Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[OH:18])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=[O:13])[CH:7]=1.[Cl:19][C:20]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=S)=[CH:30][C:21]=1[O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH3:29]>CC#N.CN(C=O)C>[Cl:19][C:20]1[CH:33]=[CH:32][C:31]([NH:34][C:35]2[O:18][C:17]3[CH:16]=[CH:15][C:4]([O:5][C:6]4[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=[O:13])[CH:7]=4)=[CH:3][C:2]=3[N:1]=2)=[CH:30][C:21]=1[O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH3:29]
Reactant: CN1CCC[C@H]1COc1cc(N=C=S)ccc1Cl
Reactant: NC(=O)c1cc(Oc2ccc(O)c(N)c2)ccn1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1COc1cc(Nc2nc3cc(Oc4ccnc(C(N)=O)c4)ccc3o2)ccc1Cl

Procedure:
To a stirring RT solution of 4-(3-amino-4-hydroxy-phenoxy)-pyridine-2-carboxylic acid amide (Step d, 217 mg, 0.884 mmol) in CH3CN (30 ml) and DMF (3 mL) was added (2S)-2-(2-chloro-5-isothiocyanato-phenoxymethyl)-1-methyl-pyrrolidine (208 mg, 0.737 mmol). The following day, the CH3CN was evaporated off, and the crude mix was diluted into 1N NaOH and EtOAc. The layers were separated. The aqueous layer was extracted 3× with EtOAc, and the combined organic layers were washed once with 1N NaOH and once with brine. The organic layer was then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography to yield the title compound. (MH+)=494.2; Calc'd 493.15 for C25H24ClN5O4.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:14]>>[CH2:19]([N:18]([CH2:21][CH3:22])[CH2:17][CH2:16][N:15]([CH2:13][CH3:14])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:20]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCNCCN(CC)CC
Product: CCCCCCC/C=C/C(=O)N(CC)CCN(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N,N′,N′-triethylethylenediamine as starting materials to give the aimed compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].O>CN(C=O)C>[CH:18]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1)([CH3:20])[CH3:19]
Reactant: O=C1CCOc2cc(O)ccc21
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc2c(c1)OCCC2=O)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
7-Hydroxy-4-chromanone (1.2 g, 7.3 mmol; Dann et al., Ann. 587, 16, 1954) and imidazole (1.0 g, 14.7 mmol) were dissolved in DMF (10 ml). Triisopropylsilyl chloride (1.8 ml, 8.2 mmol) in DMF (2 ml) was added dropwise at ambient temperature over 10 minutes. After stirring for 3 hours, the mixture was poured onto 100 ml ice and water, and extracted with ether (2×100 ml). The combined ether extracts were washed with 1M LiCl and then brine, dried over CaSO4, and concentrated to a brown oil which was purified by Kugelrohr distillation (0.5 torr, 70°-90° C). This removed a colorless, viscous oil impurity and left the brown oil product in the distillation pot (2.0 g, 85%). IR (KBr) 2945, 2867, 1685, 1605, 1268, 1163. HRMS Calcd. for MH+, 320.1807; observed, 320.1842.
Reaction SMILES: [CH3:1][C:2]1[C:13]2[N:9]([C:10]([CH2:15][CH2:16][CH3:17])=[N:11][C:12]=2[CH3:14])[C:8]2[N:7]=[CH:6][S:5][C:4]=2[N:3]=1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][C:6]1[S:5][C:4]2[N:3]=[C:2]([CH3:1])[C:13]3[N:9]([C:10]([CH2:15][CH2:16][CH3:17])=[N:11][C:12]=3[CH3:14])[C:8]=2[N:7]=1
Reactant: BrBr
Reactant: CCCc1nc(C)c2c(C)nc3scnc3n12
Solvent: ClC(Cl)Cl
Product: CCCc1nc(C)c2c(C)nc3sc(Br)nc3n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of 5,6-dimethyl-8-propyl-3-thia-1,4,7,8a-tetraaza-as-indacene from example 1 (40 mg, 0.16 mmol) in CHCl3 (10 mL) was added Br2 (78 mg, 0.5 mmol), then the solution was stirred at room temperature overnight to give a brown solution. LC-MS showed 30% of the title compound and 35% of 5,6-dimethyl-8-propyl-3-thia-1,4,7,8a-tetraaza-as-indacene. The reaction mixture was diluted with sat. NaHSO3 solution. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]#[CH:3].I[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:29][O:28][C:27]1[CH:26]=[CH:25][NH:24][C:23]=1/[CH:22]=[C:14]1\[C:15](=[O:21])[NH:16][C:17]2[C:13]\1=[C:12]([C:3]#[C:2][CH2:1][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:20]=[CH:19][CH:18]=2
Reactant: C#CCOc1ccccc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCOc3ccccc3)c21

Procedure:
Using Method C above, phenyl propargyl ether (65 mg, 0.49 mmol) (Lancaster) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2) using (Ph3P)2PdCl2 (20 mg) (Aldrich) and CuI (10 mg) (Aldrich) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h, yielding (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-(3-phenoxy-1-propynyl)-2H-indol-2-one. (Yield 92 mg, 62%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:13]=1
Reactant: Brc1ccc(I)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 140 °C

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (1.63 mL) and 1-bromo-4-iodobenzene (3 g) are dissolved in toluene (75 mL), treated with sodium tert-butoxide (1.53 g) and purged for 10 minutes with argon. Acetato-(2′-di-tert.-butylphosphino-1,1′-biphenyl-2-yl)-palladium-(II) (245 mg) is added and the mixture is heated for 15 minutes at 140° C. Then the mixture is partitioned between saturated aqueous NH4Cl solution and ethylacetate. The organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. LC (method 2): tR=1.06 min; Mass spectrum (ESI+): m/z=298 [M+H]+.
Reaction SMILES: [NH3:1].CO.[CH:4]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[C:14]([CH:18]=O)[NH:15]3)=[CH:11][CH:10]=2)[CH2:6][CH2:5]1>[Ni]>[CH:4]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[C:14]([CH2:18][NH2:1])[NH:15]3)=[CH:11][CH:10]=2)[CH2:6][CH2:5]1
Reactant: N
Reactant: O=Cc1cc2ccc(OCC3CC3)cc2[nH]1
Agent: [Ni]
Solvent: CO
Product: NCc1cc2ccc(OCC3CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To an ammonia-methanol (5 mL) solution of 6-cyclopropylmethoxy-1H-indole-2-carbaldehyde (144 mg, 669 μmol) described in Production Example 73-1-4 was added Raney nickel, which was stirred at room temperature for 8 hours under hydrogen atmosphere. The reaction mixture was filtered through Celite and the filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (91 mg, 63%) as a pale brown oil.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:14])=[C:11]([CH:13]=1)N.N([O-])=[O:16].[Na+]>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:14])=[C:11]([OH:16])[CH:13]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 50.7 %

Procedure:
A solution of concentrated sulphuric acid (6 mL) in distilled water (75 mL) was added to 5-bromo-2-methylaniline (1 g, 5.38 mmol). The resultant suspension was heated to 90° C. and stirred for 4.5 h. The reaction mixture was then cooled using an ice bath and a solution of sodium nitrite (384 mg, 5.57 mmol) in water (5 mL) was added to the reaction mixture at 0° C. The reaction was then allowed to warm to ambient temperature. The reaction mixture was then added to a solution of concentrated sulphuric acid (6 mL) in water (75 mL) which had been preheated to 90° C. The reaction mixture was stirred for 1 h at 90° C. and allowed to cool, on standing, overnight. A precipitate was observed in the reaction mixture. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to afford 5-bromo-2-methylphenol as a brown solid (510 mg, 2.73 mmol, 51%). M.S. (ESI) (m/z) 185, 187[M−H]−
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].CC([O-])(C)C.[K+].F[C:13]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1.O>[F:1][CH:2]([F:5])[CH2:3][O:4][C:13]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: OCC(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1OCC(F)F
Reaction time: 0.08 h

Procedure:
A mixture of 2,2-difluoroethanol (0.178 mL, 2.82 mmol) and KOtBu (0.319 g, 2.70 mmol) in 10 mL THF was stirred for 5 min, then ethyl 2-fluoro-5-nitrobenzoate (0.500 g, 2.35 mmol) was added and it was stirred at rt overnight. Additional 60 μL 2,2-difluoroethanol and 110 mg KOtBu were added and it was stirred for 2 h. The mixture was diluted with H2O, concentrated i.vac. and extracted 2× with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated to furnish the subtitle compound. Yield: 0.52 g (81%); TLC: Rf=0.85 (silica gel, DCM:EtOH 99:1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][C:22]1([CH3:28])[CH2:24][CH:23]1[C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH:8][C:25]([CH:23]1[CH2:24][C:22]1([CH3:28])[CH3:21])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(N)C(=O)OC(C)(C)C
Reactant: CC1(C)CC1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(NC(=O)C1CC1(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 8.98 g (48 mmole) of DL-norleucine t-butyl ester and 5.05 g (50 mmole) of triethylamine in 100 ml of CH2Cl2 stirred in an ice bath under a drying tube was added dropwise (over a period of 75 min.) a solution of 6.39 g (48 mmole) of 2,2-dimethylcyclopropanecarbonyl chloride (M. Elliot and N. R. James, British Pat. No. 1,260,847 (1972)) in 50 ml of CH2Cl2. Precipitation of Et3N HCl occurred during the addition, especially toward the end. As the ice gradually melted, the mixture was allowed to warm to room temperature. After 16 hrs, the mixture was shaken with 200 ml of 0.5 N HCl. The CH2Cl2 fraction was washed with an additional 200 ml of 0.5 N HCl, then with 2×200 ml of 0.5 N NaOH, and finally 200 ml of H2O. The CH2Cl2 fraction was dried with MgSO4, treated with charcoal, and filtered through Celite. The filtrate was concentrated on the rotovac (finally under high vacuum). Yield of light orange residual oil=11.93 g (88%). Tlc (2:1 hexane-EtOAc) showed a single spot. NMR and IR were in accord with the assigned structure. After standing for several days, the unused porition of this material crystallized: m.p. 52->65°.
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([C:18](=[O:36])[CH2:19][CH2:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29]COCCOC)=[CH:25][CH:24]=3)=[O:22])[CH:16]=[CH:17][C:9]1=2>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([C:18](=[O:36])[CH2:19][CH2:20][C:21]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)=[O:22])[CH:16]=[CH:17][C:9]1=2
Reactant: COCCOCOc1ccc(C(=O)CCC(=O)c2ccc3c(c2)OCCO3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCC(=O)c1ccc2c(c1)OCCO2)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat TFA (0.5 mL) was added to a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(4-((2-methoxyethoxy)methoxy)phenyl)butane-1,4-dione 11 (0.35 mmol) in CH2Cl2 (5 mL) stirred at room temperature. The solution was further stirred overnight at room temperature. The volatiles were evaporated under vacuum. The residue was purified by flash chromatography over silica gel eluting with 1% methanol in CH2Cl2 to get 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(4-hydroxyphenyl)butane-1,4-dione 4 as an off white solid (21% yield). 1H NMR (CDCl3, 400 MHz): δ ppm 3.37 (m, 4H), 4.29 (m, 2H), 4.33 (m, 2H), 5.76 (s, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.93 (m, 1H), 7.60 (m, 2H), 7.94 (d, J=8.8 Hz, 2H); ESIMS found C18H16O5 m/z 313 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:61][N:62]1[CH:66]=[C:65]([CH2:67][C:68](O)=[O:69])[CH:64]=[N:63]1>CN(C)C(=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][C:68](=[O:69])[CH2:67][C:65]6[CH:64]=[N:63][N:62]([CH3:61])[CH:66]=6)=[C:7]5[CH:8]=[N:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:21][CH:22]=1
Reactant: Cn1cc(CC(=O)O)cn1
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
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: CC(=O)N(C)C
Product: CN1C=CC(NC(=O)Cc2cnn(C)c2)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1

Procedure:
A stock solution of Example 14e and N,N-diisopropylethylamine (0.11 M and 0.33 M in N,N-dimethylacetamide, respectively, 350 μL, 0.038 mmol Example 14e and 0.11 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.13 M in N,N-dimethylacetamide, 350 μL, 0.046 mmol), and 2-(1-methyl-1H-pyrazol-4-yl)acetic acid (0.40 M in N,N-dimethylacetamide, 113 μL, 0.050 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to yield the title compound as an impure mixture. The material was dissolved in methanol (1 mL) and manually injected into the HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) give 0.0067 g (38%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.49 (d, J=2.44 Hz, 1H), 8.45 (d, J=2.75 Hz, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.40 (s, 1H), 7.07 (s, 1H), 6.87 (m, 2H), 6.57 (m, 2H), 4.60 (m, 2H), 4.07 (s, 3H), 3.81 (s, 3H), 3.55 (s, 2H). MS (APCI+) m/z 484.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:20][N:21]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:5][O:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.Br[C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36]>O1CCOCC1>[OH:3][C@@H:4]([CH2:20][N:21]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:34]([CH3:39])([C:35](=[O:36])[NH2:37])[CH3:38])=[CH:28][CH:27]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:5][O:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(Br)C(N)=O
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OC(C)(C)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Sodium hydride (10.8 mg of a 60% dispersion in oil, 0.27 mmol) was added to a solution of the phenol prepared in example 91 (100 mg, 0.25 mmol) in dry dioxane (1 ml) and the mixture stirred for 1 h at room temperature. 2-Bromo-2-methylpropanamide(Coutts, I.G.C., Southcott, M. R. J. Chem. Soc. Perkin Trans. 1, 1990, 767) was then added and the mixture heated at 100° C. for 8 h. The reaction mixture was filtered, concentrated in vacuo, and purified by flash chromatography (1:1 ethyl acetate: hexanes) to afford a light yellow solid (94.4 mg, 94%). MS (FD+) 489.6, Mp 84-86° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH2:16]([C:10]1[C:11](=[O:15])[NH:12][C:13]([CH3:14])=[C:8]([C:6]2[O:7][C:3]([CH2:2][NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[CH:4][CH:5]=2)[CH:9]=1)[CH3:17]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCc1cc(-c2ccc(CN)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(CNC(=O)c3ccc(OC)cc3)o2)c(C)[nH]c1=O

Procedure:
Example 269 is substantially repeated except for utilizing 5-(5-aminomethylfuran-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one and 4-methoxybenzoyl chloride to afford the title compound. MS: m/e=367 (M+H).
Reaction SMILES: C(OC(N[C@H](CCCCNC(OC(C)(C)C)=O)C(NCCC([O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=O)=O)=O)(C)(C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CO>[OH:17][CH:18]([CH2:19][N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)[CH2:42][O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Reactant: C1COCCN1
Solvent: CO
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OCC(O)CN3CCOCC3)cc1[C@@H](NC(C)=O)CC2
Yield: 55 %

Procedure:
A solution of N-[(5S)-3-(2,3-epoxypropoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (1) (0.092 g; 0.22 mmol) and morpholine (40 μl; 0.44 mmol) in methanol was heated at reflux for 4 hours. After evaporation to dryness the residue was purified by flash chromatography eluting with dichloromethane/ethanol (90/10) to give N-[(5S)-3-(2-hydroxy-3-morpholinopropoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide as a yellow foam.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][N:15]=2)[C:8]1=[O:28])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][N:15]=2)[C:8]1=[O:28]
Reactant: CC1(C)CN(c2ccc(C#Cc3ccccc3)cn2)C(=O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CN(c2ccc(C#Cc3ccccc3)cn2)C(=O)C1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
(100 mg, 0.18 mmol) (3RS)-3-(tert-Butyl-diphenyl-silanyloxy)-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 14, step 6) was dissolved in THF (1 ml) and TBAF (1M in THF) (184 μl, 0.184) was added drop wise at room temperature. The mixture was stirred for 1 hr at 60° C. The reaction mixture was extracted with sat. NaHCO3-solution and two times EtOAc. The organic layers were extracted with water, dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired (3RS)-3-hydroxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one (44 mg, 78% yield) was obtained as a white solid, MS: m/e=307.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:36].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:36][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:14]=2)[CH2:25][CH:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (1.13 g) in acetic acid (12.2 mL) was added ammonium acetate (3.01 g), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (855 mg, yield 79%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 445 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:29]#[N:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][C:39](=[O:40])[N:38]([CH3:42])[CH3:37])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([C:29]#[N:30])[CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(OC(=O)N(C)C)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 65 °C

Procedure:
To a suspension of the product of Example 57 in CHCl3 was added TEA (84 μL, 0.6 mmol) and dimethylcarbamoyl chloride (56 μL, 0.6 mmol). The resulted suspension was heated to 65° C. overnight with shaking. Solvent was removed under vacuum to give a crude, which was purified by chromatography on silica gel, eluting by MeOH-DCM (5:95) to afford the title compound (38.6 mg). 1H-NMR indicated one isomer. 1H-NMR (DMSO-d6): δ 97.73 (1H, d), 7.28-7.39 (7H, m), 7.14 (1H, d), 6.97 (1H, dd), 6.63 (1H, dd), 5.12 (2H, s), 4.98 (1H, t), 3.78 (3H, s), 3.05 (6H, m), 2.91 (3H, s), 0.99 (3H, t); MS (ESI): 585 (MH+).