Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].O1CCCC1.[CH:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[OH:19][CH:10]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: O=CCCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
Vinylmagnesium Bromide (120 mmol, 1M) in ether was added to 80 ml of dry tetrahydrofuran and cooled under inert atmosphere to 0° C. Hydrocinnamaldehyde (8.0 ml, 61 mmol) was added dropwise, and the solution was stirred for 10 min, quenched cautiously with saturated aqueous ammonium chloride, extracted with ether, washed with saturated brine, dried over MgSO4, and concentrated to give 9.82 g (98.6%) of the crude desired product.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]([F:31])([F:30])[C:8]([F:29])([F:28])[C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5])[CH3:2].[H-].[Na+].[CH2:34]([O:41][C:42]([N:44]1[CH2:46][CH2:45]1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:1]([N:3]([CH2:46][CH2:45][NH:44][C:42]([O:41][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:43])[S:4]([C:7]([F:31])([F:30])[C:8]([F:28])([F:29])[C:9]([F:26])([F:27])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5])[CH3:2]
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCNC(=O)OCc1ccccc1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C

Procedure:
5.272 g (10 mmol) of perfluorooctylsulfonic acid-N-ethylamide is dissolved in 30 ml of dimethylformamide. With exclusion of moisture, it is mixed with 330 mg (11 mmol) of sodium hydride (80% in oil). After gas generation is completed, the solution of 2.093 g (10 mmol) of N-benzyloxycarbonyl-aziridine is added dropwise to it. It is poured into 300 ml of ice water, extracted with dichloromethane, the organic solution is washed with water, it is dried on sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel with dichloromethane/methanol. The title compound is a glass-like solid.
Reaction SMILES: [CH2:1]([C@H:3]1[N:13]2[C@@H:7]([S:8][CH2:9][CH2:10][C@H:11]([NH:15]C(=O)OC(C)(C)C)[C:12]2=[O:14])[CH2:6][CH2:5][CH2:4]1)[CH3:2].[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[NH2:15][C@H:11]1[CH2:10][CH2:9][S:8][C@H:7]2[CH2:6][CH2:5][CH2:4][C@@H:3]([CH2:1][CH3:2])[N:13]2[C:12]1=[O:14]
Reactant: CC[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl (4S,7R,10aS)-7-ethyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (52 mg, 0.16 mmol) in DCM (1 mL) was added TFA (1.0 mL, 13 mmol). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was concentrated and dried under high vacuum to afford (4S,7R,10aS)-4-amino-7-ethylhexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5(7H)-one trifluoroacetate (54 mg, 0.16 mmol, 100% yield) as an oil. Anal. Calcd. for C11H20N2OS m/z 228.3. found: 229.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]([CH3:10])=[N:6][CH:7]=[CH:8][CH:9]=1.[CH2:11]([O:13][C:14]([C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1)=[O:15])[CH3:12]>CN(C=O)C>[CH2:11]([O:13][C:14]([C:16]1[N:17]=[N:18][C:19]([O:3][C:4]2[C:5]([CH3:10])=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:20][CH:21]=1)=[O:15])[CH3:12]
Reactant: Cc1ncccc1O
Reactant: CCOC(=O)c1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2cccnc2C)nn1
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
Sodium hydride (0.21 g of an 80% dispersion in oil, 7.0 mmol) was added to a solution of 3-hydroxy-2-methylpyridine (0.88 g, 8.0 mmol) in DMF (15 ml). After 1.5 h at r.t. a solution of 6-chloropyridazine-3-carboxylic acid ethyl ester (Chem. Pharm. Bull. 1994, 42(2), 371) (1.0 g, 5.4 mmol) in DMF (10 ml) was added and the mixture was stirred for a further 1.5 h. The DMF was removed in vacuo and the residue partitioned between dil. aq. NaOH (50 ml) and CH2Cl2 (100 ml). After drying (Na2SO4) the organics were evaporated to give the title compound as an off-white solid (1.09 g, 78%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH3:9])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=1)=[O:27]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A mixture of {(S)-1-[4-fluoro-2-(6-fluoropyridin-3-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (276 mg, 0.70 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at RT for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a yellow oil (193 mg, 94%). LCMS (Method C): RT 0.29 and 1.93 min [M+H]+ 293.2.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[C@H:3]([OH:8])[CH:4]=[C:5]([CH3:7])[CH3:6].C([O-])(=O)C.[Na+].[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>C(Cl)Cl>[C:19]([O:8][C@@H:3]([C:2]([Cl:10])([Cl:9])[Cl:1])[CH:4]=[C:5]([CH3:7])[CH3:6])(=[O:20])[CH2:18][C:17]([CH3:16])=[O:21]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)=C[C@@H](O)C(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)CC(=O)O[C@H](C=C(C)C)C(Cl)(Cl)Cl
Yield: 85.2 %

Procedure:
A mixture of (2R)-1,1,1-trichloro-4-methyl-3-penten-2-ol (1.50 g., 7.35 mmole) from Example IA.1.(a) and a trace of sodium acetate was treated under nitrogen at 100° with freshly distilled diketene (0.70 g, 8.36 mmole) added dropwise over 1 hr. After stirring and heating an additional hour at 80°-83°, the cooled reaction mixture was diluted with 3 ml of CH2Cl2 and chromatographed on 8 (20×20 cm) preparative tlc plates, developed in CH2Cl2. Isolation and extraction afforded (1R)-3-methyl-1-trichloromethyl-2-butenyl acetoacetate (1.80 g, 85% isolated yield) as a pale yellow oil; [α]D31 =+21.1° (hexane).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][NH:6][C:7](=[O:28])[CH2:8][CH2:9][C:10]1[O:14][C:13]([N:15]2[CH:19]=[CH:18][N:17]=[C:16]2[CH3:20])=[N:12][C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1>CN(C)C=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:11]2[N:12]=[C:13]([N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[CH3:20])[O:14][C:10]=2[CH2:9][CH2:8][C:7]2[O:28][CH2:4][CH2:5][N:6]=2)=[CH:22][CH:23]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)NCCCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC2=NCCO2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Sodium hydride (60% dispersion in oil, 265 mg) was gradually added to a solution of N-(2-chloroethyl)-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide (1.30 g) in N,N-dimethylformamide (30 ml), at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was poured into ice water, and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgSO4), and the solvent was evaporated. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[2-(2-oxazolin-2-yl)ethyl]oxazole (1.07 g, 91%). This was recrystallized from acetone-isopropyl ether to give colorless prisms. mp 119-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[N:11][NH:12][CH:13]=2)[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].[O-]S(C(F)(F)F)(=O)=O.F[N+:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:13]=[N:12][N:11]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)[N:10]=2)[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(-c2c[nH]nn2)ccc1-c1ccccn1
Reactant: F[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cs+]
Solvent: CO
Product: COc1cc(-c2cnn(-c3ccccn3)n2)ccc1-c1ccccn1
Reaction time: 8 h

Procedure:
To a solution of 2-[2-methoxy-4-(1H-1,2,3-triazol-4-yl)phenyl]pyridine (180 mg, 0.71 mmol) in anhydrous MeOH was added Cs2CO3 (462 mg, 1.42 mmol) and 1-fluoropyridinium triflate (350 mg, 1.42 mmol). The resulting reaction mixture was stirred overnight. The mixture was partitioned between 10% aqueous NaOH (10 ml) and EtOAc (60 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3×60 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified on silica gel (1:2 hexane-ethyl acetate) to afford 2-[4-(3-methoxy-4-pyridin-2-ylphenyl)-2H-1,2,3-triazol-2-yl]pyridine which was dissolved in ether and HCl (1N in ether) was added. The solution was filtered to give a HCl salt as white solid. 1H NMR (500 MHz, CD3OD) δ 8.86-8.47 (m, 1H), 8.72-8.68 (m, 1H), 8.64-8.62 (m, 2H), 8.39-8.37 (m, 1H), 8.26-8.25 (m, 1H), 8.15-8.11 (m, 1H), 8.07-8.04 (m, 1H), 8.02 (m, 1H), 7.91-7.80 (m, 2H), 7.60 (m, 1H). MS (ESI) 330 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C>[CH3:25][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[CH:17][CH:18]=3)[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNC1
Reactant: COc1ccc2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)[nH]c(-c3cc(C)c(OCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy-3H-quinazolin-4-one (0.30 g, 0.74 mmol) in DMF (5 mL) was added pyrrolidine (0.31 g, 4.36 mmol) and the reaction mixture was stirred at room temperature for 15 hours. DMF was removed under reduced pressure, and the residue was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.13 g (44%). MP 218-220° C. 1H NMR (400 MHz, DMSO-d6): δ 12.13 (br s, 1H), 8.03 (d, J=8.98 Hz, 1H), 7.90 (s, 2H), 7.16 (d, J=2.3 Hz, 1H), 7.07 (dd, J=8.9 and 2.7 Hz, 1H), 3.92-3.89 (m, 5H), 2.83 (t, J=5.8 Hz, 2H), 2.54-2.50 (m, 4H), 2.31 (s, 6H), 1.73 (m, 4H). MS (ES+) m/z: 394.62 (M+1).
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.Cl.[CH3:26][C:27]1([NH2:30])[CH2:29][CH2:28]1.C([O-])(O)=O.[Na+]>CS(C)=O>[CH3:15][C:3]1[C:2]([NH:30][C:27]2([CH3:26])[CH2:29][CH2:28]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12](=[O:14])[CH3:13])[N:4]=1
Reactant: CC1(N)CC1
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc2nc(C)c(NC3(C)CC3)nc12
Temperature: 85 °C

Procedure:
To a 250 mL round-bottomed flask was added 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (126g) (14.5 g, 71 mmol), DMSO (100 mL), DIEA (27 mL, 156 mmol) and finally 1-methylcyclopropanamine hydrochloride (8.02 g, 92 mmol) (ChemBridge Corporation, San Diego, Calif.). The solution was heated at 85° C. for 7 h. After cooling to RT, the solution was poured into sat NaHCO3 (250 mL) and extracted with EtOAc (3×250 mL). The combined extracts were washed with H2O (3×250 mL) and brine and then dried (Na2SO4) and concentrated to afford 1-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)ethanone (611a) as a purple solid, which was used directly in the subsequent step. m/z (ESI, +ve) 256.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][C:3]=1[C:24](OCC)=[O:25].Cl.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[CH:13][C:14]([S:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[CH:4][C:3]=1[C:24](=[O:25])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Reactant: Nc1ccccc1
Agent: Cl
Product: O=C(Nc1ccccc1)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Temperature: 180 °C
Reaction time: 3 h

Procedure:
Dissolving 280 mg of 7-hydroxy-6-ethoxycarbonyl-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine in 3 ml of aniline, the mixture was stirred for 3 hours at 180° C. After allowing to cool, 10% hydrochloric acid was added, the precipitate was filtered, washed with water and dried, and the title compound was obtained (220 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][C:20](B(O)O)=[CH:21][CH:22]=2)[CH:17]=[N:16]1>CN(C=O)C.CCOC(C)=O.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>[Cl:1][C:2]1[N:6]=[C:5]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:15]([CH3:14])[N:16]=[CH:17]3)[S:4][N:3]=1
Reactant: Clc1nsc(Cl)n1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ncc2cc(-c3nc(Cl)ns3)ccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 3,5-dichloro-1,2,4-thiadiazole (100 mg, 0.645 mmol), Na2CO3 (0.968 mL, 1.935 mmol) and (1-methyl-1H-indazol-5-yl)boronic acid (114 mg, 0.645 mmol) in DMF (4 mL) was degassed under N2 for 10 min. Pd(Ph3P)4 (149 mg, 0.129 mmol) was added and the mixture was stirred at 80° C. for 2 h. The reaction mixture was cooled to ambient temperature and diluted with EtOAc. The organics were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH/DCM) to afford the title compound as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.12 (s, 3H) 7.50 (d, J=8.79 Hz, 1H) 7.94 (d, J=8.79 Hz, 1H) 8.11 (s, 1H) 8.39 (s, 1H). LC/MS (m/z) ES+=251(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]1[OH:21].O1CCCC1.CC([O-])(C)C.[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC1=CC2=C(CC1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Yield: 65.3 %

Procedure:
3-Methoxyestra-2,5(10)-dien-17β-ol 1 (2.0 g, 6.9 mmol) was added to a solution consisting of tetrahydofuran (15 ml), DMSO (5 ml) and t-BuOK (20.7 mmol). The resultant solution was stirred at ambient temperature for 10 hours at which time the solution was concentrated to Å5 ml and chromatographically filtered with 50% ethylether/petroleum ether (light) through 10 g of silica gel. The subsequent dimethyl sulfoxide (DMSO) free -powder was flash chromatographed affording 4 as white needles (1.30 g, 65% conversion, 91% based on recovered 1), Alternatively, crystallization by selective seeding (ether/methanol) was utilized, thereby circumventing chromatographic purification. 1H NMR (d6-acetone) δ4.629 (s, 1H), 3.505 (t, J=8.09 Hz, 1H), 3.431 (s, 3H), 2.15-0.98 (complex, 20H), 0.644 (s, 3H). 13C NMR (CDCl3) δ156.71, 126.56, 123.88, 96.55, 81.31, 54.19, 50.18, 46.03, 39.91, 37.54, 30.64, 30.58, 30.21, 27.71, 27.17, 25.67, 25.24, 23.22, 11.37.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[Si:23]([O:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.7 %

Procedure:
A mixture of (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.7 mmol), imidazole (5.54 g, 81.4 mmol) and t-butyldimethylsilyl chloride (6.6 g, 45 mmol) in DMF (50 ml) was stirred and r.t. for 4 days. The mixture was diluted with EtOAc and washed with H2O and sat. NH4Cl. The organic layer was dried over MgSO4 and concentrated. 14 g of an oil product was obtained and used without further purification.
Reaction SMILES: S(=O)(O)[O-].[Na+].[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22]>C(O)C>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]2[NH:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)=[CH:9][CH:8]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1ccc(Br)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 71.3 %

Procedure:
Sodium bisulfite (14.4 g) is added to 4-bromobenzaldehye (17.1 g) in ethanol (100 mL) and the mixture stirred at reflux for 15 minutes. 1,2-Diaminobenzene (10 g) is added and the mixture stirred at reflux for 16 hours. The solvent is evaporated and the residue is washed with water and ethanol to afford 18.0 g of the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:34]>O>[C:22]([O:21][C:19]([N:11]([C:3]1[C:4]([CH3:10])=[CH:5][C:6]([C:8]#[N:9])=[CH:7][C:2]=1[NH:1][C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:34])[C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCCCCCOC(=O)Cl
Reactant: Cc1cc(C#N)cc(N)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCOC(=O)Nc1cc(C#N)cc(C)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Di-t-butyl (2-amino-4-cyano-6-methylphenyl)imidodicarbonate (104 mg, 0.3 mmol) obtained in Step 2 was added with pyridine (0.24 mL, 3 mmol, 10 eq) and heptyl chloroformate (0.11 mL, 0.6 mmol, 2 eq), and the mixture thus obtained was stirred at room temperature for 10 minutes, followed by further stirring at 80° C. for 2 hours. Upon completion of the reaction, the resulting product was added with distilled water, and extracted with ethyl acetate. The organic layer thus obtained was dried over MgSO4, and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (EA:Hex=1:9) to obtain the title compound in a colorless liquid (146 mg, yield: 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([CH3:12])[C:3]=1N.[C:13]([O-])([O-])=[O:14].[K+].[K+]>CC(C)=O>[CH3:13][O:14][C:3]1[C:2]([CH3:1])=[CH:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][C:5]=1[CH3:12]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(C)cc([N+](=O)[O-])cc1C

Procedure:
2,6-Dimethyl-4-nitroaniline (15 g) Me2SO4 (22 g) and K2CO3 (23 g) were dissolved in 150 mL acetone and refluxed for 3 hours. The reaction mixture was filtered and concentrated. The organic residue was dissolved in warm hexane and let to crystallize out in the fridge. After filtration, 2-methoxy-1,3-dimethyl-5-nitrobenzene was collected as white solid (12 g). 1H-NMR (300 MHz, CDCl3): δ=7.95 (s, 2H), 3.80 (s, 3H), 2.38 (s, 6H) ppm. MS: m/z 182 (100, M+H)+
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1>>[N:18]1[CH:23]=[C:22]([C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:21]=[N:20][CH:19]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: OB(O)c1cncnc1
Product: c1cc(-c2cncnc2)c2[nH]c3c(c2c1)CN1CCC3CC1

Procedure:
The product of Example 1B (100 mg, 0.32 mmol) and pyrimidine-5-boronic acid (64 mg, 0.52 mmol; MayBridge) were processed as described in Example 4 to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 2.01-2.17 (m, 4 H), 2.60 (s, 3 H), 3.03-3.14 (m, 3 H), 3.20-3.29 (m, 2 H), 4.27 (s, 2 H), 7.03-7.06 (m, 1 H), 7.10 (t, J=7.6 Hz, 1 H), 7.34 (dd, J=7.6, 1.2 Hz, 1 H), 7.42 (d, J=8.2 Hz, 1 H), 7.96 (dd, J=7.9, 2.4 Hz, 1 H), 8.63 (d, J=2.1 Hz, 1 H); MS (ESI+) m/z 291 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[O:10][C:9](=[O:17])[CH:8]=[CH:7]2)[CH:2]=[CH2:3].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:18]([O:14][C:13]1[C:12]([O:15][CH3:16])=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:17])[O:10]2)=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1cc2ccc(=O)oc2c(OC)c1O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=CCc1cc2ccc(=O)oc2c(OC)c1OC(C)=O
Reaction time: 2 h

Procedure:
A solution of 2.32 g. (0.010 mole) of 6-allyl-7-hydroxy-8-methoxycoumarin in 8 ml. of chloroform was treated with 4.5 ml. of acetic anhydride/pyridine, 1:2. The reactants were stirred at 25° for 2.0 hours and then partitioned between 1 N HCl/methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, and evaporated to afford pure 7-acetoxy-6-allyl-8-methoxycoumarin as a white solid, mp 101°-102°. Recrystallization from ethanol afforded an analytical sample, mp 102°14 103°.