Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=O)[CH:35]=[CH:36][CH:37]=2)[CH:25]=1.[CH2:44]([S:46]([NH2:49])(=[O:48])=[O:47])[CH3:45]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]([CH3:43])([CH3:42])[C:39]([NH:49][S:46]([CH2:44][CH3:45])(=[O:48])=[O:47])=[O:41])[CH:35]=[CH:36][CH:37]=2)[CH:25]=1
Reactant: CCS(N)(=O)=O
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)NC(=O)C(C)(C)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (44 mg, 0.23 mmol) is added to a stirred ice cold solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid (100 mg, 0.22 mmol), ethanesulfonamide (25 mg, 0.23 mmol) and 4-Dimethylaminopyridine (27 mg, 0.22 mmol) in dry DCM under nitrogen atmosphere. The ice bath is removed and the reaction mixture is stirred overnight at 60° C. The volatiles are removed under reduced pressure, the residue is dissolved in ethyl acetate, washed with 0.1 N HCl, brine and water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by chromatography (SiO2 packed column), eluting with EtOAc/DCM to afford ethanesulfonic acid [2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionyl]-amide [67 mg, Example 95(a)]. LCMS: RT=2.49 minutes, MS: 551, 553 (M+H).
Reaction SMILES: [CH2:1]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[CH:22]=O>>[CH3:28][O:27][C:25]1[CH:24]=[C:21]([CH:20]=[C:19]([O:18][CH3:17])[CH:26]=1)[CH:22]=[C:9]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]1=2
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: COc1cc(C=O)cc(OC)c1
Product: COc1cc(C=C2c3ccccc3CCc3ccccc32)cc(OC)c1
Yield: 40.6 %

Procedure:
Following procedures essentially as described in Preparation 5 and Example 28, above, and using dibenzosuberone (2.00 g, 10.29 mmol) and 3,5-dimethoxybenzaldehyde (1.71 g, 10.29 mmol), affords 1.43 g (41%) of the title compound as a yellow foam. 1H-NMR (CDCl3) δ 2.79-3.64 (br m, 4H), 3.55 (s, 6H), 6.20 (d, 2H), 6.25 (t, 1H), 6.72 (s, 1H), 7.06-7.30 (m, 7H), 7.48 (m, 1H); HPLC shows 99% purity.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33]Br)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][N:7]2[C:6]3[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:29]=[CH:30][CH:31]=1
Reactant: Clc1cccc(CCBr)c1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(CCc3cccc(Cl)c3)c12
Yield: 73 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 2-(3-chlorophenyl)ethyl bromide as starting materials, the title compound was obtained in a yield of 73% as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](B3OC(C)(C)C(C)(C)O3)=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:8]=[CH:9]2)=[CH:4][N:3]=1.[OH:28]OS([O-])=O.[K+]>CO.ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:28])=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:8]=[CH:9]2)=[CH:4][N:3]=1
Reactant: O=S([O-])OO
Reactant: CC1(C)OB(c2c(-c3ccccc3Cl)ncc3cc(Cl)ncc23)OC1(C)C
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: Oc1c(-c2ccccc2Cl)ncc2cc(Cl)ncc12

Procedure:
A mixture of 7-chloro-3-(2-chlorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,6-naphthyridine (60 mg, 0.1 mmol) and Oxone® (370 mg, 0.6 mmol) in wet methanol (0.6 mL) and dichloromethane (0.2 mL) was stirred at 35° C. for 3 hours. The cooled reaction mixture was diluted with dichloromethane (50 mL) and washed with 1.0M citric acid in water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford an orange/red residue that was used in the next step without further purification (50 mg, 100%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH:15][C:16]3[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C.O1CCOCC1>[NH2:22][C:21]1[C:16]([NH:15][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(Nc2ncccc2[N+](=O)[O-])cc1OC1CCCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncccc2N)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 2-[(3-cyclopentyloxy-4-methoxyphenyl)-amino]-3-nitropyridine (1.30 g) and 10% palladium on carbon (0.3 g) in ethanol (20 ml) and 1,4-dioxane (20 ml) was stirred under hydrogen (3 atm) at room temperature for 1 hours. The catalyst was removed by filtration and the solvent was evaporated. The resulting solid was collected and washed with isopropyl ether to give 3-amino-2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]pyridine (992 mg).
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])#[N:12].CCN(C(C)C)C(C)C.Cl>C1COCC1>[C:11]([CH:13]([CH2:1][C:2](=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:14]([O:16][CH3:17])=[O:15])#[N:12]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)CC#N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C#N)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
A solution (1 M) of phenacyl bromide in THF was added dropwise to a solution (5.5 M) of methyl cyanoacetate (1.1 eq.) and DIEA (2.4 eq.) in THF at RT. The resulting solution was stirred at RT for 20 h then the mixture was filtered and the filtrate was concentrated in vacuo to obtain an oil that was treated with little portions of aqueous HCl (1 N). The organic phase was washed with brine, dried and concentrated affording the title compound (97%) as an oil that solidified when stored in the fridge.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22]CC4C=CC([N+]([O-])=O)=CC=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]>CO.O1CCCC1.[C].[Pd]>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reaction time: 3.5 h
Yield: 63.8 %

Procedure:
To a solution of p-nitrobenzyl 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylate (syn isomer, 1.25 g.) in methanol (40 ml.) and tetrahydrofuran (50 ml.) was added 10% palladium carbon (0.65 g.), and the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure for 3.5 hours. After removing the catalyst from the reaction mixture, the filtrate was concentrated under reduced pressure. Water (80 ml.) was added to the residue, and the mixture was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate, and then the insoluble substance was filtered off. The filtrate was washed with ethyl acetate (50 ml.), and then ethyl acetate (100 ml.) was added to the solution. After adjusting to pH 1.5 with 10% hydrochloric acid, the ethyl acetate layer was separated. The remaining aqueous layer was extracted with ethyl acetate (80 ml.) twice, and the extracts were combined with the ethyl acetate layer obtained above, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure to give 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylic acid (syn isomer, 0.60 g.), m.p. 176° to 183° C. (dec.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32].O1CCOCC1>C(OCC)(=O)C>[ClH:32].[NH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Yield: 84 %

Procedure:
To a mixture of 4-[3-(5-trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (312 g, 0.718 mol) in ethyl acetate (2.8 L) at 0° C. to −5° C. was added streamwise over a 20 min period, 4.0 M hydrogen chloride in dioxane (800 mL, 3.2 mol). No significant temperature change was noted. The resulting suspension was stirred at temperatures reaching 22° C. over the next 17 h. The suspension was filtered. The solid was washed with EtOAc (500 mL) and pressed as dry as possible under suction. The damp solid was dried in vacuo at 33° C. for 7 h to afford 225 g (84%) of product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[C:34]2[CH3:38])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH:37]=[CH:36][N:35]=[C:34]4[CH3:38])[CH:28]=3)[CH2:24][C:23](=[O:39])[NH:22][C:9]=2[CH:10]=1
Reactant: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccc(F)cc3F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccn1-c1cccc(C2=Nc3ccc(-c4ccc(F)cc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from (2′,4′-difluoro-3-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K89) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (71 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COCc1cccc(B(O)O)c1
Reactant: CC(C)(C(=O)O)c1ccc(Br)cc1
Product: COCc1cccc(-c2ccc(C(C)(C)C(=O)O)cc2)c1
Yield: 82 %

Procedure:
Prepared in a similar manner to Example 1 starting from 3-(methoxymethyl)phenylboronic acid and 2-(4-bromophenyl)-2-methylpropanoic acid. Yield: 82%. 1H NMR (400 MHz, DMSO): δ 1.48 (s, 6H), 4.46 (s, 2H), 7.27-7.29 (d, 1H), 7.40-7.44 (m, 3H), 7.54-7.56 (d, 2H), 7.60-7.62 (d, 2H), 12.40 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24]([O-:26])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[CH3:27]N(C=O)C>CCN(CC)CC.[Pd]>[CH3:1][C:2]1[C:3]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24]([O:26][CH3:27])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1C#Cc1ccccc1CC(=O)[O-]
Reactant: CN(C)C=O
Agent: [Pd]
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C)c2)ncc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
10% Pd/C (53% water; 0.020 g) was added to a solution of methyl 2-(2-((5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-ylethynyl)phenyl)acetate (A115) (0.115 g, 0.318 mmol) in DMF (5 mL) and Et3N (0.5 mL) and the resulting suspension placed under a hydrogen atmosphere and stirred at room temperature for 18 hours. The mixture was filtered through Celite, washing with EtOAc (250 mL). The combined filtrates were washed with water (100 mL) then brine (100 mL) and the washing repeated 3 times. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure and the resulting oil purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in hexanes) to give the title compound A116 as a yellow solid (0.097 g, 83%); 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.83 (s, 1H), 7.46 (s, 1H), 7.25-7.17 (m, 4H), 6.75 (s, 1H), 3.89 (s, 3H), 3.72 (s, 2H), 3.67 (s, 3H), 3.09 (dd, J=9.5, 6.3 Hz, 2H), 2.91 (dd, J=9.5, 6.4 Hz, 2H), 2.07 (s, 3H). LCMS-A: rt 5.160 min; m/z 366 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([CH2:26][CH3:27])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:16][CH3:17])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:20]([CH3:25])[CH:19]=3)([CH2:26][CH3:27])[CH2:16][CH3:17])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc2ccc(C(=O)OC)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2ccc(C(=O)OC)cc2c1
Yield: 99.5 %

Procedure:
Stir a mixture of 7-[1-ethyl-1-(4-hydroxy-3-methylphenyl)propyl]naphthalene-2-carboxylic acid methyl ester (0.87 g, 2.40 mmol), 1-bromopinacolone (1.54 g, 8.68 mmol), and potassium carbonate (2.4 g, 17.4 mmol) in acetone (20 mL) for 4 h at RT. Concentrate the reaction mixture and then dilute the residue with EtOAc (100 mL) and water (50 mL). Adjust the pH of the mixture to 1 using 1 N HCl. Discard the aqueous layer. Wash the organic layer with brine, dry over Na2SO4 and filter. Concentrate the filtrate and purified by silica gel radial chromatography (5:95 EtOAc:hex to 15:85 EtoAc:hex) to give the title compound as a white solid (1.1 g, 82%). MS (ES) m/e 461 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2([C:16]([OH:18])=O)[CH2:12][CH:11]2[C:13](O)=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:19]C(N)=O>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]23[CH2:12][CH:11]2[C:13](=[O:14])[NH:19][C:16]3=[O:18])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1CC1(C(=O)O)c1cccc([N+](=O)[O-])c1
Reactant: NC(N)=O
Solvent: Cc1ccccc1C
Product: O=C1NC(=O)C2(c3cccc([N+](=O)[O-])c3)CC12
Temperature: 150 °C
Reaction time: 16 h

Procedure:
A mixture of 9.8 g of 1-(3-nitrophenyl)-1,2-cyclopropanedicarboxylic acid and 4.9 g of urea in 250 ml of xylene (mixture of isomers) is stirred for about 16 hours at a bath temperature of about 150° C. The xylene is then evaporated off in vacuo and the residue is partitioned between ethyl acetate and water. The organic phases are combined, dried over MgSO4, filtered, and concentrated in vacuo. Recrystallisation from ethyl acetate/petroleum ether gives the title compound (e) in the form of pale yellow crystals with m.p. 173°-174° C. and Rf=0.3 on thin-layer silica gel plates in the system hexane/ethyl acetate (4:6).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[N:7]=1.[C:12]([O:15][C:16](=O)[CH3:17])(=O)[CH3:13]>CO.CN(C)C=O>[CH2:12]([O:15][CH2:16][C:17]1[NH:11][C:9](=[O:10])[C:3]2[C:2](=[N:7][C:6]([OH:8])=[CH:5][N:4]=2)[N:1]=1)[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1ncc(O)nc1N
Solvent: CN(C)C=O
Solvent: CO
Product: CCOCc1nc2nc(O)cnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in Example 1, starting with 2.1 g (0.0136 mole) of 3-amino-5-hydroxy-2-pyrazinecarboxamide [prepared according to E. C. Taylor et al., J. Org. Chem. 1975, 40, 2341], 14.0 g (0.068 mole) of triethyl orthoethoxyacetate and 14.0 ml of acetic anhydride. Yld: 1.2 g (40%), m.p. 255°-256° C. (methanol/N,N-dimethylformamide).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][CH:14]([C:24]([O:26]CC)=[O:25])[C:15]([CH2:22][CH3:23])([OH:21])[C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[Si:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][CH:14]([C:24]([OH:26])=[O:25])[C:15]([CH2:22][CH3:23])([OH:21])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(O)(CC)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC(O)(C(=O)O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 22 h
Yield: 92.6 %

Procedure:
To a solution of diethyl 3-(4-t-butyldimethylsilyloxybenzyl)-2-ethyl-2-hydroxysuccinate 425 mg (0.968 mmol) in 1,4-dioxane (3.9 mL) was added 1 M lithium hydroxide aqueous solution (3.9 mL, 3.9 mmol) at room temperature, and the mixture was stirred at 60° C. for 22 h. The reaction mixture was adjusted to pH 1 with 1 M hydrochloric acid with stirring under ice cooling. The solvent was evaporated under reduced pressure, and the residue thus obtained was dissolved in ethyl acetate, and washed with water and brine. The organic layer was concentrated under reduced pressure and dried in vacuum to give 343 mg (crude) of 3-(4-t-butyldimethylsilyloxybenzyl)-2-ethyl-2-hydroxysuccinic acid as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=2)[O:10][C:11]2[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:3][CH2:2]1.[Br:21]Br>C(O)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:8][C:9]=1[O:10][C:11]1[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ncccc1Oc1cccc(N2CCOCC2)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ncccc1Oc1cc(N2CCOCC2)ccc1Br
Reaction time: 1 h
Yield: 77.5 %

Procedure:
In a 250 mL round-bottom flask, 3-(3-morpholinophenoxy)pyridin-2-amine (0.720 g, 2.654 mmol) was dissolved in 25 mL of acetic acid and Bromine (2.654 mL, 2.654 mmol) (1M in AcOH) was added slowly. After agitating for 1 hour the mixture was evaporated and the residue was distributed between dichloromethane and sodium bicarbonate solution. The organic phase was separated and evaporated. The residue was purified by column chromatography on silica gel, eluted with 1-3% methanol/dichloromethane to give the title compound (0.72 g, 77%) as white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOCC>C(O)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:19](=[N:18][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOCc1nc2cnc3ccccc3c2n1N=Cc1ccccc1
Temperature: 120 °C
Yield: 59.2 %

Procedure:
A solution of 2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-amine (1.50 g, 6.19 mmol) in 50 mL of isopropanol was treated with benzaldehyde (0.66 mL, 6.50 mmol) and 10 mg of p-toluenesulfonic acid. The reaction mixture was heated to 120° C. for 3 d. The reaction mixture was cooled, and a precipitate started to form. The reaction mixture was treated with Et2O and then filtered to give N-benzylidene-(2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.21 g) as a gray solid.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]([CH3:26])[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.O>CS(C)=O>[CH3:26][C:10]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:2][O:9]1
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCC2(C)CO2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Trimethylsulfoxonium iodide (7.8 g, 35 mmol) was gradually added to a suspension of sodium hydride (1.2 g, 35 mmol) in DMSO (120 ml), under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. To which a solution of tert-butyl 4-(3-oxobutyl)piperazine-1-carboxylate (6.1 g, 23.8 mmol) in DMSO (10 ml) was gradually added dropwise, and the mixture was stirred at room temperature for 1.5 hours, and then at 50 to 60° C. for 1.5 hours. The reaction solution was allowed to return to room temperature, poured into iced water, and extracted with ethyl acetate three times. The extracts were combined, washed with water three times and then washed with a saturated saline solution, and dried over sodium sulfate. After filtration, the filtrate was concentrated under a reduced pressure to afford tert-butyl 4-[2-(2-methyl-2-oxiranyl)ethyl]piperazine-1-carboxylate (5.6 g, 87%) as a light yellow oil.
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)=[C:9]2[CH2:24][N:25]([C:29](=[O:39])[NH:30][C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:38])[C:26]([CH3:28])([CH3:27])[C:8]2=[N:7]1)=O)C.[OH-].[Na+].O>CO>[Cl:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[NH:30][C:29]([N:25]1[CH2:24][C:9]2[C:8](=[N:7][NH:6][C:10]=2[NH:11][C:12](=[O:23])[C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=2)[C:26]1([CH3:28])[CH3:27])=[O:39]
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(C(=O)OC)cc1)CN(C(=O)Nc1c(Cl)cccc1Cl)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)c2n[nH]c(NC(=O)c3ccc(C(=O)O)cc3)c2CN1C(=O)Nc1c(Cl)cccc1Cl
Temperature: 70 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a solution of 5-(2,6-Dichloro-phenylcarbamoyl)-3-(4-methoxycarbonyl-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (0.4 g, 0.74 mmol) in methanol (5 mL), 2N NaOH aqueous solution (1.00 mL, 2.00 mmol) was added and warmed to 70° C. After 4 hours stirring, water was added (20 mL) and the aqueous solution extracted with ethyl acetate (1×20 mL). The aqueous phase was acidified with 1N HCl solution and extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over sodium sulphate, the solvent evaporated in vacuo yielding 0.33 g (yield 91%) of the title compound as white solid.