Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([F:22])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:23][C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[CH:27]=[CH:26][C:25]=1O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([F:22])=[CH:7][C:3]=1[C:4]([O:6][C:25]1[CH:26]=[CH:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])=[CH:29][C:24]=1[F:23])=[O:5]
Reactant: Oc1ccc(-c2ccccc2F)cc1F
Reactant: CCCCCc1ccc(-c2cc(F)c(C(=O)O)cc2F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCc1ccc(-c2cc(F)c(C(=O)Oc3ccc(-c4ccccc4F)cc3F)cc2F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 2,5-difluoro-4-(4-pentylphenyl)benzoic acid (28.40 mmol), 2-fluoro-4-(2-fluorophenyl)phenol (28.40 mmol), and dichloromethane (100 ml), 4-dimetylaminopyridine (34.10 mmol) is added dropwise. Then, a solution of 1,3-dicyclohexylcarbodiimide (34.10 mmol) in dichloromethane (100 ml) is added dropwise. After the addition is completed, the reaction mixture is stirred for 17 hrs at room temperature. Solid formed is filtered off, and a saturated aqueous solution of sodium chloride is added dropwise to the reaction mixture. The organic layer is washed with in the order of 3N-hydrochloric acid (300 ml), water, a saturated aqueous solution of sodium hydrogen carbonate (300 ml), and dried over anhydrous magnesium sulfate. The dichloromethane solution is concentrated under reduced pressure, purified by silica-gel chromatography, and further recrystallized to give the titled compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][NH:3][C:2]1=[O:6].[C:7](Cl)(=[O:11])[CH2:8][CH2:9][CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[O:11]=[C:7]([C:5]1[NH:1][C:2](=[O:6])[NH:3][CH:4]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=c1[nH]cc[nH]1
Reactant: CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCC(=O)c1c[nH]c(=O)[nH]1
Reaction time: 2 h

Procedure:
In 10 ml of dichloromethane is placed 1.0 g of 1,3-dihydro-2H-imidazol-2-one, 1.28 g of butyryl chloride and 4.8 g of aluminum chloride. The mixture is refluxed and stirred for 2 hours after which it is poured into water. The precipitate is collected, washed with water, and recrystallized from ethanol:water, to give the title compound, m.p. 268°-270° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 106 %

Procedure:
2-Nitrobenzenesulfonyl chloride (5.79 g) was added to a mixed solution of tetrahydrofuran (20 ml)/water (17 ml) containing (S)-proline (2.00 g), 5 N sodium hydroxide (3.5 ml) and sodium carbonate (3.77 g) under ice cooling, followed by stirring for 1 hour under ice cooling and for 22 hours at room temperature. Water (20 ml) was added to the reaction mixture, and the organic solvent was removed by evaporation under reduced pressure. Then, water (20 ml), 5 N sodium hydroxide (4 ml) and ethyl acetate (100 ml) were added, followed by extraction and solution separation, and the organic layer was extracted again with water (15 ml). Ethyl acetate (50 ml) and 6 N hydrochloric acid (20 ml) were added to the resulting aqueous layer, followed by extraction and solution separation, and the aqueous layer was extracted again with ethyl acetate (50 ml). The resulting organic layer was dried over sodium sulfate, filtered, concentrated and dried under vacuum to obtain (S)-N-(2-nitrobenzenesulfonyl)proline (5.53 g; yield: quantitative).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][N:8]=[C:9]([C:15](=[O:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.S(Cl)([Cl:23])(=O)=O>C(O)(=O)C>[Cl:23][CH2:16][C:15](=[O:17])[C:9](=[N:8][O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:19][CH:18]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NOCc1ccc(C)cc1)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCc1ccc(C)cc1)C(=O)CCl
Reaction time: 4 h
Yield: 23.8 %

Procedure:
A mixture of ethyl 2-(4-methylbenzyloxyimino)-3-oxobutyrate (syn isomer, 74.08 g.), sulfuryl chloride (41.70 g.) and acetic acid (75 ml.) was stirred at at 40° to 42° C. for 4 hours. Nitrogen gas was bubbled into the reaction mixture. After adding the mixture into ice water, the mixture was extracted with methylene chloride. The extract was washed with sodium bicarbonate saturated aqueous solution and sodium chloride saturated aqueous solution in turn and dried over magnesium sulfate. After removing the solvent in vacuo, the residue was allowed to stand in a refrigerator overnight. The precipitates were removed by filtration, and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography on silica gel and eluted with benzene and ethyl acetate. The eluate was concentrated in vacuo to give ethyl 4-chloro-2-(4-methylbenzyloxyimino)-3-oxobutyrate (syn isomer, 19.9 g.). I.R. νmaxFilm : 3000, 2950, 1740, 1710, 1600, 1440, 1400, 1370, 1340, 1270, 1200, 1000 cm-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([OH:9])=[O:8])[C:2]=1[C:10]([OH:12])=[O:11].OS(O)(=O)=O.[CH3:18]O>>[CH3:18][O:11][C:10]([C:2]1[C:3]([C:7]([OH:9])=[O:8])=[N:4][CH:5]=[CH:6][N:1]=1)=[O:12]
Reactant: O=C(O)c1nccnc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1nccnc1C(=O)O
Temperature: 75 °C
Yield: 47 %

Procedure:
To a mixture of pyrazine-2,3-dicarboxylic acid (20 g, 119 mmol, 1 equiv.) was added MeOH (80 mL) followed by dropwise addition of concentrated H2SO4 (36 mL, 680 mmol, 5.7 equiv.) over 45 minutes. This method is similar to that that cited for a different substrate (J. Am. Chem. Soc., 73, 1951, 5614-5616). The reaction was heated at 75° C. for 16 hours and then cooled and quenched with water (200 mL). It was extracted with EtOAc (4×60 mL) and the organic layer washed several times with water (3×50 ml), saturated NaHCO3 (50 ml), brine solution (50 mL). It was dried over Na2SO4, filtered and concentrated in vacuo to yield pyrazine-2,3-dicarboxylic acid methyl ester 241 as a brown solid (47%, 10.97 g, 55.9 mmol). 1H NMR (300 MHz) CDCl3 δ 8.79 (d, J=2.7 Hz, 2 H), 4.05 (s, 3 H), 4.04 (s, 3 H). TLC Rf: 0.7 ethyl acetate/methanol (9/1)
Reaction SMILES: FC(F)(F)C([O-])=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3[CH2:20][NH:21][CH2:22][CH2:23][C:18]=3[NH2+:17][N:16]=2)=[CH:11][CH:10]=1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]3[CH2:20][N:21]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:22][CH2:23][C:18]=3[NH:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc(C2=N[NH2+]C3=C2CNCC3)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCc2[nH]nc(-c3ccc(Br)cc3)c2C1
Reaction time: 2.5 h
Yield: 50.8 %

Procedure:
To a stirred solution of 3.11 g (11.1 mmol) of 3-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinium trifluoroacetate and 4.71 mL (33.5 mmol) of Et3N in DMF (55 mL) was slowly added 1.21 mL (15.6 mmol) of methanesulfonyl chloride. After 2.5 h, the solvent was removed under reduced pressure and the residue was diluted with CH2Cl2 (100 mL) and saturated NaHCO3 (100 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×30 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by column chromatography (silica, 0-5% MeOH/CH2Cl2) afforded 2.01 g (50%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): m/z calculated for C13H14BrN3O2S [M++H] 356.00, observed 356.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13]3=[C:14]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=N[CH:23]=[CH:24][CH:25]=4)=[CH:18][N:12]3[C:11]3[CH:10]=[CH:9][C:8]([Cl:27])=[CH:7][C:6]=3[S:5]2)[CH:15]=1.[CH:28](=O)C1C=CC=CC=1>>[CH2:19]([C:17]1[C:16](=[O:26])[C:14]2[CH:15]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:13]=2[N:12]([CH:18]=1)[C:11]1[CH:10]=[CH:9][C:8]([Cl:27])=[CH:7][C:6]=1[S:5]3)[C:20]1[CH:21]=[CH:28][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(Cl)cc13)Sc1cc(Cl)ccc1-2
Product: O=c1c(Cc2ccccc2)cn2c3c(cc(Cl)cc13)Sc1cc(Cl)ccc1-2
Yield: 60 %

Procedure:
According to Example 1<step 4>, the compound (30 mg) produced in Example 5<step 3 >was reacted with benzaldehyde (15 μl) to obtain the title compound (23 mg; 60%).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[O:29])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[O:32]1[CH:33]=[CH:34][C:30]([C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[C:26]([C:2]3[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:25]=2)=[O:29])=[CH:31]1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)nc2)c1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-)phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 3.17 min, MH+ 442. NMR: δH [2H6]-DMSO 9.99,(1H, s), 9.29,(1H, t), 9.15,(1H, d), 8.38,(1H, s), 8.34,(1H, dd), 7.81,(2H, m), 7.75,(1H, d), 7.67,(1H, d), 7.31–7.25,(2H, m), 7.00 (1H, s), 6.94,(2H, m), 6.84,(1H, d), 4.51,(2H, d), 3.75,(3H, s), 2.32,(3H, s).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[NH:1][CH2:2][CH2:3][CH2:4]3)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1NCCC2
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2NCCC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (173 mg, 0.97 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (200 mg, 0.97 mmol), HATU (553 mg, 1.46 mmol) in anhydrous DMF (20 mL) is added DIPEA (241 μL, 1.46 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (63) as white solid (300 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)[C:15]2=[O:20].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][N:14]([CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:15]3=[O:20])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2Cc3c(N)cccc3C2=O)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CCN2Cc3c(NC(=O)c4ccc(Cl)s4)cccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 0.97 g (5.35 mmol) of 5-chlorothiophene-2-carbonyl chloride is added dropwise to a suspension of 1.48 g (4.12 mmol) of tert-butyl 4-[2-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl) ethyl]-1-piperidinecarboxylate, 1.7 ml (20.6 mmol) of pyridine and 25 mg (0.206 mmol) of 4-DMAP in 21 ml of absolute THF. The mixture is slowly warmed to room temperature and stirred overnight. The reaction mixture is concentrated and then separated by chromatography on silica gel (dichloromethane/methanol 97:3).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[N:5]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O>CC(N(C)C)=O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:6]2[N:5]=[C:4]([CH2:3][CH2:2][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=[C:8]([NH:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: C1COCCN1
Reactant: COc1cccc(-c2cc(Nc3cccnc3)nc(CCBr)n2)c1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cccc(-c2cc(Nc3cccnc3)nc(CCN3CCOCC3)n2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Compound 15 (1 eq) is dissolved in 3 ml of dimethyl acetamide and morpholine (5 eq) is added. The reaction mixture is stirred at 60° C. for 4 h, then cooled down to room temperature. Water is added to the mixture and the crash out is filtered off, washed with water and purified by reverse phase preparatory HPLC, obtaining [6-(3-methoxyphenyl)-2-(morpholin-4-ylethyl)pyrimidin-4-yl]-3-pyridylamine 16.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:16][CH2:15][C@H:14]([NH:13][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH3:17])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (0.64 mL) was added dropwise to an ice-cooled mixture of (R)-(+)-2-(tert-butoxycarbonylamino)-propanol (1.31 g) and triethylamine (1.6 mL) in methylene chloride (20 mL) with stirring, and the mixture was stirred at that temperature for 1 hr. The reaction mixture was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (1.93 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH3:12][O:13][C:14]1[CH:24]=[CH:23][C:17]([CH2:18][CH2:19][C:20](Cl)=O)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:20][CH2:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:24][CH:23]=1)[CH2:6][CH2:5]2
Reactant: COc1ccc(CCC(=O)Cl)cc1
Reactant: Oc1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCCN2CCc3cc(O)ccc3C2)cc1

Procedure:
5.4 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline are acylated twice with 14.2 g of 4-methoxydihydrocinnamoyl chloride in methylene chloride in the presence of 7.5 g of triethylamine, the mixture is extracted by shaking with water, and the organic phase is dried and evaporated in a rotary evaporator. The crude product is dissolved, without further purification, in tetrahydrofuran, and added dropwise, with cooling, to a solution of 1.5 g of lithium aluminum hydride in dry tetrahydrofuran. After destroying the reagent with water, inorganic material is filtered off and the filtrate is dried. The residue from filtration is dried, extracted twice by boiling with methanol, and the methanol and tetrahydrofuran are evaporated together in a rotary evaporator. After triturating the oily residue with ethyl acetate, 3.5 g of colorless product (33% of theory) are obtained. Melting point: 163°-164°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][C:16]=2[CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([CH3:25])=[CH:17][C:18]([NH2:22])=[CH:19][C:20]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(N)cc(C)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3,5-dimethylnitrobenzene (2.24 g) in a mixture of ethanol (30 ml) and tetrahydrofuran (10 ml) was added palladium on carbon (0.20 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (1.94 g, yield 95%) as a pale rose solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1cnn(-c2ccc(C=O)cc2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: Cc1cnn(-c2ccc(C=CC=O)cc2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methyl-1H-pyrazol-1-yl)-benzaldehyde (prepared as described in Reference Example 4) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([CH2:27][NH2:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:28][CH2:27][C:23]4[CH:22]=[C:21]5[C:26](=[CH:25][CH:24]=4)[N:18]([CH3:17])[CH:19]=[CH:20]5)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: Cn1ccc2cc(CN)ccc21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2cc(CNc3nccc(Nc4cc(C5CC5)[nH]n4)n3)ccc21
Temperature: 120 °C

Procedure:
A microwave vial was charged with 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (160 mg, 0.68 mmol), 296 (800 mg, 5.59 mmol), DIPEA (1 ml), and IPA (5.0 mL), sealed and heated at 120° C. for 18 h. It was concentrated and purified by SiO2 chromatography, and then preparative HPLC to afford 30 mg (12%) of I-33 as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]4[C:30](=[O:31])[CH2:29][CH2:28][C:27]4=[O:32])[CH2:20][CH2:19]3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].I[CH2:35][CH3:36]>>[CH2:35]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([CH3:15])([CH3:16])[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]4[C:27](=[O:32])[CH2:28][CH2:29][C:30]4=[O:31])[CH2:20][CH2:19]3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH3:36]
Reactant: CCI
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1O
Product: CCOc1cc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)ccc1OC

Procedure:
Prepared analogously as described for example 5 using 1-(2-{4-[3-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl)}-2-oxoethyl)pyrrolidine-2,5-dione (compound A4) and iodoethane as starting compounds.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:10](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:10][O:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Cl)c(O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C)ccc1Cl
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 3-hydroxy-4-chlorotoluene (25 g, 0.175 mol) in 400 ml of acetone was added 30.11 g (0.22 mol) of milled potassium carbonate and 31.22 g (0.22 mol) of methyl iodide, and the mixture was refluxed with stirring for 16 hours. The mixture was cooled, filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in ether, washed with water, and the organic layer was dried over sodium sulfate and concentrated in vacuo to afford 25.6 g of 3-methoxy-4-chlorotoluene as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1
Yield: 56 %

Procedure:
Synthesis of the compounds of general class III begins with the reaction of 2-amino4-chloro-5-nitrophenol at 0-50° C., preferably at room temperature, with benzyl bromide in the presence of potassium carbonate and tetra-N-butylammonium iodide in DMF to give 2-benzyloxy-5-chloro-4-nitroaniline in 56% yield. Subsequent reaction of 2-benzyloxy-5-chloro-4-nitroaniline (25-80° C.), preferably refluxing, with benzoyl chloride in the presence of triethylamine provided N-(2-benzyloxy-5-chloro-4-nitrophenyl)benzamide in 85% yield. Reaction of N-(2-benzyloxy-5-chloro4-nitrophenyl)benzamide with sodium dimethyl malonate anion, generated from reaction of dimethyl malonate with sodium hydride in DMSO, in a DMSO solution at 80-150° C., preferably at 110° C., overnight gave dimethyl 2-(5-benzamido-4-benzyloxy-2-nitro)phenylmalonate in 36% yield. When dimethyl 2-(5-bybenzamido-4-benzyloxy-2-nitro)phenylmalonate was treated with NaOH in ethanol at 25-100° C., preferably refluxing, followed by acidification with HCl and mild heating at 25-100° C., preferably refluxing, provided the desired compound 2-(5-amino-4-benzyloxy-2-nitro)phenylacetic acid in 93% yield. Treatment of 2-(5-amino-4-benzyloxy-2-nitro)phenylacetic acid at 0-50° C., preferably at 5° C. then gradual warming to room temperature, with borane in THF selectively reduced the carboxylic acid group to an alcohol, 2-(5-amino-4-benzyloxy-2-nitro)phenylethanol in 52% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][C:25]4[CH:30]=[CH:29]C([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[S:44]1C=C(CO)[N:46]=[N:45]1>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][CH2:25][C:30]4[N:46]=[N:45][S:44][CH:29]=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: OCc1csnn1
Reactant: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)OCc1csnn1

Procedure:
A solution of 0.50 g (0.50 mmol) of 4-nitrophenyl 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-ethylcarbamate, prepared in step 1.5., 0.128 g (0.99 mmol) of N,N-diisopropylethylamine, 0.030 g (0.25 mmol) of N,N-dimethylaminopyridine and 0.079 g (0.5 mmol) of [1,2,3]thiadiazol-4-ylmethanol (Acta Pharmaceutica Suecica (1973), 10(4), 285-96) in 5 mL of 1,2-dichloroethane is heated in a reactor tube at 80° C. for 12 hours.