Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1([NH2:13])[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)[CH:4]=[CH2:5].[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][N:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:22]2=[O:25])=[CH:17][C:16]=1F>CC(N(C)C)=O>[CH2:3]([C:6]1([NH2:13])[CH2:11][CH2:10][CH:9]([O:12][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][C:15]=2[Cl:14])[C:22](=[O:25])[N:21]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH:20]=[CH:19]3)[CH2:8][CH2:7]1)[CH:4]=[CH2:5]
Reactant: C=CCC1(N)CCC(O)CC1
Reactant: COc1ccc(Cn2ccc3cc(F)c(Cl)cc3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CCC1(N)CCC(Oc2cc3ccn(Cc4ccc(OC)cc4)c(=O)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
155 mg (3.86 mmol) of sodium hydride (60%) were suspended in 3 mL of dimethyl acetamide and 220 mg (1.42 mmol) of 4-allyl-4-amino-cyclohexanol (16), dissolved in 1 mL of dimethyl acetamide, were added dropwise. After 1 h, 409 mg (1.29 mmol) of 2-(4-methoxy-benzyl)-6-fluoro-7-chloro-2H-isoquinolin-1-one (10), dissolved in another 2 mL of dimethyl acetamide, were added. The reaction mixture was stirred at room temperature until the reaction was complete. The mixture was quenched by dropwise addition of water, extracted with a mixture of dichloromethane and 2-propanol (3:1) and the combined organic layers were evaporated. Water was added and the crude product was subjected to lyophilization to remove remainders of dimethyl acetamide. The obtained crude product was purified by silica gel chromatography to yield 148 mg of the title compound (17) as diastereomeric mixture. Rt=1.35 min, 1.40 min (Method B). Detected mass: 453.3 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCS(=O)(=O)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A mixture of 3-(1,1-dioxo-1-thiomorpholin-4-yl)-azetidine-1-carboxylic acid tert-butyl ester (3.35 g, 11.5 mmol) and TFA (15 mL) in DCM (30 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 4-Azetidin-3-yl-thiomorpholine 1,1-dioxide as a white solid (2.0 g, 91%). 1H NMR (CDCl3, 300 MHz): δ 3.64-3.53 (m, 4H); 3.49-3.39 (m, 1H); 3.08 (m, 4H); 2.86-2.79 (m, 4H); 1.83 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl.CN(C)CCCN=C=NCC.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)O)cc1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 10 mL glass vial was added 4-tert-butyl-trans-cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) followed by CH2Cl2 (5 mL), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (225 mg, 1.17 mmol, Bachem) and aniline (98 uL, 100 mg, 1.08 mmol, Aldrich). The reaction mixture was magnetically stirred at 25° C. for 24 h. EtOAc was added (60 mL) and the mixture washed successively with 1 N NaOH (2×20 mL), 1 N HCl (20 mL), water (20 mL) and satd NaCl (20 mL), dried over MgSO4, filtered and concentrated. Recrystallization from hexane and CH2Cl2 provided the title product as white crystals. MP 141° C. MS (ESI, pos. ion) m/z: 280 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.CCOC(C)=O.[Cu](I)I>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:12])=[N:8][N:9]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)n[nH]c1C
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(C)nn(-c2cncc(C(F)(F)F)c2)c1C
Temperature: 160 °C
Yield: 22.3 %

Procedure:
3,5-Dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.10 g, 1 mmol) (prepared as described in Tett 2002, 58, 18, p 3639), 3-bromo-5-trifluoromethyl-pyridine (0.16 g, 1 mmol), copper iodide (0.02 g, 0.2 mmol) and cesium carbonate (1.0 g, 3 mmol) were suspended in DMA (0.5 ml) and heated to 160° C. for 16 h. The reaction was diluted with EtOAc, washed repeatedly with ammonium hydroxide, brine and dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (EtOAc:n-heptane 1:9-2:8 gradient affording the title compound (0.07 g, 35%) as a yellow oil. MS: 314.2 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:25])=[C:22]([OH:24])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:25])=[C:22]([CH:23]=1)[O:24][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Nc1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)c(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 26.9 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (800 mg, 2.44 mmol), 5-amino-2-chlorophenol (422 mg, 2.93 mmol), potassium carbonate (843 mg, 6.1 mmol) and N,N-dimethylformamide (6.0 mL) as starting materials and in the same manner as in Example 91, the title compound (226 mg, 27%) was obtained as a brown solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:26][OH:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C.C(#N)C>[OH:1][C@H:2]([CH2:26][OH:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[C:12]([F:29])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: F[B-](F)(F)F
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H](O)CO)cnc21
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H](O)CO)cnc21
Yield: 25.4 %

Procedure:
To a solution of (S)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 5) (1.25 g, 2.58 mmol, 1 eq) in DMF (26 mL) was added a mixture of Selectfluor (1.187 g, 3.35 mmol, 1.3 eq) in acetonitrile (26 mL). The reaction mixture was irradiated with microwave at 82° C. for 10 minutes and filtered. The filtrate was purified by preparatory LC/MS (30-55% CH3CN in H2O) to give (S)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 19) as an off-white solid (331 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.36-3.42 (m, 1 H) 3.42-3.51 (m, 1 H) 3.59 (s, 3 H) 3.63-3.72 (m, 1 H) 3.73-3.81 (m, 1 H) 4.32 (dd, J=13.14, 3.03 Hz, 1 H) 4.79 (br. s., 1 H) 5.10 (br. s., 1 H) 6.98 (td, J=8.46, 5.31 Hz, 1 H) 7.52 (dd, J=8.46, 1.14 Hz, 1 H) 7.68 (dd, J=10.36, 1.77 Hz, 1 H) 8.51 (s, 1 H) 10.24 (d, J=2.27 Hz, 1 H). [M+H] calc'd for C17H15F21N4O4, 505; found, 505.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:14]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=1.CS(O)(=O)=O>O1CCOCC1.C(OCC)(=O)C>[I:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([NH:1][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: COC(=O)c1cc(N)cc(I)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
To a flask containing methyl 3-amino-5-iodobenzoate (500 mg, 1.81 mmol) was added a solution of 2-chloro-4-(trifluoromethyl)pyrimidine (379 mg, 2.08 mmol) in dioxane (5.6 mL). Methanesulfonic acid (199 mg, 2.08 mmol) was added and the reaction was heated at 100° C. overnight. The reaction was cooled, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield methyl 3-iodo-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}benzoate (538 mg, 1.27 mmol, 71% yield). MS ESI: [M+H]+ m/z 424.0.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[Mg]>>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Mg]
Product: OC1(c2ccc(C(F)(F)F)cc2)CCC2(CC1)OCCO2
Yield: 94.5 %

Procedure:
This compound was prepared from 1,4-cyclohexanedione monoethylene ketal (10.9 g, 70 mmole) and the Grignard reagent prepared from 4-bromobenzotrifluoride (25.0 g, 110 mmole) and magnesium (2.7 g, 110 mmole) in a manner similar to example 3. The crude product was crystallized from petroleum ether to give the product (20 g, 94.8% ).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1.O>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH2:31][N:9]2[C:10]3[C:15](=[N:14][CH:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3cccnc3c2=O)cc1C
Reaction time: 0.08 h
Yield: 12.2 %

Procedure:
To a solution of 0.060 g (0.216 mmol) of 3-(3,4-Dimethyl-benzoyl)-1H-[1,5]naphthyridin-4-one in 2.0 mL of N,N-dimethylformamide was added 10.4 mg (0.259 mmol, 60% dispersion in oil) of sodium hydride and the reaction was stirred for 5 min. 65 mg (0.259 mmol) of 2-bromo-6-bromomethyl-pyridine was added and the reaction was stirred at room temperature for 3 h. Water was added and the solid collected by filtration. The crude brown solid was purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 11.8 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-1H-[1,5]naphthyridin-4-one as an off white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:25][CH2:24][CH2:23][CH2:22][C:21]([C:26]([O:28]CC)=[O:27])=[CH:20][C:19]=3[CH:31]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:25][CH2:24][CH2:23][CH2:22][C:21]([C:26]([OH:28])=[O:27])=[CH:20][C:19]=3[CH:31]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCO3)cc1
Reaction time: 8 h
Yield: 32.5 %

Procedure:
Ethyl 8-[4-(2-butoxyethoxy)phenyl]-3,4-dihydro-1-benzoxocin-5-carboxylate (527 mg) was dissolved in THF (40 ml) and methanol (40 ml). Aqueous 1N sodium hydroxide solution (12.4 ml) was added to the solution and the resulting solution was stirred overnight. After neutralization with 1N hydrochloric acid at 0° C., the solution was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from hexane-ethyl acetate to obtain colorless crystals of 8-[4-(2-butoxyethoxy)phenyl]-3,4-dihydro-2H-1-benzoxocin-5-carboxylic acid (160 mg).
Reaction SMILES: [CH2:1]([C:5]1[NH:14][C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]2[C:32]#[N:33])=[CH:21][CH:20]=1>CS(C)=O>[CH2:1]([C:5]1[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]3[C:32]#[N:33])=[CH:23][CH:24]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1c(Cl)c(Cl)cn1-c1ccc(CBr)cc1
Reactant: CCCCc1nc2c(C)ccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)c(Cl)c2C#N)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 41.5 %

Procedure:
To a solution of 2-butyl-7-methyl-3H-imidazo[4,5-b]-pyridine (568 mg) in dimethyl sulfoxide (7 ml) was added sodium hydride (132 mg, 60% oil dispersion) at ambient temperature. The mixture was stirred for 40 minutes at the same temperature. To the mixture was added dropwise a solution of 1-(4-bromomethylphenyl)-3,4-dichloropyrrole-2-carbonitrile (990 mg) in dimethyl sulfoxide (3 ml). The mixture was stirred for 2 hours at ambient temperature and ice water (30 ml) was added therein. The separated oil was extracted twice with ethyl acetate. The extracts were washed with water, dried, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted by 50% ethyl acetate in n-hexane to give 2-butyl-3-[4-(2-cyano-3,4-dichloro-1-pyrrolyl)benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (546 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: Cc1ccc(OCc2ccc(Cl)cc2C(=O)O)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccc(C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(4-methylphenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][CH:7]1[C:15](=[O:16])[N:10]2[CH2:11][CH2:12][NH:13][CH2:14][C@@H:9]2[CH2:8]1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][CH:7]1[C:15](=[O:16])[N:10]2[CH2:11][CH2:12][N:13]([S:28]([C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:32])[F:33])=[CH:27][CH:26]=3)(=[O:30])=[O:29])[CH2:14][C@@H:9]2[CH2:8]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C1C(Cc2cccc(F)c2)C[C@H]2CNCCN12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C(Cc2cccc(F)c2)C[C@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CCN12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
The product from Example 213B (20 mg, 0.070 mmol) was suspended in CH2Cl2 (0.5 mL), 4-(trifluoromethyl)benzene-1-sulfonyl chloride (21 mg, 0.084 mmol) and triethylamine (0.049 mL, 0.35 mmol) were added, and the resulting mixture was stirred at room temperature for 90 minutes. The mixture was partitioned between water and CH2Cl2, and the organic layer was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% CH3OH in CH2Cl2 to give the title compound (30 mg, 94%). 1H NMR (300 MHz, CDCl3) δ ppm 1.16-1.51 (m, 1H) 1.59-1.72 (m, 1H) 1.88-2.03 (m, 1H) 2.09-2.32 (m, 1H) 2.64-3.12 (m, 4H) 3.27-3.64 (m, 1H) 3.73-3.86 (m, 2H) 4.11 (dd, J=13.22, 2.37 Hz, 1H) 6.68-6.98 (m, 3H) 7.08-7.29 (m, 1H) 7.77-7.89 (m, 4H); MS (ESI) m/z 457 (M+H)+.
Reaction SMILES: C([O:4][C:5]([CH3:7])=[CH2:6])(=O)C.C[O-].C([Sn+](CCCC)CCCC)CCC.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH:31]=[CH:32][CH:33]=[O:34].C(O)(=O)CC(O)=O>CCOCC>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH:31]=[CH:32][CH:33]([OH:34])[CH2:6][C:5](=[O:4])[CH3:7]
Reactant: O=CC=Cc1ccc(Cl)cc1Cl
Reactant: C=C(C)OC(C)=O
Agent: CCCC[Sn+](CCCC)CCCC
Agent: C[O-]
Agent: O=C(O)CC(=O)O
Solvent: CCOCC
Product: CC(=O)CC(O)C=Cc1ccc(Cl)cc1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-Acetoxypropene (3.3 ml, 30 mmole) and tri-n-butyltin methoxide (5.7 g, 24 mmole) were combined and stirred at 60°-70° C. under N2 for 1 hour then placed under vacuum for an additional 30 minutes. 3-(2,4-Dichlorophenyl)propenal (4 g, 20 mmole) was added and the reaction mixture was stirred at 70° C. under N2 for 4 hours. The clear reaction mixture was then cooled, treated with malonic acid (1 g, 10 mmole) in ether (20 ml) and refluxed for 30 minutes. After cooling to -20° C., the reaction mixture was filtered and the precipitate was washed with ether (4×10 ml). The ethereal solutions were combined, evaporated and the residual oil was chromatographed on a 60 mm column with 15 cm of silica gel (230-400 mesh). Elution with chloroform-methanol (99:1, v:v; 2.0 L) provided the title compound as a thick yellow oil (4.2 g, 81%), pmr (CDCl3) 2.2 (3H, s), 2.73 (2H, d), 4.73 (H, m), 6.10 (H, dd).
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:9])[CH2:7][CH:8]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[CH3:16][C:17]1([CH3:27])[C@H:19]([CH:20]=[C:21]([CH3:23])[CH3:22])[C@H:18]1[C:24](Cl)=[O:25]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[CH3:16][C:17]1([CH3:27])[C@H:19]([CH:20]=[C:21]([CH3:22])[CH3:23])[C@H:18]1[C:24]([O:9][CH:6]1[CH2:7][CH:8]=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]1)=[O:25]
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: C=CCC1=CCC(O)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCC1=CCC(OC(=O)[C@@H]2[C@@H](C=C(C)C)C2(C)C)C1
Yield: 65.6 %

Procedure:
To a mixture of (RS)-3-(2-propenyl)-3-cyclopenten-1-ol (115 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (5 mg) and toluene (5 ml), (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarbonyl chloride (171 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 165 mg of (RS)-3-(2-propenyl)-3-cyclopenten-1-yl (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate (Compound No. 41). Yield 65% DD27 1.4895
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:11][C:12]([CH2:14][N:15]2[CH2:21][CH:20]3[N:22](C(OC(C)(C)C)=O)[CH:17]([CH2:18][CH2:19]3)[CH2:16]2)=[O:13])[NH:3]1.CO.[ClH:32]>O1CCOCC1>[ClH:32].[CH:20]12[NH:22][CH:17]([CH2:18][CH2:19]1)[CH2:16][N:15]([CH2:14][C:12]([NH:11][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=1[CH2:10][C:2](=[O:1])[NH:3]3)=[O:13])[CH2:21]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(CC(=O)Nc1cccc3c1CC(=O)N3)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C1Cc2c(cccc2NC(=O)CN2CC3CCC(C2)N3)N1

Procedure:
The product of step (ii) (0.8 g) was dissolved in 2M hydrogen chloride in 1,4-dioxane (10 ml), 1,4-dioxane (10 ml), methanol (10 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The solvents evaporated under reduced pressure to dryness. Yield: 0.8 g
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:23]([O:25][C:26](C)(C)[CH3:27])=[O:24])[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][C:19](C)(C)[CH3:20])=[O:17])=O)(C)(C)C.S(Cl)(Cl)=O>C(O)C>[NH2:8][C@@:9]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)[C@H]1[C@@H]2C(=O)C[C@@](N)(C(=O)OCC)[C@@H]21
Yield: 88.7 %

Procedure:
Charge a 500 mL three neck flask equipped with a condenser, nitrogen inlet and a thermometer with ditert-butyl (1S,2S,5R,6R)-2-(tert-butoxycarbonylamino)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (15 g, 36.4 mmol) in ethanol (365 mL). Add thionyl chloride (13.3 mL, 182.3 mmol) to a stirring solution at room temperature via syringe (small exotherm) then heat to reflux. After 24 hours cool the reaction to room temperature and concentrate in vacuo. Dissolve the residue in dichloromethane (50 mL) then concentrate on a rotary evaporator (repeat 3 times). Partition the residue between ethyl acetate (200 mL) and saturated sodium hydrogenate carbonate (150 mL). Wash the organic phase with brine (150 mL), dry over sodium sulfate, filter then concentrate to dryness to give the title compound as an oil (8.24 g, 32.3 mmol). MS (m/z): 256 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:16]=4[F:23])[C:13](O)=[CH:12][C:11]3=[O:25])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:16]=4[F:23])[C:13]([NH:32][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:12][C:11]3=[O:25])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC1CCCCC1
Reactant: O=C1C=C(O)C(c2cc(F)cc(F)c2F)N1c1ccc2[nH]cnc2c1
Product: O=C1C=C(NC2CCCCC2)C(c2cc(F)cc(F)c2F)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(2,3,5-trifluorophenyl)-1H-pyrrol-2(5H)-one (0.115 g, 0.3 mmol) and cyclohexylamine (0.48 ml, 4.2 mmol) according to method 7 described above.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])=[O:2].[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC=CC=1.C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:16][CH2:17][O:18][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C2OCCO2)c([N+](=O)[O-])c1
Yield: 78.3 %

Procedure:
To a solution of methyl 4-formyl-3-nitrobenzoate (9.0 g, 43.0 mmol) in toluene (150 mL) was added ethylene glycol (7.20 mL, 129 mmol) followed by p-TsOH (0.409 g, 2.152 mmol) and the reaction mixture was heated at reflux temperature with azeotropic removal of H2O using a Dean-Stark trap for 4 h. The reaction mixture was then cooled and diluted with DCM. The DCM layer was then washed with saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and concentrated to yield a residue. The residue was dissolved in minimal quantity of DCM and purified by silica gel chromatography to yield the desired product (8.53 g, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.27 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 6.38 (s, 1H), 4.00 (dt, J=3.8, 1.9 Hz, 2H), 3.94 (dt, J=3.8, 1.9 Hz, 2H), 3.91 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[C:12](=O)[NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[N:10][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3ccc(C)c(C)c3)n[nH]c(=O)c2c1
Product: COc1ccc2c(-c3ccc(C)c(C)c3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(3,4-dimethylphenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.