Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])=[O:19])=[C:4](Cl)[CH:3]=1.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[N:12]([CH:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[N:11]=[CH:10][C:9]=3[C:18](=[O:19])[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:4]=2[CH:3]=1
Reactant: COc1ccc(CNC(=O)c2cnn(C3CCOC3)c2-c2ccc(Br)cc2Cl)c(OC)c1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2c(=O)c3cnn(C4CCOC4)c3c3ccc(Br)cc32)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.6 %

Procedure:
(±)-5-(4-bromo-2-chlorophenyl)-N-(2,4-dimethoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide (1.26 g) was dissolved in THF (25 mL), and KTB (597 mg) was added at 0° C. The mixture was stirred for 12 hours while gradually warming to room temperature. The reaction mixture was cooled to 0° C., and water was added, followed by filtration. The filtration residue was separately stored. The filtrate was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 70%). The resulting fraction and the filtration residue obtained above were combined and concentrated to give the title compound (488 mg).
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:28][NH:29]2)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[C:28]([CH:14]([C:3]3[C:4](=[O:13])[CH2:5][CH:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]=3[OH:1])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:29]2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Reactant: CC(=O)NCCc1c[nH]c2cc(F)ccc12
Product: CC(=O)NCCc1c(C(C2=C(O)C(c3ccccc3)CC2=O)c2ccccc2)[nH]c2cc(F)ccc12

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-acetamide (Example 18.1.) to give the title compound as a pink solid. MS: 483.5 ([M+H]+).
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:8][CH:7]=1)=O.[CH3:16][NH2:17]>>[CH3:16][NH:17][C:4]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:8][CH:7]=1)=[O:3]
Reactant: COC(=O)c1ccc2c(c1)CNCC2
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc2c(c1)CNCC2
Temperature: 100 °C

Procedure:
1,2,3,4-Tetrahydro-isoquinoline-7-carboxylic acid methyl ester hydrochloride (113 mg, 0.5 mmol) is dissolved in aqueous methylamine (40%, 5.0 ml)) and heated at 100° C. overnight. Upon cooling to rt, the reaction mixture is evaporated to dryness under reduced pressure. The residue is taken up in water (1.0 ml), and treated with sodium hydroxide solution (1.0 N, 1.0 ml). The mixture is extracted with DCM (10 ml×3). The combined organic phase is dried over sodium sulfate, and concentrated to give the title compound. MS (+VE) m/z 191.1 (M++1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([S:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:2]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[O:1]1[C:2]2[C:9](=[O:11])[CH2:8][CH2:7][S:6][C:3]=2[CH:4]=[CH:5]1
Reactant: O=C(O)CCSc1ccoc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: O=C1CCSc2ccoc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(3-furylthio)propionic acid (4.3 g, 0.025 mol), SUPER CEL® (5 g), and P2O5 (8 g) in toluene (80 ml) was mechanically stirred under N2 at 100° C. After 2 hours, additional P2O5 (8 g) was added and the mixture heated for 3 hours at 100° C. The mixture was filtered, and the solid was washed with hot toluene (3X), and the filtrate concentrated to dryness to yield the product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)([C:11]2[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([Cl:18])[CH:12]=2)[N:3]=1.[CH3:26]OC1C=C([Mg]Br)C=CC=1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:17][C:15]1[CH:16]=[C:11]([C:4]2([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([NH2:1])=[N:3]2)[CH:12]=[C:13]([Cl:18])[N:14]=1
Reactant: NC1=NC(c2cccc(O)c2)(c2cc(Cl)nc(Cl)c2)c2ccccc21
Reactant: COc1cccc([Mg]Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(C2(c3cc(Cl)nc(Cl)c3)N=C(N)c3ccccc32)c1
Reaction time: 0.83 h
Yield: 89.3 %

Procedure:
(E)-N-((2-cyanophenyl)(2,6-dichloropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (Scheme #19, B, 0.69 g, 1.81 mmol) was dissolved in dry tetrahydrofuran (20 mL) at 0° C. to which a solution of 3-methoxyphenylmagnesium bromide (1.0 M in tetrahydrofuran, 5.44 mL, 5.44 mmol) in tetrahydrofuran was added. The reaction was stirred for 50 minutes and then quenched by addition of saturated aqueous ammonium chloride (25 mL), then further diluted with saturated aqueous sodiumhydrogen carbonate and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated. The residue was dissolved in methanol (20 mL) and treated with hydrochloride (1.0 M in diethyl ether, 3.63 mL, 3.63 mmol) for 1.5 h and then treated with saturated aqueous sodiumhydrogen carbonate and washed with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated. Purification by flash chromatography using ethyl acetate afforded 0.621 g (89% yield) of the title compound. 1H NMR (CDCl3) δ 7.59-7.43 (m, 4 H), 7.29-7.20 (m, 3 H), 6.89-6.87 (m, 3 H), 3.75 (s, 3 H). MS (AP) m/z 384 [M+1]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].P(Cl)(Cl)(Cl)=O.[C:18]1(C)C=CC=CC=1.C(N(CC)CC)C>CO>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:12][CH3:18]
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: Cc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ncnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 20 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 2.00 g (7.35 mmol) of 6-iodoquinazolin-4-one, 1.24 g (8.09 mmol) of phosphorus oxychloride, and 10 mL of toluene in a nitrogen atmosphere. While the mixture was stirred at room temperature, 0.82 g (8.09 mmol) of triethylamine was slowly added. The resulting mixture was heated to 75° C., and the reaction was carried out for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 100 mL of methanol was added. The mixture was stirred for 15 minutes at the same temperature, to give 6-iodo-4-methoxyquinazoline. Analysis of the reaction mixture by high performance liquid chromatography indicated that 2.11 g (reaction yield: 99%) of 6-iodo-4-chloroquinazoline was produced.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH:13]1[C:32](=[O:33])[N:15]2[CH:16]([C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])[C:17]([CH3:20])([CH3:19])[S:18][C@H:14]12.F[C:35]1[NH:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1>C(Cl)Cl>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[N:36]1[C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[NH:39][C:35]=1[NH:12][CH:13]1[C:32](=[O:33])[N:15]2[CH:16]([C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])=[O:22])[C:17]([CH3:19])([CH3:20])[S:18][C@H:14]12
Reactant: Fc1nc2ccccc2[nH]1
Reactant: CC(C)(C)C(=O)OCOC(=O)C1N2C(=O)C(N)[C@H]2SC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCOC(=O)C1N2C(=O)C(Nc3nc4ccccc4[nH]3)[C@H]2SC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of pivaloyloxymethyl 6-amino-2,2-dimethylpenam-3-carboxylate toluene-p-sulphonate (200 mg.) and 2-fluorobenzimidazole (108 mg.) in methylene chloride (2 ml.) was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated to dryness and the residue was triturated with ether and hexane to give pivaloyloxymethyl 6-(benzimidazol-2-yl)amino-2,2-dimethylpenam-3-carboxylate toluene-p-sulphonate (170 mg.) as a solid which had the following n.m.r. spectrum in d6DMSO: 1.14 (s, 9H); 1.43 (s, 3H); 1.60 (s, 3H); 2.24 (s, 3H); 4.55 (s, 1H); 5.5-5.9 (m, 4H); 7.0-7.54 (m, 8H).
Reaction SMILES: [OH:1][B:2]([OH:11])[C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CCOCC.CO>[CH3:14][C:13]1([CH3:15])[C:16]([CH3:18])([CH3:17])[O:1][B:2]([C:3]2[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=2)[O:11]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=C(O)c1ccc(B(O)O)s1
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CC1(C)OB(c2ccc(C(=O)O)s2)OC1(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-(Dihydroxyboryl)-2-thiophenecarboxylic acid (1 g; 5.82 mmol; 1 eq.) is dissolved in a mixture of Et2O (100 ml) and MeOH (5 ml). Pinacol (687.2 mg; 5.82 mmol; 1 eq.) is added. The reaction mixture is stirred at rt for 24 hours. To complete the reaction, some pinacol is added (200 mg; 1.7 mmol; 0.3 eq.) and the mixture is stirred for 12 additional hours. Water (50 ml) is added and the two phases are separated. Aqueous phase is extracted with ether (50 ml). Combined organic phases is dried over MgSO4, filtrated and evaporated, affording 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid as white-off solid (1.33 g; 90%). 1H NMR (DMSO-d6, 300 MHz) δ 1.13 (s, 12H), 7.37 (d, J=3.8 Hz, 1H), 7.58 (d, J=3.8 Hz, 1H), 13.12 (s, 1H). M−(ESI): 253. HPLC, Rt: 0.98 min (purity: 100%).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH:9](=[N:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[Br-:1].[CH:9](=[N:16][N+:17]1[CH:21]=[CH:20][N:19]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[C:18]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: COc1ccc(-c2nccn2N=Cc2ccccc2)cc1
Solvent: CC#N
Product: COc1ccc(-c2n(CC(=O)C(C)(C)C)cc[n+]2N=Cc2ccccc2)cc1
Product: [Br-]
Reaction time: 24 h

Procedure:
3.73 g of 1-bromo-3,3-dimethyl-2-butanone are added to a solution of 4.6 g of 1-(benzylideneamino)-2-(p-methoxyphenyl)imidazole in 250 ml of absolute acetonitrile. After stirring at 60° for 24 hours, the solution is evaporated and the residue is crystallized from ethanol/ether. There is obtained 1-(benzylideneamino)-2-(p-methoxyphenyl)-3-(pivaloylmethyl)imidazolium bromide of melting point 244°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:17]([O:24]CCO)[C:18]1C=CC=CC=1>>[OH:24][CH2:17][CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: OCCOCc1ccccc1
Reactant: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Product: O=C(O)c1cc(OCCO)cc(N2CCCC2=O)c1

Procedure:
Prepared from the methyl ester of 3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D6) by Mitsunobu reaction with 2-benzyloxyethanol, followed by saponification of the methyl ester and hydrogenolytic removal of the benzyl group.
Reaction SMILES: C(S[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH3:14])[N:5]=1)C.[I-:15].[NH4+:16].N.C(OCC)C>C(O)C>[IH:15].[NH2:16][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH3:14])[N:5]=1
Reactant: [NH4+]
Reactant: CCSC1=NC(C)Cc2ccccc21
Reactant: [I-]
Agent: N
Solvent: CCO
Solvent: CCOCC
Product: CC1Cc2ccccc2C(N)=N1
Product: I
Reaction time: 24 h
Yield: 38.9 %

Procedure:
A mixture of 1-ethylthio-3,4-dihydro-3-methylisoquinoline (M. Gittos et al, J. Chem. Soc., Perkin I, 1976, 33) (0.68 g, 3.3 mmol), ammonium iodide (0.48 g, 3.3 mmol) and ammonia (2M in methanol, 4 ml) in ethanol (4 ml) was heated at reflux for 4 h. The mixture was allowed to cool and diethyl ether (100 ml) was added. Some dark oil which separated on standing was decanted and the remaining clear solution stood at -20 ° for 24 h. The resulting crystals were collected, washed with diethyl ether and dried to afford the product as pale yellow prisms (370 mg), m.p. 114-116° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.C([Mg]Cl)(C)C.[C:28](=[O:30])=[O:29]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:28]([OH:30])=[O:29])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(I)cc(Br)cc3c2C1
Reactant: O=C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2oc3c(C(=O)O)cc(Br)cc3c2C1
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of the product of step C (300 mg, 0.62 mmol) in tetrahydrofuran (1.5 mL) was added isopropylmagnesium chloride (1 M in tetrahydrofuran) (0.75 mL, 0.75 mmol) dropwise under an argon atmosphere at −20° C. over 5 min. The reaction mixture was stirred at −15° C. to −10° C. for 1 h before dry CO2 gas was bubbled through the reaction mixture over 15 min. The reaction mixture was slowly allowed to reach to ambient temperature and stirred overnight. The mixture was quenched with aqueous saturated ammonium chloride solution (10 mL) and extracted with dichloromethane. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to give 8-bromo-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine-6-carboxylic acid (125 mg, 50%) as a white solid. The crude product was directly used for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:18][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc(Cl)cn1N
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1ccc(C(F)(F)F)cc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester (prepared according to literature: Bioorg & Med. Chem. Lett. 2006, 16, 3937-3942) and 4-trifluoromethylbenzaldehyde in refluxing methanol for 12 h. 1H NMR (CDCl3, δ in ppm): 8.43 (s, 1H), 7.95 (d, 2H, J=8.4 Hz), 7.70 (d, 2H, J=7.9 Hz), 7.23 (d, 1H, J=1.6 Hz), 6.91 (d, 1H, J=2.2 Hz), 3.84 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CC1C(C)=N[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([NH2:46])[CH:41]=2)N=1>>[CH2:2]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([NH:46][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:41]=2)[CH2:5][CH2:4][NH:3]1
Reactant: Cc1nc2ccc(N)cc2nc1C
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo-[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 2,3-dimethyl-6-quinoxalinamine by a procedure similar to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.66 (s, 6H), 6.66 (d, 1H, J=5.4 Hz), 7.19 (t, 1H, J=6.9 Hz), 7.29 (t, 2H, J=8.0 Hz), 7.43 (d, 1H, J=7.7 Hz), 7.51-7.65 (m, 3H), 7.85-7.88 (m, 2H), 7.99-8.03 (dd, 1H, J=2.3, 9.0 Hz), 8.06 (s, 1H), 8.42 (d, 1H, J=5.3 Hz), 8.60-8.64 (m, 2H), 8.91 (d, 1H, J=6.9 Hz), 10.08 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=558.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[NH:25][C:26]([CH2:46][C:47]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]4[CH2:61][CH:60]5[N:62]([CH3:63])[CH:57]([CH2:58][CH2:59]5)[CH2:56]4)[CH2:51][CH2:50]3)=[O:48])=[C:27]([C:42]([O:44][CH3:45])=[O:43])[CH:28]([C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])[C:29]=2[C:30]([O:32][CH3:33])=[O:31])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>>[Cl:40][C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:41])[C:34]=1[CH:28]1[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:24]([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[NH:25][C:26]([CH2:46][C:47]([N:49]2[CH2:54][CH2:53][N:52]([CH:55]3[CH2:56][CH:57]4[N:62]([CH3:63])[CH:60]([CH2:59][CH2:58]4)[CH2:61]3)[CH2:51][CH2:50]2)=[O:48])=[C:27]1[C:42]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)C1=C(CCc2ccccc2C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)NC(CC(=O)N2CCN(C3CC4CCC(C3)N4C)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C1=C(CCc2ccccc2C(=O)N2CCNCC2)NC(CC(=O)N2CCN(C3CC4CCC(C3)N4C)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl

Procedure:
A mixture of dimethyl 2-[2-(2-{[4-(tert-butoxycarbonyl)-1-piperazinyl]carbonyl}phenyl)ethyl]-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate (368 mg/0.41 mmol) and 2N HCl aqueous solution (8 ml/16 mmol) was refluxed for 2 hours. After cooling down, the mixture was basitified with saturated NaHCO3 aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on NH2 gel (CH2Cl2:MeOH=200:1-20:1) to afford dimethyl 4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-{2-[2-(1-piperazinylcarbonyl)phenyl]ethyl}-1,4-dihydro-3,5-pyridinedicarboxylate as a yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:20][C:21]#[N:22])[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26](O)[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:20][C:21]#[N:22])[CH2:18][CH2:17][CH:16]([O:19][C:26]4[CH:25]=[C:24]([CH3:23])[O:28][N:27]=4)[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(O)no1
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC2CCC(CC#N)(n3cc(-c4ccnc(Cl)n4)cn3)CC2)no1
Temperature: 70 °C

Procedure:
To a solution of 1-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-4-hydroxycyclohexylacetonitrile (0.6 g, 0.00189 mol) in tetrahydrofuran (9 mL) was added 5-methylisoxazol-3-ol (0.22 g, 0.0023 mol), triphenylphosphine (0.594 g, 0.00226 mol), followed by diisopropyl azodicarboxylate (0.446 mL, 0.00226 mol). The mixture was heated at 70° C. overnight. After evaporating to dryness, the residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product. LCMS (M+H) 399.1.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][NH:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH:27]1([N:26]([CH3:25])[C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]3=[N:6][CH:7]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CNC1CCCC1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Solvent: CN1CCCC1=O
Product: CN(c1cnc2c(n1)c(C(=O)C(C)(C)C)cn2COCC[Si](C)(C)C)C1CCCC1
Temperature: 200 °C
Reaction time: 72 h
Yield: 56.6 %

Procedure:
A solution of 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.051 g, 0.123 mmol) and methylcyclopentylamine (0.050 mL, 0.44 mmol) in 1 mL of N-methyl pyrrolidinone in a sealed tube was stirred at 200° C. for 20 h. Additional methylcyclopentylamine (0.100 mL, 0.88 mmol) was added, and the solution stirred at 200° C. for 3 d. After cooling, the dark orange solution was partitioned between 10 mL of ethyl acetate and 10 mL of a 10% citric acid solution. The organic layer was sequentially washed with three 10 mL portions of water and 10 mL of a sat. aq. NaCl solution, dried over MgSO4, filtered and concentrated to an orange oil. Column chromatography (0-20% EtOAc/hexanes) afforded 0.030 g (58%) of impure 1-[2-(cyclopentyl-methyl-amino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one, which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][N:7]([CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH3:38])[CH2:25][CH2:26][NH:27][C:28]([C:30]2[C:31]([CH3:37])=[N:32][CH:33]=[N:34][C:35]=2[CH3:36])=[O:29])[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])C)=[CH:10][CH:9]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[CH3:48][N:49](C)[C:50](Cl)=O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][N:7]([CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH3:38])[CH2:25][CH2:26][NH:27][C:28]([C:30]2[C:35]([CH3:36])=[N:34][CH:33]=[N:32][C:31]=2[CH3:37])=[O:29])[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])[N:49]([CH3:50])[CH3:48])=[CH:10][CH:9]=1)#[N:2]
Reactant: CC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(OC(=O)N(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of COMPOUND 138 (43 mg, 0.084 mmol) in DMF (1 mL) were added K2CO3 (38 mg, 0.27 mmol) followed by dimethylcarbamoyl chloride (15 μL, 0.16 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 146 as a white solid (27 mg, 53%) following work-up and purification. 1H NMR (CDCl3) δ 0.86-1.13 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.52-1.59 (m, 1H), 1.75-1.79 (m, 3H), 2.16 (t, 1H, J=11.4 Hz), 2.52 (s, 6H), 2.57 (t, 1H, J=10.5 Hz), 2.73-2.88 (m, 3H), 2.98 (s, 3H), 3.05 (s, 3H), 3.28-3.36 (m, 1H), 3.53-3.60 (m, 1H), 3.83-3.87 (m, 1H), 3.87 (s, 2H), 6.53 (d, 2H, J=9.0 Hz), 6.88 (d, 2H, J=9.0 Hz), 7.40-7.45 (m, 1H), 7.50-7.56 (m, 3H), 8.65-8.66 (m, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 14.72, 23.24, 30.49, 31.68, 32.01, 37.66, 37.95, 41.32, 44.90, 49.82, 53.32, 58.14, 61.53, 113.83, 115.91, 120.24, 123.71, 130.55, 131.32, 131.88, 132.15, 132.37, 143.13, 144.63, 146.97, 156.73, 158.83, 164.36, 167.61. ES-MS m/z 584 (M+H). Anal. Calcd. for C33H41N7O3.1.4H2O: C, 65.09; H, 7.25; N, 16.10. Found. C, 65.27; H, 6.88; N, 15.76.