Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([F:26])[C:19]([Cl:25])=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Br:15][C:16]1[CH:17]=[C:18]([F:26])[C:19]([Cl:25])=[C:20]([CH:24]=1)[C:21]([NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1)=[O:22]
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)c1cc(Br)cc(F)c1Cl
Product: N#Cc1cc(NC(=O)c2cc(Br)cc(F)c2Cl)n(-c2ccccc2)n1

Procedure:
The title compound was prepared according to the method described for Preparation 16 using 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53) and 5-bromo-2-chloro-3-fluorobenzoic acid.
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22](OCC)=[O:23])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>CO.CN(C)C=O>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([NH:30][CH2:29][CH2:27][OH:28])=[O:23])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccccc3)nc1-2
Reactant: NCCO
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)NCCO)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Temperature: 65 °C
Yield: 60 %

Procedure:
To a suspension of 0.30 g (0.86 mmol) of ethyl 8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in a mixture of 10 mL of methanol and 10 mL of dimethylformamide, 5 mL of ethanolamine were added. The mixture was heated in a close bottle under stirring at 65° C. After 5 hours the solvent was removed, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated. The residue was triturated with diethyl ether and the product collected by filtration (60% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[C:8]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[N+:23]([O-])=O)=[CH:7][CH2:6]2>O1CCCC1.CO.[Pd]>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2([CH3:14])[CH3:13])=[C:16]([NH2:23])[CH:17]=1
Reactant: COc1ccc2c(c1)CC=C(c1ccc(OC)cc1[N+](=O)[O-])C2(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2CCc3cc(OC)ccc3C2(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 79 %

Procedure:
To a solution of 6-methoxy-2-(4-methoxy-2-nitrophenyl)-1,1-dimethyl-1,4-dihydronaphthalene (433 mg) in tetrahydrofuran (6 ml) and methanol (6 ml) was added 10% palladium-activated charcoal (200 mg), and the solution was stirred for 3.5 hours at room temperature under a hydrogen atmosphere at 4 atmospheric pressures. After filtration through celite pad, the solvent was evaporated in vacuo, and the resulting solid was washed with hexane-diethyl ether system to provide the title compound (314 mg).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]=[CH2:19])=[C:8]2[CH3:20])=[CH:4][CH:3]=1.[N+](=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N-]>C1(C)C=CC=CC=1.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]3[CH2:19][CH:25]3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:8]2[CH3:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: CCCCCCCC(=O)O
Product: CCOC(=O)C1CC1c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 0 °C

Procedure:
To a room temperature solution of the indole from Step 1 (3.91 g, 11.0 mmol) in 20 mL toluene was added rhodium (II) octanoate dimer (109 mg, 0.14 mmol), and the solution was cooled to 0° C. A solution of ethyl diazoacetate (3.0 mL, 28.5 mmol) in 13 mL toluene was then added via syringe pump at 1.2 mL/hr. Fresh catalyst was then added along with an additional 1 mL ethyl diazoacetate in toluene over 2.5 h. The crude reaction mixture was applied directly to a silica gel column and eluted with 1% to 2.5% ethyl acetate/toluene. 1.1 g of the trans isomer of the title compound was thus obtained, followed by 1.2 g of the cis isomer of the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH2:26]([S:23]([C:20]1[CH:21]=[CH:22][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:18][CH:19]=1)(=[O:24])=[O:25])[CH3:27]
Reactant: CCS(=O)(=O)c1ccc(Br)cc1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Product: CCS(=O)(=O)c1ccc(N2CCC3(CCC4(CC3)OCCO4)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 133, step 4 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 133 step 3) and 1-bromo-4-ethylsulfonylbenzene as light yellow solid. MS (m/e): 380.153 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]2[O:17][C:16]([C@@H:18]([NH:28]C(=O)OCC3C=CC=CC=3)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])=[N:15][CH:14]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>CCOC(C)=O.CO.[Pd]>[NH2:28][C@H:18]([C:16]1[O:17][C:13]([C:12]2[C:3]([O:2][CH3:1])=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:14][N:15]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25]
Reactant: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(-c2cc3ccccc3nc2OC)o1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)CCCCC[C@H](N)c1ncc(-c2cc3ccccc3nc2OC)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
F6 was dissolved in EtOAc/MeOH (1:1, 0.025 M) and treated with Pd/C (10% w/w). Mixture was purged with N2 and stirred under H2 atmosphere at room temperature for 48 h. Then, reaction mixture was filtered through a pad of Solka-Floc® and filtrate was concentrated under vacuum to give the title compound as pale yellow solid which was used as such in the next step. MS (ES+) C21H26N4O3: 383 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1.[C:20](O)(=[O:24])[C:21]([CH3:23])=[CH2:22].C1(C=CC(O)=CC=1)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1
Reactant: OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(=O)OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Reaction time: 15.5 h

Procedure:
2-(2'-Hydroxy-5'-hydroxyethylphenyl)-2H-benzotriazole (150 g, 0.59 mol), methacrylic acid (55 ml, 0.65 mol), hydroquinone (2.4 g), p-toluenesulfonic acid monohydrate (3 g) and toluene (2 l) were placed in a 3 liter flask equipped with a Dean and Stark receiver. After 1.5 hours of refluxing the mixture, another 2.7 g of p-toluenesolfonic acid monohydrate was added and the refluxing was continued for another 15.5 hours. Approximately 10 ml of water was collected (theoretical: 10.6 g) and the yield of the desired compound was 93.7% as judged by a gas chromatography. Another 1 g of p-toluenesolfonic acid monohydrate was added and the reflusing was continued for another 3 hours. A yield of 95.6% was shown by a gas chromatography. After cooling the reaction mixture, it was washed with aqueous sodium hydrogen carbonate solution, water, 5% hydrochloric acid and water. The organic layer was dried with anhydrons magnesium sulfate and chromatographed through an alumina (Fisher, 80-200 mesh) column. After evaporation of the solvent, the residue was recrystallized from distilled methanol twice. Yield: 141.8 g (74%); Purity: >99.9% (G.C.). The IR and NMR data were consistent with the structure.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38].Cl>C1COCC1.O>[C:17]1([S:14]([N:6]2[C:7]3[C:12](=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[C:4]([C:1](=[O:3])[CH2:2][C:37]([C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[O:34][CH3:33])=[O:38])=[CH:5]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
A solution of 500 mg (1.5 mmol) of 3-acetyl-1-benzenesulfonyl-5-chloroindole in THF (5 ml) was cooled at −78° C. Subsequently, to the reaction mixture was added 1.8 ml (1.8 mmol) of 1M LHMDS in THF. The solution was gradually warmed to 0° C. and cooled again to −78° C. To the solution was added 310 mg (1.8 mmol) of 2-methoxybenzoylchloride. The reaction mixture was warmed to room temperature. After 30 minutes, the mixture was treated with water and acidified with 6 N hydrochloric acid. The mixture was extracted with ethyl acetate and washed with water, and then dried. The solvent was removed and the obtained residue was chromatographed on silica gel with ethyl acetate-n-hexane as eluent. The fraction of the objective was concentrated to give 160 mg of the titled compound as a foam. Yield: 23%.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2]1.[O-:14][C:15]#[N:16].[K+].CN(C=O)C>[Br-].C([N+](CC)(CC)CC)C.O>[CH2:4]([CH:3]1[O:1][C:15](=[O:14])[NH:16][CH2:2]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: N#C[O-]
Reactant: CCCCCCCCCCC1CO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCC1CNC(=O)O1
Yield: 65.2 %

Procedure:
4.6 g of 1,2-epoxydodecane, 12.2 g of potassium cyanate, 25 ml of DMF, 0.2 g of tetraethylammonium bromide and 1.8 ml of water were stirred and heated at 120°-130° C. for 5 hours. The disappearance of the epoxide was followed by thin layer chromatography (tlc). The cooled reaction mixtre was poured into 200 ml of water and this was extracted with ethyl acetate. The combined organic extracts were washed with water, followed by brine, dried and concentrated to give a solid. Recrystallization from methylene chloride/hexane gave 3.7 g (65.2%) of product, m.p. 86°-87° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O:28]C(C)(C)C)=[O:27])[CH:21]=4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=[O:27])[CH:21]=4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(Nc2ccc(Br)cc2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(Nc2ccc(Br)cc2)nc2cc(Oc3ccnc(C(=O)O)c3)ccc21

Procedure:
A solution of the product of step 7 in trifluoroacetic acid was treated with two drops of water at room temperature for 3-4 hours or until the reaction was determined to be complete by HPLC. The reaction was evaporated under reduced pressure to afford the product as a red-orange oil in quantitative yield. MS: MH+=439.
Reaction SMILES: Br[C:2]1[C:7]([O:8][C:9]([F:14])([F:13])[CH:10]([Cl:12])[F:11])=[CH:6][C:5]([Cl:15])=[CH:4][N:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)C>[Cl:15][C:5]1[CH:6]=[C:7]([O:8][C:9]([F:14])([F:13])[CH:10]([Cl:12])[F:11])[C:2]([O:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:29][CH:30]=2)=[N:3][CH:4]=1
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Reactant: FC(Cl)C(F)(F)Oc1cc(Cl)cnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2OC(F)(F)C(F)Cl)cc1

Procedure:
9.75 g (30 mmol) of 2-bromo-5-chloro-3-(2-chloro-1,1,2-trifluoroethoxy)pyridine, 6.94 g (33 mmol) of ethyl 4-hydroxyphenoxypropionate and 6.6 g of anhydrous potassium carbonate in 40 ml of absolute dimethyl sulfoxide were stirred for 9 hours at 80° C. under argon. After cooling, the mixture was diluted with 300 ml of diethyl ether, the potassium carbonate was filtered off, and the organic phase was washed with 5% strength KOH and subsequently with water until neutral. After drying, the compound of Example 1 was obtained in a crude yield of 13.4 g (98% of theory).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]1[N:16]=[CH:17][S:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[C:20]1([C:19]2[S:18][CH:17]=[N:16][C:15]=2[CH2:14][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: BrCc1ncsc1-c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ncsc1-c1ccccc1
Reaction time: 3 h
Yield: 52.7 %

Procedure:
Prepare a cold (0° C.) solution of potassium phthalimide (350 mg, 1.8 mmol) in dimethylformamide (25 mL). Add dropwise 4-bromomethyl-5-phenyl-thiazole (400 mg, 1.6 mmol) in dimethylformamide (10 mL). Warm the reaction to room temperature, stir for 3 hours and then concentrate. Dissolve the residue in ethyl acetate (100 mL), wash with saturated Na2CO3 (50 mL) and brine (50 mL), then dry (Na2SO4), filter and concentrate to a brown residue. Chromatograph (silica gel, 4:1 hexane/ethyl acetate) to afford 2-(5-phenylthiazol-4-ylmethyl)isoindole-1,3-dione (270 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:23]=3)[O:19][N:18]=2)=[CH:12][C:11]=1[CH2:35][CH3:36])(=O)=O.Cl.C[O:39][C:40]([CH:42]1[CH2:45][NH:44][CH2:43]1)=[O:41]>>[CH:30]1([C:24]2[CH:23]=[C:22]([C:20]3[O:19][N:18]=[C:17]([C:13]4[CH:14]=[C:15]([CH3:16])[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:44]5[CH2:45][CH:42]([C:40]([OH:39])=[O:41])[CH2:43]5)=[C:11]([CH2:35][CH3:36])[CH:12]=4)[N:21]=3)[CH:27]=[C:26]([O:28][CH3:29])[N:25]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCOS(C)(=O)=O
Reactant: COC(=O)C1CNC1
Agent: Cl
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCN1CC(C(=O)O)C1
Yield: 19.1 %

Procedure:
The title compound (29 mg) is prepared as a white solid in analogy to the procedures given in Example 1 starting from 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propyl methanesulfonate (150 mg, 0.291 mmol) and azetidine-3-carboxylic acid methyl ester hydrochloride (220 mg, 1.46 mmol); LC-MS: tR=0.96 min, [M+H]+=521.39; 1H NMR (CD3OD): δ 7.89 (d, J=1.4 Hz, 1H), 7.87 (d, J=1.4 Hz, 1H), 7.55 (d, J=1.0 Hz, 1H), 7.31 (d, J=1.1 Hz, 1H), 4.24-4.40 (m, 4H), 4.01 (s, 3H), 3.97 (t, J=5.8 Hz, 2H), 3.53-3.60 (m, 2H), 3.43-3.48 (m, 1H), 3.26-3.31 (m, 1H), 2.78 (q, J=7.5 Hz, 2H), 2.41 (s, 3H), 2.06-2.19 (m, 4H), 1.86-1.97 (m, 4H), 1.72-1.83 (m, 2H), 1.33 (t, J=7.5 Hz, 3H).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:46]=[C:45]([CH3:47])[O:44][N:43]=3)[C:37]2=[O:48])[S:31][C:32]=1[C:33]([OH:35])=O.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:46]=[C:45]([CH3:47])[O:44][N:43]=3)[C:37]2=[O:48])[S:31][C:32]=1[C:33]([NH:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)=[O:35]
Reactant: Cc1cc(CN2CCN(c3nc(C)c(C(=O)O)s3)C2=O)no1
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1cc(CN2CCN(c3nc(C)c(C(=O)NCc4cccnc4)s3)C2=O)no1
Yield: 57 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(3-((5-methylisoxazol-3-yl)methyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 57% yield: mp 185-188° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59-8.58 (m, 1H), 8.51 (d, J=4.7 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.29-7.25 (m, 1H), 6.22-6.19 (m, 1H), 5.98 (s, 1H), 4.58 (d, J=5.8 Hz, 2H), 4.49 (s, 2H), 4.12-4.06 (m, 2H), 3.61-3.55 (m, 2H), 2.60 (s, 3H), 2.40 (s, 3H); MS (ES+) m/z 413.2 (M+1).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:19][C:20]4[C:21]([CH3:28])=[CH:22][C:23]([F:27])=[C:24]([NH2:26])[CH:25]=4)[N:14]=3)[CH:10]=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[NH:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][C:20]3[C:21]([CH3:28])=[CH:22][C:23]([F:27])=[C:24]([NH2:26])[CH:25]=3)[N:14]=2)[CH:10]=[N:9]1
Reactant: COc1ccc(Cn2cc(-c3ccnc(Oc4cc(N)c(F)cc4C)n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)c(N)cc1Oc1nccc(-c2cn[nH]c2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.1 %

Procedure:
A solution of 5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylbenzenamine (0.5 g, 1.2 mmol) in dichloromethane (20 mL) was treated with TFA (5 mL) at 0° C. The mixture was then stirred at RT for 12 h. The solvent was removed in vacuo, the residue was washed with ether and treated with saturated ammonia solution. The solid was collected via filtration and dried under vacuum to give 5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylbenzenamine (240 mg, 68%, yield). 1H NMR (400 MHz, MeOD): δ 8.41 (d, J=5.2 Hz, 1H), 8.21 (br s, 2H), 7.40 (d, J=5.2, 1H), 6.90 (d, J=11.6 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 1.99 (s, 3H). MS (ESI) m/z: 286.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([OH:15])[CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.Cl>C1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]2[C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=3)[CH2:11][CH:12]([CH2:13][OH:14])[O:15]2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COc1ccc(CC(O)CO)cc1OC
Agent: Cl
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(c1cccc(Cl)c1)OC(CO)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
15.64 g (73.6 mmoles) of dl-3-(3,4-dimethoxyphenyl)-propane-1,2-diol (II) are dissolved in 200 ml of benzene. 8.03 ml (73.6 mmoles) of 3-chlorobenzaldehyde and 4.6 ml (56 mmoles) of concentrated hydrochloric acid are added to the solution and the reaction mixture is stirred for 5 hours at room temperature. The solution is then evaporated in vacuo, the oily residue is dissolved in 200 ml of 99.5% ethanol, clarified while hot, filtered and the filtrate is evaporated in vacuo. Thus 23.19 g (94%) of crude product are obtained in oily form, which can be used for the further reaction steps without purification (the purity of the product exceeds 95%).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:36]([CH:33]3[CH2:35][CH2:34]3)=[O:37])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2Cc3c(CNC(=O)C4CC4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.7 g, 4.62 mmol) was added to a stirred suspension of 3-[4-(aminomethyl)-1-oxoisoindolin-2-yl]piperidine-2,6-dione hydrochloride (0.65 g, 2.10 mmol) in acetonitrile (50 mL). After stirring for 30 min, cyclopropanecarbonyl chloride (0.24 g, 2.31 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered and the solid was recrystallized from methanol (100 mL) to afford N-{[2-(2,6-dioxo(3-piperidyl))-1-oxoisoindolin-4-yl]methyl}cyclopropylcarboxamide (0.36 g, 50%) as a white solid: mp 262-264° C.; 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 8.63 (t, J=5.7 Hz, 1H), 7.65-7.47 (m, 3H), 5.18-5.11 (dd, J=5.0 and 13.2 Hz, 1H), 4.46 (d, J=17.3 Hz, 1H), 4.38-4.31 (m, 3H), 3.00-2.85 (m, 1H), 2.65-2.30 (m, 2H), 2.04-1.99 (m, 1H), 1.64-1.54 (m, 1H), 0.69-0.65 (m, 4H); 13C NMR (DMSO-d6) δ 172.82, 172.69, 170.96, 168.03, 140.08, 134.76, 131.66, 130.70, 128.30, 121.64, 51.54, 46.15, 31.16, 22.59, 13.47, 6.27; Anal. Calcd. For C18H19N3O4: C, 63.33; H, 5.61; N, 12.31. Found: C, 62.97; H, 5.55; N, 12.33.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:8]([C:18]#[N:19])[NH:9][C:10]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH:7]=1.NC(=O)C(NC(=O)CC(O[Si](C(C)(C)C)(C)C)(C)C)C1C=C(Cl)C=CC=1[O:32]C>>[NH2:19][C:18](=[O:32])[CH:8]([NH:9][C:10]([CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:11])[C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21]
Reactant: COc1ccc(Cl)cc1C(C#N)NC(=O)C1CCOCC1
Reactant: COc1ccc(Cl)cc1C(NC(=O)CC(C)(C)O[Si](C)(C)C(C)(C)C)C(N)=O
Product: COc1ccc(Cl)cc1C(NC(=O)C1CCOCC1)C(N)=O

Procedure:
Using N-((5-chloro-2-methoxyphenyl)(cyano)methyl)tetrahydro-2H-pyran-4-carboxamide, the title compound was prepared following the synthetic procedures described for N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-(tert-butyldimethylsilyloxy)-3-methylbutanamide to give N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)tetrahydro-2H-pyran-4-carboxamide as a white solid. LCMS (ESI) m+H=327.3; 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, br, 1H); 7.31-7.31 (m, 2H); 7.24 (s, br, 1H); 7.13 (s, br, 1H); 7.05-7.01 (d, 1H); 5.62 (d, 1H); 3.91-3.81 (m, 2H); 3.79 (s, 3H); 3.30-3.24 (m, 2H); 2.55-2.54 (m, 1H); 1.56-1.55 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]([CH3:17])([CH3:16])[CH:4]=1)#[N:2].[ClH:18].[CH2:19]([OH:21])[CH3:20]>>[ClH:18].[CH2:19]([O:21][C:1]([C:3]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]([CH3:17])([CH3:16])[CH:4]=1)=[NH:2])[CH3:20]
Reactant: CC1(C)C=C(C#N)c2cc([N+](=O)[O-])ccc2O1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21

Procedure:
To a mixture of 1.04 g of 4-cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran and 20 ml of ethyl alcohol was added hydrogen chloride with stirring and cooling with ice. After being saturated with hydrogen chloride, the mixture was further stirred at 5° C. for 6 days. The reaction mixture was concentrated, and to the residue was added a 1:1 mixture of diethyl ether and ethyl alcohol. After trituration, the crystal was collected by filtration, washed with a mixture of ethyl alcohol and diethyl ether, and dried to obtain 1.13 g of 6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboximidic acid ethyl ester hydrochloride. A mixture of 0.94 g of the resulting compound, 0.31 g of triethylamine, 0.13 g of cyanamide, and 7 ml of ethyl alcohol was stirred at room temperature for 6 hours, followed by concentration. Water was added to the residue, and the mixture was extracted with dichloromethane. The extract was washed with 2N hydrochloric acid, dried over magnesium sulfate, and subjected to silica gel column chromatography (AcOEt:n-hexane=1:1) to isolate three components having different polarity. The component of the lowest polarity was recrystallized from a mixture of diethyl ether and n-hexane to obtain 0.15 g of 6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxylic acid ethyl ester represented by formula shown below.