Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24](OS(C)(=O)=O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Temperature: 25 °C
Yield: 33.6 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.856 g, 4.41 mmol), (S)-3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.17 g, 4.41 mmol) and Cs2CO3 (2.16 g, 6.61 mmol) in anhydrous DMF (11.7 mL) was heated to 100° C. for 16 h. The reaction mixture was allowed to cool to rt and was partitioned between EtOAc and H2O and separated. The aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (3×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a crude brown oil. The reaction mixture was purified by chromatography on silica gel [eluting with 12% EtOAc in CHCl3]resulting in 538 mg, 33% yield of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.31 (s, 12H), 1.46 (s, 9H), 2.36 (q, J=7.0 Hz, 2H), 3.46-3.78 (m, 3H), 3.80-3.91 (m, 1H), 4.89 (quint, J=6.1 Hz, 1H), 7.73 (s, 1H), 7.80 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10](Br)=[CH:9][C:7]=2[N:8]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1>>[NH2:1][C:2]1[CH2:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: OB(O)c1cncnc1
Reactant: CCOC(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Product: CCOC(=O)C1=Cc2ccc(-c3cncnc3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedure as described in Example 124 (Step F) using (1E,4E)-ethyl 2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylate and pyrimidin-5-ylboronic acid. MS APCI (+) m/z 309 (M+1) detected; 1H-NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 9.02 (s, 2H), 7.84 (s, 1H), 7.54 (d, 1H), 7.47 (d, 1H), 7.30 (dd, 1H), 4.34 (q, 2H), 2.99 (s, 2H), 1.40 (t, 3H).
Reaction SMILES: Br[C:2]([CH3:8])([C:4](=[O:7])[CH2:5][CH3:6])[CH3:3].[SH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][S:9][C:2]([CH3:8])([CH3:3])[C:4](=[O:7])[CH2:5][CH3:6])[CH3:15]
Reactant: CCOC(=O)CS
Reactant: CCC(=O)C(C)(C)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CSC(C)(C)C(=O)CC
Reaction time: 3 h

Procedure:
To a solution of 2-bromo-2-methyl-pentan-3-one (A1) (13.5 g, 75 mmol) in CH2Cl2 (400 ml) were added ethyl 2-mercaptoacetate (9 g, 8.2 ml, 75 mmol) and 10.42 ml triethylamine at 0° C. and stirred for 3 h. The solution was allowed to come to room temperature (12 h). The resulting suspension was filtered, the filtrate washed with water (100 ml) and brine (100 ml) and dried over Na2SO4. Removal of the solvent in vacuo gave a slightly yellow oil, which was purified by flash chromatography (ethyl acetate-petroleum ether 1:25).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[C:7]([F:20])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[C:7]([F:20])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:22]
Reactant: COc1ccc(F)cc1Oc1cc(F)c(C#N)cc1F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(F)cc1Oc1cc(F)c(C(N)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.6 %

Procedure:
To a solution of 2,5-difluoro-4-(2-methoxy-5-fluorophenoxy)benzonitrile (Preparation 52, 444 mg, 1.59 mmol) in dimethylsulfoxide (10 mL) was added potassium carbonate (440 mg, 3.18 mmol), and hydrogen peroxide (commercial 30% solution, 0.95 mL, 9.49 mmol) This suspension was stirred for 3 hours at room temperature. The reaction mixture was then quenched with saturated aqueous potassium bisulphate solution (20 mL), and the precipitated solid filtered off to afford the title compound (499 mg, 100%). This was used in the next step with no further purification.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[C:9]1[C:18](=[O:19])[CH2:17][CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10]1=[O:20])[CH2:7][CH3:8])[CH:2]=[CH2:3].[OH-].[Na+].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O.O>[CH2:1]([O:4][N:5]=[C:6]([C:9]1[C:10](=[O:20])[CH:11]2[CH:16]([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:17][C:18]=1[O:19][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCONC(CC)=C1C(=O)CC2CCCCC2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C=CCON=C(CC)C1=C(OC(=O)c2ccccc2)CC2CCCCC2C1=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(1-allyloxyaminopropylidene)decaline-1,3-dione (2 g) in acetone (30 ml), sodium hydroxide (0.2 g) in water (1 ml) was added at room temperature and then benzoylchloride (0.7 g) was added. After stirring for 5 hours, the reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with one normal sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo and an oily substance (1.8 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOCC>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:2]([Br:1])=[C:3]([CH:4]=[O:5])[CH:6]=1)[CH3:19]
Reactant: CCOC(=O)CCCBr
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)CCCOc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
A mixture of 3.5 g (17.4 mmol) of 2-bromo-5-hydroxybenzaldehyde, 3.7 g (19 mmol) of ethyl 4-bromobutyrate, 5.5 g (40 mmol) of anhydrous, granular potassium carbonate, and 40 mL of dry dimethyl sulfoxide was stirred at room temperature for 5 hr and then kept at room temperature overnight. The resulting slurry was poured into ice-water and worked-up with ether in the usual manner giving an oily product which was flash-chromatographed on silica gel. Elution with 2:1 hexane-ether afforded 4.4 g (80.3%) of 4-(4-bromo-3-formylphenoxy)butanoic acid ethyl ester as an oil.
Reaction SMILES: Br.Br.[N:3]1([CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[N:3]1([CH2:8][C:9]2([C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc2c(c1)CCNC2CN1CCCC1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CCCC2)NCCc2cc(O)ccc21

Procedure:
Prepared as Ex. No. 5, from 6 g (15.23 mmoles) of 1-(pyrrolidin-1-yl)methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 4.1 g (20.0 mmoles) of 3,4-dichlorophenylacetic acid, 5.4 ml (38.42 mmoles) of triethylamine and 6.2 g (30.24 mmoles) of dicyclohexylcarbodiimide in 145 ml of dry chloroform.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH:3]([OH:27])[CH2:4][NH:5][C:6]([C:8]1[C:13]([N:14]2C(C)=CC=C2C)=[CH:12][C:11]([C:21]([F:24])([F:23])[F:22])=[C:10]([O:25][CH3:26])[N:9]=1)=[O:7].Cl.NO>CCO.O>[F:29][C:2]([F:1])([F:28])[CH:3]([OH:27])[CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:21]([F:22])([F:24])[F:23])=[C:10]([O:25][CH3:26])[N:9]=1)=[O:7]
Reactant: COc1nc(C(=O)NCC(O)C(F)(F)F)c(-n2c(C)ccc2C)cc1C(F)(F)F
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: COc1nc(C(=O)NCC(O)C(F)(F)F)c(N)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-propyl)-amide (350 mg, 0.823 mmol) was dissolved in EtOH (14 ml) and water (7 ml). Hyroxylamine hydrochloride (572 mg, 8.23 mmol) was added followed by TEA (167 mg, 1.646 mmol) and the mixture was heated at reflux overnight. After cooling the RT, the mixture was purified by reverse phase chromatography eluting with MeOH; water (0.1% TFA) to afford the title compound as a pale yellow solid; LC-MS Rt=4.20 min[M+H]+ 348.2 (Method 10minLC_v002)
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([O:28]C)=[O:27])[CH:13]=[CH:14][C:15]=1[CH2:16][NH:17]C(OC(C)(C)C)=O)=O)(C)(C)C.[OH-].[Na+]>CO.C1COCC1.Cl>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([OH:28])=[O:27])[CH:13]=[CH:14][C:15]=1[CH2:16][NH2:17]
Reactant: COC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)c(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(CC(=O)O)cc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
The methyl 2-(3,4-bis((tert-butoxycarbonylamino)methyl)phenyl)acetate (1.1 g,) was dissolved in a mixture of MeOH/THF (50 mL, 2:1). 1N NaOH (10 mmol, 10 mL) was added and the reaction mixture was stirred at room temperature overnight. IN HCl was added to adjust the pH of the reaction to ˜3. The aqueous was extracted with EtOAc. The organic phase was washed with IN HCl, brine, dried and concentrated in vacuo to afford the product (0.38 g) as yellow solid.
Reaction SMILES: [CH:1]1([CH:4]([N:11]([CH2:15][CH2:16][CH3:17])[C:12]([NH2:14])=[S:13])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH:26]([CH3:37])[C:27]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[Cl:36])=O>C(O)C>[Cl:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]=1[C:27]1[N:14]=[C:12]([N:11]([CH:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH3:17])[S:13][C:26]=1[CH3:37]
Reactant: CCCN(C(N)=S)C(c1ccccc1)C1CC1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccccc1)C1CC1
Temperature: 75 °C
Yield: 79 %

Procedure:
To 1.35 g of N-(α-cyclopropylbenzyl)-N-propylthiourea (Compound 75) in 35 ml of ethanol, add 546 mg of triethylamine, then slowly 1.52 g of 2-bromo-1-(2,4-dichlorophenyl)-1-propanone (Compound 15). After 3 hours of heating at 75° C., remove the precipitate formed by filtration. The ethanolic solution is evaporated to dryness. Take up the residue in ethyl ether and wash with water until bromide ions have disappeared. Dry the organic phase over anhydrous sodium sulphate and then evaporate to dryness. Purify the residue on a silica column, using a mixture of cyclohexane and ethyl acetate (10:1 V/V) as eluent, to obtain the expected product. Recrystallise in acetonitrile (white crystals).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:18]1([CH3:24])[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=3)=[CH:5][CH:4]=2)[CH:17]=1
Reactant: Cc1cccc(O)c1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(OCc2ccc(-c3cc(C(N)=O)on3)cc2)c1
Temperature: 90 °C
Yield: 60.6 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added m-cresol (20 mg, 0.185 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-(4-m-tolyloxymethyl-phenyl)-isoxazole-5-carboxylic acid amide (20 mg, 61%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.00 (br. s., 1H), 7.86-7.95 (m, 3H), 7.53-7.63 (m, 4H), 7.11-7.22 (m, 1H), 6.69-6.89 (m, 3H), 5.15 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:21]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])#[N:22].CC(=O)OCC>C1COCC1>[C:21]([CH:23]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])#[N:22]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C#N)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (5 g, 22.07 mmol) and K2CO3 (6.10 g, 44.1 mmol) in THF (150 mL) was added tert-butyl 2-cyanoacetate (3.74 g, 26.5 mmol). The resulting mixture was stirred at 70° C. overnight under N2. After TLC analysis (PE/EA=10/1) showed the starting material was consumed, the solvent was removed in vacuo. The residue was dissolved in EA (100 mL) and washed with H2O (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield a solid of tert-butyl 2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate (7 g, 21.13 mmol, 96% yield): 1H NMR (400 MHz, CD3OD) δ 9.08 (s, 1H), 8.59 (br. s., 1H), 4.63 (br. s., 1H), 1.55 (s, 9H); ES-LCMS m/z: 332.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[CH2:25]([NH:27][C:28]1[C:29]([F:43])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[CH3:26]>>[CH2:25]([NH:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)[CH:31]=[N:30][C:29]=1[F:43])[CH3:26]
Reactant: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCNc1cc(B2OC(C)(C)C(C)(C)O2)cnc1F
Product: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2c(C)nn(C)c2C)c(=O)n4C)cnc1F

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 0.104 mmol) and ethyl-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (stage 154.1.1) to give the title compound as a white solid. (HPLC: tR 2.63 min (Method A); M+H=446 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.11-8.07 (m, 1H), 7.96-7.91 (m, 1H), 7.55-7.52 (m, 1H), 7.48-7.45 (m, 1H), 7.00-6.95 (m, 1H), 5.96 (t, 1H), 3.78 (s, 3H), 3.59 (s, 3H), 3.20 (qt, 2H), 2.07 (s, 3H), 1.91 (s, 3H), 1.23 (t, 3H))
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.[Cl:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:13][C:14]1[CH:21]=[C:20]([N:6]2[CH2:7][CH2:8][C@@:4]([OH:12])([CH3:1])[C@@H:5]2[CH2:9][CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(Cl)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (195 mg), 2-chloro-4-fluorobenzonitrile (320 mg) and lithium carbonate (200 mg), the title compound was obtained as a colorless solid (yield: 221.4 mg, yield: 75%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:23])=[CH:6][C:7]([CH3:22])([CH3:21])[NH:8]2.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH2:2][O:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:22])([CH3:21])[CH:6]=[C:5]2[CH3:23]
Reactant: COc1ccccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccc2c(c1COc1ccccc1)C(C)=CC(C)(C)N2
Temperature: 80 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
A mixture of 5-chloromethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound 5-1, 52 mg, 0.16 mmol), phenol (42 μL, 0.48 mmol) and potassium carbonate (88 mg, 0.64 mmol) was suspended in anhydrous N,N-dimethylformamide (2 mL), and stirred 80° C. for 5 hours. After cooling down, the reaction mixture was diluted with ethyl acetate (60 mL). The whole was washed with water (50 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (24 mg) as a colorless oil. (Yield 39%)
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])C>O1CCCC1.O>[C:12]1(=[O:13])[N:8]([CH2:7][CH2:6][CH2:5][CH:4]=[O:3])[C:9](=[O:14])[CH:10]=[CH:11]1
Reactant: CCOC(CCCN1C(=O)C=CC1=O)OCC
Solvent: C1CCOC1
Solvent: O
Product: O=CCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Maleimidobutyraldehyde diethylacetal (2 g, 8.29 mmol) in tetrahydrofuran (20 ml) and water (0.5 ml) was stirred under argon and DOWEX 50X8 ion exchange resin (H+, 2 g, ® Dow Chemical Co.) was added. After 12 hours stirring at room temperature, the solvent was decanted, dried (MgSO4) and evaporated in vacuo to afford 4-maleimidobutyraldehyde (formula III) as a yellow oil which rapidly solidified on standing (1.38 g, 99%); TLC Rf=0.4, ethyl acetate/hexane 1:1. The 4-maleimidobutyraldehyde turned out to be extremely unstable, so that it was necessary to do all work-up at low temperatures (0° C.) and under complete exclusion of oxygen (inert atmosphere).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])[CH:2]([CH3:4])[CH3:3].Br[CH:17]([C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:14]=1[O:15][CH:17]([C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(O)c(CC(C)C)c1
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccc(C(=O)OC)cc1CC(C)C)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a solution of 1.008 g (4.84 mmol) of methyl 3-iso-butyl-4-hydroxybenzoate and 1.737 g (6.05 mmol) of ethyl α-bromo-3,4-methylenedioxyphenylacetate in 10 mL of acetone was added 1.338 g (10 mmol) of finely powdered potassium carbonate. The reaction mixture was magnetically stirred and refluxed for 4 hours, then cooled to room temperature, filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 10% EtOAc-hexane; combination of the purified fractions and drying in vacuo afforded 1.518 g (76%) of the title compound as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[N:17]1[CH2:16][CH:15]2[CH2:14][N:13]([C:11]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=3[O:9][CH3:10])=[O:12])[CH2:20][CH:19]2[CH2:18]1
Reactant: COc1cccc(OC)c1C(=O)N1CC2CNCC2C1
Reactant: Clc1nc2ccccc2o1
Product: COc1cccc(OC)c1C(=O)N1CC2CN(c3nc4ccccc4o3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 41 and 2-chloro-benzooxazole. MS (ESI): mass calculated for C22H23N3O4, 393.45; m/z found 394.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29].Cl>O1CCOCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:29]
Reactant: COC(=O)/C=C/c1cc(F)c2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)/C=C/c1cc(F)c2c(c1)C(=O)CC1(CCNCC1)O2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of (E)-3-{1′-tert-butoxycarbonyl-8-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (2.78 g, 6.63 mmol) and 4 M HCl in dioxane (3 ml) in DCM (50 ml) was stirred at RT for 5 h. The solvent was removed, the residue was triturated in DCM and filtered to give the title compound as its hydrochloride salt (2.04 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].CO>C(O)(=O)C>[CH3:1][N:2]([CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:5])[C:12](=[O:14])[CH3:13]
Reactant: CNCC(C)c1ccncc1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N(C)CC(C)c1ccncc1
Reaction time: 8 h

Procedure:
dl-4-(1-Methylaminoprop-2-yl)pyridine (4.5 g.) in acetic acid (15 ml.) was treated cautiously with acetic anhydride (10 ml.) followed by allowing the mixture to stand at ambient temperature overnight. Methanol (20 ml.) was then added to destroy excess acetic anhydride, followed by evaporation in vacuo (at 40° C.) to remove methanol and methyl acetate. The residue was diluted with water and treated portionwise with sodium carbonate (anhydrous) until alkaline (pH 10-12). The oily suspension was extracted with chloroform (3×60 ml.) and the bulked extracts were dried (Na2CO3) and evaporated to dryness in vacuo to give a near-colorless oil (6.8 g.). The oil was distilled to give pure dl-4-(1-[N-methylacetamido]prop-2-yl)pyridine (3 g.), b.p. 138°-140°/0.4 mm Hg. (as a colorless oil).