Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[CH:15]=1)=[O:28]
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Reactant: O=C(O)/C=C/c1c(F)cccc1Cl
Product: CC(=O)CCCCn1cc(NC(=O)/C=C/c2c(F)cccc2Cl)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-6-fluoro-phenyl)-acrylic acid. LC-MS-conditions 01: tR=0.91 min; [M+H]+=364.10.
Reaction SMILES: [CH2:1]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Cl[CH2:18][C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[CH2:1]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][C:9]2[C:19](=[O:20])[C:18](=[C:18]3[C:19](=[O:20])[C:9]4[CH:10]=[CH:11][C:6]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=4[O:12]3)[O:12][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCl
Reactant: CCCCN(CCCC)c1cccc(O)c1
Solvent: ClC(Cl)Cl
Product: CCCCN(CCCC)c1ccc2c(c1)OC(=C1Oc3cc(N(CCCC)CCCC)ccc3C1=O)C2=O

Procedure:
1.8 g (8.1 mmol) of 3-di-n-butylamino-phenol are dissolved in 20 ml of dry chloroform with exclusion of moisture. 0.7 ml (8.8 mmol) of chloroacetyl chloride is added dropwise with vigorous stirring. Silica gel (about 10 g in total) is then allowed to trickle in until a large proportion of the reaction solution has been absorbed, and the mixture is boiled under reflux for 15 hours. Finally, the solid is filtered off and washed with chloroform until the wash solution remains virtually colourless. The organic phases are combined. After the solvent has been stripped off on a rotary evaporator, 1.4 g of a dark brown, highly viscous crude product are obtained. Working up of the crude product by column chromatography over silica gel using chloroform as the solvent gives the oxindigo colorant as a red-violet fraction in the first runnings. After the chloroform has been stripped off, the resulting colorant is dried under an oil pump vacuum at 75° C. for 5 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:19])=[CH:16][C:17]([NH2:18])=[C:12]2[N:11]=[C:10]1[CH3:20].C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][C:32](Cl)=[O:33].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:19])=[CH:16][C:17]([NH:18][C:32](=[O:33])[CH2:31][Cl:30])=[C:12]2[N:11]=[C:10]1[CH3:20]
Reactant: Cc1cc(N)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)CCl)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 25 °C

Procedure:
Treat a solution of 3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-ylamine (0.2 g, 0.65 mmol), and N,N-diisopropylethylamine, (0.12 mL, 0.72 mmol) in 1,2-dichloroethane (10 mL) with chloroacetyl chloride (0.06 mL, 30.72 mmol). Heat the solution to reflux for 2 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate. Purify by preparative TLC (5% methanol in CH2Cl2) to obtain the title compound as a yellow solid.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25]CC)=[O:24])=[CH:16][N:17]3[CH2:20][CH2:21][F:22])=[CH:12][C:11]=2[F:29])[CH2:6][CH2:5]1)(=O)C.C(O)C>Cl>[F:29][C:11]1[CH:12]=[C:13]2[C:18](=[N:19][C:10]=1[N:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1)[N:17]([CH2:20][CH2:21][F:22])[CH:16]=[C:15]([C:23]([OH:25])=[O:24])[C:14]2=[O:28]
Reactant: CCOC(=O)c1cn(CCF)c2nc(N3CCN(C(C)=O)CC3)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: O=C(O)c1cn(CCF)c2nc(N3CCNCC3)c(F)cc2c1=O
Yield: 88 %

Procedure:
A suspension of the above ester (4.8 g) in 10% hydrochloric acid (48 ml) is heated for 2 hours on a steam-bath. After cooling, an appropriate amount of ethanol is added to the mixture to precipitate crystals, which are collected by filtration, dissolved in water (about 50 ml), treated with active charcoal, and filtered. The filtrate is adjusted to pH 7.5-8 with 10% aqueous ammonia to give 3.5 g of 6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid (m.p. 223°-225° C.).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][C:21]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:20]=1[O:19][CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: COc1ccc(OC)c(N)c1
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1cc(OC)ccc1OC
Yield: 29.4 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.48 g, 10 mmol), 2,5-dimethoxyaniline (3.06 g, 20 mmol) and 1,4-dioxan (10 ml) were stirred at room temperature overnight then heated at reflux for 30 minutes. The hydrochloride salt was filtered off, converted to free base and recrystallised from aqueous ethanol to give 3-butyryl-4-(2,5-dimethoxyphenylamino)-8-methylquinoline (1.07 g), m.p. 115°-116°.
Reaction SMILES: [CH:1](=[O:12])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.C[Si]([C:17]#[N:18])(C)C>[N+](C)([O-])=O.[I-].[Zn+2].[I-]>[NH2:18][CH2:17][CH:1]([C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1)[OH:12]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C=O)cc1OC
Agent: [I-]
Agent: [Zn+2]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(O)CN)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a stirred solution of veratraldehyde(16.6 g) and zinc iodide (50 mg) in anhydrous nitromethane (200 ml) was added trimethylsilyl cyanide (12 g) dropwise under nitrogen. After the resulting mixture was stirred at room temperature for 1 hour, the solvent was removed under reduced pressure. Anhydrous tetrahydrofuran (50 ml) was added to the residue, and the resulting mixture was added under ice cooling to a suspension of lithium aluminum hydride (3.9 g) in anhydrous tetrahydrofuran (200 ml). After that, the resulting mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, insoluble matter was filtered off, and the solvent was then removed under pressure from the filtrate. Chloroform (300 ml) was added to the residue. The resulting mixture was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The thus-obtained residue was purified by a silica gel column, whereby the title compound (10.8 g, yield: 54.8%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=2[F:24])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=1[F:24]
Reactant: Cc1n[nH]c(=O)c(-c2c(F)ccc(F)c2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2c(F)ccc(F)c2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
3.50 g of 5-(4-chlorophenyl)-6-methyl-4-(2,3,6-trifluorophenyl)-2H-pyridazin-3-one and 15 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 3.68 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2,3,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (iv) of the present invention).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:11][OH:12].Br[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH:19]([O:7][C:8]1[CH:9]=[C:10]([CH2:11][OH:12])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([CH3:21])[CH3:20]
Reactant: CC(C)Br
Reactant: COc1ccc(CO)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CO)cc1OC(C)C

Procedure:
Potassium carbonate (13.5 g) was added to a solution of 3-hydroxy-4-methoxybenzyl alcohol (10.0 g) and 2-bromopropane (9.15 ml) in dry DMF (100 ml) and the mixture was heated to reflux for 72 hours. The solvent was removed under vacuum. The residue obtained was partitioned between water and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate (2×) and the combined organics were passed through a hydrophobic frit. The solvents were removed under vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH:34]=O)=[N:6][N:7]2[CH2:32][CH3:33].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH2:34][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[N:6][N:7]2[CH2:32][CH3:33]
Reactant: C1CCNC1
Reactant: CCn1nc(C=O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCn1nc(CN2CCCC2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carbaldehyde (3.5 g, 4.26 mmol) in Dichloromethane (DCM) (80 mL) was added pyrrolidine (0.370 mL, 4.48 mmol) and sodium triacetoxyborohydride (1.355 g, 6.40 mmol). The mixture was stirred at r.t. for 1 h. Then reaction mixture was washed with sat. NaHCO3 (aq.) and brine, dried over sodium sulfate and the solvent was removed in vacuo. The crude product was then purified through normal phase chromatography (CombiFlash Rf), eluting with MeOH/DCM (0-20%) to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)cinnolin-4(1H)-one (1.9 g, 3.37 mmol, 79% yield) as an orange solid. The desired product was dissolved in DCM and washed with sat. NaHCO3 (aq.) and brine, concentrated and passed through a flash column chromatography before being used for the next step. LCMS: (M+H)+: 564.4.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1)([O-])=O.[OH-].[Na+]>CCOC(C)=O>[C:9]1([N:6]2[CH:7]=[CH:8][C:4]([NH2:1])=[CH:5]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccn(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1ccn(-c2ccccc2)c1
Yield: 93.7 %

Procedure:
Amixture of 3-nitro-1-phenyl-1H-pyrrole (410 mg, 2.18 mmol) and SnCl2 dihydrate (2.00 g, 8.86 mmol) in EtOAc (15 mL) was stirred at 80 C for 3 h. Aqueous 1N NaOH was added to bring pH to 12. The mixture was filtered through celite. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 1-phenyl-1H-pyrrol-3-amine as a solid (323 mg).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14]>C1COCC1>[OH:14][CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9]
Reactant: S=C=Nc1ccccc1
Reactant: NCCCO
Solvent: C1CCOC1
Product: OCCCNC(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
A solution of phenyl isothiocyanate (200 mg) in abs. THF (2 ml) was added dropwise under argon and with stirring to a solution of 3-amino-1-propanol (114.5 mg) in abs. THF (2 ml). The reaction mixture was stirred at room temperature for two hours. After removing the solvent, the residue was dissolved in aqueous HCl and washed with ether. Subsequently, the aqueous phase was basified with potassium carbonate and extracted three times with ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative chromatography, and the product-containing fractions were combined, freed of acetonitrile, basified and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. After removing the solvent, 114 mg of the desired product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH2:10])=[N:6]1.[Cl:12][C:13]1[S:17][C:16]([C:18](O)=[O:19])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH:10][C:18]([C:16]2[S:17][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:19])=[N:6]1
Reactant: COC(=O)Cn1nnc(N)n1
Reactant: O=C(O)c1ccc(Cl)s1
Product: COC(=O)Cn1nnc(NC(=O)c2ccc(Cl)s2)n1

Procedure:
63.2 Using general method D, (5-amino-tetrazol-2-yl)-acetic acid methyl ester was coupled with 5-chlorothiophene-2-carboxylic acid to give {5-[(5-chloro-thiophene-2-carbonyl)-amino]-tetrazol-2-yl}-acetic acid methyl ester. White solid. MS 302.0 ([M+H]+)
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[CH2:7]([SH:11])[CH2:8][CH2:9][SH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[S:10]1[CH2:9][CH2:8][CH2:7][S:11][CH:3]1[C:2]([OH:6])=[O:5]
Reactant: O=CC(=O)O
Reactant: SCCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C1SCCCS1
Temperature: 25 °C

Procedure:
9.20 g (100 mmol) of glyoxalic acid monohydrate, 11.1 ml (110 mmol) of 1,3-propanedithiol and 1.72 g (10.0 mmol) of para-toluenesulphonic acid were heated in 200 ml of toluene under reflux for 3 h. The reaction mixture was cooled to RT and extracted three times with 100 ml of saturated aqueous sodium bicarbonate solution. The combined aqueous phases were washed with 200 ml of diethyl ether, acidified with aqueous hydrochloric acid (6N) and extracted four times with 200 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was used for the next step without further purification. Yield: 8.0 g (47% of theory)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70](=[O:72])[CH3:71])=[CH:66][C:65]=1[O:73][CH3:74]>>[C:70]([C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:65]([O:73][CH3:74])[CH:66]=1)(=[O:72])[CH3:71]
Reactant: COc1cc(C(C)=O)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 37.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.43 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.21 g, 0.89 mmol), then reacted with 1-(4-amino-3-methoxyphenyl)ethanone (Bionet) (0.11 g, 0.67 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-acetyl-2-methoxy-phenyl)-amide as a light yellow solid (Yield 0.098 g, 37%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55][C:54]=1[C:63]1[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=1>CN(C=O)C>[CH:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55][C:54]=1[C:63]1[CH:64]=[C:65]([NH:69][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:66]=[CH:67][CH:68]=1
Reactant: Nc1cccc(-c2ccc3ccccc3c2)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3ccccc3c2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 74.2 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.068 mmol) and HATU (0.029 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-naphthalen-2-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.024 g of product in 63% yield: LCMS (ESI) m/z 476 (MH+).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:42]2[NH:47][C:46](=[O:48])[C:45]([CH2:49][CH2:50][C:51]([OH:53])=O)=[CH:44][CH:43]=2)=[CH:24]\[C@H:25]2[CH2:29][CH2:28][C:27](=[O:30])[N:26]2[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[O:40][CH3:41])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].N>O1CCCC1>[C:13]([C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:42]2[NH:47][C:46](=[O:48])[C:45]([CH2:49][CH2:50][C:51]([NH2:3])=[O:53])=[CH:44][CH:43]=2)=[CH:24]\[C@H:25]2[CH2:29][CH2:28][C:27](=[O:30])[N:26]2[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[O:40][CH3:41])=[CH:19][CH:18]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(=O)O)c(=O)[nH]2)c(OC)c1
Agent: N
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(N)=O)c(=O)[nH]2)c(OC)c1
Reaction time: 15 h

Procedure:
1,1′-Carbonyldiimidazole (24.8 mg) was added to a solution of 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridin-3-yl)propanoic acid (77.8 mg) in tetrahydrofuran (1.6 mL). 28% aqueous ammonia (0.2 mL) was further added, followed by stirring for 15 hours. The reaction system was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridin-3-yl)propanamide as a colorless amorphous (82.6 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([O:7][CH3:8])=[O:6].[CH3:18][Sn](C)(C)C>C1(C)C=CC=CC=1.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>[CH3:18][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1ccc(CN2CCCC2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CN2CCCC2)c(C)c1
Temperature: 137.5 °C

Procedure:
A solution of methyl 3-bromo-4-[(1-pyrrolidinyl)methyl]benzoate (16 g, 53.7 mmol) in 110 mL of toluene was treated with Pd(PPh3)4 (3.1 g, 2.68 mmol) and tetramethyltin (22.3 mL, 161.1 mmol). The resulting mixture was heated at 135-140° C. for 36 hr in a sealed tube. After cooling to ambient temperature, the reaction mixture was filtered through diatomaceous earth and concentrated in vacuo. The crude brown residue was purified by PrepLC (SiO2; 97:2:1 hexanes-THF-TEA) to afford 11.4 g (48.9 mmol; 91%) of the title compound as a slightly yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[O:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>CN(C=O)C.[Cu](I)I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]2[O:9][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: c1cocn1
Reactant: Fc1ccc(I)cc1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2ncco2)cc1
Temperature: 25 °C
Yield: 25539.1 %

Procedure:
A solution of 1-fluoro-4-iodobenzene (1 g, 0.0144 mmol) in DMF (15 mL) was purged with argon, and oxazole (6.4 g/3.3 mL, 0.02898 mmol), copper iodide (5.5 g, 0.02898 mmol) and palladium (II) acetate (0.15 g, 0.000724 mmol) was added. The reaction mixture was purged with argon for 5 min and refluxed under argon for 12 h. The solution was cooled to room temperature and diluted with ice cold water (100 mL). The reaction mixture was extracted with ethyl acetate (200 mL) and filtered through Celite® reagent. The organic solvent was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure to obtain crude product. The crude product was purified by Biotage IsoleraOne® column using a 25 g column (7% ethyl acetate in hexane) to give 2-(4-fluorophenyl)oxazole (0.6 g, 26%) as yellow liquid. 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 8.03-7.99 (m, 2H), 7.34 (t, 3H); LC-MS m/z calculated for [M+H]+164.05. found 164.1.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:37]=[CH:36][C:26]2[C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:28][O:29][C:25]=2[CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:33]4[CH2:32][CH2:31][CH:30]([C:27]5[C:26]6[CH:36]=[CH:37][C:23]([F:22])=[CH:24][C:25]=6[O:29][N:28]=5)[CH2:35][CH2:34]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 6-fluoro-3-piperidine-4-yl-benzo[d]isoxazole (Table No.1, SM 8) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=506.