Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].Cl>CCO>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CCN[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NCCC(=O)O)no2)cc1C#N
Temperature: 40 °C
Reaction time: 4 h
Yield: 42.9 %

Procedure:
To (R)-methyl 3-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylamino)propanoate (71.0 mg, 0.16 mmol) in EtOH (5 ml) was added aqueous NaOH (1.9 mL, 1M). The solution was stirred at 40° C. for 4 h. The reaction mixture was poured onto ice (10 mL) and neutralized to pH 7 with 1M HCl. The solution was partitioned between DCM and H2O. The organic layer was collected, dried under vacuum, and purified by preparative HPLC to give 29.7 mg (31%) of (R)-3-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)propanoic acid 62. LCMS-ESI (m/z): calcd for: C24H24N4O4, 432.5; [M+H]+ found 433.20, tR=2.51 min. 1H NMR (400 MHz, MeOD) δ 8.46 (d, J=2.1, 1H), 8.45-8.40 (m, 1H), 8.29-8.23 (m, 1H), 7.82-7.73 (m, 1H), 7.60-7.52 (m, 1H), 7.45 (d, J=9.0, 1H), 5.06-4.92 (m, 2H), 3.69-3.52 (m, 1H), 3.51-3.37 (m, 1H), 3.26 (s, 2H), 2.75-2.58 (m, 1H), 2.56-2.46 (m, 2H), 2.44-2.29 (m, 1H), 1.46 (d, J=6.0, 6H).
Reaction SMILES: C1(O[C:8](=[O:44])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:26]4[C:25](=[O:27])[N:24]([CH:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:23][C:22]([CH3:35])([CH3:34])[O:21][C:20]=4[N:19]=[C:18]([N:36]4[CH2:42][CH:41]5[O:43][CH:38]([CH2:39][CH2:40]5)[CH2:37]4)[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH3:45][C:46]1[O:50][N:49]=[C:48]([NH2:51])[CH:47]=1.CN(C=O)C>C1COCC1>[CH3:35][C:22]1([CH3:34])[O:21][C:20]2[N:19]=[C:18]([N:36]3[CH2:37][CH:38]4[O:43][CH:41]([CH2:40][CH2:39]4)[CH2:42]3)[N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:51][C:48]4[CH:47]=[C:46]([CH3:45])[O:50][N:49]=4)=[O:44])=[CH:11][CH:12]=3)[C:26]=2[C:25](=[O:27])[N:24]([CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[CH2:23]1
Reactant: CC1(C)CN(C2CCOCC2)C(=O)c2c(nc(N3CC4CCC(C3)O4)nc2-c2ccc(NC(=O)Oc3ccccc3)cc2)O1
Reactant: Cc1cc(N)no1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)Nc2ccc(-c3nc(N4CC5CCC(C4)O5)nc4c3C(=O)N(C3CCOCC3)CC(C)(C)O4)cc2)no1
Temperature: 100 °C
Yield: 11.9 %

Procedure:
50 mg (83.38 μmol) of {4-[8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-6-(tetrahydropyran-4-yl)-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]phenyl}carbamic acid phenyl ester are placed in a microwave reactor and 25 mg (0.25 mmol) of 5-methylisoxazol-3-ylamine are added. 2 ml of DMF and 1 ml of THF are added. The reaction mixture is heated in a Biotage microwave machine for 30 minutes at 100° C. 100 mg (1.0 mmol) of 5-methylisoxazol-3-ylamine are added and the mixture is heated for 2 hours at 110° C. A further 300 mg (3 mmol) of 5-methylisoxazol-3-ylamine are added and the mixture is heated for 2 hours at 110° C. The solvents are evaporated off. The residue is taken up in water and the insoluble material is filtered off, washed three times with water, taken up in MeOH/DCM and dried. The residue is chromatographed on silica gel, eluting with an MeOH/DCM mixture from (0/100 v/v) up to (5/95 v/v) to give 6 mg of 1-{4-[8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-6-(tetrahydropyran-4-yl)-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]phenyl}-3-(5-methylisoxazol-3-yl)urea.
Reaction SMILES: [Cl:1][C:2]1([Cl:9])[N:6]=[C:5](Cl)[C:4]([Cl:8])=[N:3]1.[Cu][C:11]#[N:12]>C1(C)C(C)=CC=CC=1>[C:11]([C:5]1[C:4]([Cl:8])=[N:3][C:2]([Cl:1])([Cl:9])[N:6]=1)#[N:12]
Reactant: N#C[Cu]
Reactant: ClC1=NC(Cl)(Cl)N=C1Cl
Solvent: Cc1ccccc1C
Product: N#CC1=NC(Cl)(Cl)N=C1Cl
Yield: 40.2 %

Procedure:
A mixture of 20.5 g (0.1 mol) of 2,2,4,5-tetrachloro-2H-imidazole, 41 g (0.5 mol) of anhydrous copper-(I) cyanide and 230 ml of anhydrous xylene was heated for about 30 hours at 110° - 120° C. After cooling, the reaction mixture was filtered and the brown residue was repeatedly washed with ether. The combined solutions were shaken with active charcoal and the resulting coloured solution was concentrated in vacuo. The concentrated solution was taken up in n-hexane and the product crystallised out. It was filtered off and recrystallised from n-hexane, giving 7.9 g (40% of theory) of 4-cyano-2,2,5-trichloroimidazole (melting point 114° - 115° C).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[CH3:11][PH:12](=[O:14])[CH3:13].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:11][P:12]([C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1)([CH3:13])=[O:14]
Reactant: C[PH](C)=O
Reactant: CCc1cc(Br)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CCc1cc(P(C)(C)=O)ccc1N
Reaction time: 0.33 h
Yield: 78.1 %

Procedure:
To a solution of 4-bromo-2-ethylaniline (0.400 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) to afford the desired product (0.308 g, 78% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]3[C:11]=2[CH2:12][N:13](C)[C:14]3=[O:22])[CH:7]=[N:6]1.NC1C=CC(Br)=CC=1C(NC)=O>>[NH2:19][C:16]1[CH:17]=[CH:18][C:10]([C:8]2[CH:7]=[N:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:9]=2)=[CH:11][C:15]=1[C:14]([NH:13][CH3:12])=[O:22]
Reactant: CN1Cc2c(-c3cnn(CCCO)c3)ccc([N+](=O)[O-])c2C1=O
Agent: CNC(=O)c1cc(Br)ccc1N
Product: CNC(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Yield: 47 %

Procedure:
Prepared analogously to Compound 1D using 2-amino-5-bromo-n-methyl-benzamide (Compound 87D, 600 mg, 2.62 mmol) to afford 335 mg of the title compound (47%). 1H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.76 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.38 (dd, J=2.0, 8.3 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 4.25 (t, J=6.8 Hz, 2H), 3.54 (t, J=6.2 Hz, 2H), 2.89 (s, 3H), 2.06 (quin, J=6.5 Hz, 2H). MS (ESI): m/z 275.57 [M+H]+. UPLC: tR=0.55 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].[SH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].COC(OC)(C1C=CC=CC=1)C(C1C=CC=CC=1)=O>C1(C)C=CC=CC=1>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: COC(=O)CCS
Reactant: C=CC(F)(F)F
Agent: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)CCSCCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500 mL three-neck round bottomed flask was charged with toluene (200 mL) and cooled to <−50° C. with a dry ice/acetone bath. 3,3,3-Trifluoropropene (21.8 g, 227 mmol) was condensed into the reaction by bubbling the gas through the cooled solvent and the ice bath was removed. Methyl 3-mercaptopropionate (26.8 g, 223 mmol) and 2,2-dimethoxy-2-phenylacetophenone (2.72 g, 10.61 mmol) were added and a UVP lamp (4 watt) that was placed within 2 centimeters of the glass wall was turned on to the long wave function (366 nanometers). The reaction reached 35° C. due to heat from the lamp. After 4 hours, all of the trifluoropropene was either consumed or boiled out of the reaction. The light was turned off and the reaction stirred at room temperature overnight. After 22 hours, more trifluoropropene (3.1 g) was bubbled through the mixture at room temperature and the light was turned on for an additional 2 hours. The reaction had reached 93% conversion, so no more trifluoropropene was added. The light was turned off and the mixture concentrated on the rotovap (40° C., 20 torr) giving a yellow liquid (45.7 g, 21.3:1 linear:branched isomer, 75 wt % pure linear isomer determined by a GC internal standard assay, 34.3 g active, 71% in pot yield).
Reaction SMILES: C(C1C=C(NC(=O)[CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]([OH:27])[OH:26])=[CH:21][CH:20]=2)C=CC=1S(CC)(=O)=O)#N.BrC1C=CC(CC[CH2:38][N:39](C)[C:40]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]#[N:50])[CH:44]=2)=[O:41])=CC=1>>[C:49]([C:45]1[CH:44]=[C:43]([NH:42][C:40](=[O:41])[N:39]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([B:25]([OH:26])[OH:27])=[CH:23][CH:24]=2)[CH3:38])[CH:48]=[CH:47][CH:46]=1)#[N:50]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CN(CCCc1ccc(Br)cc1)C(=O)Nc1cccc(C#N)c1
Product: CN(CCCc1ccc(B(O)O)cc1)C(=O)Nc1cccc(C#N)c1
Yield: 91 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 22C (210 mg, 0.54 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 22D (146 mg, 91%) as a clear oil. MS (ESI) m/z 338.3 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]2[CH:25]=[CH:26][C:27]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)=[CH:28][CH:29]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Sc1ccc(C2CCCCC2)cc1
Product: O=C1CCc2cc(OCCCCSc3ccc(C4CCCCC4)cc3)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-3,4-dihydro-carbostyril (m.p.: 142°-147° C.) and 4-cyclohexyl-thiophenol.
Reaction SMILES: [Br:1][C:2]([C@H:5]1[C@H:9]([OH:10])[O:8][C:7](=[O:11])[CH2:6]1)([CH3:4])[CH3:3].[CH3:12][C@H:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]([C@H:5]1[C@H:9]([O:10][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[CH3:12])[O:8][C:7](=[O:11])[CH2:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)(Br)[C@@H]1CC(=O)O[C@H]1O
Reactant: C[C@H](O)c1cccc(Oc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(O[C@@H]1OC(=O)C[C@H]1C(C)(C)Br)c1cccc(Oc2ccccc2)c1
Reaction time: 24 h

Procedure:
A mixture of 6.07 g of dl trans 4-(2-bromo-prop-2-yl)-5-hydroxy-tetrahyrofuran-2-one, 5.83 of (S)α-methyl-3-phenoxy-benzyl alcohol, 300 mg of p-toluene sulfonic acid, 60 ml of benzene and 10 g of colored Actigel deshydratant was stirred at 20°-25° C. for 24 hours and the reaction mixture was washed with aqueous sodium bicarbonate solution. The mixture was extracted with benzene and the organic phase was dried and evaporated to dryness under reduced pressure to obtain 9.5 g of residue. The residue was chromatographed over silica gel and was eluted with methylene chloride to obtain 5 g of A and B isomers of trans 4-(2-bromo-propy-2-yl)-5-[(3-phenoxyphenyl)-methyl-methoxy]-tetrahydrofuran-2-one. Crystallization from isopropyl ether containing 30% of petroleum ether yielded 960 mg of the B isomer melting at ≃76° C. and having a specific rotation of [α]D20 =+188.5° (c=1% in benzene). Chromatography of the mother liquors over silica gel and elution with methylene chloride obtained the A isomer in the form of an oil.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([NH:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CCOC(=O)CC(NC(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1

Procedure:
Corresponding to Example 3a, 5.0 g of (1b) were acetylated by addition of benzoyl chloride. A white solid was obtained (yield: 3.3 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[C:12]3[C:18]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:17][N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:13]3=[N:14][CH:15]=2)=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:19]([C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[N:8][CH:7]=3)[N:11]=2)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:17]=1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(CO)nc3)nc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)nc3)nc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a 100 ml three necked round bottom flask, 1-(2-(6-(hydroxymethyl)pyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethylpropan-1-one (0.32 g, 0.000702 mole) was taken in CH2Cl2 (20 ml) and cooled to 0° C. Dess Martin's reagent (1.11 g, 0.00245 mole) was added at 0° C. and the reaction was warmed to room temperature and stirred for 2 hrs under nitrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through celite bed and washed with CH2Cl2. Filtrate was washed with water. Organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product which was purified using column purification by eluting with 25-30% ethyl acetate in hexanes to yield 0.173 g of 5-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl-amino)-picolinaldehyde.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[OH-].[Na+].CS(O[CH2:13][C:14]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[CH2:21])[N:17]=[C:16]([Cl:25])[N:15]=1)(=O)=O>C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:25][C:16]1[N:15]=[C:14]([CH2:13][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[CH2:21])[N:17]=1
Reactant: C=C(OCC)c1cc(COS(C)(=O)=O)nc(Cl)n1
Reactant: OCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: C=C(OCC)c1cc(COCC2CC2)nc(Cl)n1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
Cyclopropylmethanol (0.368 mL, 4.66 mmol) and sodium hydroxide (aq, 5M, 0.70 mL, 3.50 mmol) were added to a solution of (2-chloro-6-(1-ethoxyvinyl)pyrimidin-4-yl)methyl methanesulfonate (682 mg, 2.33 mmol) in benzene (8 mL). Tetrabutylammonium hydrogen sulfate was added (79 mg, 0.23 mmol). The mixture was stirred vigorously at rt over night. The organic phase was filtered through a short silica plug which was washed with 10% MeOH in EtOAc (75 mL) and the solvents were evaporated. The residue was purified by preparative HPLC to give the title compound 88 mg (14%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13]([C:22]([NH:24][CH3:25])=[O:23])=[CH:12][C:11]2=[O:26])[CH2:4][CH2:3]1.[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13]([C:22]([NH:24][CH3:25])=[O:23])=[CH:12][C:11]2=[O:26])[CH2:4][CH2:3]1
Reactant: Cc1cccc(C=O)c1
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N)CC2)c2cc(OC)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)c1cc(=O)n(CCN2CCC(NCc3cccc(C)c3)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
370 μL of a methanol solution containing 14 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinolin-4-carboxamide and 10 μL of acetic acid were added to 3.6 mg of 3-methylbenzaldehyde, and stirred at room temperature for 1 min. To the reaction mixture, 120 μL, of a methanol solution containing 3.8 mg of sodium cyanoborohydride was added, and stirred at the same temperature overnight. After the solvent was removed under reduced pressure, ethyl acetate and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate: methanol=20:1], to give 7.6 mg of (1-(2-(4-(3-methylbenzylamino)piperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinolin-4-carboxamide as a pale yellow foam.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[OH-].[K+].NN.COC1C=C(C)C=CC=1OC>C(O)COCCO>[CH3:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[CH:6][C:7]=1[CH3:8]
Reactant: COc1cc(C)c(C=O)cc1OC
Agent: COc1ccc(C)cc1OC
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Product: COc1cc(C)c(C)cc1OC

Procedure:
1.80 g of 6-methylveratraldehyde was treated with 2 g KOH, 1.4 ml 95% hydrazine, and 20 ml diethylene glycol in the manner described in the preparation of 3,4-dimethoxytoluene to give a quantitative yield of 4,5-dimethylveratrole as a cream colored solid. An analytical sample was sublimed (60°/0.05 mm Hg) to give a white powder, mp 41°-42°(Lit. 42.5°). Nmr (δ): 2.19 (s, 6H), 3.85 (s, 6H), 6.66 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:17](OC)=[O:18])=[O:9])=[CH:6][C:5]([C:21]2[S:22][C:23]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:24][CH:25]=2)=[CH:4][N:3]=1.[CH3:33][NH2:34]>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[S:22][C:23]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:24][CH:25]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:17](=[O:18])[NH:34][CH3:33])=[O:9]
Reactant: CN
Reactant: COC(=O)c1cnccc1NC(=O)c1cc(-c2ccc(CN3CCOCC3)s2)cnc1N
Solvent: C1CCOC1
Product: CNC(=O)c1cnccc1NC(=O)c1cc(-c2ccc(CN3CCOCC3)s2)cnc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg of methyl 4-[[2-amino-5-[5-(morpholinomethyl)-2-thienyl]pyridine-3-carbonyl]amino]pyridine-3-carboxylate (MSC 2392368) are dissolved in 4 ml THF and 4 ml of methylamine (40% in water) are added. The mixture is stirred for 2 h at room temperature. The mixture is evaporated and treated with petrol ether and ethyl acetate. After filtration 79 mg of a yellow solid is obtained;
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29]C)=[O:28])[CH2:22]3)=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:31])=[CH:7][CH:8]=2)[N:3]=1.O[Li].O>C1COCC1.O>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([OH:29])=[O:28])[CH2:22]3)=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:31])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)C1CCCC(NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(N2CCN(C(=O)NC3CCCC(C(=O)O)C3)CC2)c2ccc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-cyclohexanecarboxylic acid, methyl ester (150 mg, 0.33 mmol) in THF (20 mL) and water (6 mL) was added LiOH.H2O (28.0 mg). The reaction mixture was stirred at rt overnight, and then solvent was evaporated in vacuo. The resulting residue was acidified to pH 4, the precipitate was collected by filtration and dried to afford the title product. LC-MS: 432 (M++1). 1H NMR (DMSO-d6) δ 1.10 (m, 2H), 1.25 (m, 2H), 1.75 (m, 3H), 1.95 (m, 1H), 2.25 (m, 1H), 3.10 (m, 4H), 3.50 (m, 5H), 6.25 (s, 1H), 6.40 (d, 1H), 7.25 (m, 1H), 7.50 (s, 1H), 780 (d, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[O:6]=[C:7]1[CH2:16][CH2:15][CH2:14][C:13]2[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=[CH:9][C:8]1=2.CO>C1COCC1>[OH:6][C:7]1([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][CH2:14][C:13]2[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: c1cscn1
Reactant: COC(=O)c1cccc2c1CCCC2=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc2c1CCCC2(O)c1nccs1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To an oven-dried, N2-purged flask was added isopropyl magnesium chloride lithium chloride complex (7.91 mL, 10.3 mmol) and THF (18.4 mL) and the solution was cooled to 0° C. A solution of thiazole (0.813 g, 9.55 mmol) in THF (9.18 mL) was then added, and the reaction was stirred for 45 min at 0° C., and then cooled to −10° C. A solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-1-carboxylate (1.5 g, 7.34 mmol) in THF (9.18 mL) was then added, after which the reaction was allowed to warm to rt over a period of 4 h. MeOH (5 mL) was then added and the reaction was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL), then the combined organic phases were dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography using a gradient solvent system of 0-70% EtOAc/DCM. The product-containing fractions were collected and concentrated to give racemic methyl 5-hydroxy-5-(thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-1-carboxylate as a yellow oil. The enantiomers were resolved by chiral SFC using a Chiral Technology AY-H 2.1×25 cm, 5 uM column, eluting with 20%-50% MeOH+0.25% dimethyl ethylamine/CO2. At a flow rate of 70 mL/min, the two enantiomers eluted at 2.38 min and 2.79 min.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH2:22][CH3:23])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43](Cl)=[O:44].O>ClCCl>[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH2:22][CH3:23])=[CH:24][CH:25]=1)=[O:44]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cn1c(CC)c(Cc2ccc(N)cc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cn1c(CC)c(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
In a dry reaction vessel, ethyl 2-[3-(4-aminobenzyl)-2-ethyl-1H-indol-1-yl]acetate (288 mg, 0.86 mmol) was added, and dissolved in 7 mL dichloromethane. Triethylamine (0.36 mL, 2.59 mmol) was added, in an ice bath a dichloromethane solution 2 mL dissolving 2-naphthoyl chloride (163 mg, 0.86 mmol) was added slowly. After completion of dropwise addition, it was reacted in an ice bath for 1 h, and stirred at room temperature overnight. Water was added into the system, extracted with dichloromethane, rotate evaporated to dryness to obtain a crude. It was washed again with a small amount of acetonitrile to obtain the yellow product 340 mg, at a yield of 80.2%.