Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][C@@H:14]2[O:19][C:18]3[C:20]([OH:25])=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][CH2:15]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][CH:14]2[CH2:15][O:16][C:17]3[CH:23]=[CH:22][C:21]4[N:24]=[CH:26][O:25][C:20]=4[C:18]=3[O:19]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(O)c3O2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: COC(OC)OC
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4ncoc4c3O2)cc1

Procedure:
[(2R)-7-Amino-8-hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methyl-benzenesulfonate hydrochloride (1.05 g, 2.99 mmole) in trimethyl orthoformate (7 mL) was heated to reflux in the presence of 0.20 g of p-toluenesulfonic acid for 3 hours. The solvent was removed under high vacuum to yield a beige solid. The crude product was recrystallized from ethanol to give 0.81 g (75%) of the (R)-enantiomer of the title compound, MS (ESI) m/z 361 (M+H)+.
Reaction SMILES: Cl[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][SH:11].[Na]>CS(C)=O>[F:8][C:2]([F:9])([S:11][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CS
Reactant: CCOC(=O)C(F)(F)Cl
Agent: [Na]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)SC
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
A solution of ethyl chlorodifluoroacetate (7.9 g, 50.0 mmol) in dimethyl sulfoxide (20 ml) was added dropwise to a solution of sodium methyl mercaptan (4.6 g, 65 mmol) in dimethyl sulfoxide (60 ml) under cooling with ice, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water to conduct extraction with ether. The solvent was distilled out of the resultant extract under reduced pressure. The resultant residue was distilled under reduced pressure to obtain the intended product (3.7 g; yield: 43.2%) as a colorless oil.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=O)[CH2:3][CH2:2]1.[NH2:23][OH:24].[OH-].[K+]>C1COCC1>[CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:23][OH:24])=[O:21])[CH2:3][CH2:2]1
Reactant: COC(=O)CCCCCCc1nc2ccccc2n1C1CC1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCCCCCc1nc2ccccc2n1C1CC1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a solution of methyl 7-(1-cyclopropyl-1H-benzo[d]imidazol-2-yl)heptanoate (80 mg, 0.27 mmol) in THF at 0° C. was added 50% hydroxylamine solution (0.16 mL, 2.6 mmol). To this was added KOH (0.80 mL, 1M in MeOH, 0.80 mmol) dropwise. The reaction was stirred at 0° C. for 2 hr, briefly concentrated and neutralized by adding 1 N HCl solution until pH was 7. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was purified by biotage column chromatography to give 7-(1-cyclopropyl-1H-benzo[d]imidazol-2-yl)-N-hydroxyheptanamide 24 (52 mg). MS (M+1=302)
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][CH2:29][C:30](O)=[O:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:29](=[O:28])[CH2:30][OH:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)CO
Agent: Cl
Product: O=C(CO)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (52 mg, 84%), MS (ISP) m/z=389.4 [(M+H)+], mp 246° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) 2-hydroxy-acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.CI.S(OC)(O[CH3:26])(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N:11]([CH3:26])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@H](C)N[C@@H](C)c2ccccc2)c1
Reactant: COS(=O)(=O)OC
Solvent: CI
Product: COc1cccc([C@H](C)N(C)[C@@H](C)c2ccccc2)c1

Procedure:
In another embodiment, the second approach: The methylation reaction is carried out using (S)-1-(3-methoxy phenyl)-N—((S)-1-phenylethyl)ethylamine as a raw material, and methyl iodide or dimethyl sulfate as a methylation agent, so as to obtain (S)-1-(3-methoxyphenyl)-N-methyl-N—[(S)-1-phenylethyl]ethylamine. Methyl iodide or dimethyl sulfate are conventional methylation agents, and the method is common in the art. See OS, CV4, 836 (1963); OS, CV3, 753 (1955), which are incorporated herewith by reference in their entireties.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]=O>>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][N:1]1[CH:2]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]1=[O:8]
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1nc2ccccc2s1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1nc2ccccc2s1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available benzo[d]thiazole-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 383.14 g/mol.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:40][N:41]1[C:45]([C:46]([F:49])([F:48])[F:47])=[C:44]([C:50](O)=O)[CH:43]=[N:42]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:50]([C:44]2[CH:43]=[N:42][N:41]([CH3:40])[C:45]=2[C:46]([F:49])([F:47])[F:48])[O:16][N:15]=1
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Reactant: Cn1ncc(C(=O)O)c1C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cnn(C)c2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.0194 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.88 (d, J=0.9 Hz, 1H), 7.53 (d, J=8.9 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 5.40 (s, 2H), 4.01 (s, 3H), 2.96 (t, 2H), 1.87-1.68 (m, 2H), 1.03 (t, 3H); MS (ES) m/z 449 (M+1).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[N:5]1[C:12](Cl)=[N:11][C:9]([Cl:10])=[N:8][C:6]=1Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([NH:4][C:12]1[N:5]=[C:6]([NH:4][CH2:1][CH:2]=[CH2:3])[N:8]=[C:9]([Cl:10])[N:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCNc1nc(Cl)nc(NCC=C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
54.9 g (0.96 mole) of allylamine are added dropwise, in the course of 1.5 hours and while stirring, to a clear solution of 73.8 g (0.4 mole) of cyanuric chloride in 500 ml of toluene, the temperature being kept between 20° and 30° by applying gentle external cooling to the reaction vessel. After stirring for a further two hours at room temperature and for one hour at 50°, the mixture is cooled to 20°, and a solution of 16 g (0.4 mole) of sodium hydroxide in 70 ml of water is added dropwise at 20° in the course of 2 hours. After stirring for a further 2 hours at room temperature and for 6 hours at 60°, a further 16 g (0.4 mole) of sodium hydroxide in 70 ml of water are added dropwise in the course of 2 hours and stirring is continued for a further 5 hours at 60°. After the mixture has cooled to room temperature, 200 ml of water are added, and the precipitate is filtered off after stirring for approx. 30 minutes. The precipitate is thoroughly washed with water, thoroughly suction-drained and dried in vacuo at approx. 95°. The colourless 2,4-bis-allylamino-6-chloro-1,3,5-triazine thus obtained is analytically pure and has a melting point of 205°-206°; its water content is <0.3%. Yield 88.2 g (97.7% of theory).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CCN=C=NCCCN(C)C.Cl.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36]>C(Cl)Cl>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:35](=[O:36])[CH2:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH3:21]
Reactant: O=C1CCC(=O)N1O
Reactant: COCCOCCOCCOCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COCCOCCOCCOCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
N-hydroxysuccinimide (0.55 g, 4.8 mmol) and EDCl (1.15 g, 6.0 mmol) were dissolved in CH2Cl2 (7 mL). Then 4-{2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethoxy}-butyric acid (0.940 g, 3.8 mmol), dissolved in CH2Cl2 (2 mL), was added. Reaction stirred overnight at room temperature. Crude reaction was diluted with CH2Cl2 (21 mL), washed 1M HCl (30 mL), H2O (30 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate) afforded 4, a clear oil (0.556 g, 43% yield).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C[Al](C)C.[CH2:9]([C:12]1[N:13]([CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:10][CH3:11]>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:13]1[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=[C:12]1[CH2:9][CH2:10][CH3:11])[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reactant: CCCN
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCNC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21
Reaction time: 0.05 h

Procedure:
A solution of n-propylamine (3.0 mL, 36 mmol) in dichloromethane (75 mL) was cooled to 0° C.; trimethylaluminum (available as a 2 M solution in toluene, 18 mL, 36 mmol) was added dropwise with stirring over a period of three minutes. The reaction was stirred for one hour at 0° C. and 30 minutes at ambient temperature. A solution of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate (5.80 g, 17.8 mmol, prepared as described in Parts A-D of Example 1) in dichloromethane (30 mL) was added, and the reaction was then heated at reflux for three days. The work-up procedure described in Part E of Example 1 was followed to provide N-propyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(O)c2c1CCC2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)c2c1CCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of ethyl (2E)-3-(7-hydroxy-2,3-dihydro-1H-inden-4-yl)prop-2-enoate (87.4 mg, 0.38 mmol, 1.00 equiv) in ethanol (4 mL) and palladium on carbon (80 mg). The mixture was then subject to an atmosphere of hydrogen and stirred for 12 h at 25° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 79.8 mg (91%) of ethyl 3-(7-hydroxy-2,3-dihydro-1H-inden-4-yl)propanoate as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:32])C(=O)C1.O>CC(N(C)C)=O>[Br:32][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:9]([C:11]1[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=CCOC(=O)Nc1cccc(C(=O)C(Br)c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a stirring mixture of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (5 g, 14.30 mmol) in DMA (100 ml) was added NBS (2.54 g, 14.30 mmol) and mixture was stirred at 25° C. overnight. The reaction mixture was poured into water (400 ml) and extracted with EtOAc (100 ml×3). The combined organic layers were dried over Na2SO4 and evaporated to afford the title compound as a yellow oil (6.1 g, 99%). MS (ES): 427 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.[C@@H:18]1([NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:24].[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.C(Cl)Cl>[NH2:24][C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:25][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CCOC(=O)c1ccc(N2CCC(=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCC(N[C@@H]3CCCC[C@H]3N)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a round bottom flask under argon was added the ethyl 4-(3-oxopyrrolidin-1-yl)benzoate (1.23 g, 5.27 mmol), (1R,2R)-cyclohexane-1,2-diamine (0.602 g, 5.27 mmol), CH2Cl2 (30 ml), solid anhydrous Na2SO4 (2.5 gm) and HOAc (1 ml). Argon was bubbled through the reaction mixture for 1 min and then the reaction was stirred under argon at rt for 1 hr. After this time, sodium triacetoxy borohydride (2.012 g, 9.49 mmol) was added to the reaction which was then stirred at rt overnight. The reaction was filtered and water (10 ml) was added to the reaction. The reaction mixture was then diluted with CH2Cl2 (100 ml). The resulting solution was washed with saturated aqueous NaHCO3 (100 ml), water (50 ml) and saturated aqueous NaCl (50 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated to give the product ethyl 4-(3-((1R,2R)-2-aminocyclohexylamino)pyrrolidin-1-yl)benzoate (1 g, 3.02 mmol, 57.2% yield) as brown solid. Anal. Calcd. for C19H29N3O2 m/z 331.4, found: 332.1 (M+H)+.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH3:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.[CH3:15][C:16]1[N:17]=[C:18]([N:21]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=3)[C:22]2=[O:36])[S:19][CH:20]=1>>[CH3:9][C:10]1[N:11]([C:31]([C:30]2[CH:29]=[CH:28][C:27]([CH2:26][N:23]3[CH2:24][CH2:25][N:21]([C:18]4[S:19][CH:20]=[C:16]([CH3:15])[N:17]=4)[C:22]3=[O:36])=[CH:35][CH:34]=2)=[O:32])[N:12]=[CH:13][CH:14]=1
Reactant: Cc1csc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)n1
Reactant: Cc1cc[nH]n1
Solvent: NCc1ccccc1
Product: Cc1csc(N2CCN(Cc3ccc(C(=O)n4nccc4C)cc3)C2=O)n1
Yield: 24 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 3-methylpyrazole to react with 4-((3-(4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid, the title compound was obtained as a white powder in 24% yield: mp 96-97° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=2.7 Hz, 1H), 8.09 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 6.42 (d, J=0.9 Hz, 1H), 6.30 (d, J=2.7 Hz, 1H), 4.53 (s, 2H), 4.10-4.05 (m, 2H), 3.48-3.42 (m, 2H), 2.31 (s, 3H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.5, 158.7, 155.9, 154.6, 147.2, 141.1, 132.1, 131.3, 131.1, 127.7, 110.4, 106.9, 47.7, 42.3, 42.0, 17.3, 14.1; MS (ES+) m/z 382.2 (M+1).
Reaction SMILES: C(O[CH:5]([CH2:12][CH3:13])[CH:6]([N+]([O-])=O)[CH2:7][CH3:8])(=O)C.[N+:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[C-:15].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:12]([C:5]1[C:6]([CH2:7][CH3:8])=[CH:15][NH:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCC(OC(C)=O)C(CC)[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1[nH]cc(CC)c1CC
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
After 4-acetoxy-3-nitrohexane (11.34 g, 60 mmol) had been added to a reaction vessel, air in the vessel was replaced with nitrogen, and dry-THF (150 ml) and ethyl isocyanoacetate (7.28 ml, 66 mmol) were added. Then, DBU (20.76 ml, 144 mmol) was slowly dropwise added while being cooled on an ice bath, and stirred at room temperature for 12 hours. After the completion of the reaction, 1N hydrochloric acid was added, and extracted with chloroform, and the extract was washed with water and a saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After that, the concentrated product was purified by means of silica gel column chromatography to yield ethyl 3,4-diethylpyrrole-2-carboxylate (10.97 g, 94% yield).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][O:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.[C:38](OCC)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][O:27][CH2:28][CH3:38])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CCN3CCOC)cc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCOCC)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
In ethyl acetate (28 ml) was dissolved tert-butyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methoxyethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.4 g). To the solution was added 4N hydrochloric acid/ethyl acetate (14 ml) at room temperature, and the mixture was stirred at 60° C. for 2 hours. After cooled to room temperature, an aqueous saturated solution of sodium hydrogen carbonate was added to adjust pH to approximate 5. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=6/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-ethoxyethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.61 g, 49%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[C:18](Cl)=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[C:18]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3Cl)ccc12
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3N3CCCC3)ccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a mixture of ethyl(6-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (90 mg), pyrrolidine (59.6 mg) and DMF (dry) (10 mL) was added K2CO3 (57.9 mg). The mixture was stirred at 80° C. under argon atmosphere overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give title compound (46.0 mg).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Cl:14])=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH-].[K+].[CH3:17]N(C)C=O.CI>CO>[CH3:17][O:2][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Cl:14])=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(O)c1ccc2c(Cl)ccnc2c1
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CO
Product: COC(=O)c1ccc2c(Cl)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
7-Carboxy-4-chloroquinoline (5 g, 24.0 mmol) was dissolved in a mixed solution of potassium hydroxide (1.49 g, 26.6 mmol) with methanol (150 ml) and stirred at room temperature overnight. The reactant was evaporated to dryness under reduced pressure. The residue was added with dimethylformamide (DMF; 60 ml) and methyl iodide (3.5 g, 24.6 mmol) in the order named and stirred at 80° C. for an hour. The reaction mixture was poured into ice water. The resulting precipitates were collected by filtration, dried over phosphorus pentoxide and recrystallized from ethanol (20 ml) to obtain 3.6 g (61%) of 7-methoxycarbonyl-4-chloroquinoline.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:7][CH:8]=1.[Li]CCCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[S:7][C:8]=1[Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COCc1csc(NC(=O)OC(C)(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1sc(NC(=O)OC(C)(C)C)nc1COC
Temperature: -78 °C
Yield: 65.1 %

Procedure:
To a 250 mL flame-dried 3-neck round-bottomed flask was added tert-butyl 4-(methoxymethyl)thiazol-2-ylcarbamate (1.75 g, 7.2 mmol) and 200 mL of dry THF. The resulting solution was stirred at −78° C. and treated dropwise with 1.6 M n-BuLi in THF (9.4 mL, 15 mmol) over 15 minutes. The resulting pale yellow solution was stirred at −78° C. for 30 minutes and was then treated dropwise with tributyltin chloride (2.1 mL, 7.9 mmol). The reaction mixture was stirred at −78° C. for 30 minutes. The bath was then removed, and the mixture was allowed to warm to room temperature and was stirred at room temperature for 2.5 hours. The reaction was quenched by the addition of saturated NH4Cl (150 mL). The layers were separated, and the aqueous layer was washed with Et2O (3×100 mL). The organic phases were combined and washed with NaCl (100 mL) dried over MgSO4, filtered, and concentrated in vacuo to provide the crude produce as a viscous oil which was then purified by column chromatography using a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 10% to 20% EtOAc in hexane, to provide tert-butyl 4-(methoxymethyl)-5-(tributylstannyl)thiazol-2-ylcarbamate (2.5 g, 65% yield) as waxy oil. MS m/z: 535 (M+1).