Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:30].O>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2([F:30])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[O:11]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C1OC(F)(c2ccc(Cl)c([N+](=O)[O-])c2)c2ccccc21
Temperature: 0 °C
Reaction time: 1.67 h
Yield: 90.1 %

Procedure:
To a solution of 2-(4-chloro-3-nitrobenzoyl)benzoic acid (6.76 g, 22.00 mmol) in anhydrous dichloromethane (35 ml) at 0° C. pyridine (1.80 ml, 22.00 mmol) was added, followed by the dropwise addition of cyanuric fluoride (2.0 ml, 24.20 mmol) in dichloromethane (4.0 mL). The reaction mixture was stirred for 100 minutes at 0° C. Water (35 mL) was added to the reaction mixture and it was stirred for 10 min at 0° C. The resulting slurry was filtered through a pad of Celite and it was washed with dichloromethane. The filtrate was partitioned with water and the dichloromethane layer was washed with water and it was dried over anhydrous sodium sulfate. Filtration and concentration provided 3-(4-chloro-3-nitrophenyl)-3-fluoro-2-benzofuran-1(3H)-one, (6.10 g, 90% yield) as a crystalline solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6): 8.34 (d, J=2 Hz, 1H), 8.20 (dd, J1=8 Hz, J2=0.8 Hz, 1H), 8.01-7.94 (m, 3H), 7.86 (td, J1=8 Hz, J2=1.2 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H); MS (EI) for C14H7ClFlNO4: 306 (M−).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[CH3:36][C:37]1[C:41](B(O)O)=[C:40]([CH3:45])[O:39][N:38]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:36][C:37]1[C:41]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)=[C:40]([CH3:45])[O:39][N:38]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cn(-c2ccc(-c3c(C)noc3C)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (230 mg, 0.45 mmol); 3,5-dimethylisoxazole-4-boronic acid (70 mg, 0.50 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), Na2CO3 (106 mg, 1.0 mmol), DME (4 mL), and H2O (1 mL) was refluxed for 3 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with THF and recrystallized from MeOH/H2O to give the title compound (121 mg, 59% yield) as a white solid: mp 200-202° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.27 (3H, s), 2.42 (3H, s), 3.92 (3H, s), 6.49 (1H, t, J=8.3 Hz), 6.89 (1H, ddd, J=0.8, 1.9, 8.3 Hz), 7.08 (1H, dd, J=1.9, 12.1 Hz), 7.32 (1H, d, J=1.9 Hz), 7.35-7.47 (5H, m), 7.79 (1H, d, J=1.9 Hz), 7.85 (1H, d, J=2.3 Hz). LC-MS (ESI) m/z 458 [M+H]+. Anal. Calcd for C25H20FN5O3: C, 65.64; H, 4.41; N, 15.31. Found: C, 65.55; H, 4.32; N, 15.33.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[CH3:39])#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][C:38]=4[CH3:39])[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1cnccc1C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnccc4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 20 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 3-ethynyl-4-methyl-pyridine in the same manner as Example 15. ESI MS m/z 549 [C28H32N6O4S+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:2]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reaction time: 12 h

Procedure:
To a solution of Example 1B (5 g, 23.22 mmol) in dichloromethane (50 mL) was added pyridinium chlorochromate (10.01 g, 46.4 mmol) and the mixture stirred for 12 hours. The mixture was filtered through diatomaceous earth with dichloromethane, concentrated and purified by column chromatography on silica gel (Isco®, Redi-Sep® column), eluting with 40% ethyl acetate in hexane to afford the title compound. LCMS: 213.9 (M+H)+.
Reaction SMILES: O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:27][N:26]([CH2:38][CH2:39][F:40])[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][C:12](Br)=[CH:11][N:10]=1.CC1(C)C(C)(C)OB([C:50]2[CH:51]=[N:52][N:53]([CH:55]3[CH2:60][CH2:59][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][CH2:56]3)[CH:54]=2)O1>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:50]2[CH:51]=[N:52][N:53]([CH:55]3[CH2:56][CH2:57][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:59][CH2:60]3)[CH:54]=2)=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:29](=[O:30])[C:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:27][N:26]([CH2:38][CH2:39][F:40])[CH:25]=2)=[O:23])=[CH:17][CH:16]=1
Reactant: Nc1ncc(Br)cc1-c1ccc(NC(=O)c2cn(CCF)cc(-c3ccc(F)cc3)c2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4ccc(NC(=O)c5cn(CCF)cc(-c6ccc(F)cc6)c5=O)cc4)c3)cn2)CC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 120.8 %

Procedure:
Water (0.5 ml), cesium carbonate (60 mg) and tetrakis(triphenylphosphine)palladium (16 mg) were added to a solution of the compound obtained in Step 1 of Example 43 (75 mg) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (59 mg) in dimethoxyethane (4 ml). The mixture was stirred under microwave irradiation at 100° C. for 10 minutes. After leaving to cool, the reaction product was purified by silica gel column chromatography [chloroform:methanol=99:1->9:1 (v/v)]. Further, the resulting crude purified product was crystallized from ethyl acetate to give 120 mg of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([Cl:18])=[CH:13][C:12]=1Cl)=[CH:6]OCC)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:10](=[O:20])[C:11]2[C:12](=[CH:13][C:14]([Cl:18])=[C:15]([F:17])[CH:16]=2)[N:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)[CH:6]=1)=[O:21])[CH3:2]
Reactant: Nc1ccc(F)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)cc1Cl
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(F)cn2)c2cc(Cl)c(F)cc2c1=O

Procedure:
A solution of 0.747 g of 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylic acid ethyl ester (2.23 mmol) and 0.250 g of 2-amino-5-fluoropyridine (2.23 mmol) in 5 ml ethanol was stirred at reflux for 25 hrs. The reaction was monitored by TLC. The ethanol was evaporated and the last traces of ethanol were distilled from an azeotrope with a mixture of 10 ml heptane and 10 ml ethyl acetate. The yellow oil was dissolved in 10 ml of THF, reacted with 120 mg of a 50% NaH suspension in oil and stirred at reflux over night. The solvent was evaporated, the residue dissolved in dichloromethane/methanol 9:1, washed with water and brine, dried over Mg sulfate, filtered and evaporated. The residue was digested in ethyl acetate, and the solid filtered.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]([C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[O:16][CH:15]=1)(C)[C:10]([O-])=[O:11])C>C1COCC1>[CH3:24][O:23][C:22]1[C:17]2[O:16][CH:15]=[C:14]([CH:9]([CH3:7])[CH2:10][OH:11])[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: CCC(C)(C(=O)[O-])c1coc2c(OC)cccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc2c(C(C)CO)coc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(7-methoxy-1-benzofuran-3-yl)propanoate (1.24 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4, filtered and concentrated. The product, 2-(7-methoxy-1-benzofuran-3-yl)-1-propanol, was obtained as a white oil pure enough to be taken to the next step without purification. Yield: 900 mg (87%); (M+H): 207.
Reaction SMILES: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC.O.C([O:76][CH:77]([C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[CH3:78])(=O)CCCCCCCCCCCCCCC>CC(C)=O>[C:79]1([C@@H:77]([OH:76])[CH3:78])[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1
Reactant: CCCCCCCCCCCCCCCC(=O)OC(C)c1ccccc1
Agent: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC
Solvent: O
Solvent: CC(C)=O
Product: C[C@H](O)c1ccccc1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
In a 300 ml separable flask were put 3 g of Lipase PL of Alcaligenes sp. origin (a product of Meito Sangyo Co., Ltd., hereinafter the same applies) and 50 g of (R,S)-1-phenylethanol, and the mixture was subjected to ultrasonication with the same ultrasonic wave generating equipment as used in Example 1 at room temperature and at 20 kHz for 20 minutes. To the dispersion was added 150 g of tripalmitin, followed by stirring at 85° C. and 100 rpm for 30 hours to carry out interesterification. The water content of the reaction system was 0.05% by weight, and 93% of the lipase particles had a particle size of 15 to 40 μm. Gas chromatographic analysis of the reaction mixture revealed that 46 mol % of (R,S)-1-phenylethanol had been converted to 1-phenylethyl palmitate. To the reaction mixture was added 1500 ml of acetone, followed by cooling to 10° C. Lipase, unreacted tripalmitin, dipalmitin, monopalmitin, and palmitic acid were removed by filtration using Toyo Filter Paper No. 5A, and the filtrate was subjected to simple distillation at 95° C. under reduced pressure of 5 mmHg to give (S)-(-)-phenylethanol (yield: 87%; chemical purity: 99.9%; optical purity: 86.3% ee). The residue, i.e., (R)-(+)-1-phenylethanol palmitic acid ester was alkali-hydrolyzed in the same manner as in Example 1 to obtain (R)-(+)-1-phenylethanol (yield: 82%; chemical purity: 99.5%; optical purity: 98.0% ee).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[CH:15][S:16][C:12]=3[C:11](=[O:17])O[C:9]2=[O:18])=[CH:5][N:6]=1.C(N1C2N=CC=CC=2C(=O)OC1=O)CCC.[O:35]=[S:36]1(=[O:63])[C:41]2[CH:42]=[C:43]([O:46][Si:47]([CH:54]([CH3:56])[CH3:55])([CH:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])[CH:44]=[CH:45][C:40]=2[NH:39][C:38]([CH2:57]C(OCC)=O)=[N:37]1.O=S1(=O)C2C=CC=CC=2NC(CC(OCC)=O)=N1>>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[C:9](=[O:18])[C:57]([C:38]3[NH:39][C:40]4[CH:45]=[CH:44][C:43]([O:46][Si:47]([CH:51]([CH3:53])[CH3:52])([CH:54]([CH3:55])[CH3:56])[CH:48]([CH3:49])[CH3:50])=[CH:42][C:41]=4[S:36](=[O:63])(=[O:35])[N:37]=3)=[C:11]([OH:17])[C:12]3[S:16][CH:15]=[CH:14][C:13]2=3)=[CH:5][N:6]=1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2N1
Reactant: O=c1oc(=O)n(Cc2cnc(Cl)s2)c2ccsc12
Agent: CCCCn1c(=O)oc(=O)c2cccnc21
Agent: CCOC(=O)CC1=NS(=O)(=O)c2ccccc2N1
Product: CC(C)[Si](Oc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3sccc3n(Cc3cnc(Cl)s3)c1=O)N2)(C(C)C)C(C)C

Procedure:
The title compound was prepared according to the procedure of Example 1D substituting the product of Example 140A for the product of Example 1B and substituting the product of Example 307C for the product of Example 1C (0.29 g, 66%). MS (ESI−) m/z 649 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.35 Hz, 18 H) 1.28 (m, 3 H) 5.63 (s, 2 H) 7.22 (d, J=2.57 Hz, 1 H) 7.31 (dd, J=8.82, 2.94 Hz, 1 H) 7.65 (d, J=8.82 Hz, 1 H) 7.86 (d, J=5.52 Hz, 1 H) 7.95 (s, 1 H) 8.42 (d, J=5.52 Hz, 1 H) 14.05 (s, 1 H) 14.96 (s, 1 H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][C:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[C:17]1([CH2:16][CH:14]([OH:15])[CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OC(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a stirring suspension of 1.10 g of lithium aluminum hydride in 50 mL of diethyl ether under an argon atmosphere at 0° C. is slowly added a solution of 5.30 g of commercially available 1,3-diphenylacetone in 10.0 mL of diethyl ether with a 10 mL rinse. After 0.25 hours the grey suspension is warmed to room temperature. After 1.5 hours the reaction mixture is re-cooled to 0° C. and slowly treated with 1.2 mL of water followed by 5.0 mL of 1N sodium hydroxide. After 1 hour the resulting white precipitant is filtered through a pad of magnesium sulfate with diethyl ether washings. The filtrate is concentrated under reduced pressure to afford 5.2 g, of the title product as a viscous, clear, colorless oil. This product may be used directly in the next reaction without further purification. Physical characteristics are as follows:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:28])[C:13]([CH:23]([OH:27])[C:24]([OH:26])=[O:25])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[C:35](=O)([O-])O.[Na+]>CO>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:28])[C:13]([CH:23]([OH:27])[C:24]([O:26][CH3:35])=[O:25])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
52 mg of [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](hydroxy)acetic acid was dissolved in 10 ml of methanol, and 0.4 ml of concentrated sulfuric acid was added, followed by stirring at room temperature for 1 hour. Aqueous saturated sodium hydrogen carbonate was added to the reaction mixture, followed by extraction with ethyl acetate, washing with aqueous saturated sodium chloride and concentration under a reduced pressure. The resulting residue was recrystallized from aqueous methanol to obtain 53 mg of methyl [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](hydroxy)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([N+:21]([O-])=O)[CH:12]=3)=[CH:10][N:4]2[N:3]=1.CC(O)=O>[Fe].CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[C:13]([CH:12]=3)[NH2:21])=[CH:10][N:4]2[N:3]=1
Reactant: O=[N+]([O-])c1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Yield: 96.9 %

Procedure:
Iron (0.489 g) is added to a mixture of 6-chloro-2-[3-nitro-4-(trifluoromethyl)phenyl]imidazo[2,1-f]pyridazine (0.600 g, 1.75 mmol), HOAc (0.802 mL), EtOH-water (10 mL, 4:1). The mixture is heated at 80° C. for 2 hours, then cooled, concentrated, taken into sat. aqueous NaHCO3 (50 mL) and extracted with EtOAc (2×50 mL). Organic is dried and concentrated to give the title compound (530 mg), which is used without further purification. LCMS m/z=313.4 [M+H]+, tR=2.82 min.
Reaction SMILES: CCN=C=NCCCN(C)C.ON1C2N=CC=CC=2N=N1.[CH2:22]([O:29][C:30](=[O:40])[CH2:31][C:32]1([C:37]([OH:39])=O)[CH2:36][CH2:35][CH2:34][CH2:33]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OC(C1(CC(O)=O)CCCC1)=O)C1C=CC=CC=1.Cl.[C:61]([O:65][C:66](=[O:83])[CH2:67][CH:68]([NH2:82])[CH2:69][C:70]1[CH:75]=[CH:74][C:73]([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[CH:72][CH:71]=1)([CH3:64])([CH3:63])[CH3:62].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:22]([O:29][C:30](=[O:40])[CH2:31][C:32]1([C:37]([NH:82][CH:68]([CH2:69][C:70]2[CH:75]=[CH:74][C:73]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)=[CH:72][CH:71]=2)[CH2:67][C:66]([O:65][C:61]([CH3:64])([CH3:62])[CH3:63])=[O:83])=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CC(N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(CC1(C(=O)O)CCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC1(C(=O)OCc2ccccc2)CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)C1(CC(=O)OCc2ccccc2)CCCC1
Reaction time: 1.5 h

Procedure:
Next, to a solution of EDCI (51.2 mg, 0.267 mmol), 1-hydroxy-7-azabenzotriazole (36.4 mg, 0.267 mmol) and 6:1 mixture of 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid and 2-(1-(benzyloxycarbonyl)cyclopentyl)acetic acid (65.6 mg, 0.214 mmol) in DMF (1 ml), which is stirred for 1.5 hours in advance, the crude 3-amino-4-biphenyl-4-yl-butyric acid tert-butyl ester hydrochloride and DIPEA (0.093 ml, 0.535 mmol) are added. After stirring for 2.5 hours, the reaction mixture is diluted with H2O, and the products are extracted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give crude tert-butyl 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-4-yl)butanoate (38 mg).
Reaction SMILES: [C:1]([O:7]CC)(=[O:6])[CH2:2][C:3]([O-])=O.[H-].[Na+].BrC[C:14]1[S:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.N1C=CC=CC=1.O>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:18][C:14]=2[CH2:3][CH2:2][C:1]([OH:7])=[O:6])=[CH:30][CH:29]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Clc1ccc(-c2nc(-c3ccccc3)sc2CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1sc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution of ethyl malonate (17.5 g) in N,N-dimethylformamide (50 mL) was added sodium hydride (4.38 g) and the mixture was stirred at 0° C. for 30 min, after which a solution of 5-(bromomethyl)-4-(4-chlorophenyl)-2-phenylthiazole (8.0 g) in N,N-dimethylformamide (200 mL) was added at 0° C. The mixture was stirred at 0° C. for 2 hrs. and poured into dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give a yellow oil. This oil was dissolved in ethanol (140 mL) and 10% aqueous sodium hydroxide solution (140 mL) was added. The mixture was stirred at 60° C. for 2 hrs. and the reaction mixture was poured into water. The mixture was washed with diethyl ether and the aqueous layer was acidified with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give a yellow powder. This powder was dissolved in pyridine (140 mL) and the mixture was stirred at 100° C. for 2 hrs. The reaction mixture was concentrated and diluted with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 3-[4-(4-chlorophenyl)-2-phenyl-5-thiazolyl]propionic acid (5.71 g, 75%) as a yellow powder. Recrystallization from ethyl acetate-hexane gave colorless prism crystals, melting point: 142–143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C(=CC=[C:46]([O:49]C)C=3)CC2)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:19]3[C:24](=[CH:23][CH:22]=[C:21]([O:49][CH3:46])[CH:20]=3)[CH2:25][CH2:26]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCc3ccc(OC)cc32)c(CC)nc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCc2ccc(OC)cc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.21, 1.29, 1.94, 2.51, 2.67, 2.80, 2.92, 3.01, 3.81, 4.69, 5.80, 6.86, 6.95, 7.22, 7.29–7.36, 7.51; HRMS (FAB) calcd for C24H25Cl2N3O+H 442.1453, found 442.1443.