Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][CH3:18])[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2].C1COCC1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=S)=[C:30]([CH3:37])[CH:29]=1.NC(N)=S>CN(C1C=CN=CC=1)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=3[CH3:37])[N:17]([CH3:18])[C:12]=2[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2]
Reactant: Cc1cc(F)ccc1N=C=S
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc(N)c(NC)c1C#N
Agent: CN(C)c1ccncc1
Agent: NC(N)=S
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C(C)=O)c1ccc2nc(Nc3ccc(F)cc3C)n(C)c2c1C#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
To a 250 mL round-bottom flask was added 2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (10.8 g, 37.4 mmol), DMAP (228 mg, 1.87 mmole), and THF (80 mL). The solution was stirred with gentle heating until all the material was fully dissolved. The reaction mixture was then concentrated under vacuum to achieve a final volume of approximately 20 mL. After cooling to room temperature, 4-fluoro-1-isothiocyanato-2-methyl-benzene (9.36 g, 56.0 mmole) was added in one portion, and stirring was continued at room temperature for 12 hours, after which time all the diamine had been converted to the corresponding thiourea as determined by TLC analysis. To the reaction mixture was then added mercuric oxide (12.15 g, 56 mmole) and the resulting slurry stirred at room temperature. The slurry rapidly became black, indicating the formation of mercuric sulfide. After 1 hour, the reaction was complete as determined by TLC analysis. Silica gel was added to the mixture and the resulting thick slurry was filtered through a pad of celite, washing with several volumes of EtOAc. The clear filtrate was concentrated to produce a dark gray solid. To the solid was added diethylether, and the insoluble material was isolated by filtration to provide 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (8.25 g, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.46-7.42 (m, 2H), 7.14 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.06 (td, 1H, J1=2.7 Hz, J2=8.6 Hz), 6.87 (d, 1H, J=8.6 Hz), 4.28-4.19 (m, 2H), 3.95 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 1.81 (s, 3H), 1.23 (t, 3H, J=7.4 Hz); ESMS (m/z): 423 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](Cl)[N:3]=1.[C:13]([O:17][C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:21]=2)[N:3]=1
Reactant: COC(=O)c1ccc(N)nc1Cl
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 85.7 %

Procedure:
To a flask containing methyl 6-amino-2-chloronicotinate (300 mg, 1.6 mmol), 3-(tert-butoxycarbonyl)phenylboronic acid (540 mg, 2.4 mmol) and Pd(PPh3)4 (90 mg, 0.080 mmol) was added DME (16 mL) and saturated Na2CO3 aqueous solution (1.6 mL). The flask was flushed with N2 (g) and heated at 80° C. under N2 atmosphere overnight. The solution was filtered and concentrated. The residue was purified by column chromatography (0-50% ethyl acetate—hexanes) to yield methyl 6-amino-2-(3-(tert-butoxycarbonyl)phenyl)nicotinate as a white solid (450 mg, 85%). ESI-MS m/z calc. 328.1, found 329.3 (M+1)+. Retention time 1.19 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.91-7.86 (m, 3H), 7.59-7.57 (m, 1H), 7.49 (t, J=7.6 Hz, 1H), 6.86 (s, 2H), 6.48 (d, J=8.7 Hz, 1H), 3.54 (s, 3H), 1.56 (s, 9 H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].[N+:21]([CH2:24][CH3:25])([O-:23])=[O:22].O>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[N+:18]([C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[CH:24]([N+:21]([O-:23])=[O:22])[CH3:25])([O-:20])=[O:19]
Reactant: CC[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 16 h
Yield: 13.6 %

Procedure:
0.87 g of sodium carbonate in 5 ml of anhydrous toluene are placed in a 30 ml reaction vessel, and 0.11 g of benzyltriethylammonium chloride and 1.13 g of 4-chloro-3-nitrobenzotrifluoride and 0.38 g of nitroethane are added at the same time. The mixture is stirred for 16 hours at 20° C., 10 ml of water are added and the aqueous phase is separated, then acidified by a 4N solution of sulfuric acid. It is then extracted with 5 ml of methyl t-butyl ether. After removing the organic solvent, 0.18 g of a mixture is obtained which is separated by column chromatography using reverse phase silica eluting with a mixture of water and acetonitrile to obtain 0.12 g of the title compound, m.p. 48° C.
Reaction SMILES: Br[CH:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1.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]>[F:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][N:25]=2)[CH:22]=1)[CH:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Reactant: OB(O)c1cc(F)cc(Oc2ccc(C(F)(F)F)cn2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc(F)cc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 50 °C
Yield: 33.2 %

Procedure:
To a solution of tert-butyl 4-(bromomethylene)piperidine-1-carboxylate (1.1 g, 0.0039 mol) in THF (13 mL) was added 3-fluoro-5-(5-(trifluoromethyl)pyridin-2-yloxy)phenylboronic acid (1.4 g, 4.7 mmol), potassium phosphate (2.5 g, 0.012 mol) and H2O (0.23 mL) and the mixture was degassed using argon. PdCl2(dppf)2 (0.32 g, 0.4 mmol) was added and the mixture was degassed again. The reaction was heated at 50° C. for 1.5 h and then allowed to cool to RT. Water was added and the mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel column chromatography (2-4% ethyl acetate in hexane) to give the title compound (0.585 g, 19%). 1H NMR (500 MHz, CDCl3): δ 8.45 (s, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.05 (d, J=8.65 Hz, 1H), 6.81-6.75 (m, 3H), 6.30 (s, 1H), 3.51 (t, J=5.55 Hz, 2H), 3.42 (t, J=5.6 Hz, 2H), 2.47 (t, J=5.55 Hz, 2H), 2.33 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:22][CH3:23])[CH2:6][C:5]([CH2:13]OS(C(F)(F)F)(=O)=O)([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH2:4]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-:41]>C1COCC1>[F:41][CH2:13][C:5]1([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH2:6][C:3]([O:22][CH3:23])([O:2][CH3:1])[CH2:4]1
Reactant: COC1(OC)CC(COS(=O)(=O)C(F)(F)F)(C(=O)OC(C)C)C1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: COC1(OC)CC(CF)(C(=O)OC(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of Intermediate 302A (1.8 g, 4.94 mmol) in THF (30 mL) was added TBAF (5.93 mL, 5.93 mmol, 1M in THF) at −78° C. and the reaction mixture was stirred at RT for 1 h. It was then quenched with ice-cold water and extracted with ethyl acetate (3×25 mL). The combined organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (4 g REDISEP® column, eluting with 25% ethyl acetate in hexanes). Fractions containing the product were combined and evaporated to afford the Intermediate 302B as a pale yellow liquid (0.8 g, 69%). 1H NMR (400 MHz, chloroform-d) δ ppm 5.06 (s, 1H), 4.51-4.72 (m, 2H), 3.15 (s, 6H), 2.56 (dd, J=13.55, 2.01 Hz, 2H), 2.21 (d, J=14.06 Hz, 2H), 1.26 (d, J=6.02 Hz, 6H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[F:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:18]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([F:14])[CH3:12]
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: CC(F)(F)c1ccn2c(Br)cnc2n1
Product: CC(F)(F)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Yield: 24 %

Procedure:
3-Bromo-7-(1,1-difluoroethyl)imidazo[1,2-α]pyrimidine (130 mg, 0.50 mmol) was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 5′-[7-(1,1-difluoroethyl)imidazo[1,2-α]pyrimidin-3-yl]-2′-fluorobiphenyl-2-carbonitrile (45 mg, 24%) as a white powder: δH (400 MHz, CDCl3) 2.15 (3H, t, J 21), 7.34 (1H, d, J 7), 7.43 (1H, t, J 9), 7.53-7.74 (5H, m), 7.86 (1H, dd, J 8 and 1), 7.99 (1H, s), 8.95 (1H, d, J 7); m/z (ES+) 379 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:5]([NH:7][C:8]1[CH:36]=[CH:35][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:25][CH2:24]3)=[O:22])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[Na+].O.Cl>C1COCC1.C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([N:23]3[CH2:24][CH2:25][N:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][CH2:28]3)=[O:22])=[CH:17][CH:18]=2)=[CH:35][CH:36]=1)=[O:6]
Reactant: CCOC(=O)CN1CCN(C(=O)CCc2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCN(C(=O)CCc2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cc3)cc2)CC1

Procedure:
To a solution of ethyl 2-[4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazin-1-yl]acetate (0.493 g, 0.843 mmol) in THF (5 mL) and ethanol (5 mL) were added 5 M aqueous sodium hydroxide (0.253 mL, 1.27 mmol) and water (1 mL), and the resulting solution was refluxed for 1 hour. This reaction solution was concentrated under reduced pressure, and the residue was dissolved in 50% aqueous ethanol. To the resulting solution was added 5 M hydrochloric acid (0.253 mL, 1.27 mmol), and the obtained solid was collected by filtration. To this solid was dissolved in ethanol (10 mL) and 5 M hydrochloric acid (0.3 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from ethanol-diethyl ether, to thereby yield 0.381 g of the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15](C(=O)C(F)(F)F)=[CH:14][CH:13]=2)[N:7]=1)=[O:4].[C:26](OC(=O)CC)(=O)CC>O>[CH3:11][CH:9]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:26])[CH2:10]1
Reactant: CCC(=O)OC(=O)CC
Reactant: CC1CC(NC(=O)C(F)(F)F)=NN1c1ccc(C(=O)C(F)(F)F)cc1
Solvent: O
Product: CCC(=O)NC1=NN(c2ccccc2)C(C)C1
Reaction time: 16 h

Procedure:
A mixture of 5.0 g. of 3-amino-5-methyl-1-phenyl-2-pyrazoline (prepared in Example 5) and 25.0 ml. of propionic anhydride is allowed to remain at room temperature for 16 hours. The reaction mixture is poured into water to separate an oil which crystallizes. The solid is collected by filtration and dissolved in dichloromethane. The solution is passed through a short column of a hydrous magnesium silicate. The effluent is heated at reflux and hexane is added. The first heavy precipitate (purple color) is discarded. The solution is cooled and the ensuing precipitate is collected by filtration. The solid is again dissolved in dichloromethane, columnized and recrystallized with hexane to give 2.3 g. of the product of the Example as plates, m.p. 96.0°-96.5° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[N+:13]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)([O-:15])=[O:14]
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
A flask containing 1-Methoxy-3-nitro-5-trifluoromethyl-benzene (10 g) and hydrochloride pyridine (10 eq, 52.0 g) was heated to 210 C and stirred for 12 h. Once complete, the reaction was cooled and the residue was dissolved in CH2Cl2 and washed twice with water (100 mL). The organic layer was concentrated under vacuum and then set in the freezer overnight. The resulting crystalline product was filtered off and washed with ether and used as is.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:21][CH2:20]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][C:7]=1Br.C[Sn](C)(C)[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][N:33]=1)[C:30](=[O:34])[NH:29][CH2:28][CH2:27]2>O1CCOCC1.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>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:21][CH2:20]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][C:7]=1[C:24]1[N:33]=[CH:32][C:31]2[C:30](=[O:34])[NH:29][CH2:28][CH2:27][C:26]=2[CH:25]=1
Reactant: C[Sn](C)(C)c1cc2c(cn1)C(=O)NCC2
Reactant: Nc1ncc(-c2ccc(S(=O)(=O)NC3CC3)cc2)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccc(S(=O)(=O)NC3CC3)cc2)nc1-c1cc2c(cn1)C(=O)NCC2
Yield: 4.5 %

Procedure:
A solution of 4-(5-amino-6-bromopyrazin-2-yl)-N-cyclopropylbenzenesulfonamide (150 mg, 0.41 mmol), 6-(trimethylstannyl)-3,4-dihydro-2,7-naphthyridin-1(2H)-one (150 mg, 0.48 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) in dioxane (2 mL) was heated in the microwave 20 min at 150° C. At completion, the reaction mixture was purified by reverse phase preparatory HPLC to provide 4-(5-amino-6-(8-oxo-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)pyrazin-2-yl)-N-cyclopropylbenzenesulfonamide (8 mg, 5% yield) as an orange solid after lyophilization. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.02 (s, 1H), 8.87 (s, 1H), 8.59 (s, 1H), 8.35 (d, J=8.5 Hz, 2H), 8.17 (br. s., 1H), 7.84-7.99 (m, 3H), 3.51 (t, 2H), (t, J=6.3 Hz, 2H), 0.29-0.57 (m, 4 H); MS (EI) m/z=437.5 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][Cl:29]>O>[Cl:29][CH2:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: ClCCCCBr
Reactant: O=c1ccc2ccc(O)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2ccc(OCCCCCl)cc2[nH]1
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
After 7-hydroxy-1H-quinolin-2-one (10 g) and DMF (50 ml) were heated to approximately 30° C., an aqueous potassium carbonate solution (potassium carbonate: 8.6 g, water: 10 ml) was added. After the mixture was stirred at 30 to 40° C. for about 15 minutes, 1-bromo-4-chlorobutane (14.3 ml) was added and stirred at approximately 40° C. for 5 hours. Water (100 ml) was added dropwise over a period of 30 minutes or more while the temperature was maintained at 30° C. or more. After the mixture was stirred at approximately 30° C. for 30 minutes, stirring was continued at 10° C. or less for 1 hour, after which the precipitated crystals were collected by filtration. After methanol (100 ml) was added to the precipitated crystals, the mixture was stirred under reflux to ensure dissolution. This solution was cooled and stirred at 30 to 40° C. for 30 minutes and then at 5° C. or less for about 1 hour, after which the precipitated crystals were collected by filtration. The crystals were dried at 60° C. to obtain 7-(4-chlorobutoxy)-1H-quinolin-2-one as white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[CH2:13]1CCN2C(=NCCC2)CC1.CI>CN(C=O)C.CCOCC>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6]([O:8][CH3:13])=[O:7]
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1ccccc1C=CC(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)/C=C/c1ccccc1C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To 2-methylcinnamic acid (100 g; 617 mmol) in 1.2L of DMF was added DBU (112.6 g; 740 mmol) and 15 min later methyl iodide (131.3 g; 925 mmol) and left overnight. The solution was diluted in ether and washed with HCl (10%), H2O and brine. The solvent was removed to give 106.8 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19]([O:21]CCCC)=[O:20])=[CH:4][CH:3]=1.[CH:28](O)([CH3:30])[CH3:29].C1COCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19]([O:21][CH:28]([CH3:30])[CH3:29])=[O:20])=[CH:26][CH:27]=1
Reactant: CC(C)O
Reactant: CCCCOC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Solvent: C1CCOC1
Product: Cc1nc2ccccc2c(NCc2ccc(Br)cc2)c1C(=O)OC(C)C

Procedure:
Isopropyl 4-(4-bromobenzylamino)-2-methylquinoline-3-carboxylate was prepared in analogy to n-butyl 4-(4-bromobenzylamino)-2-methylquinoline-3-carboxylate (see Example 6) by transesterification of the corresponding methyl ester in an isopropanol/THF mixture, resulting in the title compound as a colorless oil. MS(ES+): 413/415.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][CH:18]([C:23]([O:25]C)=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[Na+]>CO.C1COCC1>[CH3:22][O:21][C:19](=[O:20])[CH:18]([CH2:17][C:16]1[CH:27]=[CH:28][C:13]([O:12][CH2:11][CH2:10][N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)=[CH:14][CH:15]=1)[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(Cc1ccc(OCCn2ccc3cccnc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(OCCn2ccc3cccnc32)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in Example 30 is dissolved in 5 ml of methanol and 3 ml of THF. The mixture is cooled to 0° C. and 0.44 ml of a 2M sodium hydroxide solution is added dropwise. After stirring for 1 hour 30 minutes at ambient temperature, the solvents are removed by evaporation under reduced pressure and the resulting residue is taken up in water and extracted with ethyl acetate. The aqueous phase is acidified with a 2M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered, and evaporated under reduced pressure. The resulting residue is taken up in a minimum of ethyl acetate and precipitated with pentane to yield the title product after filtration.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH3:13][C:14]1[NH:15][CH:16]=[C:17]([CH3:21])[C:18]=1[CH2:19][CH3:20].O>C(O)(=O)C.ClCCl>[CH2:19]([C:18]1[C:17]([CH3:21])=[C:16]([C:3]2[C:4](=[O:11])[C:5]3[C:10]([C:1](=[O:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:15][C:14]=1[CH3:13])[CH3:20]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CCc1c(C)c[nH]c1C
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1c(C)[nH]c(C2=CC(=O)c3ccccc3C2=O)c1C
Yield: 80 %

Procedure:
6.32 millimol of 1,4-naphthoquinone and 3.16 millimol of 2,4-dimethyl-3-ethylpyrrole were stirred in 20 ml of glacial acetic acid in a round-bottomed flask for 10 minutes at room temperature. The reaction mixture was diluted with 300 ml of dichloromethane and the resulting mixture was then poured into a large volume of water (300 ml). The organic phase was then separated out and washed four times with 100 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 2-(4-ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-[1,4]-naphthoquinone was thus isolated in a yield of 80% after purification by chromatography on a column of silica.
Reaction SMILES: BrC1C2C(Cl)=NC=NC=2N(C(C)C)C=1.[Cl:15][C:16]1[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[CH:24][C:17]=1[C:18](N(OC)C)=[O:19].[NH2:31][C:32]1[C:33]2[C:40](C(C3C=CC=C(N)C=3C)=O)=[CH:39][N:38]([CH:51]([CH3:53])[CH3:52])[C:34]=2[N:35]=[CH:36][N:37]=1>>[NH2:28][C:27]1[C:16]([Cl:15])=[C:17]([C:18]([C:40]2[C:33]3[C:32]([NH2:31])=[N:37][CH:36]=[N:35][C:34]=3[N:38]([CH:51]([CH3:53])[CH3:52])[CH:39]=2)=[O:19])[CH:24]=[CH:25][CH:26]=1
Reactant: CON(C)C(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: Cc1c(N)cccc1C(=O)c1cn(C(C)C)c2ncnc(N)c12
Agent: CC(C)n1cc(Br)c2c(Cl)ncnc21
Product: CC(C)n1cc(C(=O)c2cccc(N)c2Cl)c2c(N)ncnc21

Procedure:
The title compound was prepared from 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine and 2-Chloro-N-methoxy-N-methyl-3-nitro-benzamide by procedures analogous to those described for the preparation of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-2-methyl-phenyl)-methanone. MS: 330.3 (MH+); HPLC Rf: 1.6 min. (HPLC HPLC purity: 99%.
Reaction SMILES: [C:1]([O-:4])([O-:3])=[O:2].[K+].[K+].O[C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])[CH:11]=[CH:12][CH:13]=1>O1CCCC1>[C:16]([O:2][C:1]([O:4][C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])[CH:11]=[CH:12][CH:13]=1)=[O:3])([CH3:18])([CH3:17])[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: C=C(C)C(=O)Nc1cccc(O)c1
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1cccc(OC(=O)OC(C)(C)C)c1

Procedure:
K2CO3 (50 g) is added to a solution of 40.0 g (0.225 mol) of N-(3-hydroxyphenyl)methacrylamide in tetrahydrofuran (THF). A solution of 54.2 g (0.249 mol) of di-tert-butyl pyrocarbonate (di-tert-butyl dicarbonate) in THF is then added dropwise at room temperature while stirring. The reaction is complete after a few hours. The reaction mixture is poured onto ice and extracted with ethyl acetate, the organic phase is dried and the solvent is distilled off. A white crystalline product is obtained which is recrystallized from diisopropyl ether.
Reaction SMILES: C([O-])(O)=O.[Na+].S(O)(O)(=O)=O.[NH2:11][CH2:12][C:13]#[N:14].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.O1CCOCC1.C(Cl)Cl>[CH2:15]([O:22][C:23](=[O:24])[NH:14][CH2:13][C:12]#[N:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#CCN
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CCNC(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 56.8 %

Procedure:
NaHCO3 (1.09 g, 12.97 mmol) in water (5 mL) was added to a stirred solution of 2-aminoacetonitrile sulfate (1.0 g, 6.48 mmol) in 1,4-Dioxane (10 mL) at 0-5° C. followed by addition of Benzylchloroformate (1.3 g, 1.11 mL, 7.78 mmol) and stirring was continued at 20-35° C. for 15 h. Reaction mixture was diluted with DCM and washed it with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by Column chromatography (using Silica gel 60-120 and 10% MeOH in DCM as eluent) to afford 700 mg of the title compound.