Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:5]([CH3:10])=[C:6]([CH3:9])[CH2:7][CH:8]=1.[CH3:11]Cl>[Cl-].C([N+](CCCC)(CCCC)C)CCC>[CH3:3][C:4]1[CH2:8][C:7]([CH3:11])=[C:6]([CH3:9])[C:5]=1[CH3:10]
Reactant: CCl
Reactant: CC1=CCC(C)=C1C
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: CC1=C(C)C(C)=C(C)C1

Procedure:
A stainless steel autoclave is charged with 50% sodium hydroxide (57 g, 0.7 mole), 80 percent tri-n-butylmethylammonium chloride (1 g, 0.0034 mole), and trimethylcyclopentadiene (mixed isomers, 32.4 g, 0.3 mole). Methyl chloride (15.7 g, 0.31 mole) is added at 60 psi and 25°-30° C. After reaction completion, the organic product phase is separated from the lower aqueous phase containing excess base and sodium chloride slurry. The mixture of crude tetramethylcyclopentadienes is subject to pyrolysis as described in Example 1C to obtain 1,2,3,4-tetramethylcyclopentadiene.
Reaction SMILES: O[Li].O.C(OC(N(C)[C@@H](C)C(N[C@H]1C2(CCOCC2)OC2C=CC=CC=2N(C[C:33]2[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[C:39]3[C:34]=2[CH:35]=[CH:36][C:37]([C:45]([O:47]C)=[O:46])=[CH:38]3)C1=O)=O)=O)(C)(C)C.Cl>O.C1COCC1>[CH3:44][O:43][C:42]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([C:45]([OH:47])=[O:46])[CH:36]=[CH:35]2
Reactant: COC(=O)c1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C4(CCOCC4)Oc4ccccc43)c(OC)ccc2c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)O)ccc2c1
Reaction time: 18 h
Yield: 281.9 %

Procedure:
A solution of LiOH.H2O (35.0 mg, 835 μmol, Eq: 5) in H2O (4 mL) was added to a solution of methyl 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-2-naphthoate (110.5 mg, 167 μmol, Eq: 1.00) in THF (3 mL). After 18 h, the mixture was poured into 1 M HCl (20 mL) and extracted with EtOAc. The combined organic extracts were washed with H2O, brine, dried over Na2SO4 and concentrated. The residue was dissolved in MeCN/H2O, and lyophilized to afford 5-((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-2-naphthoic acid (95.2 mg, 88%) of white solid which was used without purification. MS m/z 648.2 (MH+)
Reaction SMILES: [CH3:1][C:2]1[NH:7][CH:6]=[C:5]([C:8](O)=[O:9])[C:4](=[O:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:55][S:56]([C:59]1[CH:60]=[CH:61][C:62]([CH2:65][NH2:66])=[N:63][CH:64]=1)(=[O:58])=[O:57]>CN1C(=O)CCC1.CO.O>[CH3:55][S:56]([C:59]1[CH:60]=[CH:61][C:62]([CH2:65][NH:66][C:8]([C:5]2[C:4](=[O:11])[C:3]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=3)=[C:2]([CH3:1])[NH:7][CH:6]=2)=[O:9])=[N:63][CH:64]=1)(=[O:58])=[O:57]
Reactant: Cc1[nH]cc(C(=O)O)c(=O)c1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(CN)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1[nH]cc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid (preparation 5b, 0.800 g, 2.69 mmol), HBTU (1.07 g, 2.81 mmol), DIPEA (1.37 mL, 8.08 mmol) in NMP (5 mL) is stirred for 30 min. Then, C-(5-methanesulfonyl-pyridin-2-yl)-methylamine (0.55 g, 2.95 mmol) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is diluted with a small amount of MeOH. Upon addition of water a precipitate forms which is collected by filtration and dried. Yield: 0.78 g (62% of theory); ESI mass spectrum: [M+H]+=466; Retention time HPLC: 1.09 min (V003—003).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)O)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>[OH-].[Pd+2].[OH-].CO.C(OCC)(=O)C>[CH3:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[OH:9])=[CH:19][CH:20]=1)(=[O:25])=[O:26]
Reactant: CS(=O)(=O)c1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(Cc2ccccc2O)cc1
Reaction time: 6 h
Yield: 84.8 %

Procedure:
In a nitrogen stream, a 20% palladium hydroxide catalyst (299 mg) and 36% HCl (150 μL, 1.78 mmol) were added to a solution of (2-benzyloxyphenyl)-(4-methane-sulfonylphenyl)methanol (3.00 g, 8.14 mmol) in a mixture of methanol (30 mL) and ethyl acetate (30 mL), and the mixture was stirred under a hydrogen atmosphere for six hours. To the reaction mixture was added sodium hydrogencarbonate and the mixture was stirred for 30 minutes to be neutralized, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:2)] to obtain the title compound (1.81 g, 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[C:28]([O:36][CH3:37])=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>CN(C=O)C>[F:26][C:27]1[C:28]([O:36][CH3:37])=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: COc1c(F)cccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: COc1c(F)cccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 3-fluoro-2-methoxyphenylboronic acid (CAS RN 762287-59-2) and using DMF as reaction solvent. Off-white solid (27%). MS (ESI): m/z=473.2 [M+H]+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[OH:6][CH2:7][CH2:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12].C(O)(=O)CS.OO>O>[OH:6][CH2:7][CH2:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12].[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Agent: C=CC(=O)OCCO
Agent: O=C(O)CS
Agent: OO
Solvent: O
Product: C=CC(=O)[O-]

Procedure:
Acrylic acid (8.53%), hydroxyethylacrylate (2.84%) and water (31%) were charged to a reaction vessel placed under a nitrogen atmosphere. Thioglycolic acid (1.8%) and 35% aqueous hydrogen peroxide (1.8%) were charged with mixing to the same vessel with flushing between charges. At the completion of the exotherm. Sodium hydroxide (6.4%) aqueous was added with the stirring while maintaining a temperature below 70° C. Seven percent water is added and the material mixed further to produce Composition A.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([OH:12])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[O:12])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20]
Reactant: Nc1cnccn1
Reactant: CSc1ccc(C(C[C@H]2CCCO2)C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C(C[C@H]2CCCO2)C(=O)Nc2cnccn2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of 2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid (67 mg, 0.20 mmol) in methylene chloride (5 mL) was treated with N,N-dimethylformamide (3 drops) and then cooled to 0° C. The reaction mixture was then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.11 mL, 0.22 mmol). The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to 25° C., and then was concentrated in vacuo to remove solvents and excess oxalyl chloride. The resulting residue was re-dissolved in dry tetrahydrofuran (5 mL) and was treated dropwise with a solution of 2-aminopyrazine (57 mg, 0.60 mmol) in tetrahydrofuran (2 mL) and pyridine (0.065 mL, 0.80 mmol). The resulting reaction mixture was stirred at 25° C. for 1.5 h. The reaction mixture was then diluted with water (50 mL) and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 1/1 hexanes/ethyl acetate) afforded 2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-furan-2(R)-yl)-propionamide (51 mg, 61%) as a colorless gum: EI-HRMS m/e calcd for C19H20F3N3O2S (M)+ 411.1228, found 411.1229.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[N+](=[CH2:27])=[N-].B(F)(F)F.CCOCC>ClCCl>[C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][CH3:27])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)O[C@@H]1O[C@H](CO)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC[C@H]1O[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h

Procedure:
A solution of 1,2,3,4-tetra-O-acetyl-β-D-mannopyranose (2.94 g) in dichloromethane (30 ml) at 0° C. is reacted with excess diazomethane in dichloromethane containing boron trifluoride etherate (0.12 ml). After 2 hours, the reaction mixture is filtered and excess diazomethane is destroyed with glacial acetic acid. The filtrate is washed successively with aqueous sodium hydrogencarbonate and water, dried, and evaporated in vacuo to a syrup (3.0 g). A portion of the product is crystallized from ethanol, m.p. 102°-103°, [α]D27 -16.0±1.0° (C 1.02, chloroform).
Reaction SMILES: [O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12]Cl)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].O>CS(C)=O>[O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12][NH:27][CH2:26][CH2:25][CH2:24][C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[C:15]([F:14])[CH:16]=4)[NH:20][CH:19]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Reactant: ClCCOc1cccc2c1OCC2
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4c3OCC4)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 77.2 %

Procedure:
A solution of 2-(2,3-dihydrobenzofuran-7-yloxy)ethylchloride (0.38 g, 1.9 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (0.93 g, 4.8 mmol), triethylamnine (0.48 g, 4.8 mmol) in anhydrous DMSO (20 ml) was allowed to stir at 90° C. for 12 hours. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.52 g (77%) of product as a yellow oil.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26][S:27][CH2:28][CH2:29]N>C(O)C>[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26][S:27][CH2:28][CH2:29][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: NCCSCc1nccs1
Solvent: CCO
Product: COc1ccc(Cc2cnc(NCCSCc3nccs3)[nH]c2=O)cn1
Yield: 60 %

Procedure:
An equimolar mixture of 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone and 2-(2-thiazolylmethylthio) ethylamine was refluxed in ethanol for 18 hours. The solid which crystallised out on cooling was recrystallised from ethanol to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone, m.p. 95-97° in 60% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[H-].[Na+].[CH3:15][O:16][C:17](=O)[O:18]C.Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[C:17]([O:16][CH3:15])=[O:18]
Reactant: COC(=O)OC
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1ccc(Cl)cc1
Reaction time: 0.67 h

Procedure:
At 35° C. a solution of 4-chlorophenylacetic acid methyl ester (52 g) in THF (170 ml) was carefully added over a period of 70 min to a suspension of NaH (15.6 g) in dry THF (550 ml). Stirring was continued for 40 min without heating and the temperature dropped to 290C. The evolution of gas had stopped before dimethylcarbonate (94.8 ml) was added dropwise while the temperature of the mixture was maintained at 25–28° C. After the evolution of gas had ceased, the mixture was diluted with THF (200 ml) and stirring was continued for 72 h at rt. The mixture was carefully acidified with aq. HCl before bulk of the THF was removed in vacuo. The residue was dissolved in diethyl ether (1200 ml), washed three times with 1 N aq. HCl and once with brine, dried over MgSO4 and evaporated. The residue formed was collected, washed with diethyl ether and dried to give 2-(4-chloro-phenyl)-malonic acid dimethyl ester (42 g) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[S:16][C:15]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:14][N:13]=2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[O:32][C:31]([CH2:33][C:34]2[CH:35]=[C:36]([CH2:40][C:41](O)=[O:42])[CH:37]=[CH:38][CH:39]=2)=[N:30][N:29]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:27][C:28]1[O:32][C:31]([CH2:33][C:34]2[CH:35]=[C:36]([CH2:40][C:41]([NH:1][C:2]3[N:7]=[N:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]4[S:16][C:15]([NH:17][C:18](=[O:26])[CH2:19][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[N:14][N:13]=4)=[CH:4][CH:3]=3)=[O:42])[CH:37]=[CH:38][CH:39]=2)=[N:30][N:29]=1
Reactant: Nc1ccc(CCCCc2nnc(NC(=O)Cc3ccccc3)s2)nn1
Reactant: Cc1nnc(Cc2cccc(CC(=O)O)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(Cc2cccc(CC(=O)Nc3ccc(CCCCc4nnc(NC(=O)Cc5ccccc5)s4)nn3)c2)o1
Yield: 7.3 %

Procedure:
A solution of N-(5-(4-(6-aminopyridazin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)-2-phenylacetamide 348 (0.035 g, 0.094 mmol), 2-(3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)acetic acid 1107 (0.023 g, 0.094 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.045 g, 0.235 mmol), 1-hydroxybenzotriazole (0.032 g, 0.235 mmol) in DMF (1.75 mL) was stirred for 16 hours and diluted with water (20 mL). The mixture was extracted with EtOAc (3×20 mL) the organic layers combined, washed with water (3×20 mL), brine (2×20 mL) and dried over Na2SO4. The Na2SO4 was removed by filtration and the volatiles removed under reduced pressure. The crude material was purified by reverse phase chromatography giving 0.004 g of 2-(3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)-N-(6-(4-(5-(2-phenylacetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)acetamide 652. 1H NMR 300 MHz DMSO-d6: δ 12.62 (s, 1H), 11.24 (s, 1H), 8.16 (d, 1H, J=12.2 Hz), 7.54 (d, 1H, J=12.2 Hz), 7.3-7.1 (m, 9H), 4.20 (s, 2H), 3.78 (s, 2H), 3.74 (s, 2H), 2.99 (m, 2H), 2.87 (m, 2H), 2.41 (s, 3H), 1.72 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:11][CH2:12][CH2:13][C:14]([C:7]1[CH:6]=[C:5]([CH3:8])[C:4]([CH3:9])=[C:3]([CH3:10])[C:2]=1[CH3:1])=[O:15]
Reactant: Cc1ccc(C)c(C)c1C
Reactant: O=C(Cl)CCCl
Product: Cc1cc(C(=O)CCCl)c(C)c(C)c1C

Procedure:
3-Chloro-1-(2,3,4,5-tetramethyl-phenyl)-propan-1-one is prepared from 1,2,3,4-tetramethyl-benzene and 3-chloro propionyl chloride by a procedure analogous to that of Preparation 1.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:9]([O:18][CH3:19])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])(OCC)=O.CCOCC>O.C(#N)C>[C:32]1(=[O:41])[N:1]([CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:9]([O:18][CH3:19])[CH:8]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]12
Reactant: CCCCOc1ccc(C(N)CC(=O)O)cc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: CCCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a stirred solution of 3-amino-3-(4-butoxy-3-methoxyphenyl)propionic acid (1.31 g, 4.98 mmol) and sodium carbonate (0.554 g, 5.23 mmol) in a mixture of 100 mL of water and 100 mL of acetonitrile (mixture was warmed gently to dissolve solid, small amount of brown solid did not dissolve removed by filtration) was added N-carbethoxyphthalimide (1.09 g, 4.98 mmol). The mixture was stirred for 1 hour, then partially concentrated in vacuo to remove the acetonitrile. The pH was adjusted to 0-1 with 4 N Hydrochloric acid. An oil formed, 3 mL of ether was added and the mixture stirred overnight. The oil did not solidify and was extracted in methylene chloride. The organic layer was dried (sodium sulfate) and concentrated to a yellow oil which was purified by flash chromatography (silica gel, 5/95 methanolmethylene chloride) to afford 1.02 g of 3-phthalimido-3-(4-butoxy-3-methoxyphenyl)propionic acid containing an unidentified impurity as a yellow oil which slowly crystallized: 1H NMR (DMSO-d6) δ7.95-7.8 (m, 4H, Ar), 7.03 (s, 1H), 6.9 (m, 2H), 5.61 (dd, 1H, J=9, 6.7 Hz), 3.91 (t, 2H, J=6.4 Hz), 3.74 (s, 3H), 3.47 (dd, 1H, J=16.5, 6.7 Hz), 3.27 (dd, 1H, J=16.5, 6.7 Hz), 1.75-1.55 (m, 2H) 1.5-1.3 (m, 2H), 0.91 (t, 3H, J=7.3 Hz);13C NMR (DMSO-d6) δ171.8, 167.7, 148.8, 147.8, 134.6, 131.3, 131.1, 123.2, 119.3, 112.9, 111.4, 67.8, 55.5, 50.1, 30.8, 18.7, 13.6.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].BrN1C(=O)CCC1=O.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:3]2[C:4]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[O:1][N:2]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1onc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Reaction time: 2 h

Procedure:
In 50 g of benzene was dissolved 3.05 g of methyl 5-hydroxyimino-4,5-bis(4-methoxyphenyl-3-pentenoate obtained in Example 3. Thereto was added gradually 3.91 g of N-bromosuccinimide at room temperature and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, ethyl acetate was added to the reaction mixture for dilution, and the organic layer was washed with an aqueous solution of potassium carbonate and then with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated at a reduced pressure, and the residue was subjected to silica gel column chromatography (eluants: ethyl acetate-n-hexane) and crystallized from ether, giving the above-identified compound.
Reaction SMILES: [C:1]1([C:13]23[CH2:20][CH2:19][C:16]([NH2:21])([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1.[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1>CN(C=O)C.O>[C:1]1([C:13]23[CH2:20][CH2:19][C:16]([NH:21][S:25]([CH:22]4[CH2:24][CH2:23]4)(=[O:27])=[O:26])([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NC12CCC(c3n[nH]c4cnc5[nH]ccc5c34)(CC1)CC2
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(NC12CCC(c3n[nH]c4cnc5[nH]ccc5c34)(CC1)CC2)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.6 %

Procedure:
To a mixture of 4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-amine (0.075 g, 0.267 mmol) in DMF (2.5 mL) was added TEA (0.06 mL, 0.40 mmol) and cyclopropanesulfonyl chloride (0.027 mL, 0.27 mmol, Matrix). The reaction mixture was stirred at ambient temperature for about 16 h. Cyclopropanesulfonyl chloride (0.014 mL, 0.133 mmol, Matrix) was added to the reaction mixture and the reaction continued to stir at ambient temperature for about 4 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concd under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to give N-(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.015 g, 15%) as a white solid: LC/MS (Table 1, Method b) Rt=1.72 min; MS m/z: 386 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[N:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([O:34][CH3:35])=[C:27]([O:32][CH3:33])[CH:28]=2)[N:23]=1>C(O)CCCC>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:22]3[N:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([O:34][CH3:35])=[C:27]([O:32][CH3:33])[CH:28]=4)[N:23]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Reactant: COc1cc2cnc(Cl)nc2cc1OC
Solvent: CCCCCO
Product: COc1cc2cnc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)nc2cc1OC
Temperature: 120 °C
Reaction time: 12 h
Yield: 20.8 %

Procedure:
4-(Piperidin-4-ylamino)benzoic acid tert-butyl ester (49) (0.15 g, 0.54 mmol), was added to a solution of 2-chloro-6,7-dimethoxy-quinazoline (0.07 g, 0.31 mmol) in n-pentanol (5 mL) at 25° C. The mixture was stirred at 120° C. for 12 h. The reaction mixture was then cooled to room temperature and concentrated to a brown solid residue. Purification of the residue by flash column chromatography (gradient elution 30 to 40% EtOAc/hexanes) provided the title compound (0.03 g, 18%): TLC (Rf =0.50; 50% EtOAc/hexanes); 1H NMR (DMSO) δ 8.93 (s, 1H), 7.62 (d, 2H, J=8.7), 7.20 (s, 1H), 6.91 (s, 1H), 6.61 (d, 2H, J=8.8), 6.37 (d, 1H, J=7.9), 4.67 (d, 2H, J=13.2), 3.89 (s, 3H), 3.82 (s, 3H), 3.65 (m, 1H), 3.16 (t, 2H, J=11.5), 1.97 (d, 2H, J=10.4), 1.48 (s, 9H), 1.36 (m, 2H); 13C NMR (DMSO) δ 165.3, 158.6, 158.4, 156.1, 151.5, 149.3, 146.5, 130.9, 117.5, 113.9, 111.1, 105.4, 104.4, 78.9, 55.8, 55.6, 48.9, 42.5, 31.2, 28.0; HRMS (FAB) m/z 465.2503 (M+H)+ (C26H32N4O4 requires 465.2494); Anal. (C26H32N4O4 ·1/4HCl·1/4H2O) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:19][CH2:18]1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (420 mg, 1.48 mmol) was reacted with tert-butyl trans-4-aminocyclohexylcarbamate (642 mg, 3.00 mmol) to afford the desired product (550 mg, 80%) as an off-white solid: ESI MS m/z 462 [C22H28BrN3O3+H]+.