Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[CH3:33][NH:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:37]4[CH2:38][CH:35]([NH:34][CH3:33])[CH2:36]4)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)ccc1F
Reactant: CNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)c(N)n4)c3c2Br)C1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
To 250 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-5-fluoropyridine-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-methylaminoazetidine dihydrochloride, and 200 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 10 minutes. After adding 0.5 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 66 mg of the title compound as a colorless powder.
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([Br:35])[CH:33]=3)[NH:28][CH:27]=2)OC)=[CH:19][N:18]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Br:35][C:32]1[CH:33]=[C:34]2[C:26]([CH2:23][C:20]3[CH:21]=[CH:22][C:17]([NH:7][CH2:8][C:9]4[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=4)=[N:18][CH:19]=3)=[CH:27][NH:28][C:29]2=[N:30][CH:31]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(OC)c3c[nH]c4ncc(Br)cc34)cn2)cn1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNc2ccc(Cc3c[nH]c4ncc(Br)cc34)cn2)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 61.8 %

Procedure:
To {5-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methoxy-methyl]-pyridin-2-yl}-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (154, 0.35 g, 0.63 mmol) in 20.0 mL of acetonitrile, triethylsilane (1.0 mL, 6.3 mmol) and trifluoroacetic acid (0.50 mL, 6.5 mmol) were added and the reaction stirred at 80° C. for 4 hours. The reaction was concentrated under vacuum and combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-2017, 165.1 mg). MS (ESI) [M+H+]+=423.8, 425.8
Reaction SMILES: [CH:1]1(C2CCC3C(=C(Cl)C(Cl)=C(OC)C=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([CH3:34])[C:32]=1[CH3:33])[C:29](=[O:35])[CH2:28][CH2:27][CH2:26]2.CI.C1(Br)CCCC1>>[CH:1]1([CH:28]2[CH2:27][CH2:26][C:25]3[C:30](=[C:31]([CH3:34])[C:32]([CH3:33])=[C:23]([O:22][CH3:21])[CH:24]=3)[C:29]2=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2c(c(C)c1C)C(=O)CCC2
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Agent: BrC1CCCC1
Solvent: CI
Product: COc1cc2c(c(C)c1C)C(=O)C(C1CCCC1)CC2

Procedure:
By the procedure of Example III, Step 1, but substituting for the 2-cyclopentyl-6-methoxy-7,8-dichloro- 1-tetralone used therein an euivalent amount of 6-methoxy- 7,8-dimethyl-1-tetralone, and for the methyl iodide there used an equivalent amount of cyclopentyl bromide, then 2-cyclopentyl-6-methoxy-7,8-dimethyl-1-tetralone is obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][N:3]1[P:5](=[O:20])([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:21]1([Mg]Cl)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>Cl[Cu].C1COCC1>[C:21]1([CH2:4][CH:2]([NH:3][P:5](=[O:20])([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:1])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1CN1P(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: Cl[Mg]c1ccccc1
Agent: Cl[Cu]
Solvent: C1CCOC1
Product: CC(Cc1ccccc1)NP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 48 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A 100 mL, 3-necked flask equipped with an overhead stirrer, reflux condenser and pressure equalizing addition funnel was charged with 2b (10.0 g, 34.6 mmol), THF (50 mL) and CuCl (42 mg, 1 mol %) and the stirrer was started. The stirred mixture was heated to 48° C. and the pressure equalizing addition funnel was charged with PhMgCl (2M in THF, 17.4 mL). This solution was added slowly while maintaining a reaction temperature of 48-51° C. The reaction was allowed to stir at 48-51° C. for an additional 2 hours until the GC analysis indicated the consumption of 2b (<1.0%) and the reaction mixture was cooled to ambient temperature. The reaction was quenched by slow addition to a cooled solution of saturated aqueous ammonium chloride/water mixture (50/50 v/v, 60 mL) while maintaining the batch temperature below 20° C. Heptanes (60 mL) was used to rinse the reactor and was transferred to the quench mixture. The biphasic mixture was agitated for 15 minutes and the aqueous layer was removed. The organic layer washed with deionized water (20 mL) and the organic phase concentrated under reduced pressure to give viscous oil. This residue was dissolved in heptanes (50 mL) and the solution was concentrated under reduced pressure. The residue was crystallized from ethanol (1 g/5 mL) to give 6b as a white solid (9.05 g, 72% yield, 99.85% GC purity containing 0.05% of 8b). Mp 102-103° C. (lit1 101-102° C.). 1H NMR (300 MHz, CDCl3) δ 7.38-7.11 (m, 15H), 3.83-3.65 (m, 1H), 3.00-2.89 (m, 1H), 2.86-2.78 (m, 1H), 2.73-2.62 (m, 1H), 1.15 (d, J=10.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C.O.C1(P([Pd-4](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)C=CC=CC=1>[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OC[C@H]1CC(c2ccc(Br)cn2)=NO1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NO[C@@H](CO)C4)nc3)c(F)c2)C(=O)O1
Temperature: 75 °C

Procedure:
[(5R)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (Intermediate 12, 0.5 g, 1.95 mmol), (0.35 g, 0.9 mmol), potassium carbonate (0.622 g, 4.5 mmol), N-({(5S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (Intermediate 13, 0.736 g, 1.95 mmol) and tetrakis(triphenylphosphino)palladium(0) (0.225 g, 0.195 mmol) were combined and suspended in DMF (7 ml) and water (1 ml). The mixture was heated at 75° C. for 2 hours, then was poured into cold water (30 ml). The solids formed were collected, rinsed with water and washed with dichloromethane, dried under vaccum and collected as the title compound (0.42 g)
Reaction SMILES: C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:32]=[C:33]1[C:44]2[C:45]3[C:37](=[C:38]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[NH:39][C:40]=3[CH:41]=[C:42]([NH:46][C:47](=[O:53])[CH2:48][CH2:49][C:50](O)=[O:51])[CH:43]=2)[CH:36]=[N:35][NH:34]1>CN(C)C=O>[O:32]=[C:33]1[C:44]2[C:45]3[C:37](=[C:38]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[NH:39][C:40]=3[CH:41]=[C:42]([N:46]3[C:50](=[O:51])[CH2:49][CH2:48][C:47]3=[O:53])[CH:43]=2)[CH:36]=[N:35][NH:34]1
Reactant: O=C(O)CCC(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(N4C(=O)CCC4=O)cc1c23
Temperature: 22 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
Triethylamine (0.18 mmol, 0.025 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.04 mmol, 0.013 g) were added to a solution of the title compound of Example 8 (0.013 g, 0.036 mmol) in N,N-dimethylformamide (0.05 M, 0.75 mL). The reaction mixture was stirred at 22° C. for 12 hours and concentrated under reduced pressure. The yellow solid was triturated with methanol (3.0 mL), collected by filtration, and washed with methanol (4.0 mL) and diethyl ether (5.0 mL) to afford the title compound (5.8 mg) in 47% yield.
Reaction SMILES: S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Cl:11][C:12]1[C:21]([N+:22]([O-])=O)=[C:20]([NH:25][CH2:26][C:27]#[CH:28])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>C(O)C.C(#N)C>[Cl:11][C:12]1[C:21]([NH2:22])=[C:20]([NH:25][CH2:26][C:27]#[CH:28])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: C#CCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: C#CCNc1c(N)c(Cl)nc2ccccc12
Yield: 62 %

Procedure:
An aqueous solution (1.5 L) of sodium dithionate (265 g, 1.52 mol) was added to a solution of 2-chloro-3-nitro-N-prop-2-ynylquinolin-4-amine (79.3 g, 0.303 mol) in ethanol (750 mL) and acetonitrile (950 mL). A fine white precipitate formed within seconds. The reaction was worked-up after thin layer chromatography (TLC) analysis of the reaction mixture indicated that the reaction was complete. The solids were removed by filtration and the filter cake was rinsed with dichloromethane. The filtrate was concentrated under reduced pressure to remove the volatiles, leaving an aqueous solution that was extracted with several portions of dichloromethane. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated to yield 2-chloro-N4-prop-2-ynylquinoline-3,4-diamine (43.5 g) that was approximately 60% pure and was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:20]N1C(=O)CCC1=O.O>ClCCl>[Br:20][C:10]1[N:9]=[C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: CC(=O)N1CCN(c2ncc3c(C)nccn23)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2nc(Br)c3c(C)nccn23)CC1
Yield: 88.1 %

Procedure:
To 1-(4-(8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)ethanone (0.208 mmol, 54 mg) in dichloromethane (1 ml) at room temperature was added N-bromosuccinimide (0.208 mmol, 37.1 mg). After stirring at room temperature for 5 minutes water was added and the mixture extracted three times with dichloromethane. The combined organic extracts were dried over a phase separation filter and concentrated in vacuo to give 1-(4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)ethanone (62 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[C:10]([CH2:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=3)=[CH:9][NH:8][C:6]=2[N:7]=1.CN1CCOCC1.ClC1C=C(OC)NN(OC)N=1.Cl.[CH3:42][O:43][C:44](=[O:53])[C@H:45]([CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[NH2:46]>CN(C)C=O>[CH3:42][O:43][C:44](=[O:53])[C@H:45]([CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[NH:46][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:13]([CH2:12][CH2:11][C:10]2[C:5]3[C:4](=[O:22])[NH:3][C:2]([NH2:1])=[N:7][C:6]=3[NH:8][CH:9]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)O)cc3)c2c(=O)[nH]1
Agent: COC1=CC(Cl)=NN(OC)N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CC[C@H](NC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1)C(=O)OC
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To 2.00 g (6.74 mmol) of 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid, prepared in Preparation 4, in 23 ml dimethylformamide under nitrogen was added 1.40 g (13.8 mmol) of N-methylmorpholine and 1.17 g (6.70 mmol) of 4-chloro-2,6-dimethoxytriazine. The formation of the active ester was monitored by the HPLC analysis of aliquots. After 40 minutes at room temperature 0.70 g (6.9 mmol) of N-methylmorpholine was added followed by 1.56 g (7.37 mmol) L- glutamic acid dimethyl ester hydrochloride. After 30 minutes HPLC analysis indicated substantially complete consumption of the active ester and formation of N-[4-[2-[2-Amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5- yl]ethyl] benzoyl]glutamic acid dimethyl ester. The reaction mixture was filtered and the above product concentrated and purified by silica chromatography (elution 1:4 methanol:methylene chloride). The pure fractions were pooled and provided 1.30 g of the above product in a yield of 43 percent. 1H NMR (DMSO-d6) δ 2.01 (m, 2H), 2.40 (t, J =7.4 Hz, 2H), 2.80 (m, 2H), 2.92 (m, 2H), 3.53 (s, 3H), 3.59 (s, 3H), 4.40 (m, 1H), 5.99 (s, 2H),6.26 (d, J=1.9 Hz, 1H), 7.23 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.2 Hz, 2H), 8.62 (d, J=7.5 Hz, 1H), 10.15 (S, 1H), 10.57 (d, J=1.9 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([NH:14][CH3:15])=[O:13])[CH:11]=1)[C:5](OC)=[O:6].C(O)C.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([CH:9]=[C:4]([CH2:5][OH:6])[CH:3]=1)[C:12]([NH:14][CH3:15])=[O:13]
Reactant: CNC(=O)c1cc(Cl)cc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(CO)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
(Step 1) To a mixed solution of methyl 3-chloro-5-[(methylamino)carbonyl]benzoate (2.5 g) in tetrahydrofuran:ethanol=10:1 (110 ml) was added lithium tetrahydroborate (0.36 g) at room temperature. After stirring at 60° C. for 4 hr, the reaction solution was quenched with ice and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by silica gel chromatography (ethyl acetate) to give 3-chloro-5-(hydroxymethyl)-N-methylbenzamide (1.2 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([C:18]1[C:19](=[O:38])[N:20]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1O)[CH3:17].O>N1C=CC=CC=1>[CH2:16]([C:18]1[C:19](=[O:38])[N:20]([CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)[CH:21]=[CH:22][C:23]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1c(O)ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Solvent: O
Solvent: c1ccncc1
Product: CCc1c(OS(=O)(=O)C(F)(F)F)ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Reaction time: 0.5 h

Procedure:
Trifluoromethanesulfonic anhydride (1.76 mL) was added at 0 C to a mixture of tert-butyl 4-(3-ethyl-4-hydroxy-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate (1.12 g) in pyridine (17.4 mL), and the mixture was stirred at 0 C for 30 minutes in a nitrogen atmosphere. Water was added thereto, and then, the solvent was distilled off under reduced pressure. Water was added again to the residue, followed by extraction with ethyl acetate. The obtained organic layer was washed with 1 M hydrochloric acid and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.14 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[N:5]=[C:4]([CH:13]=[O:14])[CH:3]=1.[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O>CC#N>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: Nc1cc(C=O)nc(CC2CC2)c1F
Solvent: CC#N
Product: Nc1c(F)c(CC2CC2)nc(C=O)c1Cl
Yield: 42.7 %

Procedure:
Using the procedure for Example 15, 4-amino-6-(cyclopropylmethyl)-5-fluoropicolinaldehyde (0.5 g, 2.57 mmol), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.279 g, 1.416 mmol) and CH3CN (26 mL) gave 4-amino-3-chloro-6-(cyclopropylmethyl)-5-fluoropicolinaldehyde (138 mg, 0.604 mmol, 23.44%) as an orange oil: 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 4.83 (s, 3H), 2.75 (dd, J=7.0, 2.8 Hz, 3H), 1.26 (t, J=7.1 Hz, 1H), 0.50 (m, 3H), 0.28 (dt, J=6.2, 4.6 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −139.49; 13C NMR (101 MHz, CDCl3) δ 190.47, 148.35, 147.05, 145.79, 143.11, 139.40, 116.45, 36.23, 10.04, 4.51.
Reaction SMILES: [OH-].[Li+].[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][CH:17]=1.Cl>C1COCC1>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[O:3][C:4]3[C:5]([C:11](=[O:13])[CH:12]=2)=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=3)=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=O)c3ccc(O)cc3o2)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (38.7 mmol, 3 equivalents) is added in one portion to a well-stirred solution of 2′,4′-dihydroxyacetophenone (12.9 mmol) in dry THF (15 ml) at −78° C. under an argon atmosphere. The reaction mixture is stirred at −78° C. for one hour and subsequently at −10° C. for two hours. After re-cooling it −78° C., a solution of 4-methoxybenzoyl chloride (14.2 mmol) in THF (20 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied onto a mixture of ice (300 g) and concentrated HCl (10 ml) and extracted with dichloromethane (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (100 ml) and sulfuric acid (0.5 ml) are added to the residue, and the mixture is heated at 95–100° C. under an argon atmosphere for from 30 minutes to one hour. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised from methanol to give 4′-methoxy-7-hydroxyflavone. 1H NMR (250 MHz, d6-DMSO): δ 10.90 (br s, OH), 8.01–7.11 (dm, 4H), 7.87 (d, 1H), 7.00 (d, 1H), 6.93 (d, 1H), 6.81 (s, 1H), 3.86 (s, 3H); 13C NMR (62.90 MHz, d6-DMSO): δ176.24 (s), 162.58 (s), 162.00 (s), 161.87 (s), 157.39 (s), 127.93 (s), 126.41 (s), 123.42 (s), 116.07 (s), 114.83 (s), 114.48 (s), 105.07 (s), 102.48 (s), 55.46 (s); EI-MS (70 eV) m/e (rel. abund.)=268.07356 (100). The product is beige and exhibits the UV absorption maximum at λ=323 nm with ε=26450 (in 2-propanol) (cf. FIG. 2).
Reaction SMILES: CS[C:3]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]4[O:21][CH2:20][CH2:19][N:18]([C:22]5[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24][CH:23]=5)[CH2:17][C:16]=4[CH:32]=3)[CH:10]=[CH:11][C:5]=2[N:4]=1.[CH2:33]([NH2:35])[CH3:34]>C(O)C>[CH2:33]([NH:35][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]4[O:21][CH2:20][CH2:19][N:18]([C:22]5[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24][CH:23]=5)[CH2:17][C:16]=4[CH:32]=3)[CH:10]=[CH:11][C:5]=2[N:4]=1)[CH3:34]
Reactant: CSc1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Reactant: CCN
Solvent: CCO
Product: CCNc1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Temperature: 150 °C

Procedure:
A solution of 7-[2-(methylthio)-1H-benzimidazol-6-yl]-4-quinolin-4-yl-2,3,4,5-tetra-hydro-1,4-benzoxazepine (52 mg, 0.12 mmol, prepared according to the method of example 19) and ethylamine (1.5 mL) in ethanol (3 mL) heated with microwave irradiation at 150° C. for 8 h. Purification of the crude material by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided the title Compound as acetate salt (4 mg, 7% yield) as a colorless solid. 1H NMR (400 MHz, methanol-d4): 8.55 (d, 1H), 8.15 (d, 1H), 7.95 (d, 1H), 7.73 (m, 1H), 7.60-7.50 (m, 3H), 7.42 (m, 1H), 7.33 (dd, 1H), 7.29 (d, 1H), 7.09 (m, 2H), 4.69 (s, 2H), 4.41 (m, 2H), 3.92 (m, 2H), 3.44 (q, 2H), 1.94 (s, 3H), 1.31 (t, 3H); MS (EI) for C27H25N5O: 436 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=2[OH:14])=[CH:4][CH:3]=1.[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:7]1[CH:6]=[C:5]([C:8]2[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=2[OH:14])[CH:4]=[CH:3][C:2]=1[Cl:1])([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(Cl)nnc1-c1ccc(Cl)cc1
Product: O=[N+]([O-])c1cc(-c2nnc(Cl)cc2O)ccc1Cl
Temperature: 0 °C

Procedure:
3-(4'-Chlorophenyl)-4-hydroxy-6-chloropyridazine (12 g, 0.04978 mol) was introduced into cooled, highly-concentrated nitric acid in the course of 15 minutes at a temperature of 0°-5° C. The mixture was stirred for 30 more minutes at 0° C., and the reaction mixture was then stirred into ice-water. The resulting yellow solid product was isolated, washed with water and reprecipitated using NH4OH/HCl. After drying, 11 g, 0.0385 mol, of 3-(3'-nitro-4'-chlorophenyl)-4-hydroxy-6-chloropyridazine of m.p. 204°-209° C. were obtained, which corresponds to a crude yield of 77.25%. According to TLC analysis (SiO2 /10% ethanol/chloroform), the sample proves to be largely uniform. Recrystallized from ethanol, the compound melts at 208°-211° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([CH2:11][O:12][CH3:13])[CH:3]=1.[CH3:14][N:15](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[CH3:13][O:12][CH2:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=1)[C:14]#[N:15]
Reactant: CN(C)C=O
Reactant: COCc1cc(Br)cc(COC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: COCc1cc(C#N)cc(COC)c1
Temperature: 80 °C
Yield: 79 %

Procedure:
To a solution of 1-bromo-3,5-bis-methoxymethyl-benzene (522 mg, 2.130 mmol) in dimethylformamide (5 mL) at room temperature was added zinc cyanide (150 mg, 1.278 mmol). The reaction mixture was degassed by passing argon through for I h before tetrakis(triphenylphosphine)palladium (148 mg, 0.128 mmol) was added. The reaction mixture was heated at 80° C. under argon for 12 h. The reaction mixture was taken up in toluene (30 mL) and washed with 10% ammonium hydroxide (2×40 mL), brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 20% ethyl acetate in hexanes yielded 3,5-bis-methoxymethyl-benzonitrile (320 g, 79%).