Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]2[O:10][CH2:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14](=[O:15])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:20])(=[O:3])[CH3:2].[Na].[C:22](OCC)(=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[CH2:26]([O:25][C:23]([C:22]1[O:20][C:5]2[CH:6]=[CH:7][C:8]3[C:14](=[O:15])[C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][O:10][C:9]=3[C:4]=2[C:1](=[O:3])[CH:2]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(O)ccc2c1OCc1ccccc1C2=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2c3c(ccc2o1)C(=O)c1ccccc1CO3
Temperature: 25 °C

Procedure:
8.04 g (30 mmol) 4-acetyl-6,11-dihydro-3-hydroxydibenz[b,e]oxepin-11-one is added to a solution of 4.14 g (180 mmol) sodium in 250 ml ethanol, it is heated for 10 minutes to reflux, cooled to room temperature, admixed with 14.6 g (100 mmol) diethyl oxalate, heated for 90 minutes to reflux, allowed to cool and filtered. The precipitate is taken up in 100 ml ethanol, the suspension is saturated with hydrogen chloride and subsequently heated for 1 hour to 50° C. After cooling it is poured onto ice and filtered. 7.8 g of the title compound (74% of theory) of melting point 178°-180° C. (from ethanol) remain.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl.O>[Si:20]([O:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CNc1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CNc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a solution of [4-(methylamino)phenyl]methanol (500 mg, 3.7 mmol) and imidazole (248 mg, 3.7 mmol) in DCM (20 mL) was added TBSCl (548 mg, 3.7 mmol) at r.t., and the reaction was stirred for 2 h. The reaction was diluted with water (50 mL) and extracted with DCM (50 mL×3). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=40:1) to give 600 mg (66%) of the title compound as a yellow oil. [M+H] Calc'd for C14H15NOSi, 252. Found 252.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6′-methyl-[2,3′-bipyridin]-2′-yl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 471 (M+H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([N:21]([CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([N:36]3[CH2:41][CH2:40][N:39]([C:42](OC4C=CC([N+]([O-])=O)=CC=4)=[O:43])[CH2:38][CH2:37]3)=[N:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1)[CH3:22])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C=O)C>[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([N:21]([CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([N:36]3[CH2:41][CH2:40][N:39]([C:42]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:43])[CH2:38][CH2:37]3)=[N:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1)[CH3:22])=[O:20])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)CO
Reactant: CN(Cc1cccc(-c2cnc(N3CCN(C(=O)Oc4ccc([N+](=O)[O-])cc4)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COC(=O)N1CCN(c2ncc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cn2)CC1
Reaction time: 0.17 h
Yield: 10.9 %

Procedure:
Ethyl glycolate (116 mg) was dissolved in DMF (4 ml), and NaH (73 mg) was added thereto under ice-cooling. After stirring at the same temperature for 10 minutes, a solution of 4-nitrophenyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (340 mg) in DMF (3 ml) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2-ethoxy-2-oxoethyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (35 mg).
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[Cl:12][CH:13]1[CH:25]=[C:17]2[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:15]([C:16]=32)[C:14]1([C:28]1[N:33]=[C:32]([S:34](=O)(=[O:37])NC)[N:31]=[C:30]([NH2:39])[N:29]=1)[C:26]#[N:27]>C(Cl)Cl>[Cl:12][CH:13]1[CH:25]=[C:17]2[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:15]([C:16]=32)[C:14]1([C:28]1[N:33]=[C:32]([S:34]([CH3:2])=[O:37])[N:31]=[C:30]([NH2:39])[N:29]=1)[C:26]#[N:27]
Reactant: CNS(=O)(=O)c1nc(N)nc(C2(C#N)c3cccc4c3C(=CC2Cl)COC4)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc(N)nc(C2(C#N)c3cccc4c3C(=CC2Cl)COC4)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
m-Chloroperbenzoic acid (7.10 g, 31.9 mmol) was added to a solution of 4-(5-chloro-6-cyano-1H,3H benzo[de]isochromen-6-yl)-6-methylsulfamyl-[1,3,5]triazin-2-ylamine (10.0 g, 29.0 mmol) in methylene chloride (100 mL) at room temperature. After the reaction solution was stirred at room temperature for 15 hours, the precipitate was collected by filtration. The resulting precipitate was suspended in methylene chloride, and stirred at room temperature for 3 hours. The insoluble material was collected by filtration, washed with methylene chloride, and dried under reduced pressure. The title compound was obtained as light brown solid (8.34 g, 79%).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:21]1([S:27]([CH2:30][C:31]2[C:36]([C:37](O)=[O:38])=[C:35]([OH:40])[C:34]([Br:41])=[CH:33][CH:32]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C1C=CN=CC=1)C.C1COCC1>[C:21]1([S:27]([CH2:30][C:31]2[C:36]([C:37]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:38])=[C:35]([OH:40])[C:34]([Br:41])=[CH:33][CH:32]=2)(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)O
Reactant: O=C(O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Reaction time: 18 h

Procedure:
tert-Butanol (1 mL) and N,N′-dicyclohexylcarbodiimide (0.4 g) were added to a solution of 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoic acid (Intermediate 39, 0.48 g) and DMAP (0.016 g) in THF (10 mL) and the mixture was stirred for 18 hours. It was evaporated to dryness and the residue was suspended in DCM and the insoluble material was removed by filtration. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with DCM to give tert-butyl 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoate (0.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:23](=[O:24])[CH2:22][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Cc1ccccc1)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.00 g (0.032 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 50 ml of pyridine and 7.42 g (0.048 mol) of phenylacetyl chloride were added dropwise thereto at 0°. After stirring overnight at room temperature the mixture was poured into water, extracted with ethyl acetate, dried with magnesium sulphate and the solvent was distilled off in vacuo. Chromatography (silica gel, chloroform-hexane, 1:1) gave 8-chloro-4-(phenylacetyl)-1,2,3,4,5,6-hexahydrobenzo[f]quinoline in the form of an oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-:16].[Na+]>Cl>[CH3:15][S:14][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:16])[CH:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: [OH-]
Reactant: CSc1nccc(-c2ccnc(F)c2)n1
Agent: Cl
Agent: [Na+]
Product: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Temperature: 25 °C
Yield: 49 %

Procedure:
A suspension of 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (6.83 g, 30.9 mmol) in 2N HCl (100 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and placed in an ice bath. The pH was adjusted to about 7 with 2N NaOH (about 100 mL). The resulting solids were collected by filtration, washed with water and dried to give 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (5.07 g) as a solid. This material was placed in the thimble of a Soxhlet apparatus and was attached to a 1 L flask charged with ethyl acetate (500 mL). The material was continuously extracted for 3 days. The resulting white precipitate from the ethyl acetate layer was collected by filtration (3.3 grams, 49% yield). 1H NMR (400 MHz, (CD3)2SO) δ 11.85 (br, s, 1H), 8.75 (d, J=5.0 Hz, HA), 7.79 (d, J=5.0 Hz, 1H), 7.54 (d, J=7.0 Hz, 1H), 7.13 (s, 1H), 6.86 (d, J=7.0 Hz, 1H), 2.58 (s, 3H); m/z (APCI-pos) M+1=220.0.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:12][CH:11]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].[C:25]([Si:29]([CH3:32])([CH3:31])Cl)([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Si:29]([N:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:12][CH:11]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:32])[CH3:31]
Reactant: C1=C(c2cnc3[nH]ccc3c2)CCC(N2CCCOCC2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(C3=CCC(N4CCCOCC4)CC3)cnc21
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
To a stirred solution of azaindole (XXVa-101) (12.65 g, 42.5 mmol) in DMF (120 mL) was added 60% NaH dispersion in mineral oil (2.04 g, 51.0 mmol) portionwise over 3 min. After 15 min, tert-butyldimethylchlorosilane (8.33 g, 55.3 mmol) was added and the mixture stirred for a further 66 h. The mixture was diluted with EtOAc (150 mL) and saturated NaHCO3 solution (100 mL) and partitioned. The aqueous layer was extracted with EtOAc (4×150 mL) and CH2Cl2 (100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to yield a honey coloured viscous oil. This was purified by means of SGC using hexane:CH2Cl2 (gradient elution from 100:0 to 0:100, v/v) followed by CH2Cl2:MeOH (gradient elution from 100:0 to 90:10, v/v) to afford the silylated azaindole (XXVIIa-101) (15.37 g, 87%). 1H NMR (400 MHz, CDCl3) δ 0.62 (s, 6H), 0.92 (s, 9H), 1.68 (m, 1H), 1.87-1.93 (m, 2H), 2.05-2.10 (m, 1H), 2.18-2.26 (m, 1H), 2.36-2.43 (m, 1H), 2.57-2.63 (m, 2H), 2.83-2.86 (m, 5H), 3.75 (t, J=4.7 Hz, 2H), 3.82 (t, J=6.0 Hz, 2H), 6.02-6.05 (m, 1H), 6.49 (d, J=3.5 Hz, 1H), 7.21 (d, J=3.5 Hz, 1H), 7.81 (d, J=2.3 Hz, 1H), 8.33 (d, J=2.3 Hz, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH:23]=2)[N:18]=[CH:17]1.[CH:34]1([NH2:38])[CH2:37][CH2:36][CH2:35]1>N1C=CC=CC=1>[CH:34]1([NH:38][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:7]([CH3:6])=[C:8]([N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)[CH:23]=4)[N:18]=[CH:17]3)[CH:9]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCC1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NC2CCC2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 120 °C

Procedure:
Phosphorus oxychloride (0.08 ml) was added to a mixture of 4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.30 g), cyclobutylamine (0.09 ml) and pyridine (5 ml) and the resultant was heated to 120° C. for 5 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The mixture was evaporated. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was dried (magnesium sulphate) and evaporated and the residue purified by column chromatography on a silica column using initially methylene chloride and then a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.16 g); NMR Spectrum: (DMSOd6) 1.68 (m, 2H), 2.05 (m, 2H), 2.14 (s, 3H), 2.20 (m, 2H), 2.24 (s, 3H), 2.48 (m, 4H), 3.29 (m, 4H), 4.42 (m, 1H), 7.49 (d, 1H), 7.53 (d, 1H), 7.65 (m, 2H), 7.87 (d, 1H), 7.92 (m, 1H), 8.10 (s, 1H), 8.60 (d, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: C(O)(=[O:3])C.[CH3:5][C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1.O>[CH2:15]([O:14][C:12]([C:7]1[NH:8][C:9]([CH:11]=[O:3])=[CH:10][C:6]=1[CH3:5])=[O:13])[CH3:16]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1[nH]c(C=O)cc1C
Temperature: -7.5 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
Acetic acid (360 mL) and water (300 ml) was added to a solution of ethyl 3,5-dimethyl-2-pyrrolecarboxylate (5 g, 29.9 mmol) in THF (300 ML). The mixture was cooled to −10 to −5° C. for 30 minutes. To the mixture was then added ceric ammonium nitrate (CAN, 67.21 g, 122.6 mmol) over a period of 30 minutes. The mixture was stirred at −10 to −5° C. for 1.5 hours. The reaction was diluted with water (800 mL) and extracted with dichloromethane (3×). The combined extracts were washed with sodium bicarbonate solution until the aqueous layer was basic, dried and concentrated. The residue was purified on a silica gel column (10% EtOAc in hexane) to give 2.4 g (44%) of 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.61 (br s, 1H, NH), 9.64 (s, 1H, CHO), 6.78 (s, 1H), 4.27 (q, J=7.17 Hz, 2H, OCH2CH3), 2.26 (s, 3H, CH3), 1.30 (t, J=7.17 Hz, 3H, OCH2CH3). MS 182 [M++1].
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([OH:19])[C:12]([OH:20])=[N:11]2)=[N+:6]=[N-:7].[K+].[Br-]>>[N:5]([C:8]1[C:9]([N+:1]([O-:4])=[O:2])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([OH:19])[C:12]([OH:20])=[N:11]2)=[N+:6]=[N-:7]
Reactant: O=[N+]([O-])O
Reactant: [N-]=[N+]=Nc1cc2nc(O)c(O)nc2cc1Cl
Agent: [Br-]
Agent: [K+]
Product: [N-]=[N+]=Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
15 ml 89% nitric acid was ice-cooled and then gradually added 1 g (4,2 mmol) 6-azido-7-chloro-2,3-dihydroxyquinoxaline. After stirring at 0° C. for 15 min, the reaction mixture was poured into 100 ml ice-water. The crude product was recrystallized (acetone-methanol-water) to give 0,95 g (80%) 6-azido-7-chloro-2,3-dihydroxy-5-nitroquinooxaline. IR (KBr): 2450 cm-1 (N3). NMR (DMSO-d6) 12.3 (2H, broad s), 7.07 (1H,s).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:27]([CH2:35][C:36](=O)[CH3:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:37]/[C:36](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[CH:35]/[C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Product: C/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of example 1) from a suspension of 113 mg (0.32 mmol) of Intermediate 54 and 52 mg (0.32 mmol) of benzoylacetone to yield 44 mg (28%) of example 54: TLC (DCM/MeOH, 4/1): Rf=0.55; 1H NMR (DMSO-d6, 300 MHz) δ11.43 (d, 1H, J=9.0), 7.92-7.88 (m, 2H), 7.8 (m, 2H), 7.48 (m, 3H), 7.38-7.38 (m, 3H), 7.16 (d, 2H, J=8.4), 6.9 (d, 2H, J=8.4), 5.53 (s, 1H), 4.91 (s, 1H), 4.15 (m, 1H), 3.2 (m, 2H), 2.83-2.74 (m, 1H), 2.37 (s, 3H), 1.67 (s, 3H); low resolution MS (ES+)m/e 497.07 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1([CH3:23])[CH2:11][C:10]2[C:12]([CH3:22])=[C:13]([NH:18]C(=O)C)[C:14]([CH3:17])=[C:15]([CH3:16])[C:9]=2[O:8]1)C.[ClH:25]>CO>[ClH:25].[NH2:18][C:13]1[C:14]([CH3:17])=[C:15]([CH3:16])[C:9]2[O:8][C:7]([CH:6]=[CH:5][C:4]([O:3][CH3:1])=[O:24])([CH3:23])[CH2:11][C:10]=2[C:12]=1[CH3:22]
Reactant: CCOC(=O)C=CC1(C)Cc2c(C)c(NC(C)=O)c(C)c(C)c2O1
Agent: Cl
Solvent: CO
Product: COC(=O)C=CC1(C)Cc2c(C)c(N)c(C)c(C)c2O1
Yield: 74.7 %

Procedure:
3-[5-Acetylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl] acrylic acid ethyl ester (0.5 g, 1.58 mmol) was dissolved in methanol (5 ml). Conc. hydrochloric acid (5 ml) was added to the solution and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled and the crystals precipitated were filtered. The crude crystals obtained were recrystallized from ethanol-isopropyl ether to obtain the desired compound (0.35 g, yield: 74.7% yield), m.p. 225°-234° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C(OC(=O)C)(=O)C>C(O)(C)C>[CH2:4]1[CH:5]2[N:6]([C:9](=[O:11])[CH2:8][CH2:7]2)[C:2](=[O:1])[CH2:3]1
Reactant: O=C(O)CCC1CCC(=O)N1
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCC2CCC(=O)N12
Temperature: 90 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
5-Oxo-2-pyrrolidinepropanoic acid (15.7 g, 0.1 mol) was added to 45 ml of acetic anhydride and the mixture was heated slowly to 90° C. and held at that temperature for six hours. The mixture was cooled and the volatile materials stripped off at a temperature of 60° C. under vacuum. The residue (14.2 g) was dissolved in 230 ml of isopropyl alcohol, the solution decolorized, filtered, and concentrated to 30 ml. This solution was cooled 0°-5° C. for two hours, and the solid which separated was collected by filtration, washed twice with 25-ml portions of isopropyl alcohol to yield 12.5 g (89.9%) of dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione, mp 180.2°-181.8° C. which was found to be 99.5% pure by high pressure liquid chromatographic (HPLC) analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]CC2C=CC(OC)=CC=2)[N:6]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.C([O-])(O)=O.[Na+].C(Cl)Cl>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1ccc(COc2cc(OC)nc(-c3ccccc3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(O)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
4-Methoxy-6-(4-methoxybenzyloxy)-2-phenylpyrimidine was dissolved in a mixture of TFA:DCM (1:2, 30 ml). The mixture was stirred at RT for 2 h. NaHCO3 and DCM was added and the organic layer was separated off, dried, filtered and evaporated to give the title compound (1.04 g, 83%), MS (M+H)+203.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].Cl[C:14]([O:17]C(Cl)=O)(Cl)Cl>O1CCOCC1>[N:1]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])=[C:14]=[O:17]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N=C=O)c(C)c1

Procedure:
1.50 g (9.08 mmol) methyl 4-amino-3-methyl-benzoate are dissolved in 250 ml dioxane combined with 1.3 ml (10.7 mmol) trichloromethyl-chloroformate and refluxed for 5.5 hours with stirring. Then the mixture is evaporated down i. vac. and the residue is further reacted without any more purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:14]([CH3:23])[C:13](=[N:24][C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=3[CH3:33])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[F:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:46](=[O:47])[C:45]4[CH:49]=[CH:50][C:42]([F:41])=[CH:43][CH:44]=4)[CH2:21][CH2:22]3)[N:14]([CH3:23])[C:13](=[N:24][C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=3[CH3:33])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N3CCNCC3)n2)cc1OC
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N3CCN(C(=O)c4ccc(F)cc4)CC3)n2)cc1OC
Temperature: 25 °C

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-2-(1-piperazinyl)-4-(2,4,6-trimethylphenylimino)pyrimidine (0.31 g) in tetrahydrofuran (10 ml) were added triethylamine (0.11 ml) and 4-fluorobenzoyl chloride (0.69 ml). The mixture was stirred at ambient temperature for an hour and the reaction was quenched by adding methanol (5 ml). After evaporation of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using a mixture of chloroform and methanol (95:5) to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-[4-(4-fluorobenzoyl)piperazin-1-yl]-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (0.34 g).
Reaction SMILES: [CH2:1]([CH:3]([C:12]([OH:14])=[O:13])[NH:4][C:5](=[O:11])[C:6]([O:8]CC)=O)[CH3:2].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19]>CC(O)C>[CH2:1]([CH:3]([C:12]([OH:14])=[O:13])[NH:4][C:5]([C:6]([NH:19][CH2:18][CH:17]([O:20][CH3:21])[O:16][CH3:15])=[O:8])=[O:11])[CH3:2]
Reactant: CCOC(=O)C(=O)NC(CC)C(=O)O
Reactant: COC(CN)OC
Solvent: CC(C)O
Product: CCC(NC(=O)C(=O)NCC(OC)OC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the oxamate 3 (84.0 g, 414 mmol) in 2-propanol (500 mL) was added aminoacetaldehyde dimethyl acetal 4 (45.7 g, 435 mmol) in one portion. After stirring overnight at room temperature, the reaction mixture was concentrated to a thick orange oil. This thick slurry was diluted with 2-propanol (300 mL) and the solid was broken up with a spatula. Filtration afforded a solid which was further rinsed with an additional portion of 2-propanol. Removal of residual 2-propanol was accomplished via high vacuum to afford a light orange solid 5.: 1H NMR (CDCl3) δ7.82 (br s, 1H), 7.50 (br s, 1H), 4.41 (t, 1H, 5.3 Hz), 4.24 (q, 2H, 2.71 Hz), 4.09 (d, 2H, 5.9 Hz), 3.47 (dd, 2H, 5.3, 6.2 Hz), 3.40 (s, 6H), 1.30 (t, 3H, 7.1 Hz).