Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1csc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1csc(-c2ccc(F)cc2)n1
Yield: 30 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (55 mg, yield 30%). 1H NMR (400 MHz, CDCl3) δ 8.53 (m, 1H), 8.26-8.24 (d, J=7.8 Hz, 1H), 8.13-8.11 (m, 1H), 8.07-8.05 (d, J=7.5 Hz, 1H), 7.92-7.89 (m, 2H), 7.62-7.58 (t, J=7.8 Hz, 1H), 7.06-7.02 (m, 3H), 3.71-3.69 (d, J=5.3 Hz, 2H), 1.49 (s, 6H). MS (ESI) m/z: Calculated for C23H18F4N4O2S: 490.11. found: 491.0 (M+H)+.
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH2:16]([O:18][C:19]([CH:21]=[CH:22][CH:23]1[NH:28][CH:27]([C:29]2[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=2)[CH2:26][N:25]([C:38]([O:40][CH3:41])=[O:39])[CH2:24]1)=[O:20])[CH3:17].[CH:42]([CH2:44][C:45](O)=[O:46])=[CH2:43].Cl>C1COCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:45]([N:28]1[CH:27]([C:29]2[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=2)[CH2:26][N:25]([C:38]([O:40][CH3:41])=[O:39])[CH2:24][CH:23]1[CH:22]=[CH:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])(=[O:46])[CH2:44][CH:42]=[CH2:43]
Reactant: C=CCC(=O)O
Reactant: CCOC(=O)C=CC1CN(C(=O)OC)CC(c2cc(F)c(F)c(F)c2)N1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(=O)N1C(C=CC(=O)OCC)CN(C(=O)OC)CC1c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
BOPCl (557 mg) was added to a solution of methyl 3-(2-ethoxycarbonylvinyl)-5-(3,4,5-trifluorophenyl)piperazine-1-carboxylate (422 mg), triethylamine (0.61 mL), and vinylacetic acid (0.19 mL) in THF (15 mL), and the reaction solution was stirred at room temperature for 20 hours. 1 N aqueous hydrochloric acid and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 643 mg of an E/Z isomer mixture crude product of the title compound. The property value of the compound is as follows.
Reaction SMILES: [H-].[Na+].O[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[NH:12].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1C[O:39]CC1>>[CH2:28]([O:39][CH:8]([CH2:7][CH2:6][CH2:5][CH3:4])[CH2:9][N:10]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[NH:12])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC(=N)N(CCCCCCO)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CCCCC(CN(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 34 %

Procedure:
1.300 g (32.49 mmol, 1.3 eq.) of sodium hydride were suspended under nitrogen in 170 mL of dry THF. 8.983 g (24.99 mmol, 1 eq.) of 1-(6-hydroxyhexyl)-N,N′-di-Boc-guanidine dissolved in dry THF were added dropwise to the suspension. The reaction was stirred at room temperature for 45min. 3.6 mL (29.99 mmol, 1.2 eq.) of benzyl bromide were added dropwise in 10min. The reaction was stirred overnight at room temperature. The reaction was checked by TLC and the reaction wasn't complete. 0.833 g (20.82 mmol) of sodium hydride were added. After 1 hour, the TLC was the same and 0.810 g (20.24 mmol) of sodium hydride were added. After 3 hours, no evolution was seen on TLC, 1.396 g (34.89 mmol) of sodium hydride and 1.6 mL (13.33 mmol) of benzyl bromide were added. The reaction was stirred overnight and TLC was still the same. The reaction was quenched by addition of water until clear solution. THF was removed in vacuo. Aqueous phase was extracted 3 times with ether. Organic phase was dried over anhydrous Na2SO4 and evaporated to obtain 15.44 g of a slightly yellow oil. This oil was purified by flash chromatography over silica (eluant AcOEt:pentane 1:9; Rf=0.43) to obtain 3.78 g of 1-(2-(benzyloxy)hexyl)-N,N′-di-Boc-guanidine as a colorless oil (yield=34%). 1H-NMR (500 MHz, CDCl3): δ=1.39 (m, 5H), 1.50 (s, 9H), 1.51 (s, 9H), 1.61 (m, 5H), 3.45 (m, 4H), 4.50 (m, 2H), 7.28 (m, 1H), 7.34 (m, 4H).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)(O)=[O:6]>>[ClH:3].[Cl:3][C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2ccnc3c(C(F)(F)F)cccc23)c2ccccc12
Product: Cl
Product: O=C(Cl)c1cn(-c2ccnc3c(C(F)(F)F)cccc23)c2ccccc12

Procedure:
5 cm3 of thionyl chloride are added to 0.5 g (1.4 mmol) of 3-carboxy-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole under an argon atmosphere. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated three times with 30 cm3 of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.58 g of 3-chlorocarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a yellow powder which is used directly in the following step.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:27])/[CH:24]=[CH:25]/[CH3:26])=[CH:16][CH:15]=1>C(O)C.COCCOCCOC>[CH2:7]([O:6][C:4]([CH:3]1[CH:25]([CH3:26])[CH2:24][C:23](=[O:27])[N:22]([CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[C:2]1=[O:10])=[O:5])[CH3:8]
Reactant: C/C=C/C(=O)NCCc1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: COCCOCCOC
Product: CCOC(=O)C1C(=O)N(CCc2ccc(F)cc2)C(=O)CC1C

Procedure:
Sodium (1.5 g, 65.1 mmol) was dissolved in ethanol (50 mL) and the solution was concentrated under vacuum. The residue was suspended in toluene (50 mL) and bis(2-methoxyethyl)ether (30 mL). Diethyl malonate (4.0 mL, 26.5 mmol) was added, followed by a suspension of trans-2-butenoic acid [2-(4-fluoro-phenyl)ethyl]amide (5.00 g, 24.1 mmol) in bis(2-methoxyethyl)ether (20 mL). The mixture was heated at reflux for 6 hours. The cooled mixture was washed with 1.0 N aqueous hydrochloric acid, then with water, and dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 25% ethyl acetate in hexane, to provide a pale yellowish oil which slowly crystallized (5.81 g, 75%). This appeared to be a mixture of cis and trans isomers (approximately 15% cis). 1H NMR (300 MHz, CDCl3) δ7.20 (m, 2H), 6.99 (t, J=9 Hz, 2H), 4.28 (m, 2H), 4.00 (m, 2H), 3.66 (d, J=5 Hz, 0.15H), 3.27 (d, J=10 Hz, 0.85H), 2.82 (m, 3H), 2.53 (m, 1H), 2.33 (dd, J=17, 10 Hz, 1H), 1.34 (m, 3H), 1.09 (d, J=7 Hz, 3H). Mass spec (AP+) m/z 322.0 (M+H+, 100%).
Reaction SMILES: ClC[CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2C(C3C=CC(O)=CC=3)=C(C(F)(F)F)C3C=CC(O)=CC=3[O:12]2)=[CH:7][CH:6]=1.[I-].[K+].O.C(OCC)(=[O:38])C>N1CCCCC1>[CH3:3][S:4]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1)=[O:38]
Reactant: Oc1ccc(C2=C(C(F)(F)F)c3ccc(O)cc3OC2c2ccc(SCCCl)cc2)cc1
Reactant: CCOC(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCNCC1
Solvent: O
Product: CS(=O)c1ccc(C=O)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
220 mg of 2-[4-(3-chloro-1-thiapropyl)-phenyl]-7-hydroxy-3-(4-hydroxyphenyl)-4-(trifluoromethyl)-2H-1-benzopyran in 2 ml of piperidine is mixed with 42.7 mg of potassium iodide and stirred for 6 hours at 100° C. After cooling, it is poured into water and shaken out three times with ethyl acetate. The combined organic phases are washed twice with water, dried on magnesium sulfate and concentrated by evaporation in a rotary evaporator. The purification of the product is carried out on silica gel with dichloromethane/methanol-9:1. 274 mg of product accumulates.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:19])[CH2:12][CH:13]([CH3:18])[CH2:14][C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][N:27]2[CH3:30])=[CH:23][C:22]=1[NH2:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:19])[CH2:12][CH:13]([CH3:18])[CH2:14][C:15]([NH:31][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[Cl:20])[N:27]([CH3:30])[CH:26]=[CH:25]3)=[O:17])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)c(Cl)c1
Reactant: Cn1ccc2cc(N)c(Cl)cc21
Product: CC(CC(=O)Nc1ccc(C#N)c(Cl)c1)CC(=O)Nc1cc2ccn(C)c2cc1Cl

Procedure:
Using 5-(3-chloro-4-cyanophenylamino)-3-methyl-5-oxopentanoic acid and 6-chloro-1-methyl-1H-indol-5-amine, and by the reaction and purification in the same manner as in the method described in Step 2 of Example 3, the title compound was obtained.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[I:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C[CH2:20][O:21][C:22](C)=[O:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Pd].C1COCC1>[CH3:20][O:21][CH2:22][O:23][CH2:7][CH2:6][NH:3][S:15]([C:12]1[CH:13]=[CH:14][C:9]([I:8])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COCOCCNS(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A suspension of {N-[2-(methoxymethoxy)ethyl)]carbamoyloxymethyl}phenyl (Method 38, 2.4 g, 10 mmol) and 10% palladium on carbon (300 mg) in THF (20 ml) was stirred under an atmosphere of hydrogen at ambient temperature for 18 hours. The catalyst was removed by filtration and the filtrate was placed under nitrogen. Triethylamine (1 ml, 7.5 mmol) and 4-iodophenylsulphonyl chloride (1.82 g, 6 mmol) were added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into a mixture of EtOAc (30 ml) and 1M aqueous citric acid solution (30 ml). The phases were separated and the aqueous phase washed with EtOAc (30 ml). The organic extracts were combined, washed 1M aqueous citric acid solution (2×30 ml), brine (30 ml), dried and the volatiles removed by evaporation to yield the title compound (2.18 g, 98%) as a waxy solid. NMR 3.15 (q, 2H), 3.31 (s, 3H), 3.59 (t, 2H), 4.53 (s, 2H), 4.96 (t, 1H), 7.58 (d, 2H), 7.90 (d, 2H); m/z 370 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:26]=[CH:25][C:16]([O:17][CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:15]([CH3:27])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:28].C(N(CC)CC)C.C(Cl)Cl.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl.ClCCl>[CH3:21][C:20]([CH3:22])([CH3:23])[C:19](=[O:24])[CH2:18][O:17][C:16]1[CH:25]=[CH:26][C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])=[C:3]([CH3:28])[CH:4]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:14][C:15]=1[CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC)(c1ccc(N)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(NS(C)(=O)=O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a 0° C. mixture of 1-{4-[1-(4-amino-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (763 mg, 2 mmol), triethylamine (0.42 mL, 3 mmol) and CH2Cl2 (7 mL) is added methanesulfonyl chloride (0.155 mL, 2 mmol). The reaction is warmed to RT and stirred for 3 h. The reaction is diluted with CH2Cl2 dichloromethane and washed with 0.2 N HCl. The organic phase is Na2SO4 dried, concentrated, and chromatogrpahed (0% to 25% EtOAc/Hex) to give the title compound (800 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=1.P([O-])(OCC)(SCC)=[S:14]>C1COCC1.O>[C:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12])(=[S:14])[NH2:11]
Reactant: COC(=O)c1cccc(C#N)c1
Reactant: CCOP([O-])(=S)SCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(C(N)=S)c1
Temperature: 80 °C
Yield: 102.4 %

Procedure:
Preparation H11, Step 2: A solution of 2 g (0.01 mol) of methyl-3-cyanobenzoate in 32 ml of THF and 8 ml of water was charged with 2.3 g (0.012 mol) of diethyl dithiophosphate and heated at 80° C. for 24 h. THF was removed and the residue was taken in ethyl acetate. The extract was washed with water and concentrated to afford methyl 3-carbamothioylbenzoate (2.0 g) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]([CH3:25])[CH2:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[CH:11]=[C:10]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:8].O.C(OCC)(=O)C>C1COCC1>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:9]2[C:7](=[O:8])[CH2:6][C@@H:5]([CH3:25])[CH2:4][C:3]([OH:26])=[O:2])=[CH:13][CH:14]=1
Reactant: CCCCCCc1cc2ccc(Cl)cc2n1C(=O)C[C@@H](C)CC(=O)OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCc1cc2ccc(Cl)cc2n1C(=O)C[C@@H](C)CC(=O)O
Reaction time: 30 h

Procedure:
To the solution of 5-(6-Chloro-2-hexyl-indol-1-yl)-3-(R)-methyl-5-oxo-pentanoic acid methyl ester in THF was added 1.2N HCL and was stirred at 60 0 C for 30 hours. The reaction mixture was then treated with water and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]([CH2:19][OH:20])=[CH:12]3)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]([CH:19]=[O:20])=[CH:12]3)=[O:7])=[CH:4][CH:3]=1
Reactant: Cn1c(CO)cc2cc(NC(=O)c3ccc(Br)cc3)ccc21
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cn1c(C=O)cc2cc(NC(=O)c3ccc(Br)cc3)ccc21
Temperature: 25 °C
Reaction time: 22 h
Yield: 92.2 %

Procedure:
To a solution of 4-bromo-N-[2-(hydroxymethyl)-1-methyl-1H-indol-5-yl]benzamide (13.63 g) obtained in Example 20 in DMSO (136 mL) were added triethylamine (21.1 mL) and pyridine-sulfur trioxide complex (24.16 g), and the mixture was stirred at room temperature for 22 hr. The reaction mixture was poured into ice water (400 mL), and the precipitated crystals were collected by filtration, washed with water, and dried to give the title compound (12.49 g, yield 92%) as a pale-brown solid. The solid was used without purification for the next reaction.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[Cl:16][C:17]1[CH:22]=[C:21](O)[CH:20]=[CH:19][C:18]=1[CH:24]([CH3:43])[C:25]([C:31]1[CH:42]=[CH:41][C:34]2[N:35]([CH3:40])[C:36](=[O:39])[CH2:37][O:38][C:33]=2[CH:32]=1)([OH:30])[C:26]([F:29])([F:28])[F:27].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[C:21]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:20]=[CH:19][C:18]=1[CH:24]([CH3:43])[C:25]([OH:30])([C:31]1[CH:42]=[CH:41][C:34]2[N:35]([CH3:40])[C:36](=[O:39])[CH2:37][O:38][C:33]=2[CH:32]=1)[C:26]([F:28])([F:29])[F:27]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)OCC(=O)N2C)C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccc2c(c1)OCC(=O)N2C)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (0.12 ml) was added to 7-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (150 mg, Example 158 step 2) and triethylamine (0.2 ml) in DCM (5 ml). The mixture was stirred for 2 h at room temperature. 10% aqueous citric acid was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and then concentrated to give the title compound (140 mg) as light yellow foam. MS (m/e, ISP neg. ion)=546.2 [M−H+].
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[F:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([F:20])[CH:26]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1cccc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (4.0 g) in tetrahydrofuran (100 mL), 3-fluorophenylmagnesium bromide (1.0 M solution in tetrahydrofuran; 17.1 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction from the reaction solution with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 5.5 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([NH2:27])=[O:26]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 33.1 %

Procedure:
The mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (6.77 g, 30.7 mmol), K2CO3 (5 g, 36.2 mmol) and 2-bromoacetamide (4.46 g, 32.3 mmol) in acetonitrile (250 ml) was heated to reflux for 4 hours. The insolubles were filtered and rinsed with dichloromethane (DCM). The solvents were removed. The residual solid was dissolved in DCM and upon concentration of this solution, 2.3 g of product crystallized out and was collected when the volume was reduced to about 50 ml. The rest of the product in DCM was purified by flash chromatography over a silica gel column (80 gm, SiO2; eluted with DCM and 1% CH3OH in DCM). The total product (4.2 g) thus purified was recrystallized from ethanol to yield 2.82 g of white crystals, m.p. 170°-172° C. dec. ANALYSIS: Calculated for C14H16FN3O2: 60.64%C 5.82%H 15.15%N Found: 60.66%C 5.87H 15.10%N
Reaction SMILES: [Si]([O:18][C:19]1[CH:54]=[CH:53][C:22]([O:23][CH2:24][C@@H:25]([OH:52])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([S:36][CH:37]3[CH2:42][CH2:41][N:40]([C:43]([NH:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:44])[CH2:39][CH2:38]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl.C(Cl)(Cl)Cl.CO>[C:46]1([NH:45][C:43]([N:40]2[CH2:41][CH2:42][CH:37]([S:36][C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:52])[CH2:24][O:23][C:22]4[CH:53]=[CH:54][C:19]([OH:18])=[CH:20][CH:21]=4)=[CH:31][CH:32]=3)[CH2:38][CH2:39]2)=[O:44])[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(SC3CCN(C(=O)Nc4ccccc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCC(Sc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 69.7 %

Procedure:
4-{[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)phenyl]sulfanyl}-N-phenyl-1-piperidinecarboxamide (0.25 g, 0.33 mmol) was reacted according to Procedure H (eluant: 12:3:1 dichloromethane-chloroform-methanol) to give the title compound (0.12 g, 0.23 mmol).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:19])[CH2:11][C:12]([CH2:15][N:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:18][N:16]([CH2:15][C:12]1[CH2:11][C:10](=[O:19])[C:9]([OH:8])=[CH:14][N:13]=1)[CH3:17]
Reactant: CN(C)CC1=NC=C(OCc2ccccc2)C(=O)C1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1=NC=C(O)C(=O)C1
Yield: 147.4 %

Procedure:
5-Benzyloxy-2-(N,N-dimethylamino)methyl-4-pyridone 1.0 g) in methanol (15 ml) was subjected to catalytic reduction with 10% palladium on activated carbon (200 mg) at atmospheric pressure. After removal of catalyst, the solution was concentrated under reduced pressure to give 2-(N,N-dimethylamino) methyl-5-hydroxy-4-pyridone (0.96 g).
Reaction SMILES: [F:1][C:2]([F:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21].O>COC(C)(C)C>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (0.243 g, 941 mmol) in t-butyl methyl ether (4 ml), lithium hydroxide monohydrate (38.2 mg, 910 mmol) was added and the mixture was stirred for one hour at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.250 g, 627 mmol) in t-butyl methyl ether (3 ml) was added thereto, and the mixed solution was heat refluxed for approximately 42 hours. After cooling to room temperature, the reaction mixture was added to water and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia FL-60D: 100 g; ethyl acetate:hexane=1:3), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (0.173 g; 326 mmol; yield: 52.0%).