Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[NH:25][C:34]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[Cl:26])=[O:35])[CH2:12][CH2:11]2)=[N:2]1
Reactant: Nc1ccc(F)cc1CCN1CCN(c2nsc3ccccc23)CC1
Reactant: O=C=Nc1ccccc1Cl
Product: O=C(Nc1ccccc1Cl)Nc1ccc(F)cc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 58.8 %

Procedure:
Starting from 2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-phenylamine (142 mg, 0.4 mmol) and 2-chlorophenyl isocyanate (56 μL, 0.4 mmol) and following the procedure as outlined in Example 60, 120 mg of 1-{2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-phenyl}-3-(2-chloro-phenyl)-urea was isolated as an off white powder in 100% purity @ 254 nm; LCMS (APCI): 508 [M-2H]−.
Reaction SMILES: [F:1][C:2]1([F:34])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([CH3:31])=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=5)[C:20]([CH3:32])=[C:19]([CH3:33])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[Si](I)(C)(C)C.CO.C(OCC)(=O)C>CC#N>[F:34][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH3:33])[C:20]([CH3:32])=[C:21]([C:23]5[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]=5[CH3:31])[N:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)c(C)n1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(-c2ccc(=O)[nH]c2C)c1C
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a suspension of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,3,4-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (41.6 mg, 0.09 mmol) in CH3CN (1.8 mL) was added TMSI (25.3 μL, 0.18 mmol) drop wise. The suspension became clear solution on TMSI addition. The reaction was stirred at 55° C. for 2 hours and 30 minutes. The reaction was allowed to cool down to room temperature. Methanol (1.0 mL) was added followed by ethyl acetate (6 mL). The organic layer was washed with NaHSO3 (2×), and brine (1×). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4,5-dimethyl-6-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a white solid (30 mg, 74%). ESI-MS m/z calc. 453.4. found 454.3 (M+1)+. Retention time 1.50 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])/[CH:9]=2)=[N:5][N:4]=[N:3]1.[Cl:35][C:36]1[CH:37]=[C:38]([S:43](/[N:46]=[C:47]2\[CH:48]=[C:49](Cl)[C:50](=[O:57])[C:51]3[C:56]\2=[CH:55][CH:54]=[CH:53][CH:52]=3)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1[Cl:42]>>[Cl:35][C:36]1[CH:37]=[C:38]([S:43](/[N:46]=[C:47]2\[CH:48]=[C:49]([S:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[C:50](=[O:57])[C:51]3[C:56]\2=[CH:55][CH:54]=[CH:53][CH:52]=3)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1[Cl:42].[CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:21])=[O:22])/[CH:9]=2)=[N:5][N:4]=[N:3]1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2C1=O
Product: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O

Procedure:
(E)-3,4-dichloro-N-(3-(1-methyl-1H-tetrazol-5-ylthio)-4-oxonaphthalen-1(4H)-ylidene)benzenesulfonamide (13z) was prepared according to the procedure for 13x except using 12g, affording 94.7 mg (98.5%) title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:27])[C:10](=[CH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([CH3:25])=[CH:21][C:20]3=[O:26])[C:11](=O)[CH3:12])[CH:6]=[CH:7][CH:8]=1.[NH2:28]/[C:29](/[CH3:36])=[CH:30]\[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([CH3:25])=[CH:21][C:20]3=[O:26])[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:29]([CH3:36])[NH:28][C:11]=1[CH3:12])=[O:27]
Reactant: COc1cccc(C(=O)C(=Cc2cccc3c(=O)cc(C)oc23)C(C)=O)c1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)c2cccc(OC)c2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
245 mg (0.67 mmol) of 1-(3-methoxyphenyl)-2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-butane-1,3-dione are heated with 87 mg (0.67 mmol) of ethyl 3-aminocrotonate in 5 ml of 2-propanol under reflux overnight. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 102 mg (32% of theory) of the title compound are obtained.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5][C:4]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH:31]O>C(O)(=O)C>[ClH:2].[ClH:1].[Cl:2][C:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5](=[O:31])[C:4]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1CCN(CCCN2C(=O)C(Cl)=C(c3ccccc3)Sc3ccccc32)CC1
Reactant: OO
Agent: Cl
Solvent: CC(=O)O
Product: CN1CCN(CCCN2C(=O)C(Cl)=C(c3ccccc3)S(=O)c3ccccc32)CC1
Reaction time: 16 h

Procedure:
3-Chloro-5-[3-(4-methyl-1-piperazinyl)propyl]-2-phenyl-1,5-benzothiazepin-4(5H)-one, hydrochloride (prepared as described in Example 1) is treated with one equivalent of hydrogen peroxide in dilute acetic acid, and allowed to stand for about 16 hours. Solvent removal yields the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH2:17]([NH2:26])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:26][CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2)(=[O:3])[CH3:2]
Reactant: NC/C=C/c1ccccc1
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Agent: Cl
Product: CC(=O)Nc1cccc2c1CCC(NC/C=C/c1ccccc1)C2

Procedure:
Starting from 1.02 g (0.005 mol) of 5-acetylamino-2-tetralone and 1.7 g (0.01 mol) of trans-cinnamylamine-hydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 1.1 g (61.6% of theory) and with a melting point of 257° C., which does not change after recrystallisation from methanol/ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].[Cl:10][C:11]1[CH:24]=[CH:23][C:22]2[C:21](=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=O)[C:13]=2[CH:12]=1.Cl.O.O.Cl[Sn]Cl>C1COCC1.C(O)(=O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[C:15]3[C:20]([C:21]([C:2]4[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=4)=[C:22]4[C:13]=2[CH:12]=[C:11]([Cl:10])[CH:24]=[CH:23]4)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Reactant: Cc1ccc(Br)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(-c2c3ccccc3c(-c3ccc(C)cc3)c3cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
213.8 g of 4-bromotoluene dissolved in anhydrous THF(200 ml) was slowly added to 32.6 g of magnesium in 500 ml of anhydrous THF for 2 hours. The mixed solution was refluxed for 3 hours, and then cooled to room temperature. 121 g of 2-chloroanthraquinone was added to cooled solution. The resulting solution was stirred for 3 hours, and then refluxed for 3 hours. Then, 400 ml of 10% aqueous hydrochloric acid solution was added to the resulting solution. An organic layer was separated from the solution. The resulting solvent was distilled under a vacuum, by which a brown solution was obtained. 500 ml of Glacial acetic acid and 100 g of SnCl2.2H2O were added to the brown solution. The mixed solution was stirred at room temperature for 1 hour, heated for 3 hours and refluxed. The solution was further stirred at room temperature for 3 hours. Thus, a pale yellow product was obtained. This product was recrystallized using glacial acetic acid. In this way, a pure product was obtained in the form of pale yellow crystals(153 g, m.p. 202-203.5° C., yield 78%). Results of 1H NMR(200 MHz, CDCl3) and IR(KBr) for the obtained compound are described in the following Table 1.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([CH2:20][CH2:21][C:22](OC)=[O:23])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:26]>ClCCl.CO>[CH3:1][NH:2][C:22](=[O:23])[CH2:21][CH2:20][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:26])[N:4]([CH3:3])[C:13]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Reactant: CN
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stream of gaseous methylamine is passed into a 250 ml round-bottomed flask containing a solution of 1.25 g (3.85 mmol) of methyl 2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-4-propanoate in 20 ml of dichloromethane and 80 ml of methanol until saturation and the mixture is left stirring at room temperature for 3 days. The solvents are evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate ranging from 100/0 to 80/20 and then with a 95/5 mixture of dichloromethane and methanol. After recrystallizing from acetonitrile, 0.85 g (2.65 mmol) of white crystalline solid is obtained. Melting point: 185°-186° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH3:39]>>[CH3:34][O:35][CH2:36][CH2:37][N:38]([CH3:39])[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: CNCCOC
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCCN(C)c1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-mopholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-(2-methoxyethyl)-methylamine. ES-MS m/e (%): 458 (M+H+, 100).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:15]CC)(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].N1CCCCC1>>[C:9]([O-:15])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].[CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: O=Cc1ccccc1
Product: CC(=O)CC(=O)[O-]
Reaction time: 72 h

Procedure:
The mixture of benzaldehyde (21.22 g) and ethyl acetoacetate (52.06 g) was cooled in an ice bath. Piperidine (3.3 ml) was added with stirring. The resulting mixture was kept at rt for 3 days whereupon it solidifies. The solid was recrystallised from ethanol (100 ml) to give a light yellowish solid (the bis-adduct of acetoacetate to benzaldehyde). The powdered solid was added in portions to 50% NaOH (200 ml) with stirring. The resulting yellow slurry was diluted with ethanol (70 ml) and stirred at reflux for 2 h. After addition of ice water (100 ml) and cooling in an ice bath the mixture was acidified with conc. HCl to give a white precipitate. The solid was collected by suction filtration and washed with water. After drying in vacuo 3-phenylglutaric acid (16.4 g) was obtained as colourless crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH:9]1[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11][CH2:10]1>C(O)C.[Pd]>[NH:12]1[CH2:11][CH2:10][CH:9]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:2]2=[O:1])[CH2:14][CH2:13]1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCCCCC2=O)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCCCCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 101 %

Procedure:
To a solution of benzyl 4-(2-oxoazepan-1-yl)piperidin-1-carboxylate (0.25 g) obtained in Example 9a) in ethanol (10 mL) was added 10% palladium on carbon (containing 50% water; 0.03 g), and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the solvent was distilled off under reduced pressure to obtain the title compound (0.15 g, quantitative) as a brown oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@@H:6]([C:11]([NH:13][C@H:14]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].Cl>C(O)(=O)C>[NH2:1][CH2:2][C:3]([NH:5][C@@H:6]([C:11]([NH:13][C@H:14]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)CNC(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)CN)C(N)=O
Yield: 55 %

Procedure:
Condensation of BocDLeuOH (2.49 g.) and HMetNH2 (1.85 g.) by the mixed anhydride method using isobutyl chloroformate gave BocDLeu-MetNH2 in 47% yield. De-t-butoxycarbonylation of BocDLeu-MetNH2 (1.70 g.) using hydrogen chloride in acetic acid gave HDLeu-MetNH2 in 78% yield. Condensation of BocGlyOSu (1.8 g.) and HDLeu-MetNH2 (1.0 g.) by the activated ester method gave BocGly-DLeu-MetNH2 in 95% yield. De-t-butoxycarbonylation of BocGly-DLeu-MetNH2 (1.35 g.) using hydrogen chloride in acetic acid gave HGly-DLeu-MetNH2 in 55% yield.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[OH:10][C@:11]([CH3:47])([CH2:45][OH:46])[C:12](=[O:44])[C@@H:13]([NH:21][C:22](=[O:43])[C@@H:23]([NH:27][C:28](=[O:42])[C@@H:29]([NH:33][C:34]([C:36]1[S:40][C:39]([CH3:41])=[N:38][CH:37]=1)=[O:35])[CH2:30][O:31][CH3:32])[CH2:24][O:25][CH3:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]([F:9])([F:8])[CH2:3][S:4]([O:46][CH2:45][C@:11]([OH:10])([CH3:47])[C:12](=[O:44])[C@@H:13]([NH:21][C:22](=[O:43])[C@@H:23]([NH:27][C:28](=[O:42])[C@@H:29]([NH:33][C:34]([C:36]1[S:40][C:39]([CH3:41])=[N:38][CH:37]=1)=[O:35])[CH2:30][O:31][CH3:32])[CH2:24][O:25][CH3:26])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:6])=[O:5]
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)CC(F)(F)F

Procedure:
Prepared according to procedures described above, by reacting 2,2,2-trifluoroethanesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C27H35F3N4O10S2 m/z: 697 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]>CO.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:18])[CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(c2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1-ethyl-4-(3-fluoro-4-nitro-phenyl)-piperazine (7 g, 27.7 mmol) and Pd (10%) on carbon (0.35 g) in MeOH (140 mL) is stirred for 3 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) to afford the title compound as a white solid: ESI-MS: 224.1 [MH]+; TLC: Rf=0.54 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][C:4]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:5][C:4]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)=[N:3]1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccccc3)n(C)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(-c2ccc(C(=O)O)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A mixture of methyl 4-(1-methyl-5-phenyl-1H-1,2,4-triazol-3-yl)benzoate (0.700 g), 1 M aqueous sodium hydroxide solution (4.8 ml), tetrahydrofuran (10 ml) and methanol (5 ml) was stirred at room temperature for 2 hrs., and acidified by adding 1 M hydrochloric acid. The crystals were collected by filtration to give 4-(1-methyl-5-phenyl-1H-1,2,4-triazol-3-yl)benzoic acid (0.650 g, yield 97%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: 243–244° C.
Reaction SMILES: I[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=2[N:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([O:21][CH3:22])[CH:13]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:11][C:10]1[C:5]2[N:4]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([O:21][CH3:22])[CH:13]=3)[N:3]=[C:2]([C:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=3)[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(-n2nc(I)c3ncnc(N)c32)ccc1[N+](=O)[O-]
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
Solvent: O
Product: COc1cc(-n2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c32)ccc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 60.2 %

Procedure:
A mixture of 3-iodo-1-(3-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (300 mg, 0.728 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (270 mg, 0.874 mmol), sodium carbonate (185 mg, 1.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.044 mmol) in 1,2-dimethoxy ethane (6 mL) and water (3 mL) was heated in an 85° C. oil bath for 1.75 hours. tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (45 mg, 0.146 mmol) was added to the mixture and then it was heated in the 85° C. oil bath for another 16 hours. The solvents were evaporated under reduced pressure then the residue was partitioned between water (10 mL) and ethyl acetate (15 mL). The layers were separated and then the aqueous layer was extracted with ethyl acetate (10 mL), dichloromethane (20 mL) and then a 10% solution of methanol in dichloromethane (20 mL). The organic solutions thus obtained were combined and evaporated to a residue which was purified by flash chromatography on silica gel using ethyl acetate as an eluent to provide the title compound as a yellow solid (205 mg, 60%): 1H NMR (DMSO-d6, 400 MHz) δ 8.40 (s, 1H), 8.10 (d, 1H), 7.50 (m, 1H), 7.42 (s, 1H), 7.31 (d, 1H), 7.1 (bs, 2H), 4.13 (m, 2H), 3.99 (s, 3H), 3.58 (m, 2H), 2.67 (m, 2H), 1.44 (s, 9H) RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 21.42 min; MS: M−H+ 466.3
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:17]([O:19]CC)=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2].C1COCC1.O.[OH-].[Li+]>CO>[CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1nccc(-c2cc(C(=O)OCC)c(=O)[nH]n2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1nccc(-c2cc(C(=O)O)c(=O)[nH]n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 400 mg of ethyl 6-(2-ethylaminopyrimidin-4-yl)-3-oxo-2,3-dihydro-pyridazine-4-carboxylate, 2 ml of THF, 2 ml of water, 2 ml of methanol and 100 mg of lithium hydroxide is stirred at room temperature for 1 hour, and the volatile constituents are removed in vacuo. A pH of 4 is adjusted by dropwise addition of 2N hydrochloric acid, and the precipitate which has formed is filtered off with suction, stirred with 10 ml of isopropanol and filtered off with suction and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O-]CC.[Na+].[Na].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]#[N:10])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 45.3 g. (0.31 mol.) of p-chlorophenylacetonitrile and 107 g. (0.72 mol., 99 ml.) of diethyl oxalate in an alcoholic sodium ethoxide solution [prepared by dissolving 7.13 g. (0.31 g.-atom) of sodium in 120 ml. of absolute ethanol] was refluxed with stirring for 2 hours. The cooled reaction mixture was diluted with 700 ml. of water, acidified with acetic and cooled to ice bath temperature. The resulting solid was collected and recrystallized from aqueous methanol to give ethyl 3-(p-chlorophenyl)-3-cyanopyruvate, m.p. 134°-135°.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].Br[CH2:31][CH2:32][CH:33]=[CH2:34]>>[CH2:34]([O:28][C:5]1[CH:6]=[C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:1])[F:29])[CH2:33][CH:32]=[CH2:31]
Reactant: C=CCCBr
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: C=CCCOc1cc(-c2nc(CNC(=O)c3ccccc3OCC)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 347 and 4-bromo-1-butene, white powdery N-[2-(3-but-3-enyloxy-4-difluoromethoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.