Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:8][C:9]=1[F:10].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1>C1COCC1>[Cl:17][C:18]1[CH:23]=[C:22]([O:16][CH:11]([C:6]2[CH:7]=[CH:8][C:9]([F:10])=[C:4]([F:3])[CH:5]=2)[C:12]([F:13])([F:14])[F:15])[N:21]=[CH:20][N:19]=1
Reactant: OC(c1ccc(F)c(F)c1)C(F)(F)F
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(C(Oc2cc(Cl)ncn2)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.8 %

Procedure:
NaH (80 mg, 60%, 3.0 mmol) was added to a solution of 1-(3,4-Difluoro-phenyl)-2,2,2-trifluoro-ethanol (212 mg, 1 mmol) in 5 ml of THF, the mixture was stirred for 20 minutes at room temperature. 4,6-Dichloro-pyrimidine (149 mg, 1 mmol) was added and then the reaction mixture was heated at 70° C. for 1 hour. After cooling, THF was evaporated. The residue was dissolved in 15 ml of EtOAc, and then washed with water, dried over sodium sulfate. The solvent was removed by rotovap to give 230 mg of 4-chloro-6-[1-(3,4-difluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine, yield 70%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1F)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:17][C:16]1[C:11]2[O:10][CH2:9][CH2:8][NH:7][C:12]=2[C:13]([N+:18]([O-:20])=[O:19])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCOc1c(F)ccc([N+](=O)[O-])c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(F)c2c1NCCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.1 %

Procedure:
To an ice-cold solution of [2-(2,6-difluoro-3-nitrophenoxy)ethyl]carbamic acid tert-butyl ester (450 mg, 1.416 mmol) in DCM (20 mL) was added TFA (4 mL). The reaction mixture was stirred at RT for 2.5 h, then toluene was added and volatiles were removed under reduced pressure. The resulting residue was dissolved in acetonitrile (10 mL), 2M Na2CO3 (10 mL) was added and the mixture stirred at RT for 1 h. The reaction mixture was partitioned between EtOAc and brine, the organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, eluant 10-30% EtOAc in cyclohexane) affording the title compound as an orange solid (250 mg, 89%). 1H NMR (CDCl3, 300 MHz): 7.94 (1H, bs), 7.78 (1H, dd, J=9.7, 5.4 Hz), 6.45 (1H, t, J=9.5 Hz), 4.31 (2H, t, J=4.6 Hz), 3.70-3.66 (2H, m)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)[C:5]([N+:16]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)[C:5]([NH2:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1Nc1ccnc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Br)nc1Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(6-Bromo-3-nitro-pyridin-2-yl)-(2-chloro-pyridin-4-yl)amine (step 1) (1 eq, 0.303 mmol, 100 mg) is dissolved in MeOH/THF (6 ml of a 1:1 mixture) and stirred for 5 minutes at RT. Zinc (22 eq, 6.6 mmol 350 mg) is added and the reaction mixture is stirred for a further 20 minutes. Saturated aqueous ammonium chloride (0.8 ml) is added to the reaction mixture and stirring continued at room temperature for 30 minutes. The mixture is filtered through CELITE® and the filtrate is diluted with water (10 ml) and extracted with EtOAc (2×10 ml). The organic portions are combined, dried (MgSO4) and concentrated in vacuo to afford the title compound; [M+H]+300.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C.[C].[Pd]>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:4]1[NH:3][CH:2]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1
Reactant: CCOC(=O)c1cc(-c2c(F)cccc2F)[nH]c1Cl
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2c(F)cccc2F)c1
Temperature: 40 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
To a solution of ethyl 2-chloro-5-(2,6-difluorophenyl)-1H-pyrrole-3-carboxylate (9.82 g) in ethanol (200 mL) was added 10% palladium carbon (50% containing water, 4.91 g), and the mixture was stirred under a hydrogen atmosphere at 40° C. for 72 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as colorless crystals (yield 3.80 g, 24%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[CH2:18]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Under a nitrogen atmosphere, 3,6-dibromocarbazole (9.75 g, 30 mmol) was slowly added to a suspension of sodium hydride (45 mmol) in dried THF (100 mL), and then stirred for 30 minutes at room temperature. Benzylbromide (6.72 g, 40 mmol) was dropped into the reaction mixture to be stirred for 20 hours. After addition of water (about 100 mL), a precipitated solid was filtrated, and the filtrate (residuum of the filtration) was washed with an aqueous sodium hydrogencarbonate solution, and then was dissolved in ethanol. The solution was dried by magnesium sulfate, filtrated and concentrated. The residuum was recrystallized with ethanol to give N-benzyl-3,6-dibromocarbazole as a white solid. The yield was 61%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]([OH:15])=O)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:57][CH2:58][C:59]1[CH:60]=[C:61]([OH:65])[CH:62]=[CH:63][CH:64]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:15])[NH:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([OH:65])[CH:60]=2)=[CH:8][C:9]=1[CH:10]([CH3:11])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C(C)C
Reactant: NCc1cccc(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.7 %

Procedure:
To a solution of 3-Isopropyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (110 mg, 0.48 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.20 mL, 1.45 mmol), HBTU (0.27 g, 0.72 mmol), HOBT (78 mg, 0.58 mmol), and 3-Aminomethyl phenol (65 mg, 0.53 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-60% EtOAc in hexane to afford the desired product (0.070 g, 44% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:13]=[C:12]([OH:22])[CH:11]=2)=[N:4]1)[CH3:2].[N:24]1([C:28]([C:30]2[CH:31]=[C:32]([Cl:37])[C:33](Cl)=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:24]1([C:28]([C:30]2[CH:31]=[C:32]([Cl:37])[C:33]([O:22][C:12]3[CH:11]=[C:10]([CH:15]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:13]=3)[C:9]([NH:8][C:5]3[CH:6]=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=3)=[O:23])=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: CCn1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)COC)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1ccc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)COC)c2)n1
Temperature: 160 °C
Yield: 85.6 %

Procedure:
A solution of N-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide (128 mg, 0.4 mmol) and the 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (111 mg, 0.48 mmol) in acetonitrile (2 mL) containing potassium carbonate (111 mg, 0.8 mmol) was heated in a microwave reactor at 160° C. for 6 hours. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure and purified by chromatography on silica, eluting with 50-100% ethyl acetate in hexane to give the required product as a white foam (176 mg).
Reaction SMILES: C(OC(=O)[N:7]([C:38]1[CH:39]=[N:40][C:41](Cl)=[CH:42][CH:43]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:36])[C:15]2[C:23]3[C:22]([O:24][CH3:25])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:16]=2)=[C:10]([F:37])[N:9]=1)(C)(C)C.ClCCl.[CH:49]1([Mg]Br)[CH2:51][CH2:50]1.O>C1(C)C=CC=CC=1.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]>[CH:49]1([C:41]2[N:40]=[CH:39][C:38]([NH:7][C:8]3[N:9]=[C:10]([F:37])[C:11]([CH:14]([C:15]4[C:23]5[C:22]([O:24][CH3:25])=[N:21][CH:20]=[N:19][C:18]=5[N:17]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:27]([CH3:29])[CH3:28])[CH:30]([CH3:32])[CH3:31])[CH:16]=4)[OH:36])=[CH:12][CH:13]=3)=[CH:43][CH:42]=2)[CH2:51][CH2:50]1
Reactant: Br[Mg]C1CC1
Reactant: COc1ncnc2c1c(C(O)c1ccc(N(C(=O)OC(C)(C)C)c3ccc(Cl)nc3)nc1F)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COc1ncnc2c1c(C(O)c1ccc(Nc3ccc(C4CC4)nc3)nc1F)cn2[Si](C(C)C)(C(C)C)C(C)C
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
To (6-chloro-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(4-methoxy-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (72, 105 mg, 0.160 mmol) in 3.8 mL of toluene, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (13.0 mg, 0.016 mmol) is added under an atmosphere of nitrogen. The reaction is stirred for 5 minutes, then cyclopropylmagnesium bromide (17, 1.60 mL, 1.0 M in tetrahydrofuran, 1.60 mmol) is added slowly. The reaction is heated at 65° C. for 5 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (73, 70 mg). MS (ESI) [M+H+]+=563.6.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:26]([CH3:28])[CH3:27].C(Cl)(Cl)Cl>CC(N(C)C)=O.CO>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:26]([CH3:28])[CH3:27])=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: CC(C)Br
Reactant: Fc1nc(NCc2cccnc2)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (2-fluoro-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (1.00 g, 1 eq, 4.10 mmol) in DMA (12 mL) under an argon atmosphere, at RT, was added K2CO3 (powdered, anhydrous, 2.75 g, 4.85 eq, 19.90 mmol) followed 2-bromopropane (3.75 mL, 9.75 eq, 39.93 mmol). The reaction mixture was stirred at RT for 48 h, when TLC (CHCl3:MeOH; 90:10) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between water (200 mL) and EtOAc (100 mL), the aqueous phase was separated and extracted with more EtOAc (2×50 mL). The bulked organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo, and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→95:5), to afford the title compound as a white solid. Yield: 0.73 g (62%). Mp 131-133° C. 1H-NMR (d6-DMSO, 250 MHz): δ1.49 (2×s, 6H, —CH(CH3)2), 4.63 (m, 3H, —CH(CH3)2 & —HNCH2-Pyr), 7.34, 7.24, 8.44, 8.58 (4×m, 4H, Pyr), 8.26 (s, 1H, —N═CH—N—), 8.95 (bs, 1H, —HNCH2-Pyr). FABMS m/z (relative intensity): 287 ([M+H]+, 100), 245 (8), 154 (23), 136 (18). Accurate Mass (M+H): Actual: 287.1420, Measured: 287.1412. Microanalysis (Expected: Measured) C14H15N6F: C, 58.73; 58.57; H, 5.28; 5.21; N, 29.35; 29.27.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:42]([CH3:43])[CH3:44])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C(C)C)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K22) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (197 mg, 47%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]([CH3:8])[N:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[C:11]([CH3:19])[N:10]=2)[C:3]1=[O:20].[CH3:21][C:22]1[C:23]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:21][C:22]1[C:23]([N:29]2[CH2:30][CH2:31][N:32]([C:13]([C:12]3[CH:17]=[CH:18][C:9]([N:4]4[CH:5]([CH3:8])[C:6](=[O:7])[N:2]([CH3:1])[C:3]4=[O:20])=[N:10][C:11]=3[CH3:19])=[O:15])[CH2:33][CH2:34]2)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=1
Reactant: COC(=O)c1ccc(N2C(=O)N(C)C(=O)C2C)nc1C
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)nc3C)CC2)c(C)c1
Yield: 80.9 %

Procedure:
Using methyl 6-(3,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-methylnicotinate (19 mg) described in Preparation Example 255 and 1-(3,5-dimethylpyridin-2-yl)piperazine (13 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (24 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:27])C>[Zn]>[NH2:22][C:17]1[CH:18]=[CH:19][C:20]([OH:27])=[CH:21][C:16]=1[CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccccc1CNC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)O
Agent: [Zn]
Product: Nc1ccc(O)cc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
(1-Benzyl-piperidin-4-yl)-(2-nitro-benzyl)-amine (0.25 g, 0.7 mmol) and zinc dust (0.2 g, excess) were combined in 75% aqueous acetic acid (8 mL) and stirred at 60° C. for 2 h. After cooling to room temperature, the solvents were removed in vacuo and the resultant crude mixture dissolved in water (10 mL), followed by addition of ammonium hydroxide until pH 3 was attained. The solution was extracted with methylene chloride (3×). The organic layers were pooled together, washed with water (2×), brine (2×), dried over sodium sulfate, filtered, and concentrated to afford 0.18 g (79%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([O:18]CC)=[O:17])=[N:15][N:6]3[C:5](=[O:21])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:29]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:6]3[C:5](=[O:21])[C:4]=2[CH:3]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1cc2n(C)c3ccc(N)cc3c(=O)n2n1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c2ccc(NC(=O)c3ccccc3)cc2c(=O)n2nc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7-amino-4,9-dihydro-4-methyl-9-oxopyrazolo[5,1-b]quinazoline-2-carboxylic acid, ethyl ester (0.75 g, 2.62 mmol, Example 2) and triethylamine (0.46 mL, 3.30 mmol) in 500 mL of methylene chloride was added dropwise a solution of benzoyl chloride (0.34 mL, 2.93 mmol) in 50 mL of methylene chloride at room temperature. A yellow solid slowly formed. The mixture was stirred at room temperature for 12 hours and filtered. The yellow solid was washed with methylene chloride and diethyl ether and vacuum-dried, affording the title compound as its ethyl ester, mp 275°-278° C., dec.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[CH3:36][C:37]1([C:40](O)=[O:41])[CH2:39][CH2:38]1>>[CH3:36][C:37]1([C:40]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:41])[CH2:39][CH2:38]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: CC1(C(=O)O)CC1
Product: CC1(C(=O)N2CCC(n3cc(-c4cnn5c(-c6cccc(NC(=O)NCC(F)(F)F)c6)cnc5c4)cn3)CC2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 1-methylcyclopropanecarboxylic acid (Aldrich, Cat. No. 205605). LCMS (M+H)+: m/z=567.3.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1B(O)O.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:30]2[CH:29]=[CH:28][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc(C)n(-c2ccc3ccccc3c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 2-naphthylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.13 g, 83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=O)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[Na+].C(=O)([O-])[O-]>C(OC(=O)C)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])/[CH:5]=[C:15]1\[N:14]=[C:11]([CH3:12])[O:18][C:16]\1=[O:17]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC1=N/C(=C\c2ccc(O)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 85 %

Procedure:
Commercially available 3-fluoro-4-hydroxybenzaldehyde (14 g, 0.1 mol), N-acetylglycine (14 g, 0.12 mol), sodium carbonate (10.6 g, 0.1 mol) and sodium acetate (16.6 g, 0.2 mol) were mixed at r.t. in 60 mL of acetic anhydride and stirred at moderate heating until full dissolution of carbonate. Then the mixture was refluxed for 2 hours, cooled down to r.t. and diluted with water (200 mL). The precipitate was filtered and used without further purification: 22.34 g. (Yield ˜85%)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([CH2:14][CH2:15][C:16]2=O)[CH:12]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC=CC=1[Se]C#N)([O-])=[O:26].C(P(CCCC)CCCC)CCC.OO.Cl>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([CH:14]([OH:26])[CH:15]=[CH:16]2)[CH:12]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Se]c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C1C2CCC(=O)C2CN1C(=O)OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Agent: OO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C1C2C(O)C=CC2CN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A solution of the compound prepared as described in Example 3 (6.89 g) and 2-nitrophenyl selenocyanate (4.72 g) in tetrahydrofuran (100 ml)was cooled to about -20° C. under a nitrogen atmosphere. The cooled solution was treated with tributylphosphine (5.2 ml)in one portion. After one hour, the reaction solution was treated with pyridine (100 ml) and the resulting mixture allowed to warm to room temperature. The reaction was then treated with 30% hydrogen peroxide (35 ml). After an additional two hours, the reaction mixture was added to 1N hydrochloric acid (200 ml), and the title compound was extracted with diethyl ether. The diethyl ether extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC, eluting with a linear gradient of hexane to hexane/ethyl acetate (1:1), to give 4.97 g of compound 7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])[CH:7]=1.BrC1C=C2C(N[C@@H](CC)C(=O)N2)=CC=1>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:15][C:10](=[O:11])[C@H:9]([CH2:13][CH3:14])[NH:8]2
Reactant: CC[C@H](Nc1cc(Br)ccc1[N+](=O)[O-])C(=O)O
Agent: CC[C@@H]1Nc2ccc(Br)cc2NC1=O
Product: CC[C@@H]1Nc2cc(Br)ccc2NC1=O

Procedure:
(2S)-2-[(5-bromo-2-nitrophenyl)amino]butanoic acid was treated according to the procedure for the preparation of (3S)-7-bromo-3-ethyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 31) to yield (3S)-6-bromo-3-ethyl-3,4-dihydroquinoxalin-2(1H)-one.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=[NH:10])OC)([O-:3])=[O:2].CO[CH:16](OC)[CH2:17][NH2:18]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[NH:18][CH:17]=[CH:16][N:10]=2)[CH:11]=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: COC(=N)c1cccc([N+](=O)[O-])c1
Reactant: COC(CN)OC
Solvent: CO
Product: O=[N+]([O-])c1cccc(-c2ncc[nH]2)c1
Yield: 48.7 %

Procedure:
A stirred solution of methyl 3-nitrobenzimidate (7.57 g) and aminoacetaldehyde dimethylacetal (5.57 g) in methanol (20 ml) is heated under reflux for 24 hours. The cool solution is evaporated, and the residue treated with water (9.5 ml) and conc. hydrochloric acid (21 nil). The mixture is heated (steam bath) for 15 minutes and evaporated under reduced pressure. Water (50 ml) is added to the residue and the insoluble solid filtered and washed with water. The filtrate is neutralized with potassium carbonate solution and the precipitated solid filtered and washed with water. The combined solids are charcoaled and recrystallised from ethanol to give 3.87 g of 2-(3nitrophenyl)imidazole, mp 193-194.5° C.