Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:16]([NH:19][C:20](=[CH2:25])[C:21]([O:23][CH3:24])=[O:22])(=[O:18])[CH3:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]([NH:19][C:20](=[CH:25][C:5]1[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[C:21]([O:23][CH3:24])=[O:22])(=[O:18])[CH3:17]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC(C)=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere 50.0 g (171 mmol) 3,5-bis-(trifluoromethyl)-bromobenzene, 25.0 g (171 mmol) methyl 2-acetylamino-acrylate in 475 mL triethylamine and 250 mL acetonitrile were combined with 3.9 g (12.4 mmol) tri-o-tolyl-phosphane and 2.8 g (12.5 mmol) Pd(OAc)2 and stirred for 18 h at 80° C. After the reaction had ended the reaction mixture was evaporated down i. vac. to approx. 200 mL, combined with 400 mL EtOAc and 400 mL water, the precipitate was suction filtered and the phases were separated. The organic phase was dried over Na2SO4, combined with activated charcoal, filtered and evaporated to dryness. The residue was stirred with DIPE, suction filtered and dried i. vac.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[CH:14])[N:8]=1.[CH3:15][C:16]([CH3:18])=[O:17]>O1CCCC1>[Br:6][C:7]1[N:8]=[C:9]([C:13]#[C:14][C:16]([CH3:18])([OH:17])[CH3:15])[CH:10]=[CH:11][CH:12]=1
Reactant: C#Cc1cccc(Br)n1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#Cc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.6 mL of 1.6M in hexanes, 0.96 mmol) was added to a cooled (−78° C.) solution of 2-bromo-6-ethynylpyridine (150 mg, 0.82 mmol) in tetrahydrofuran (4.1 mL). A tan slurry formed. The mixture was stirred for 30 minutes while warming to −30° C. at which time acetone (0.3 mL, 4.1 mmol) was added. The slurry dissolved to form a light orange solution. The reaction was stirred for an additional 2 hours while warming to 0° C. The reaction was quenched via the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo and purified via flash chromatography (0-50% ethyl acetate/hexanes) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.S(=O)(=O)(O)O.[CH3:25]O>>[CH3:25][O:18][C:17](=[O:19])[CH2:16][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=2)[NH:13][CH:14]=1
Reactant: CO
Reactant: Cn1cc(-c2cnc3[nH]cc(CC(=O)O)c3c2)cn1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c[nH]c2ncc(-c3cnn(C)c3)cc12
Yield: 70 %

Procedure:
[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid (200 mg, 0.78 mmol) was suspended in Methanol (4 mL). Next, sulfuric acid (125 uL) was added and the solution was heated to reflux for 2 hours. The solution was concentrated under vacuum and the crude material was dissolved in dichloromethane, transferred to a separatory funnel and washed with sat. NaHCO3 (aq). The organic layer was dried over Na2SO4 and concentrated down. The crude product was purified by flash chromatography (0-10% Methanol/dichloromethane gradient) to afford the title compound (148 mg, 70% yield). MS m/z=271 [M+H+]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])([CH2:33][O:34][Si](C(C)(C)C)(C)C)[CH2:25][O:26][P:27]([O:31][CH3:32])([O:29][CH3:30])=[O:28])=[C:18]([Cl:50])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([NH:42][C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])([CH2:33][OH:34])[CH2:25][O:26][P:27]([O:29][CH3:30])([O:31][CH3:32])=[O:28])=[C:18]([Cl:50])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COP(=O)(OC)OCC(CCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COP(=O)(OC)OCC(CO)(CCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a THF solution (30 mL) of the compound of Example 243 (2.70 g), 1 mol/L tetrabutylammonium fluoride in THF (5 mL) was added and the mixture was stirred for 1 hour at room temperature. Following addition of water, the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the desired product as a colorless oil (2.30 g).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.Cl[C:24]1[C:25]2CN(C(OCC3C=CC=CC=3)=O)CCC=2N=C(C)N=1.P(Cl)(Cl)(Cl)=O>>[CH2:24]([O:1][C:2]1[C:3]2[CH2:12][NH:11][CH2:10][CH2:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1)[CH3:25]
Reactant: Cc1nc(Cl)c2c(n1)CCN(C(=O)OCc1ccccc1)C2
Reactant: Cc1nc(O)c2c(n1)CCN(C(=O)OCc1ccccc1)C2
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1nc(C)nc2c1CNCC2

Procedure:
Benzyl 4-hydroxy-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate, which may be prepared using the general method of E. Kretzschmar and P. Meisel, Pharmazie 1988, 43, 475-476, was converted to benzyl 4-chloro-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate via treatment with phosphorus oxychloride. Chloride displacement with sodium ethoxide was followed by hydrogenolytic removal of the protecting group to afford the requisite 4-ethoxy-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH:15][CH:16]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.CS(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:16](=[O:15])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1
Reactant: COc1ccccc1C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccccc1C(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a stirring solution of phosphorus pentoxide (0.30 g, 1.10 mmol) in DCM (8 mL) at 0° C. was added a solution of 5-{4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione (0.20 g, 0.54 mmol) in DCM (8 mL) followed by dimethyl sulfoxide (0.20 mL, 2.80 mmol). After stirring for 15 minutes, N,N-diiisopropylethylamine (0.28 mL, 1.60 mmol) was added. After 45 minutes, the reaction mixture was cast into cold saturated NaHCO3 and extracted with EtOAc (×2). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 0-10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 175 mg (88%) of the title compound as a light yellow solid. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[I:18])[C:11](OC)=[O:12])[CH2:4][CH2:5][CH3:6].Cl>O1CCCC1>[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH2:11][OH:12])[CH:15]=[CH:16][C:17]=1[I:18])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1cc(C(=O)OC)ccc1I
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOc1cc(CO)ccc1I
Temperature: 60 °C
Yield: 100.1 %

Procedure:
8.17 g (0.375 mol, 3 eq) of lithium borohydride are added to a solution of 41.78 g (0.125 mol, 1 eq) of methyl 3-butoxy-4-iodobenzoate in 210 ml of tetrahydrofuran. The reaction medium is heated at 60° C. for 2 hours and then hydrolyzed cautiously in ice-cold saturated ammonium chloride solution. The reaction medium is neutralized with concentrated hydrochloric acid and then extracted with ethyl acetate. The organic phases are washed with water and dried over magnesium sulfate. The solvent is evaporated off and 38.31 g of (3-butoxy-4-iodophenyl)methanol are obtained in the form of a whitish oil. Yield=100%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:6][C:7](=[O:10])[O:8][CH3:9].C[O-].[Na+].[CH3:20][C:21](=[CH:23][CH2:24][CH2:25]/[C:26](=[CH:28]/CO)/[CH3:27])[CH3:22].CO>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:5]([CH2:4][C:3]([O:2][CH2:1]/[CH:28]=[C:26](/[CH2:25][CH2:24][CH:23]=[C:21]([CH3:20])[CH3:22])\[CH3:27])=[O:16])[CH2:6][C:7](=[O:10])[O:8][CH2:9]/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22])/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])\[CH3:22]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: COC(=O)CN(CC(=O)OC)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)=CCC/C(C)=C/COC(=O)CN(CC(=O)OC/C=C(\C)CCC=C(C)C)CC(=O)OC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
To a mixture of N,N-bis(2-methoxy-2-oxoethyl)glycine methyl ester (7.0 g, 30 mmol, 1 eq) in toluene (80 ml) under argon was slowly added some sodium methoxide (0.49 g, 0.009 mol, 3*0.10 eq) and geraniol (14.57 g, 95 mmol, 3*1.05 eq). The mixture was heated under vacuum (10 mm Hg) and the methanol produced by the transesterification reaction is distilled with toluene over two hours after which the reaction appeared completed by 1H NMR. Any remaining toluene is evaporated under vacuum. Diethyl ether was added (200 ml) and the mixture stored at 4° C. for one hour prior to filtration. The filtrate was then concentrated under vacuum yielding to the expected N,N-bis(2-geranyloxy-2-oxoethyl)glycine geranyl ester as a yellow oil (quantitative yield).
Reaction SMILES: C(O[C:4]([CH:6]1[C:14](=[O:15])[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:16])=[O:5])C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:25][C:4]([CH:6]2[C:14](=[O:15])[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:16])=[O:5])[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)C1C(=O)c2cccnc2C1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cccc(NC(=O)C2C(=O)c3cccnc3C2=O)c1
Temperature: 25 °C

Procedure:
5,7-Dioxo-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid ethyl ester (100 mg) (see D. Binder, Monatshefte für Chemie, Vol. 105, Pp. 179-186, 1974), m-anisidine (0.124 ml) and acetic acid (0.052 ml) were suspended in toluene (5 ml). This mixture was refluxed for 2 hours under nitrogen. The mixture was cooled to room temperature and the ppt was collected with suction. The ppt was washed with toluene and dichloromethane and dried under reduced pressure to give a brown powder (112 mg). ESI−MS: m/z 297 (MH+); 1H-NMR (DMSO-d6): δ3.74 (3H, s), 6.54 (1H, dd, J=8.5 Hz, J=2.5 Hz), 7.04 (1H, bd, J=8.5 Hz), 7.16 (1H, t, J=8.5 Hz), 7.38 (1H, dd, J=7.0 Hz, 4.5 Hz), 7.44 (1H, t-like, 2.5 Hz), 7.70 (1H, dd, J=7.0 Hz, 1.5 Hz), 8.57 (1H, dd, J=4.5 Hz, 1.5 Hz), 10.79 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:16]([O:18]CC)=O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[N:9]=1)=[O:4].C(N(CC)C(C)C)(C)C>CO>[CH3:15][O:14][C:10]1[N:9]=[C:8]([CH2:7][CH:6]2[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:16]2=[O:18])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@H](Cc1cccc(OC)n1)NC(=O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cccc(CC2NC(=O)CNC2=O)n1
Temperature: 70 °C
Reaction time: 48 h
Yield: 53.9 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl glycyl-3-(6-methoxy-2-pyridinyl)alaninate (945 mg, 3.36 mmol) and N,N-diisopropylethylamine (0.58 mL, 3.36 mmol) in MeOH (20 mL). The reaction mixture was stirred at 70° C. for two days. The mixture was allowed to cool to room temperature. The solid that formed was collected by filtration, washed with MeOH, and dried to give 3-((6-methoxy-2-pyridinyl)methyl)-2,5-piperazinedione (426 mg) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][CH2:22][NH2:23])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][CH2:22][NH:23][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(CCN)cc1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)c2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 45 parts of benzoyl chloride in 149 parts of chloroform is added portionwise over a 30 minute period to a solution of 78 parts of 3-benzyloxy-4-methoxyphenethylamine in 72 parts of triethylamine and 596 parts of chloroform. The mixture is stirred at room temperature for an additional 90 minutes. It is then washed twice with water and once with dilute aqueous sodium bicarbonate solution, dried over anhydrous calcium sulfate and stripped to a low volume under reduced pressure. Addition of n-hexane results in crystallization of N-(3-benzyloxy-4-methoxyphenethyl)benzamide. That product melts at about 136°-138°C.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][CH2:53][O:54][CH3:55])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)Cl>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][CH2:53][O:54][CH3:55])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:2][CH2:3]1
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCOC)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCOC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution tert-butyl (3R,4S)-3-({cyclopropyl[3-(2-methoxyethoxy)-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)-ethoxy]phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in DCM (0.05 M) was added 4 M HCl in dioxane (10 eq.) and stirred at rt for 5 h. The reaction was concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 5% [2 M NH3 in MeOH] in DCM) to afford the title compound as a colorless oil. 1H NMR (acetone d-6): δ 7.28 (s, 2H), 7.20 (d, 2H), 6.84 (d, 2H), 6.62 (s, 1H), 6.48 (s, 1H), 6.4 (s, 1H), 4.47-4.25 (m, 6H), 4.05 (t, 2H), 3.71 (t, 2H), 3.56 (m, 1H), 3.38 (s, 3H), 3.33 (t, 2H), 3.28 (s, 3H), 3.25 (m, 1H), 3.11 (m, 2H), 2.76 (m, 2H), 2.55 (t, 2H), 2.34 (s, 3H), 2.32 (m, 1H), 1.78 (m, 4H), 0.77 (m, 3H), 0.49 (m, 1H). LRMS [M+H]=699.0
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH:26]([C:28]1[C:36]2[C:31](=[C:32]([CH2:37][N:38]([CH3:46])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=O>CO.N1CCCCC1>[C:41]([O:40][C:39]([N:38]([CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[NH:30][CH:29]=[C:28]2/[CH:26]=[C:7]1\[O:8][C:4]2[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[C:6]\1=[O:9])[CH3:46])=[O:45])([CH3:44])([CH3:43])[CH3:42]
Reactant: CN(Cc1cccc2c(C=O)c[nH]c12)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CN(Cc1cccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c12)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.029 g, 0.10 mmol) obtained in Example A16, Step 1 in methanol (3.0 mL) was added with tert-butyl (3-formyl-1H-indole-7-yl)methyl(methyl)carbamate (0.038 g, 0.11 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (99:1→95:5)) to obtain tert-butyl (Z)-4-({2-[(7-{[tert-butoxycarbonyl(methyl)amino]methyl}-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.044 g, 71%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22]Br)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCCC2=O)CC1
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 113.4 %

Procedure:
To a solution of 2-pyrrolidone (86 mg) in anhydrous dimethylformamide (5 ml) was added sodium hydride (45 mg). the reaction mixture was stirred under nitrogen at 50° C. for 35 minutes. 4-Bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (86 mg) in anhydrous dimethylformamide (5 ml) was added. The reaction mixture was stirred at 70° C. overnight. The solvents were removed in vacuo and the crude residue was partitioned between dichloromethane and water, the combined organic extracts were washed with brine, dried (MgSO4) and the solvents removed in vacuo to give a crude product. This was purified using flash chromatography to yield 4-(2-Oxo-pyrrolidin-1-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester (99 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][C:8]=1[O:15][CH3:16].[S:27]1[CH2:33][C:31](=[O:32])[NH:30][C:28]1=[S:29].CCO>CCOC(C)=O>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[C:33]2[S:27][C:28](=[S:29])[NH:30][C:31]2=[O:32])=[CH:9][C:8]=1[O:15][CH3:16]
Reactant: COc1cc(C=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=C1CSC(=S)N1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C=C2SC(=S)NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 14 h
Yield: 22 %

Procedure:
To a flask was added 4-(2,4-bis(trifluoromethyl)benzyloxy)-3-methoxybenzaldehyde from Step A (164 mg, 433 μmol), rhodanine (58 mg, 433 μmol), absolute EtOH (7 mL), and TEA (120 μL, 870 μmol). The reaction solution was allowed to stir at 65° C. for 14 h. The reaction solution was diluted with EtOAc (100 mL), washed with sat. NH4Cl (75 mL×3), dried over Na2SO4, filtered, and concentrated to ⅓ the original volume. The yellow precipitates were isolated by filtration under reduced pressure, washed with EtOAc (50 mL) and Et2O (50 mL) to afford the title compound (47 mg, 23%). 1H NMR (DMSO-d6) δ 13.25 (1H, br s), 7.90 (1H, d, J=8.1 Hz), 7.86 (1H, s), 7.80 (1H, d, J=8.60 Hz), 7.48 (1H, s), 6.99 (1H, dd, J=2.0 Hz, 8.6 Hz), 6.96 (1H, d, J=2.0 Hz), 6.86 (1H, d, J=8.3 Hz), 5.35 (2H, s), 3.88 (3H, s); MS (ESI) 494 (MH+).
Reaction SMILES: [CH:1]1([C:6](=[O:11])[CH2:7][CH2:8][C:9]#[CH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N[CH:16]([CH3:18])[CH3:17])(C)C>CN(C=O)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([C:6](=[O:11])[CH2:7][CH2:8][C:9]#[C:10][C:3]2[CH:2]=[C:1]([CH3:5])[C:6]([OH:11])=[CH:18][C:16]=2[CH3:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCCC(=O)C1CCCC1
Reactant: CC(C)NC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C#CCCC(=O)C2CCCC2)c(C)cc1O
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of 1-cyclopentyl-pent-4-yn-1-one (0.33 g, 2.2 mmol) from example F(7), Step 2,4-iodo-2,5-dimethyl-phenol (0.54 g, 2.2 mmol), copper (I) iodide (33 mg, 0.18 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (63 mg, 0.09 mmol), and diisopropylamine (2.2 mL) in DMF (2.2 mL) was heated to 100° C. for 30 minutes. The reaction was cooled to room temperature and diluted with 10 mL of EtOAc. The resulting slurry was filtered, and the mother liquor was concentrated to a black oil. The oil was then purified by flash chromatography to give the desired product (112 mg, 19% yield). 1H NMR (CDCl3) δ: 1.58-1.84 (m, 8H), 2.15 (s, 3H), 2.29 (s, 3H), 2.68-2.70 (m, 2H), 2.75-2.79 (m, 2H), 2.90 (p, J=8.08 Hz, 1H), 6.57 (s, 1H), 7.10 (s, 1H).
Reaction SMILES: C([O:4][NH:5][C:6]([CH:8]1[C:13]([OH:15])([CH3:14])[CH2:12][CH2:11][CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])C=C.C([O-])=O.C([NH+](CC)CC)C.C(#N)C>O>[OH:4][NH:5][C:6]([CH:8]1[C:13]([OH:15])([CH3:14])[CH2:12][CH2:11][CH2:10][N:9]1[S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17])=[O:7]
Reactant: C=CCONC(=O)C1N(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)CCCC1(C)O
Agent: CC[NH+](CC)CC
Agent: O=C[O-]
Solvent: CC#N
Solvent: O
Product: CC1(O)CCCN(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)C1C(=O)NO
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
To a solution 1-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid allyloxy-amide (0.14 g, 0.29 mmol), triethylammonium formate (0.35 mL of a 3M solution in water, 1.0 mmol) and acetonitrile (1.5 mL) was added tetrakistriphenylphosphine palladium (0.033 g, 0.029 mmol). After stirring for 30 min at 90-100° C., the mixture was cooled to room temperature and concentrated in vacuo and purified by silica gel chromatography eluting with 1:1 to 1:0 ethyl acetate-hexane, affording 0.030 g of 1-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide as a colorless solid after trituration from CH2Cl2-hexane: