Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[CH:17]=[C:16]([C:35]([F:38])([F:37])[F:36])[CH:15]=1>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[CH:17]=[C:16]([C:35]([F:37])([F:38])[F:36])[CH:15]=[C:14]([NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)[N:19]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: COc1cc(Nc2cc(C(F)(F)F)cc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C(F)(F)F)cc(Nc3cccc(OC(F)(F)F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-(trifluoromethoxy)aniline and (6-chloro-4-trifluoromethyl-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a yellowish solid (Yield=63%). MS ISP (m/e): 524.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.65 (d, 1H), 7.42 (s broad, 1H), 7.35-7.25 (m, 2H), 7.19 (d, 1H), 7.12 (d, 1H), 7.00 (dxd, 1H), 6.95-6.85 (m, 2H), 6.77 (d, 1H), 6.50 (s, 1H), 6.46 (s, 1H), 3.73 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-])O.[K+].CI>CN(C)C=O.O>[CH3:19][O:17][C:16]([CH:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:18]
Reactant: O=C([O-])O
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.1 %

Procedure:
To a solution of 28.83 g of (±)-N-benzyloxycarbonyl-2-pyrrolidine carboxylic acid in 180 ml of N,N-dimethylformamide, 23.23 g of potassium hydrogen carbonate and 10.8 ml of methyl iodide were added. After stirring at room temperature for 15 hours, the reaction solution was diluted with water and then extracted twice with diethyl ether. After the extract was washed with an aqueous 5% sodium hydrogen sulfite solution and water and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 26.52 g of the desired compound as a yellowish oily substance.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]2[NH:27][CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CN(C)C=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]2[NH:27][CH:28]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:29]2)=[CH:13][CH:12]=1
Reactant: Fc1ccc(Cn2c(NC3CCNC3)nc3ccccc32)cc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cn2c(NC3CCN(CCc4ccccc4)C3)nc3ccccc32)cc1
Temperature: 70 °C
Yield: 12 %

Procedure:
A mixture of 1.85 parts of (2-bromoethyl)benzene, 3.1 parts of 1-[(4-fluorophenyl)methyl]-N-(3-pyrrolidinyl)-1H-benzimidazol-2-amine, 1.06 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of N,N-dimethylformamide was stirred and heated overnight at 70° C. The reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 0.5 parts (12%) of 1-[(4-fluorophenyl)methyl]-N-[1(2-phenylethyl)-3-pyrrolidinyl]-1H-benzimidazol-2-amine; mp. 126.1° C. (compound 127).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:33][O:34][CH2:35][CH2:36]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:9][C:6]1[CH:5]=[C:4]([O:10][CH2:36][CH2:35][O:34][CH3:33])[C:3]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[C:7]=1[F:8]
Reactant: O=[N+]([O-])c1c(O)cc(F)c(F)c1F
Reactant: COCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3,4,5-trifluoro-2-nitrophenol (1.93, 10 mmol), Ph3P (3.93 g, 15 mmol), and 2-methoxy-ethanol (1.18 ml, 15 mmol) in anhydrous THF (25 ml) a solution of diisopropyl azodicarboxylate (2.91 ml, 15 mmol) in THF (5 ml) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The volatiles were evaporated and the residue was dissolved in CH2Cl2 (100 ml) and the organic layer was washed with water (100 ml), brine (100 ml) dried (MgSO4) and evaporated. The residue obtained was purified over flash silica gel chromatography to obtain the titled product in 68% (1.70 g) yield. 1H NMR (300 MHz, CDCl3): δ 6.78 (ddd, J=2.4, 6.0, 11.7 Hz, 1H), 4.19 (t, J=4.5 Hz, 2H), 3.72 (t, J=4.5 Hz, 2H), 3.39 (s, 3H).
Reaction SMILES: C(O[C@H](C)[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:42]2[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]2)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:57])[C@@H:14]1[OH:58])=[O:11])C1C=CC=CC=1.N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N[C:81](=O)[C@H:82]([O:84]CC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH:27][C:23]2[N:22]=[C:21]([N:42]3[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]3)[N:20]=[C:19]3[C:24]=2[N:25]=[CH:26][N:18]3[C@@H:16]2[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[CH2:81][CH2:82][OH:84])[C@@H:14]([OH:58])[C@H:15]2[OH:57])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Product: O=C(CCO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-3-hydroxy-propionamide (Intermediate ZG) for (R)—N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[C:9](OC)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:16])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: COC(=O)c1cccnc1
Product: O=C(Cc1cccc(Cl)n1)c1cccnc1

Procedure:
In a similar manner as described in Example 1 from 6-chloro-2-picoline (9.3 g, 73 mmol) and methyl nicotinate (10.0 g, 73 mmol), 2-(6-chloro-2-pyridinyl)-1-(3-pyridinyl)ethanone was obtained as a syrup. This syrup (10 g, 70 mmol) was treated with hydroxylamine hydrochloride (24.3 g, 350 mmol) followed by the addition of a sodium hydroxide solution (14 g, 350 mmol in 30 mL of water) as described in example 1 to give 2-(6-chloro-2-pyridinyl)-1-(3-pyridinyl)ethanone oxime (14.4 g, 80%) as a white solid. 1H NMR (CDCl3): δ 8.84 (d, 1H), 8.40 (dd, 1H), 8.00 (m, 1H), 7.50 (t, 1H), 7.2–7.4 (m, 3H), 4.26 (s, 2H); MS m/z 248 (M+1).
Reaction SMILES: C(C1C(CC(N)=O)=C2N(C=1)C=CC=C2)C.C(Cl)(=O)CC.N#N.[CH2:23]([C:25]1[C:26]([CH2:38][C:39]([NH2:41])=O)=[C:27]2[N:32]([C:33]=1[C:34](=O)[CH2:35][CH3:36])[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH3:24].[H-].[Al+3].[Li+].[H-].[H-].[H-]>ClC(Cl)C.C(OCC)C.C(N(CC)CC)C>[CH2:23]([C:25]1[C:26]([CH2:38][CH2:39][NH2:41])=[C:27]2[N:32]([C:33]=1[CH2:34][CH2:35][CH3:36])[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH3:24]
Reactant: CCC(=O)c1c(CC)c(CC(N)=O)c2ccccn12
Agent: CCC(=O)Cl
Agent: CCc1cn2ccccc2c1CC(N)=O
Agent: N#N
Solvent: CC(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCc1c(CC)c(CCN)c2ccccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2-ethylindolizin-1-yl)acetamide (1.0 g, 5 mmol) was dissolved in dichloroethane (30 mL) to which was added triethylamine (TEA, 0.65 mL) N,N-dimethylaminopyridine (DMAP, 60 mg) and propionyl chloride (0.7 mL). The reaction mixture was heated under reflux in a N2 atmosphere overnight. The cooled reaction mixture was partitioned between water and methylene chloride. The phases were separated and the aqueous phase was extracted with methylene chloride 3 times. The organic layers were combined and evaporated to give a residue which was purified by silica gel column chromatography eluting with ethyl acetate. A total of 600 mg of 2-(2-ethyl-3-propionylindolizin-1-yl)-acetamide was recovered. 2-(2-ethyl-3-propionylindolizin-1-yl)-acetamide (400 mg, 1.5 mmol) was suspended in anhydrous ethyl ether to which lithium aluminum hydride (LAH, 380 mg) was added. The suspension was heated under reflux in a N2 atmosphere overnight. After cooling to room temperature the reaction mixture was partitioned between ether and aqueous Rochelle salt. After stirring for 1 h, the phases were separated. The aqueous phase was extracted with ether 2 times. Evaporation of the combined organic layers gave a residue which was purified on silica gel eluting with 1 L each of 5%, 10%, 12% methanol in methylene chloride containing 4 mL of conc. NH4OH. The title compound was isolated (85 mg), dissolved in ethanol and treated with an ethanolic solution of fumaric acid (65 mg). The ethanol was evaporated and the residue was recrystallized from methyl ethyl ketone (MEK) to give the title compound as the fumaric acid salt, mp: 154-158° C.; Mass sSpectrum [M+H]+ 231 m/z.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:17][CH2:18][O:19][C:20]([CH3:22])=[O:21]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:22]2[CH2:17][CH2:18][O:19][C:20]2=[O:21])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCCC1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a solution of 4-nitrophenol (278 mg, 2.0 mmol) in DMF (6 mL) at room temperature under a nitrogen atmosphere was added powdered K2CO3 (552 mg, 2.0 mmol) followed by3-bromo-dihydrofuran-2-one (330 mg, 2.0 mmol). After stirring at room temperature under a nitrogen atmosphere for 16 hours, the mixture was diluted to 30 mL with EtOAc and washed with water (4×30 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to provide the product (240 mg, 54%) as tan oil that later solidified.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]([Cl:26])([Cl:25])[C:11]1[N:16]=[C:15](C(Cl)(Cl)Cl)[N:14]=[C:13]([C:21]([Cl:24])([Cl:23])[Cl:22])[N:12]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([NH:8][C:15]1[N:16]=[C:11]([C:10]([Cl:9])([Cl:26])[Cl:25])[N:12]=[C:13]([C:21]([Cl:23])([Cl:24])[Cl:22])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: ClC(Cl)(Cl)c1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: ClC(Cl)(Cl)c1nc(NCc2ccccc2)nc(C(Cl)(Cl)Cl)n1
Reaction time: 72 h
Yield: 84.7 %

Procedure:
Benzylamine (3.21 g., 0.03 mole) is added to 2,4,6-tris(trichloromethyl)-s-triazine (13 g., 0.03 mole) in dry benzene (75 ml.). Triethylamine (3.24 g., 0.03 mole) is then added to the reaction mixture and the solution set aside for 3 days. Evaporation to a residual oil and crystallization from methanol-water (9:1) gives the product 10.7 g., 85%, m.p. 96.5°-97°.
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:16]([OH:19])[C:17]#[CH:18]>C(Cl)Cl>[OH:19][CH2:16][C:17]#[C:18][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: C#CCO
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)OC)c(C#CCO)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
500 mg of dimethyl 5-bromodicarboxylate (from Example 3) and 121 mg of propargyl alcohol are dissolved in methylene chloride in a flask flushed with argon, and 840 μl of triethylamine are added dropwise. The mixture is stirred at room temperature for 15 minutes, 25 mg of ((C6H5)3P)2PdCl2 and 4 mg of CuI are added and the mixture is boiled under reflux for 30 hours. After cooling, the mixture is diluted with methylene chloride and washed with water and sodium chloride solution and the combined organic phases are dried over potassium carbonate. After evaporation and chromatography on silica gel, 260 mg of a white solid remain.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[C:9](=O)([O:13]CC)[O:10][CH2:11][CH3:12]>>[Br:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:1][C:9]([O:10][CH2:11][CH3:12])=[O:13])[CH:7]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CCOC(=O)OCC
Product: CCOC(=O)Cc1cc(Br)ccn1

Procedure:
Scheme 15 illustrates a synthesis of the indolizine-1-carboxylate ring system. In a similar manner to that in the literature (Parrick J, et al. J. Chem. Research (Synopses) 1990; 64-65), 2-methyl-4-bromopyridine may be deprotonated and treated with diethyl carbonate to give ethyl 2-(4-bromopyridin-2-yl)acetate (84). The ester (84) may then be treated with a bromoacetophenone (e.g. 2-bromo-1-(4-methoxyphenyl)ethanone) to give the indolizine ring system (85). The ester may be converted to the carboxaldehyde (86) by methods known to those skilled in the art. The aldehyde may be manipulated to the nitrile (87); and (86) and (87) both further transformed as described hereinabove.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][C:25]([N:27]4[CH2:43][CH2:42][C:30]5([CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]5)[CH2:29][CH2:28]4)=[O:26])[CH:22]=3)[CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[C:6]([CH3:44])[CH:5]=1>CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH3:44])[C:7]([S:11]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][C:25]([N:27]4[CH2:28][CH2:29][C:30]5([CH2:34][NH:33][CH2:32][CH2:31]5)[CH2:42][CH2:43]4)=[O:26])[CH:22]=3)[CH2:17][CH2:16][CH2:15]2)(=[O:12])=[O:13])=[C:8]([CH3:10])[CH:9]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCc3ccc(CC(=O)N4CCC5(CC4)CCN(C(=O)OC(C)(C)C)C5)cc32)c(C)c1
Agent: Cl
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N2CCCc3ccc(CC(=O)N4CCC5(CCNC5)CC4)cc32)c(C)c1
Reaction time: 0.5 h

Procedure:
Hydrogen chloride (1.25 M solution in methanol, 6.5 ml) was added at room temperature to a solution of tert-butyl 8-(2-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)acetyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.5 g, 0.817 mmol) in methanol (5 ml), and the reaction mixture was refluxed for 1 h. The solvent was removed in vacuo and the residue was taken up in a small amount of acetone and added dropwise to cooled diethyl ether. Stirring was then carried out for 30 min. in an ice bath, and the resulting solid was filtered out and dried. Yield: 0.32 g (71%)
Reaction SMILES: O[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: COc1ccc(Cn2nc(C)c(C(=O)c3ccccc3)c2O)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Cn2nc(C)c(C(=O)c3ccccc3)c2Cl)cc1
Temperature: 40 °C

Procedure:
A solution containing 400 mg of [5-hydroxy-1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone in 5 ml of phosphorus oxychloride was heated at 40° C. for 30 min. The mixture was poured into iced saturated sodium hydrogen carbonate and extracted with dichloromethane three times. The combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using diethyl ether/hexane (1:3) for the elution to give 170 mg of [5-chloro-1-(4-methoxybenzyl)-3-methyl -1H-pyrazol-4-yl]-phenyl-methanone as a yellow gum.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#[CH:16].CCN(CC)CC>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:19]([O:18][C:14]([C:15]1[O:1][N:2]=[C:3]([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[CH:16]=1)=[O:17])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(C(Cl)=NO)cc1
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)no1
Temperature: 80 °C
Yield: 51.5 %

Procedure:
To a solution of N-hydroxy-4-nitro-benzimidoyl chloride (2.0 g; 10 mmol) and ethyl propiolate (2.02 ml; 20 mmol) in toluene (25 ml) was added Et3N (1.46 ml; 10.5 mmol) drop wise for 10 minutes. The resulting reaction mixture was heated at 80° C. for 2.5 hours, and then diluted with EtOAc (50 ml) and transferred in a separating funnel. The EtOAc layer was washed with 0.1N HCl (10 ml) followed by water (3×10 ml) and brine (10 ml). The EtOAc layer was dried over anhydrous Na2SO4, solvent was evaporated and the residue was crystallized from CHCl3 and light petroleum to afford the title compound of step 1 (1.35 g; 51.7%). Mass (ES+), 263 (M++1); 1H NMR (CDCl3) δ: 1.45 (t, 3H), 4.48 (q, 2H), 7.26 (s, 1H), 8.02 (d, 2H), 8.35 (d, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:27])[CH2:21][C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)[CH2:10][CH:9]1[OH:28])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].OS([O-])(=O)=O.[K+]>CO>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH3:27])[CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:19]=2)[CH2:10][CH:9]1[OH:28])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)CC(C)c1ccc(C2CCN(C(=O)OC(C)(C)C)C(O)C2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(CC(=O)O)c1ccc(C2CCN(C(=O)OC(C)(C)C)C(O)C2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 12-2 (400 mg, 1.0 mmoles), 1N NaOH (4 mL, 4.0 mmoles), and CH3OH (5 mL) was stirred at ambient temperature for 4.0 hours. The reaction mixture was acidified with 10% KHSO4 and then extracted with EtOAc (2×). The combined extracts were washed with brine, dried (MgSO4), and then concentrated to give 12-3 as a white solid. Rf 0.66 (silica, 10/0.5/0.5 CH2Cl2 /CH3OH/HOAc).
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH2:23]([N:27]([CH2:37][CH2:38][CH2:39][CH3:40])[C:28]([C:30]1[C:34]([Cl:35])=[C:33]([CH3:36])[NH:32][N:31]=1)=[O:29])[CH2:24][CH2:25][CH3:26]>>[Cl:35][C:34]1[C:30]([C:28](=[O:29])[N:27]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:23][CH2:24][CH2:25][CH3:26])=[N:31][N:32]([C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][C:3]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:33]=1[CH3:36]
Reactant: CCOC(=O)c1cc(C(=O)OCc2ccccc2)ccc1F
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)OCC)c(C)c1Cl
Yield: 78.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, 1-benzyl 3-ethyl 4-fluoroisophthalate (1.50 g, 4.96 mmol) and N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Intermediate 1B, 2.02 g, 7.44 mmol) were converted to the title compound (2.15 g, 78%). 1H NMR (CDCl3) δ 8.69 (d, J=2.0 Hz, 1H), 8.33 (dd, J=8.1, 2.0 Hz, 1H), 7.51-7.36 (m, 6H), 5.43 (s, 2H), 4.19 (d, J=7.0 Hz, 2H), 3.50 (s, 2H), 3.41 (s, 2H), 2.15 (s, 3H), 1.70-1.60 (m, 2H), 1.58-1.50 (m, 2H), 1.46-1.34 (m, 2H), 1.25-1.16 (m, 5H), 0.96 (t, J=7.4 Hz, 3H), 0.83 (t, J=7.3 Hz, 3H); MS(ESI+) m/z 554.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].Cl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(NC(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC
Temperature: 50 °C
Reaction time: 4 h
Yield: 86.8 %

Procedure:
A suspension of diethyl 2-t-butyloxycarbonylaminomalonate (5.0 g), potassium carbonate (3.0 g), and ethyl 2-bromoacetate (3.9 g) in DMF (20 mL) was stirred at 50° C. for 4 hours. The reaction mixture was cooled, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and then purification was performed with n-hexane/ethyl acetate (5:1), to obtain the title compound (5.7 g, yield: 79%) as colorless oil.
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[CH2:16][CH2:15]2)[N:11]=[CH:10][N:9]=1)(C)(C)C.C[Al](C)C.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[CH2:20]([N:17]1[CH2:16][CH2:15][N:14]([C:12]2[N:11]=[CH:10][N:9]=[C:8]([NH:7][C:6]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:22])[CH:13]=2)[CH2:19][CH2:18]1)[CH3:21]
Reactant: CCN1CCN(c2cc(NC(=O)OC(C)(C)C)ncn2)CC1
Reactant: C1CCNCC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCN1CCN(c2cc(NC(=O)N3CCCCC3)ncn2)CC1
Temperature: 120 °C
Yield: 18.5 %

Procedure:
A mixture of 1.6 g (7.75 mmol) 6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-ylamine (intermediate 4), 2.03 g (9.3 mmol) di-tert-butyl dicarbonate and 1.17 g (11.6 mmol) NEt3 in 30 mL DCM was stirred at 50° C. in a sealed tube for 16 h. After evaporation of all volatiles the residue was purified with flash column chromatography on silica. The combined product fractions were evaporated to dryness to yield [6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-carbamic acid tert-butyl ester. MS(m/e): 308.4 (MH+). A mixture of 28 mg (0.09 mmol) [6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-carbamic acid tert-butyl ester, 0.18 mL (0.36 mmol) 2M AlMe3 solution in toluene and 30 mg (0.36 mmol) piperidine in 1 mL toluene were heated to 120° C. for 16 h. After removal of all volatiles under reduced pressure the residue was taken up in methanol/NEt3 and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 5.3 mg (18%) of the title compound. MS (m/e): 319.1 (MH+).