Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([C:17](O)=[O:18])=[N:12][CH:11]=[C:10]([O:20][CH3:21])[C:9]=3[C:8]2=[O:22])=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([C:17]([Cl:27])=[O:18])=[N:12][CH:11]=[C:10]([O:20][CH3:21])[C:9]=3[C:8]2=[O:22])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cnc(C(=O)O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Product: COc1cnc(C(=O)Cl)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 0.5 h

Procedure:
A solution of 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylic acid (1.11 g, 3.36 mmol) in thionyl chloride (0.4 g, 3.36 mmol) was heated to 110° C. After 0.5 hours, the product mixture was concentrated under vacuum. The residue was suspended in toluene, evaporated, then suspended in chloroform and evaporated to give the title compound. The product was assayed by quenching in methanol solution to produce the methyl ester. ES MS M+1=345 (methyl ester forms after quench in methanol)
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:27])=[N:9][C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(Cl)Cl.O1CCCC1>[C:19]([C:15]1[CH:14]=[C:13]([C:12]2[CH:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=[C:8]([CH3:27])[C:7]=2[NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:18]=[CH:17][CH:16]=1)#[N:20]
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1NC(=O)CCCl
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1NC(=O)CCN1CCOCC1
Yield: 88.1 %

Procedure:
A mixture of 3-(3-chloropropionylamino)-4-(3-cyanophenyl)-2-methyl-6-phenylpyridine (0.45 g) and morpholine (0.23 g) in a mixture of methylene chloride (5 ml) and tetrahydrofuran (10 ml) was refluxed for 8 hours. The mixture was concentrated, diluted with water (20 ml) and chloroform (20 ml). The separated organic layer was washed with water, dried and concentrated in vacuo. The residue was triturated with diethyl ether to give 4-(3-cyanophenyl)-2-methyl-3-(3-morpholinopropionylamino)-6-phenylpyridine (0.45 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:15][CH2:14]1>CCOC(C)=O.CO>[CH3:1][C:2]1[C:3]([N:13]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:23])=[O:24])[CH2:15][CH2:14]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reaction time: 2 h
Yield: 90 %

Procedure:
1-[2-Methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]hexahydro-1H-1,4-diazepine (0.70 g, 1.9 mmol) was placed in a 200 mL high pressure vessel and dissolved in 40 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/C (0.51 g, 0.132 mmol) was added followed quickly by a rubber septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (60 psi). The solution stirred for 2 h. The vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step C (0.585 g, 1.71 mmol, 91%). 1H NMR (400 MHz, DMSO-d6) δ 6.54 (s, 1H), 6.38 (s, 1H), 4.27 (br. s., 2H), 3.67 (s, 3H), 3.24 (t, J=6.59 Hz, 2H), 3.02 (s, 3H), 2.86-2.97 (m, 6H), 2.75 (t, J=5.49 Hz, 2H), 2.68-2.73 (m, 2H), 2.05 (s, 3H), 1.74-1.81 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26](OC)=[O:27])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:30]#N.N>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([NH2:30])=[O:27])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)c3c(cc1n2Cc1ccccc1)CCCC3
Reactant: N#N
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)c3c(cc1n2Cc1ccccc1)CCCC3
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-benzyl-11-hydroxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazol-1-carboxylic acid, methyl ester, (0.097 g, 0.25 mM) in 8 mL THF was placed in an Ace Glass pressure tube (203 mm×38 mm) with a small stirring bar. A N2(g) stream was installed over the solution surface. The pressure tube and reaction solution were cooled to −78° C., and ˜8 mL NH3(l) was condensed into the reaction vessel by introduction of an NH3(g) stream. The pressure tube was sealed with a teflon O-ring screw cap, the resultant brown solution stirred at −78° C. for 10 minutes, then the cooling bath was removed and the reaction solution allowed to warm to ambient temperature behind a blast shield. After 24 h, the pressure tube was re-cooled to −78° C. and the internal NH3(g) pressure was released by careful removal of the Teflon cap. The reaction solution was allowed to slowly warm to room temperature while NH3(g) bubbled off, then the solution was concentrated in vacuo to afford 0.92 g (quantitative) of the title compound 5-benzyl-11-hydroxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazole-1-carboxylic acid amide as a tan solid (MP 225° C. dec, MW 370.46).
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([OH:25])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:43][C@H:44]([C:48]([OH:50])=[O:49])[CH:45]([CH3:47])[CH3:46]>>[C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([NH:43][C@H:44]([C:48]([OH:50])=[O:49])[CH:45]([CH3:47])[CH3:46])=[O:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)O
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)N[C@H](C(=O)O)C(C)C
Yield: 72.3 %

Procedure:
Starting from 3-(9-octadecenoyloxy)-11-eicosenoic acid (3.2 g) prepared by the method described in Preparation 8 and L-valine (4.42 g), N-[3-(9-octadecenoyloxy)-11-eicosenoyl]-L-valine (2.7 g) was obtained as powders according to a similar manner to that of Example 6.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[S:6][C:5]([N:7]3[CH2:15][CH:14]4[CH2:16][N:10]5[CH2:11][CH:12]([CH2:17][CH:8]3[CH2:9]5)[CH2:13]4)=[N:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1cnc(N2CC3CC4CC2CN(C4)C3)s1
Product: Cc1ccc(-c2cnc(N3CC4CC5CC3CN(C5)C4)s2)cc1

Procedure:
The title compound was prepared from the product of Example 105A and 4-methylphenylboronic acid according to General Method C: LC-MS Method D (ESI+) m/z 326.0 (M+H)+, retention time 1.54 minutes.
Reaction SMILES: O[CH2:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].O=S(Cl)[Cl:17].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:17][CH2:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(CO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(CCl)c1ccccc1
Yield: 45.6 %

Procedure:
To ethyl 3-hydroxy-2-phenylpropionate (2.55 g, 13.1 mmol) in dichloromethane (15 ml), SOCl2 (1.87 g, 15.7 mmol) in dichloromethane (1 ml) was added while chilling with ice. After the resulting solution was stirred to cause reaction at room temperature for 3 hours, saturated aqueous sodium bicarbonate was added while chilling with ice. The prepared solution was extracted with dichloromethane, and the extract was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. Subsequently, the solvent was removed by distillation under reduced pressure to obtain a crude product. The product was purified by silica gel column chromatography using acetone/hexane=1/3 to obtain 1.27 g of the titled compound as a colorless oil (yield: 45.5%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:40])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:39]>>[CH3:39][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:32]=[C:33]([O:18][C:9]3[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:34]=[C:35]([CH3:37])[CH:36]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:40])=[O:20]
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Reactant: Oc1cc(C(F)(F)F)ccc1Oc1ccccc1
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2cc(C(F)(F)F)ccc2Oc2ccccc2)c1
Yield: 34 %

Procedure:
The compound of 2-phenoxy-5-trifluoromethyl-phenol is reacted with 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester as in Example 18 to afford 0.262 g (34%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C30H25O5F3 522, found 523 (M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:13]([O:22][CH3:23])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:25]>O1CCOCC1>[NH2:25][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:13]([O:22][CH3:23])[CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)cc(NS(C)(=O)=O)c1
Solvent: C1COCCO1
Product: COc1cc(NC(=O)c2c(N)ncnc2Cl)cc(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 155.7 %

Procedure:
4,6-Dichloro-N-(3-methoxy-5-(methylsulfonamido)phenyl)pyrimidine-5-carboxamide (617 mg, 73% purity, 1.14 mmol) was dissolved in dioxane (5 ml) and cooled in an ice bath. Ammonia (819 μl, 7N in MeOH, 5.7 mmol) was added dropwise and the mixture stirred at 0° C. for 6 h and at room temperature overnight. The solvent was removed and ethyl acetate added. The solid precipitate was filtered off and the filtrate was concentrated to give 660 mg (100% yield) of the title compound as an oil that was used in the next step without further purification. Purity 65%
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[F:15][C:16]1[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1cccc(C(F)(F)F)c1F
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc(C(F)(F)F)c1F

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-fluoro-3-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)O1.Br[C:32]1[CH:41]=[CH:40][C:35]([C:36]([NH:38][CH3:39])=[O:37])=[C:34]([F:42])[CH:33]=1>>[F:42][C:34]1[CH:33]=[C:32]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[N:14][C:13]=3[CH:29]=2)[CH:41]=[CH:40][C:35]=1[C:36](=[O:37])[NH:38][CH3:39]
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Reactant: CNC(=O)c1ccc(Br)cc1F
Product: CNC(=O)c1ccc(-c2ccc3oc(C4CCN(C(=O)OC(C)C)CC4)nc3c2)cc1F
Yield: 33.7 %

Procedure:
Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.54 mmol) and 4-bromo-2-fluoro-N-methylbenzamide (200 mg, 0.54 mmol) as a brown solid. M.P.: 116-120° C. MS (m/z): 440.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](Br)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:31]=2)O1>>[CH2:1]([NH:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:27]3[CH:28]=[N:29][N:30]([CH:32]4[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]4)[CH:31]=3)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc2ccn(NCc3ccccc3)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(NCc5ccccc5)c4c3)cn2)CC1

Procedure:
This intermediate was prepared using Suzuki coupling reaction of N-benzyl-6-bromo-1H-pyrrolo[3,2-b]pyridine-1-amine and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate as described in example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]([C:6](=[O:7])[C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:23][C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1Cl
Reactant: O=Cc1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(=O)C(=Cc1cccnc1)Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In this example 5.0 grams (0.019 mole) of t-butyl 2,4-dichlorophenoxymethyl ketone and 2.1 ml (0.022 mole) of 3-pyridinecarboxaldehyde are added to 50 ml of methanol containing 0.1 g of sodium methoxide. The mixture is then stirred at room temperature for 5 hours and then evaporated to remove the methanol solvent, affording a semi-solid residue. The residue was then partitioned between diethyl ether and water. The separated ethyl ether phase was then extracted sequentially with 1N. aqueous sodium hydroxide, washed three times with water and then one time with brine. The diethyl ether phase was then dried over magnesium sulfate, filtered, then concentrated in vacuo affording a yellow oil. The yellow oil was then chromatographed on silica gel eluting with hexane ethyl acetate mixtures. The chromatographed fractions were combined by a thin layer chromatographed profile and then concentrated by evaporation affording the title compound as a viscous oil, 5.9 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:25](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:25])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(CC(c1ccc(Br)cc1)C1CCC1)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)C2CCC2)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-cyclobutyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow oil, MS (ESI+): m/z=374.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:14][CH2:15]O>Cl>[CH2:14]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: COc1ccc(CC(=O)O)cc1Br
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 80 °C

Procedure:
3-Bromo-4-methoxyphenylacetic acid (4.1 g, 16.7 mmol) in EtOH (100 mL) was treated with concentrated HCl (2 drops) and heated to 80° C. for 3 days. After cooling to room temperature, the mixture was concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:18])[CH3:17]>C(OCC)C>[C:16]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)(=[O:18])[CH3:17]
Reactant: Oc1ccc(Br)cn1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)Oc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
A suspension of 0.5 g (2.87 mmol) of 5-bromo-2-pyridinol in 10 ml of ethyl ether is prepared and 1 ml (7.1 mmol) of triethylamine and then 1 ml (14 mmol) of acetyl chloride are added at ambient temperature. The mixture is stirred at ambient temperature for 24 hours and then the insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure and the crude product is purified by chromatography on silica gel, elution being carried out using a toluene/2-propanol mixture (9/1; v/v). The expected product is obtained in the form of a pale yellow powder with a yield of 52%.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10](=[O:22])[C:11]([C:19](=[O:21])[CH3:20])=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])[CH3:4]>Br>[Br:1][CH2:20][C:19]([C:11]1[C:10](=[O:22])[NH:9][C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=1)=[O:21]
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Reactant: BrBr
Agent: Br
Product: CCOC(=O)c1cc(C(=O)CBr)c(=O)[nH]c1C(=O)OCC
Temperature: 0 °C

Procedure:
Bromine (8.0 g, 0.050 mol) in 48% HBr is added dropwise to a stirred solution of diethyl-5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (14.05 g, 0.05 mol) in 48% HBr (200 mL). Upon completion of this bromine addition the reaction mixture is poured onto ice (200 g) and the mixture is stirred until the ice has melted. The crude product is collected by filtration and crystallized twice from an ethyl acetate-hexane mixture (1/2) affording diethyl 5-(bromoacetyl)-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate with mp 141°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.C(NC(=NC(C)C)O[C:18]([CH3:21])([CH3:20])[CH3:19])(C)C>C1COCC1>[C:18]([O:9][C:8]([C:6]1[CH:5]=[C:4]([Cl:11])[N:3]=[C:2]([Cl:1])[CH:7]=1)=[O:10])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of 2,6-dichloropyridine-4-carboxylic acid (8.28 g, 43.1 mmol, Aldrich) in dry THF (30 ml) was added N,N′-diisopropyl-O-t-butylisourea (17 ml, 3.6 M) dropwise over 1 minute. The resulting mixture was stirred at room temperature overnight. The material was then heated to 65° C. and additional N,N′-diisopropyl-O-t-butylisourea (10 ml) was added dropwise. The mixture was stirred for 1 hour and cooled to room temperature. After removing volatiles, the remainder was purified by flash silica gel column (EtOAc/hexanes 5:95 followed by 7.5:92.5) affording tert-butyl-2,6dichloro-4-pyridine carboxylate (7.83 g, 73%) as a white solid. MS (ES+): 248.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:14].[K+].[K+]>O.C(#N)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[C:7]2[C:8](=[O:14])[C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CC1(C)Cc2c(Br)cccc2O1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)Oc2cccc(Br)c2C1=O
Yield: 67 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 3.0 grams (0.013 mole) 4-bromo-2,3-dihydro-2,2-dimethylbenzofuran, 10.7 grams (0.039 mole) of potassium persulfate, and 3.3 grams (0.013 mole) of copper(II) sulfate pentahydrate in 30 mL of water and 30 mL of acetonitrile was heated at reflux for one hour. After this time the reaction mixture was poured into 200 mL of water. The mixture was then extracted with one 200 mL portion of diethyl ether. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 1:1 petroleum ether and methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.1 grams of 4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone. The NMR spectrum was consistent with the proposed structure. Steps A through C were repeated.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]2[C@@H:21]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C:32]4=[O:37])=[CH:27][CH:26]=3)=[O:23])[CH2:20]S[CH2:18]2)=[O:16])=[CH:10][CH:9]=1>O.CO>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]2[C@@H:21]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C:32]4=[O:37])=[CH:27][CH:26]=3)=[O:23])[CH2:20][S:3](=[O:5])(=[O:2])[CH2:18]2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=S([O-])OO
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1CSCN1C(=O)Nc1ccc(Cl)cc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1CS(=O)(=O)CN1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.1 A solution of 4.54 g (54.0 mmol) of sodium hydrogencarbonate and 3.60 g (27.0 mmol) of 2-(S)-thiazolidine-4-carboxylic acid in 50 ml of water is heated to 80° C., and 8.46 g (54.0 mmol) of 4-chlorophenyl isocyanate are added. The reaction mixture is stirred at this temperature for 1 hour. The mixture is allowed to cool, and the precipitate formed is filtered off. The filtrate is acidified using 1N HCl, and the precipitate formed is filtered off and dried, giving (S)-3-(4-chlorophenylcarbamoyl)thiazolidine-4-carboxylic acid as a colourless solid; ESI 287. 3.2 498 mg (2.60 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) are added to a solution of 573 mg (2.00 mmol) of (S)-3-(4-chlorophenylcarbamoyl)thiazolidine-4-carboxylic acid and 384 mg (2.00 mmol) of 4-(4-aminophenyl)morpholin-3-one in 4 ml of dimethylformamide (DMF), and the mixture is stirred at room temperature for 18 hours. The reaction mixture is added to saturated sodium hydrogencarbonate solution, and the precipitate formed is filtered off, giving 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(S)-thiazolidine-3,4-dicarboxamide (“A3”) as a colourless solid; ESI 461. 3.3 A solution of 1.9 g of oxone in 30 ml of water is added to a suspension of 450 mg (0.976 mmol) of “A3” in 50 ml of methanol, and the reaction mixture is stirred at room temperature for 24 hours. The reaction mixture is added to water, and the precipitate formed is filtered off and dried, giving 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(S)-1,1-dioxo-1λ6-thiazolidine-3,4-dicarboxamide (“A4”) as a colourless solid; ESI 493.