Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[NH:56][CH2:55][CH2:54][N:53](C(OC(C)(C)C)=O)[CH2:52]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:56]6[CH2:55][CH2:54][NH:53][CH2:52][C@@H:51]6[CH3:50])[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)n1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4CCNC[C@@H]4C)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (39.0 mg. 0.059 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (0.177 mmol, 3.0 eq) and acetic acid (3.55 mg, 0.059 mmol) and fitted magnetic stir bar. The result solution was stirring at room temperature for 4 h. MP-B(OAc)3H (0.591 mmol, 138 mg, 10.0 eq) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and MeOH (2.0 mL) and 1 drop of concentrated HCl was added to the solution. The solution was heated at 60° C.° for 12 h. Purification was completed via a Gilson HPLC (acidic conditions). The product was dissolved in 3 mL of MeOH and passed through 0.5 g amine columns (washed with 8 mL MeOH) to afford 14.5 mg (33.03%) of the title compound. LC-MS m/z 744 (M+H)+, 1.43 min (ret time).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:13]=1)[C:6](OC)=[O:7].[NH3:29].[Cl-].[Na+]>C(O)CO>[CH:15]1([NH:14][C:12]2[CH:13]=[C:4]3[C:3](=[O:2])[NH:29][C:6](=[O:7])[C:5]3=[CH:10][C:11]=2[NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: N
Reactant: COC(=O)c1cc(NC2CCCCC2)c(NC2CCCCC2)cc1C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Product: O=C1NC(=O)c2cc(NC3CCCCC3)c(NC3CCCCC3)cc21
Reaction time: 12 h

Procedure:
Analogously to Example 1, 194 mg (0.5 mmol) of 4,5-bis(cyclohexylamino)phthalic acid dimethyl ester in 15 ml of ethylene glycol are heated at 120°, ammonia gas being passed through the mixture, with stirring, for 12 hours. The reaction mixture is cooled, saturated with sodium chloride and extracted with ethyl acetate. The ethylacetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed onsilica gel with hexane/ethyl acetate 3:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of orange crystals, m.p. 170°-175° C., FAB-MS: 342 [M+ +H].
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH3:20][N:21]=[C:22]=[O:23]>>[NH2:17][C:16]1[C:4]([C:2]#[N:3])=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:22]([NH:21][CH3:20])=[O:23]
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CN=C=O
Agent: [Cl-]
Product: CNC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Yield: 53 %

Procedure:
Prepared as in Example 191a from (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 191b) and methyl isocyanate in 53% yield as a white solid. MS 275 (MH+).
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1.[NH2:13][C:14]1[CH:15]=[C:16]([C:21]2[C:25]([Cl:26])=[C:24]([O:27][CH:28]([F:30])[F:29])[N:23]([CH3:31])[N:22]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]>O1CCCC1>[Cl:26][C:25]1[C:21]([C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([NH:13][C:10]([CH:7]3[CH2:9][CH2:8]3)=[O:11])[CH:15]=2)=[N:22][N:23]([CH3:31])[C:24]=1[O:27][CH:28]([F:30])[F:29]
Reactant: O=C(Cl)C1CC1
Reactant: Cn1nc(-c2ccc(Cl)c(N)c2)c(Cl)c1OC(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1nc(-c2ccc(Cl)c(NC(=O)C3CC3)c2)c(Cl)c1OC(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1.0 g (13 mmol) of pyridine and 0.7 g (6.5 mmol) of cyclopropanecarbonyl chloride were added to a solution of 2.0 g (6.5 mmol) of 3-(3-amino-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole in 30 ml of tetrahydrofuran. The solution was stirred at room temperature overnight and at 50° C. for 2 hours, an then concentrated. The residue was taken up in ethyl acetate. The ethyl acetate was washed in succession with cold 1N hydrochloric acid, water and saturated sodium chloride solution, then dried over magnesium sulfate and finally concentrated. Yield: 2.2 g.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:18]=O)[CH:13]=[N:14][C:15]=1[O:16][CH3:17].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:9][C:10]1[CH:11]=[C:12]([CH2:18][NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)[CH:13]=[N:14][C:15]=1[O:16][CH3:17]
Reactant: Nc1cccc(F)n1
Reactant: COc1ncc(C=O)cc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ncc(CNc2cccc(F)n2)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To 6-fluoro-pyridin-2-ylamine (43, 1.50 g, 13.4 mmol) in 52.9 mL of acetonitrile, 5-fluoro-6-methoxy-pyridine-3-carbaldehyde (57, 2.00 g, 12.9 mmol), triethylsilane (10.6 mL, 66.3 mmol), and trifluoroacetic acid (5.3 mL, 69.0 mmol) were added. The reaction was stirred at 80° C. overnight, then concentrated under vacuum, combined with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as white solid (58, 3.21 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH:35]([CH3:37])[CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:38]([O:40][C:41]1[CH:47]=[C:46]([N:48]2[CH2:53][CH2:52][CH:51]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:50][CH2:49]2)[C:45]([CH3:60])=[CH:44][C:42]=1[NH2:43])[CH3:39].Cl>FC(F)(F)CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:45]([CH3:60])[C:46]([N:48]4[CH2:53][CH2:52][CH:51]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:50][CH2:49]4)=[CH:47][C:41]=3[O:40][CH2:38][CH3:39])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH:35]([CH3:37])[CH3:36]
Reactant: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: CC(C)Oc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC(C)C)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 24 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]benzamide (Intermediate Example 7) (0.13 g, 0.25 mmol) and 2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (0.087 g, 0.25 mmol) in 2,2,2-trifluoroethanol (1.5 mL) was added HCl (4M in dioxane) (0.13 mL, 0.50 mmol). The reaction was heated to 180° C. for 40 min in a microwave. The reaction was determined to be complete by HPLC. The reaction mixture was quenched with saturated NaHCO3 and sequentially extracted with DCM and EtOAc. The organic layer was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound (0.05 g, 0.06 mmol, 24%). 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.36 (d, J=5.9 Hz, 1H), 8.37 (s, 1H), 8.28 (d, J=4.9 Hz, 1H), 8.09 (br. s., 1H), 7.74 (dd, J=14.1, 8.9 Hz, 2H), 7.56 (s, 1H), 7.27-7.52 (m, 3H), 7.21 (t, J=7.9 Hz, 2H), 6.96 (t, J=6.6 Hz, 1H), 6.75 (s, 1H), 6.63 (d, J=4.8 Hz, 1H), 4.79-4.97 (m, 1H), 4.07 (q, J=6.7 Hz, 2H), 3.12-3.24 (m, 2H), 3.05 (d, J=11.1 Hz, 2H), 2.98 (s, 3H), 2.61 (t, 2H), 2.14 (s, 3H), 1.62-1.87 (m, 4H), 1.17-1.59 (m, 12H). MS (M+H, ES+) 824.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[C:2]=1[C:10]([OH:12])=[O:11].C(OC(=O)C)(=O)C>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:9])[O:12][C:10](=[O:11])[C:2]=12
Reactant: O=C(O)c1cccnc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2ncccc21
Temperature: 115 °C
Yield: 86.7 %

Procedure:
A mixture of pyridine-2,3-dicarboxylic acid (2 g, 12 mmol) and acetic anhydride was heated at 115° C. for 4 h. Excess reagent was removed under reduced pressure. The remaining solid was triturated with hot carbon tetrachloride. After cooling, the solid was collected by vacuum filtration and dried overnight under vacuum at 60° C. to give furo[3,4-b]pyridine-5,7-dione (1.55 g, 10.4 mmol). 1H NMR (400 MHz, DMSO-d6) δ 9.10 (dd, J=4.9, 1.5 Hz, 1H), 8.50 (dd, J=7.8, 1.5 Hz, 1H), 7.90 (dd, J=7.8, 4.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([N:8]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][O:17][C:11]=3[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([C:26](=[O:34])[C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:24][CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][O:17][C:11]=3[CH:10]=2)=[O:7])=[CH:35][CH:36]=1)(=[O:39])[CH3:38]
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc3c(c2)OCO3)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc3c(c2)OCO3)cc1
Yield: 79 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3,4-methylenedioxyphenyl)benzamide (245.0 mg, 0.501 mmol) and acetic anhydride (0.057 ml, 0.60 mmol), the procedure of Inventive Example 94 was repeated to obtain 210.3 mg (79.0%) of the title compound in a colorless amorphous form.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:6]=[N:5][CH:4]=1.[CH3:18]I>C1COCC1.CCOC(C)=O>[CH3:18][N:9]([C:7]1[CH:8]=[N:3][CH:4]=[N:5][CH:6]=1)[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]
Reactant: N#Cc1cccc(Nc2cncnc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cncnc1)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
NaH (148 mg, 6.17 mmol, 1.10 eq) was added to a flame-dried round-bottom flask and anhydrous THF (14 mL) was added. The slurry was cooled to 0° C. and compound 15 (1.098 g, 5.596 mmol, 1.000 eq) was added as a solution in THF (14 mL). After stirring at 0° C. for 30 minutes methyl iodide (384 μL, 6.17 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 735 mg (62%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.57 (s, 2H), 7.58-7.56 (m, 1H), 7.51-7.44 (m, 2H), 7.44-7.38 (m, 1H), 3.35 (s, 3H); [M+1]+: 211.2.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:44]([N:51]1[CH2:55][C@H:54]2[C@H:56]([NH2:59])[CH2:57][CH2:58][C@H:53]2[CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl>[CH2:44]([N:51]1[CH2:55][C@H:54]2[C@H:56]([NH:59][C:8](=[O:10])[C@@H:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:57][CH2:58][C@H:53]2[CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(C)C[C@@H](C(=O)O)N1CCCS1(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCCS1(=O)=O
Reaction time: 0.25 h

Procedure:
(2S)-2-(1,1-Dioxidoisothiazolidin-2-yl)-4-methylpentanoic acid (359 mg, 1.526 mmol) was combined with triethylamine (0.387 mL, 2.77 mmol) in dichloromethane (10 mL). 1-Hydroxybenzotriazole (234 mg, 1.526 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.270 mL, 1.526 mmol) were added, and the reaction mixture was stirred for 15 minutes. Then (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (300 mg, 1.387 mmol) from Example 16 Step E was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with 10 mL of aqueous sodium bicarbonate and extracted with 3×20 mL of dichloromethane. The solvent was removed in vacuo. The crude material was applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS15-24) and eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.76 (d, J=6.9, 1H), 7.46-7.39 (m, 2H), 7.40-7.33 (m, 2H), 7.26 (dd, J=9.9, 17.2, 1H), 4.52 (t, J=7.7, 1H), 4.44-4.34 (m, 1H), 3.93 (dt, J=7.0, 14.5, 1H), 3.57 (dd, J=5.4, 13.1, 1H), 3.49-3.36 (m, 2H), 3.30-3.20 (m, 2H), 2.83-2.74 (m, 1H), 2.62-2.45 (m, 2H), 2.44-2.37 (m, 1H), 2.33-2.17 (m, 4H), 2.11 (qd, J=6.5, 12.5, 1H), 1.92-1.78 (m, 3H), 1.77-1.59 (m, 2H), 1.45-1.32 (m, 1H), 0.88 (d, J=6.6, 3H), 0.83 (dd, J=2.5, 6.5, 3H); MS (ESI+) m/z 434 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8]S(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[CH2:36][CH2:35][CH2:34]2.O>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[CH2:36][CH2:35][CH2:34]2
Reactant: CS(=O)(=O)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)ccc21

Procedure:
1.1 g of methanesulfonic acid 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl ester, 1.1 g of potassium carbonate and 0.45 g of 6-hydroxy-1-tetralone are stirred in 10 ml of dimethylformamide at 50° C. for 17 hours. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, 6-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-3,4-dihydro-2H-naphthalen-1-one is obtained.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([NH:9][CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3].[CH2:15]1[O:17][CH2:16]1>C(O)C>[NH:1]([C:5]1[CH:13]=[CH:12][C:8]([N:9]([CH2:15][CH2:16][OH:17])[CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3]
Reactant: C1CO1
Reactant: CCNc1ccc(NC(C)=O)c(C)c1
Solvent: CCO
Product: CCN(CCO)c1ccc(NC(C)=O)c(C)c1

Procedure:
15.2g (0.08 mole) of 4-acetamino-3-methyl-N-ethylaniline obtained in Example 1, Part C, 4.2g (0.09 mole) of ethylene oxide and 50ml of ethanol were fed into an autoclave and reacted for 1 hour at 120° to 130° C in the closed autoclave. Thereafter, ethanol was distilled off to obtain crystals of 4-acetamino-3-methyl-N-(β-hydroxyethyl)-N-ethylaniline. The crystals were recrystallized from ethyl acetate to obtain 18.5g of white crystals.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[CH2:18][C@H:17]2[C:19]([O:21]CC)=[O:20])=[CH:12][C:11]=1[CH3:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[CH2:18][C@H:17]2[C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[CH3:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccccc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc([C@@H]2C[C@H]2C(=O)O)ccc1NC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 6.5 h
Yield: 49 %

Procedure:
To a solution of ethyl trans-2-[4-(benzoylamino)-3-methylphenyl]cyclopropanecarboxylate (1.29 g) in ethanol (7.98 mL) was added 1N aqueous sodium hydroxide solution (7.98 mL). The reaction mixture was stirred at 50° C. for 6.5 hr, 1N hydrochloric acid (10 mL) was added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. The precipitate was collected by filtration to give the title compound (576.9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[N:17][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[N:17][CH:18]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCCC(=O)O)nc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: c1ccncc1
Product: O=C(O)CCCc1ccc(NS(=O)(=O)c2cccc(Cl)c2)cn1
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A solution of 3-chlorobenzenesulphonyl chloride (1.17 g), dissolved in 5 ml pyridine, was added dropwise to a solution of 4-(5-aminopyrid-2-yl)butanoic acid (1 g) in pyridine (10 ml). The resulting solution was allowed to stand at room temperature overnight when the solvent was removed under reduced pressure. The residue was taken up in dilute sodium hydroxide solution (40 ml) and extracted with chloroform (4×50 ml) the chloroform extracts were discarded. The aqueous layer was adjusted to pH 4 with hydrochloric acid, extracted with chloroform (3×100 ml) and then ethyl acetate (2×100 ml). Chloroform and ethyl acetate extracts were dried over magnesium sulphate, solvents removed and residue recrystallised from acetonitrile/water to give the title compound (1.29 g) as a white solid. m.p. 141°-142° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:17])[CH3:16])[CH2:4][CH2:3]1.C([O:22][C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][N:27]=1)(C)(C)C.[OH-].[K+]>CCO.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:17])/[CH:16]=[CH:32]/[C:29]2[CH:30]=[CH:31][C:26](/[CH:25]=[CH:24]/[C:23]([OH:34])=[O:22])=[N:27][CH:28]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)c1ccccc1CN1CCN(C)CC1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(Cc2ccccc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)nc2)CC1
Temperature: 4 °C
Reaction time: 8 h
Yield: 133.2 %

Procedure:
A mixture of 1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-ethanone (obtained as described in Preparation 11, 250 mg, 1.07 mmol), (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 251 mg, 1.07 mmol) and 1.7 M KOH (0.633 ml) in EtOH (10 ml) was stirred at 4° C. overnight. The resulting solution was diluted with water and extracted with AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 95:5:0.2) and the resulting product was dissolved in DCM (10 ml) and TFA (2 ml) and stirred at room temperature for 4 h. The solvent was evaporated to give 558 mg of (E)-3-(5-{(E)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid as its tris-trifluoroacetate salt.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46](C)[CH2:47]CN.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][CH2:29][CH2:30][N:46]([CH3:47])[CH3:45])=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CN(C)CCN
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)NCCN(C)C)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing N,N-dimethylethylenediamine as the aniline component. (23%, MS=578.3 (M+H))
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11](=[O:32])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][C:24]2[CH:29]=[C:28](Br)[CH:27]=[C:26](Br)[CH:25]=2)=[CH:16][CH:15]=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:9][O:10][C:11](=[O:32])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][C:24]2[CH:29]=[C:28]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:27]=[C:26]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:25]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(Br)c2)cc1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#Cc3ccccc3)cc(C#Cc3ccccc3)c2)cc1

Procedure:
A solution of phenylacetylene (0.20 g, 1.98 mmol), {4-[3-(3,5-dibromo-phenyl)-prop-2-ynyloxy]-phenoxy}-acetic acid methyl ester (0.3 g, 0.66 mmol), Pd(PPh3)4 (0.11 g, 0.1 mmol) and CuI (0.05 g, 0.26 mmol) in triethylamine (10 ml) was heated in a sealed tube in a microwave own at 65° C. for 1 hour. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified on HPLC using acetonitril/water as eluent to give {4-[3-(3,5-bis-phenylethynyl-phenyl)-prop-2-ynyloxy]-phenoxy}-acetic acid methyl ester in 150 mg (46%) yield.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:24]Br>>[CH3:20][C:21]1[CH:28]=[C:27]([CH:26]=[C:23]([CH3:24])[CH:22]=1)[CH2:29][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(C)cc(C)c2)c(=O)[nH]c1=O
Yield: 57.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dimethylbenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (217 mg, yield: 57.3%).