Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[N:27]=[C:26]3[N:28](C4CCCCO4)[N:29]=[CH:30][C:25]3=[C:24]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=3)[N:23]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(Cl)Cl>[OH:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[N:27]=[C:26]3[NH:28][N:29]=[CH:30][C:25]3=[C:24]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=3)[N:23]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(O)c3)nc3c2cnn3C2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(O)c3)nc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 51.9 %

Procedure:
2,2,2-trifluoroacetic acid (526 mg, 4.62 mmol) was added to a solution of N-(3-(6-((3-hydroxy-4-morpholinophenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide (100 mg, 0.185 mmol) in DCM (10 ml). The reaction mixture was stirred at room temperature overnight (about 8-12 h), after which the solvent was removed in vacuo. The residue was purified by flash chromatography (MeOH/DCM 5%) to yield the title compound (45 mg, 0.096 mmol, 52.2% yield) as a solid. 1NMR (CD3OD, 400 MHz): 8.98 (s, 1H), 8.39 (s, 1H), 8.05 (d, 1H, J=7.2 Hz), 7.94 (s, 1H), 7.62 (d, 1H, J=8.4 Hz), 7.56 (t, 1H, J=8.0 Hz), 7.36-7.29 (m, 2H), 6.54-6.43 (m, 2H), 5.85 (dd, 1H, J=2.8 & 9.6 Hz), 4.03 (m, 4H), 3.54 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH2:25])[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1.Br[C:30]1[S:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][N:34]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH:25][C:30]2[S:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][N:34]=2)[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1
Reactant: NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Reactant: O=[N+]([O-])c1cnc(Br)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)s1
Temperature: 130 °C

Procedure:
100 mg (0.238 mmol) of the amine (Example 8A) are introduced into 3 ml of DMSO, 76 mg (0.357 mmol) of 2-bromo-5-nitro-1,3-thiazole and 154 mg (1.19 mmol) of DIEA are added, and the mixture is heated in a microwave at 130° C. for 30 min. Purification by preparative HPLC results in 35 mg (33% of theory) of the product as a solid.
Reaction SMILES: [CH:1]([N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8](Cl)=[N:9][C:10]=2[C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1)([CH2:3][CH3:4])[CH3:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CC(N(C)C)=O>[CH:1]([N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[N:9][C:10]=2[C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: C1COCCN1
Reactant: CCC(C)n1cnc2c(-c3cnc(N)nc3)nc(Cl)nc21
Solvent: CC(=O)N(C)C
Product: CCC(C)n1cnc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Temperature: 94 °C
Yield: 70 %

Procedure:
To a solution of 5-(9-sec-butyl-2-chloro-9H-purin-6-yl)-pyrimidin-2-ylamine (1.12 mmol) in dimethyl acetamide (18 ml) was added morpholine (3.5 mmol). The reaction mix was heated on an oil bath maintained at 94° C. for 12 h. The reaction was monitored for the absence of the give 5-(9-sec-butyl-2-chloro-9H-purin-6-yl)-pyrimidin-2-ylamine, by LC-MS. The crude material was directly loaded onto a preparative HPLC column and purified by chromatography to get the title compound in a yield of 70%. 1H NMR, DMSO-d6: 9.52 (s, 2H); 8.27 (s, 1H); 7.28 (s, 2H); 4.5 (m, 2H); 3.8 (m, 4H); 3.70 (m, 4H); 2.0 (m, 1H); 1.9 (m, 1H); 1.6 (d, 3H); 0.79 (t, 3H). m/z: 355.45 [MH]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][N:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7]2.C(Cl)CCl.[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[O:18][C:17](=[O:19])[CH2:16][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH3:2])[CH:5]=2)[CH2:10]1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1cc2c(cc1OC)CN(CC(=O)O)CC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirred suspension of 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid hydrochloride (822 mg, 2.86 mmol) in anhydrous DCM (30 ml), DMAP (523 mg, 4.28 mmol) and EDC (712 mg, 3.71 mmol) were added. The mixture was stirred at room temperature for 1 hour and then (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1.200 g, 2.86 mmol) was added. The mixture was stirred at room temperature for 48 hours, then diluted with DCM and washed with 1N HCl, dried over Na2SO4 and evaporated. The desired product was first purified by flash chromatography on silica gel (DCM:MeOH 10:0.2) followed by preparative HPLC (Method 2). The title compound was obtained (1.354 g, 73% yield). MS/ESI+ 653.18 [MH]+; [αD]=−43.91, c=0.69 in MeOH); 1H NMR (300 MHz, DMSO-d6) δ ppm 8.60 (s, 2H) 7.20 (d, 1H) 7.13 (d, 1H) 7.01 (dd, 1H) 7.07 (t, 1H) 6.64 (s, 1H) 6.58 (s, 1H) 6.10 (dd, 1H) 3.81-3.99 (m, 2H) 3.70 (s, 3H) 3.71 (s, 3H) 3.35-3.56 (m, 4H) 3.19-3.28 (m, 2H) 2.57-2.81 (m, 4H) 1.11-1.34 (m, 1H) 0.49-0.67 (m, 2H) 0.16-0.44 (m, 2H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f26) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:7]([C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[C:6]([O:22]CC2C=CC=CC=2)[C:5]=1[O:30]CC1C=CC=CC=1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([C:4]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:7]([C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[C:6]([OH:22])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: COc1ccc(-n2c(C(C)=O)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-n2c(C(C)=O)c(O)c(O)c2C(=O)N(C)C)cc1
Yield: 70.7 %

Procedure:
A solution of 5-acetyl-3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrrole-2-carboxamide (34) (100 mg, 0.20 mmol) in MeOH (5 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 20° C. under H2 (full H2 mode). The output was concentrated in vacuo. The crude compound was purified by preparative HPLC (C-18 column, 21.2 mm i.d.×100 mm, 5 micron particle size, gradient 5-95% MeCN in 0.1% aq. formic acid over 16 min) to afford 5-acetyl-3,4-dihydroxy-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrrole-2-carboxamide (UL1-091) (45 mg, 70%) as a pale yellow solid: m/z 319 (M+H)+ (ES+), 317 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 9.77 (s, 1H), 8.57 (s, 1H), 7.09-7.07 (m, 2H), 6.88-6.86 (m, 2H), 3.77 (s, 3H), 2.81 (br s, 6H), 2.05 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.[OH-].[K+].Br[CH2:17][CH2:18][CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:25]([O:24][P:20]([CH2:19][CH2:18][CH2:17][O:1][CH2:2][C:3]1([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:4][CH2:5]1)([O:21][CH2:22][CH3:23])=[O:27])[CH3:26]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: CC(C)(C)OC(=O)NC1(CO)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(CCCOCC1(NC(=O)OC(C)(C)C)CC1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 1-(hydroxymethyl)cyclopropylcarbamate (1 eq, from the previous step) in THF (0.1 M) at room temperature was added KOH (5 eq), tetrabutylammonium bromide (0.1 eq), and diethyl 3-bromopropylphosphonate (2 eq). The reaction was stirred at room temperature overnight. The mixture was concentrated en vaccuo and then taken up in DCM/water. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried over anhydrous MgSO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-100% ethyl acetate in hexanes and then 100% ethyl acetate to give the product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:28][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:29])=[CH:27][CH:26]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c1
Temperature: 110 °C
Yield: 70.1 %

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid methyl ester (15.0 g, 68 mmol), (4-hydroxy-phenyl)-carbamic acid tert-butyl ester (14.7 g, 68 mmol) and K2CO3 (18.9 g, 136 mmol) in DMF (300 mL) was heated at 110° C. for 1 hour under N2, cooled to room temperature, and then poured into ice-H2O (1200 mL) under stirring. The aqueous mixture was extracted with AcOEt (600 mL). The extract was washed with H2O (3 times) and brine, dried over MgSO4, and evaporated to give pale brown crystal, which was purified by washing with i-Pr2O and dried at 40° C. overnight under reduced pressure to give the title compound as pale yellow crystal (18.5 g, 70%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>C(Cl)Cl.CO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:36][CH:35]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)cc2)CC1
Yield: 62 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2,5-dichloropyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 62% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.53 (d, 1H, J=8.2 Hz), 8.11 (s, 1H), 7.84 (dd, 1H, J=8.2, 1.3 Hz), 7.54 (m, 1H), 7.45 (d, 2H, J=8.2 Hz), 7.22 (m, 3H), 3.47 (s, 2H), 2.72 (s, 6H), 2.48 (bs, 8H), 2.29 (s, 3H); MS (ESI): 516.3 [M+H]+, 258.8 [M+2H]2+.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C@H:9]([C:17](=[O:19])[NH2:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[NH:15])=[O:7])=[CH:4][C:3]=1[O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32].[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1>>[C:17]([C@@H:9]([NH:8][C:6]([C:5]1[CH:20]=[CH:21][C:2]([NH:1][C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:3]([O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH:4]=1)=[O:7])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[NH:15])(=[O:19])[NH2:18]
Reactant: N=C(N)NCCC[C@H](NC(=O)c1ccc(N)c(OCCc2ccc(Cl)cc2Cl)c1)C(N)=O
Reactant: O=C1CCC(=O)O1
Product: N=C(N)NCCC[C@H](NC(=O)c1ccc(NC(=O)CCC(=O)O)c(OCCc2ccc(Cl)cc2Cl)c1)C(N)=O

Procedure:
The third part of the resin obtained in Example 2 (116 mg) was coupled with 160 mg of succinic anhydride analogously to the procedure described in Example 3. The resin was washed and dried, and the final product was cleaved off and processed as described in Example 1.
Reaction SMILES: [C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45].O>C(Cl)(Cl)Cl>[C:44]([N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C@@H:15]2[N:19]([C:20]([C@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[NH:28][C:29](=[O:36])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:21])[CH2:18][CH2:17][C@H:16]2[C@@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)Cl
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1c2ccccc2[C@H]2[C@@H](CCN2C(=O)[C@H]2CCCC[C@H]2NC(=O)c2ccccc2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
The compound (130 mg, 0.27 mmol) of Example 1 and triethylamine (69 mg, 0.30 mmol) were dissolved in chloroform (2 ml), acetyl chloride (99 mg, 0.33 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. and at 60° C. for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated. The residue was subjected to column chromatography using silica gel (150 g), and eluted with hexane-ethyl acetate (3:1-0:1, v/v) to give the title compound (65 mg, 46%) as an amorphous form.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=C)[N:16]=3)=[C:9]([F:30])[CH:8]=1.[O:31]=[O+][O-]>C(Cl)Cl.CO>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:31])[N:16]=3)=[C:9]([F:30])[CH:8]=1
Reactant: O=[O+][O-]
Reactant: C=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylvinyl)thiazolo[5,4-b]pyridine (2.66 g, 6.4 mmol) in 3:1 CH2Cl2/MeOH (128 mL) at −78° C. was treated with ozone for 15 min. The solution was then sparged with O2, dimethyl sulfide (18 mL) was added, and the bath was allowed to expire. The resulting solution was stirred at 25° C. for 3 d and then concentrated in vacuo. This residue was taken up in CH2Cl2 (400 mL) and sequentially washed with water and brine, then concentrated in vacuo to provide (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridine-5-yl)(phenyl)methanone as a yellow solid. MS (ESI) m/z: Calculated: 420.1; Observed: 421.1 (M++1).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][C:22]3[N:27]=[C:26]([S:28][C:29]#[N:30])[C:25]([N+:31]([O-])=O)=[CH:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].CN1CCCC1=O.Cl.[OH-].[Na+]>C(O)C>[NH2:30][C:29]1[S:28][C:26]2[N:27]=[C:22]([NH:21][C:17]3[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:20]=[CH:19][CH:18]=3)[N:23]=[CH:24][C:25]=2[N:31]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Nc3ncc([N+](=O)[O-])c(SC#N)n3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Nc3ncc4nc(N)sc4n3)c2)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 60.4 %

Procedure:
To a suspension of 2-{[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenyl]amino}-5-nitropyrimidin-4-yl thiocyanate (844 mg, 1.84 mmol) and reduced iron (513 mg, 9.20 mmol) in ethanol (16 mL)/1-methylpyrrolidin-2-one (8 mL) was added 1N hydrochloric acid (4 mL), and the mixture was stirred at 100° C. for 1.5 hr. The reaction mixture was neutralized with 2N aqueous sodium hydroxide solution (3 mL), and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 2×20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (477 mg, 60%) as pale-purple crystals.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)=[C:10]2[CH:9]=1)(C)C.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>C(O)C.O>[NH2:29][C:25]1[CH:24]=[C:23]([C:15]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)=[C:10]3[CH:9]=[C:8]([CH2:7][OH:6])[CH:13]=[CH:12][N:11]3[N:14]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccn2nc(-c3cccc([N+](=O)[O-])c3)c(-c3ccncn3)c2c1
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2nn3ccc(CO)cc3c2-c2ccncn2)c1
Temperature: 100 °C
Yield: 96.4 %

Procedure:
To a suspension of 5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-(3-nitrophenyl)-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine (1.75 g, 3.79 mmol) in ethanol (88 mL), sodium sulfide nonahydrate (4.56 g, 19.0 mmol) in H2O (90 mL) was added. The mixture was heated at 100° C. under reflux for 2 h. The mixture was evaporated under reduced pressure to remove ethanol, and following the addition of H2O was cooled to 0° C. The resulting precipitate was filtered to give the product (1.16 g) as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[CH2:8][CH2:7]1>[Pd].C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A solution of 1-(3,4-dichlorobenzyl)-4-(2-nitro-phenyl)-piperazine (1.19 g) in 50 mL of 4/1 ethyl acetate/methanol was treated with 5% palladium on carbon (55 mg) and placed under a hydrogen atmosphere. After stirring at ambient temperature overnight, the reaction was filtered using a pad of silica and the pad was washed with 17% ethyl acetate in hexanes, then 33% ethyl acetate in hexanes. Removal of solvent afforded 0.75 g of the product as a solid.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.N([O-])=O.[Na+].N(O)=O.[H+].[B-](F)(F)(F)[F:27]>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([F:27])=[CH:3][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1ccc(N)cc1-c1ccccc1
Agent: O=NO
Agent: O=N[O-]
Agent: [H+]
Product: COC(=O)c1ccc(F)cc1-c1ccccc1

Procedure:
A solution of methyl 4-amino-2-phenylbenzoate (1.0 equivalent) in dilute aqueous HBF4 is treated with NaNO2 (1.1 equivalents) until an excess of nitrous acid persists. The mixture is extracted into ethyl acetate which is dried and evaporated. The title ester is purified by chromatography on silica gel.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:12]=[CH:11][C:9]([OH:10])=[C:5]([O:6][CH2:7][CH3:8])[CH:4]=1.[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:7]([O:6][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:9]=1[O:10][CH2:15][CH:14]=[CH2:13])[CH:2]=[O:1])[CH3:8]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C=O)cc1OCC

Procedure:
Ethyl vanillin (21.6 g, 0.130 mol) and allyl bromide (19.9 g, 0.160 mol) were heated under reflux together with potassium carbonate (27.3 g, 0.200 mol) in 150 ml acetone (abs.) for 8 hours. After cooling, the solid was filtered off and washed with acetone. A yellow oil was obtained after a thorough concentration of the organic phases.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:7])[CH2:5][CH3:6])[CH3:3].[C:8](O)(=[O:12])/[CH:9]=[CH:10]/[CH3:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:5]([CH:4]([O:7][C:8](=[O:12])[CH:9]=[CH:10][CH3:11])[CH:2]([CH3:3])[CH3:1])[CH3:6]
Reactant: C/C=C/C(=O)O
Reactant: CCC(O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OC(CC)C(C)C
Yield: 79.4 %

Procedure:
A reaction flask was charged with ethylmagnesium chloride (CH3CH2MgCl) (2 M, 2.17 L) and cooled to −10° C. Isobutyraldehyde ((CH3)2CHCHO) (295 g) was fed over about 1 hour while the temperature was kept under 15° C. The reaction mixture was aged to room temperature over about 6 hours and then poured into a mixture of ice and acetic acid (CH3COOH) (293 g). Hexanes (C6H14) (350 mL) were added and aqueous and organic layers were split. The organic layer was separated, washed sequentially with sodium bicarbonate (NaHCO3), brine, and water, and further distilled to provide 2-methyl-pentan-3-ol (336 g). 2-Methyl-pentan-3-ol (250 g), crotonic acid (CH3CH═CHCOOH) (198 g), toluene (250 mL), and para-toluenesulfonic acid (PTSA) (10 g) were then charged into to 2-L reaction flask fitted with a Bidwell-Sterling trap. The reaction mixture was heated to reflux. Water was collected and removed via the Bidwell-Sterling trap. The reaction mixture was aged at reflux for about 22-30 hours till the Gas Chromatography (“GC”) analysis showed completion of the reaction. The resulting reaction mixture was washed sequentially with brine, sodium carbonate (Na2CO3), and brine, and further purified by fractional distillation to provide but-2-enoic acid 1-ethyl-2-methyl-propyl ester (311 g) with a boiling point of 65° C. at 0.6 mmHg.