF (180 mL) solution containing the intermediate from Step B above (24.1 g, 98 mmol), zinc cyanide (6.93 g, 59.0 mmol), 1,1′-bis(diphenylphosphino)ferrocene (4.36 g, 7.87 mmol) and tris(dibenzylideneacetone)dipalladium (3.60 g, 3.93 mmol) was heated at 120° C. for 1.5 hours. The solution was cooled to room temperature and diluted with water. The precipitated product was collected and dried under vacuum with a nitrogen sweep to give the title compound. 1H NMR (400 MHz, CH3CN-d3): δ 12.42 (s, 1H); 8.67 (dd, J=4.48, 1.53 Hz, 1H); 8.29 (dd, J=8.22, 1.53 Hz, 1H); 7.40 (dd, J=8.23, 4.48 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([OH:14])=O)[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].ClC(OCC(C)C)=O.CN1CCOCC1.Cl.[CH3:45][NH:46][C:47](=[O:50])[CH2:48][NH2:49]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C.C(#N)C.O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:49][CH2:48][C:47]([NH:46][CH3:45])=[O:50])=[O:14])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: CNC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: O
Product: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
To a cold solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (0.8 g, 1.7 mmol) in anhydrous dimethylacetamide (3.2 mL) was added isobutyl chloroformate (0.23 mL, 1.7 mmol) followed by N-methylmorpholine (0.25 mL, 2.2 mmol). The reaction mixture stirred under argon atmosphere at 0° C. for 10 min and then at room temperature for 30 min. At which time another equivalent of N-methylmorpholine (0.29 mL, 2.5 mmol) was added to reaction mixture, followed by the addition of glycine methyl amide HCl (0.33 g, 2.5 mmol) and DMAP (ca.). The reaction mixture stirred for 2 h at room temperature and then diluted with acetonitrile/water (2:1 v/v) to be purified by reverse phase HPLC using a 10-90% acetonitrile in water containing 0.5% TFA (30 min) gradient at a 80 mL/min flow rate. The appropriate fractions (M+H m/z=521) were collected and concentrated to a reduced volume. The resulting suspension was diluted with dichloromethane (30 mL) and washed with 5% NaHCO3 (2×50 mL). The organic extracts were washed with water (2×25 mL) and dried over Na2SO4 (anhydrous). The organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (364.4 mg, 37%) as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.96 (dd, 1H, J=2 Hz), 7.80 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 3.98 (s, 2H), 2.74 (s, 3H), 2.20 (s, 3H); ES-HRMS m/z 521.0650 (M+H C22H20BrF2N4O4 requires 521.0630).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH:7]([NH2:10])([CH3:9])[CH3:8]>CO>[CH3:1][NH:2][C:3](=[O:6])[CH2:4][CH2:5][NH:10][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)N
Reactant: C=CC(=O)NC
Solvent: CO
Product: CNC(=O)CCNC(C)C
Yield: 108.2 %

Procedure:
N-Methylacrylamide (851 mg, 10.00 mmol) and isopropylamine (1.71 mL, 1.18 g, 20.00 mmol) in MeOH (10 mL) were irradiated to 140° C. for 30 mins in a microwave reaction vessel. The reaction mixture was cooled and loaded onto a SCX-2 column and washed with MeOH (100 mL). The crude product was then eluted from the SCX-2 column with NH3 (100 mL, 7M in MeOH) and the volatiles removed under reduced pressure to afford the title compound (1.56 g, Quant.) as an oil, which was used without further purification.
Reaction SMILES: Cl.[C:2]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)(=O)[CH3:3].Cl.[CH2:14]([O:17][NH2:18])[C:15]#[CH:16]>CO>[CH2:14]([O:17][N:18]=[C:2]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)[CH3:3])[C:15]#[CH:16]
Reactant: CC(=O)C1CN2CCC1CC2
Reactant: C#CCON
Agent: Cl
Solvent: CO
Product: C#CCON=C(C)C1CN2CCC1CC2
Yield: 56.2 %

Procedure:
1.8 g of 3-acetyl quinuclidine hydrochloride and 1.02 g of O-2-propynyl-hydroxylamine hydrochloride are heated for 20 minutes to reflux in 30 cm3 of methanol. After evaporating to dryness, the residue is chromatographed on silica (eluant: methanol-ethyl ether). An aqueous solution of potassium carbonate is added and extraction is carried out with ethyl acetate. The extracts are dried and distilled at 170° C. under 0.2 mbar. After cooling, 1.1 g of expected product is obtained. M.p.=56°-58° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:46]1[CH:50]=[CH:49][S:48][CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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]>[S:48]1[CH:49]=[CH:50][C:46]([C:2]2[CH:3]=[C:4]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:47]1
Reactant: Brc1ccsc1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccsc3)c2)cc1
Temperature: 80 °C
Yield: 22.9 %

Procedure:
Methyl 4-[(3-bromophenyl)methoxy]benzenepropanoate (0.96 g, 2.8 mmol), bis(pinacolato)diboron (0.77 g, 3.0 mmol) and potassium acetate (0.81 g, 8.3 mmol) were dissolved in N,N-dimethylformamide (30 mL) and, after argon substitution, 1,1′-bis(diphenyphosphino)ferrocenedichloropalladium (II) (0.067 g, 0.083 mmol) was added. The reaction mixture was heated overnight under an argon atmosphere at 80° C. The reaction mixture was cooled, and 3-bromothiophene (0.43 g, 2.6 mmol), 1,1′-bis(diphenyphosphino)ferrocenedichloropalladium (II) (0.067 g, 0.083 mmol) and 2N aqueous sodium carbonate solution (6.9 mL, 14 mmol) were added to the reaction mixture. The reaction mixture was heated overnight under an argon atmosphere at 80° C. The reaction mixture was cooled, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=15:1) to give the title compound (0.21 g, yield 22%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7](S(Cl)(=O)=O)[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].Cl.N[C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([NH:11][S:12]([C:27]2[CH:37]=[CH:36][C:30](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])=[CH:29][CH:28]=2)(=[O:14])=[O:13])[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: Nc1ccc(C=CC(=O)O)cc1
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1Oc1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(NS(=O)(=O)c2ccc(/C=C/C(=O)O)cc2)cc1Oc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 7 h

Procedure:
3-(2,4-Dichlorophenoxy)-4-methylsulphonylaminobenzene-sulphonic acid chloride (1.1 g, 2.55 mmol) was dissolved in CH2Cl2 (5 ml) and at 0° C. added dropwise to a solution of 4-aminocinnamic acid hydrochloride (0.65 g, 43.3 mmol) and DMAP (0.44 g, 3.6 mmol) in pyridine (20 ml). The mixture was stirred for 7 hours at 0° C. and then evaporated down. The residue was dried in vacuo and purified by chromatography (silica gel, petroleum ether/ethyl acetate/HOAc 1/1/0.1). Yield: 0.43 g=30% 13C (100 MHz, DMSO-d6) δ 167.68, 149.54, 147.56, 143.23, 139.25, 130.47, 130.33, 130.07, 129.89, 129.42, 129.21, 126.45, 123.19, 122.96, 122.71, 120.18, 118.42, 114.28, 113.74, 41.10
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=1)(=[O:5])[NH2:4].O.Cl>CC(C)=O.O>[Cl:20][C:16]1[CH:15]=[C:14]([C:13]2[NH:4][C:3](=[O:5])[C:6]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:12]=2)[CH:19]=[CH:18][N:17]=1
Reactant: NC(=O)c1ccccc1NC(=O)c1ccnc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=c1[nH]c(-c2ccnc(Cl)c2)nc2ccccc12
Reaction time: 8 h

Procedure:
Sodium hydroxide (5M, 5 mL) was added to a suspension of N-(2-carbamoylphenyl)-2-chloroisonicotinamide (4.14 g, 15.02 mmol) in acetone/water (1/1, 100 mL). The reaction was heated to reflux and stirred overnight. The resulting solid was put into solution with water and was adjusted to pH 7 using 5M HCl. The precipitate was filtered and concentrated with toluene (3×) to give 2-(2-chloro-pyridin-4-yl)-3H-quinazolin-4-one as a light brown solid. MS (ES−): 256 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21](O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:24]CCl.C(Cl)(C(Cl)=O)=O>CN(C)C=O>[Cl:24][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:22]=1
Reactant: ClCCl
Reactant: COc1cc(-c2nc(O)c3ccccc3n2)cc(OC)c1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(Cl)c3ccccc3n2)cc(OC)c1OC
Temperature: 0 °C

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed 2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol (12 g, 38.5 mmol, 1.00 equiv), dichloromethane (500 mL) and N,N-dimethylformamide (0.5 mL). This was followed by the addition of (COCl)2 (15 g) dropwise with stirring at 0° C. The resulting solution was heated to reflux for 1 h in an oil bath. The reaction was then quenched by the addition of 50 mL of sodium bicarbonate (sat.). The resulting solution was extracted with 2×100 mL of dichloromethane and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:dichloromethane:petroleum ether (1:1:4). This resulted in 10 g (78.7%) of 4-chloro-2-(3,4,5-trimethoxyphenyl)quinazoline as a white solid. MS (ESI) m/z 332 ([M+H]+).
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([C:24]([OH:26])=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH:22]=[CH2:23])[CH:16]=2)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C:12]1[C:13]([C:24]([OH:26])=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH2:22][CH3:23])[CH:16]=2
Reactant: [H][H]
Reactant: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2cc(N)c(C(=O)O)nc2c1

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-7-vinylquinoline-2-carboxylic acid (673.9 mg, 1.934 mmol) in MeOH (25.0 mL) was added 10 wt % Pd on carbon (100.1 mg, 0.09406 mmol). The mixture was stirred at room temperature hydrogen (1 atm) for 15 h. The reaction mixture was filtered through a pad of diatomaceous earth (eluted with MeOH) and then concentrated under reduced pressure. The resulting crude sub-title compound was used directly in the next step residue without further purification (380.6 mg, 91%). LCMS calc. for C12H13N2O2 (M+H)+: m/z=217.1. found 217.0.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)(=[O:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1.CO>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc(C2=C(OC(C)=O)c3ccc(OC)cc3CC2)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CO
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2OC(C)=O)c1

Procedure:
A solution was prepared of 52.7 g (162 mmol) of 1-acetyloxy-2-(3-methoxyphenyl)-6-methoxy-3,4-dihydronaphthalene and 36.9 g (162 mmol) of DDQ in 500 mL of p-dioxane. The solution was heated to reflux for two hours under a nitrogen atmosphere. The reaction was allowed to cool and the solvent removed by evaporation. The residue was extracted by stirring in CHCl3 for sixteen hours, then filtering to remove the insoluble material. The CHCl3 extract was further purified by chromatography on a silica gel column eluted with CHCl3. This resulted in a red oil, which was suspended in MeOH and crystallized at −70° C. This yielded 46.5 g of the title compound as a low melting solid.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][CH2:30][CH2:31][CH3:32])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CC#N
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O

Procedure:
Methanesulfonic anhydride (0.6 g, 3.4 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (1.0 g, 3.2 mmol) and acetonitrile (200 ml). A precipitate formed within a few minutes. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The fractions were separated and the organic fraction was dried (MgSO4), filtered and concentrated to yield the crude product as a white solid. Recrystallization from methyl acetate provided N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a white crystalline solid, m.p. 195.1–196.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J=7.4 Hz, 1H), 7.61 (dd, J=8.3, 1.2 Hz, 1H), 7.50 (dt, J=7.5, 1.1 Hz, 1H), 7.26 (dt, J=7.5, 1.2 Hz, 1H), 6.99 (t, J=5.7 Hz, 1H), 6.44 (broad s, 2H), 4.52 (t, J=7.5 Hz, 2H), 3.02–2.86 (m, 7H), 1.82 (m, 4H), 1.62 (m, 2H), 1.46 (q, J=7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H); IR (KBr) 3348, 3299, 3152, 2952, 2931, 2869, 1642, 1584, 1530, 1480, 1323, 1155, 1142, 1094, 982, 765 cm−1; MS (EI) m/e 389.1889 (389.1885 calcd for C19H27N5O2S); Anal calcd for C19H27N5O2S: C, 58.59; H, 6.99; N, 17.98. Found: C, 58.26; H, 6.64; N, 17.69
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.N[C:11](N)=[O:12]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][C:11](=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Br)cnc1N
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Br)cnc2[nH]1
Temperature: 100 °C
Yield: 35.3 %

Procedure:
A mixture of 5-bromopyridine-2,3-diamine (2 g, 10.6 mmol) and urea (2.5 g, 41.6 mmol) was dissolved in DMF and heated to 100° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4 then concentrated to provide 6-bromo-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.80 g, 36%) as an off white solid which was used without further purification. LCMS Method W: retention time 0.98 min; [M+2]=212, 214.0.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:36][CH2:35][CH2:34][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: NCCN1CCCCC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCN3CCCCC3)sc2Br)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (200 mg; 0.48 mmol; 1 eq), is dissolved in anhydrous DCM (10 ml). The reaction mixture is cooled down to 0° C. and put under nitrogen. Triethylamine (0.4 ml; 2.88 mmol; 6 eq) and 2-piperidin-1-yl-ethylamine (0.16 ml; 1.16 mmol; 2.4 eq) are added successively and the reaction mixture is stirred at 0° C. for 2 hours. The mixture is washed with water, NaHCO3 and dried over MgSO4, affording the title compound (170 mg; 68%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc(Br)cc2)CC1

Procedure:
1-(4-bromobenzoyl)-4-methylpiperazine was prepared according to the general procedure in Example 4 Step 1 using 4-bromobenzoyl chloride (1 g, 4.56 mmol) and 1-methylpiperazine (0.532 mL, 4.78 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[CH2:18]([NH:25][C:26]([NH2:28])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:28][C:26]([NH:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])[CH:10]=2)=[O:5])[CH3:2]
Reactant: NC(=O)NCc1ccccc1
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Product: CCOC(=O)c1ncc2cc(NC(=O)NCc3ccccc3)ccc2c1O

Procedure:
7-(3-Benzyl-ureido)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared from 7-bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(a) using benzyl urea. The crude product was used in the following steps without purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[S:6][C:7]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH:35]=[CH2:36])[N:30]=2)=[C:8]([C:10]2[C:11]([F:28])=[C:12]([NH:16][S:17]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])[CH3:3].[CH3:37][S:38]([OH:40])=[O:39].[Na].C(O)C>C(O)(=O)C.O>[CH3:4][C:2]([C:5]1[S:6][C:7]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][CH2:36][S:38]([CH3:37])(=[O:40])=[O:39])[N:30]=2)=[C:8]([C:10]2[C:11]([F:28])=[C:12]([NH:16][S:17]([C:20]3[C:21]([F:27])=[CH:22][CH:23]=[CH:24][C:25]=3[F:26])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[N:9]=1)([CH3:1])[CH3:3]
Reactant: C=Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Reactant: CS(=O)O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(CCS(C)(=O)=O)n2)s1
Yield: 81 %

Procedure:
N-{3-[2-(1,1-dimethylethyl)-5-(2-ethenyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.15 g, 0.283 mmol) and methane sulfinic acid, sodium salt (0.144 g, 1.414 mmol) were stirred in acetic acid (1.5 ml) and ethanol (1.5 ml) at RT in a screw-top vial overnight. The reaction mixture is diluted with water and extracted 2× with EtOAc. The EtOAc is washed with brine, dried over MgSO4, filtered, and concentrated. The crude mixture was placed on silica gel and chromatography (0 to 80% DCM/EtOAc, gradient) to obtain the title compound (173 mg, 81%). 1H NMR (400 MHz, DMSO-d6) ppm 10.87 (s, 1H), 8.54 (d, J=5.31 Hz, 1H), 7.68 (ddd, J=14.56, 8.42, 6.13 Hz, 1H), 7.43 (t, J=7.32 Hz, 2H), 7.32 (t, J=7.97 Hz, 1H), 7.23 (t, J=9.06 Hz, 2H), 6.75 (d, J=5.31 Hz, 1H), 3.53 (m, 2H), 3.29 (m, 2H), 3.03 (s, 3H), 1.44 (m, 9H); MS (ESI): 611 [M+H]+.