Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:37]1([CH2:43][C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:44](=[O:45])[CH2:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.027 ml phenyl-acetyl chloride (0.2 mmol). After 5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 89 mg light yellow solid (86%). MS (ISP) 619.4 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[N-:6]=[C:12]=[O:13].[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6]
Reactant: O=C(Cl)Cl
Agent: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: [N-]=C=O

Procedure:
A three-neck 1 liter round bottom flask, fitted with gas inlet, mechanical stirrer, reflux condenser and gas outlet connected to a 30% aqueous NaOH trap was charged with L-leucine methyl ester hydrochloride (61.0 g, 0.336 mmol) and dry toluene (250 ml). The mixture was heated to gentle reflux for 0.5 hr. while a vigorous stream of phosgene was continuously introduced. Following dissolution of the solids (0.5 hr.) phosgene was introduced for an additional 15 min. The product was isolated by initially removing the toluene under vacuum and fractionally distilling the remaining residue under vacuum to give the product (48.0 g), bp=71°-73° C. at 0.8 torr.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1I>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][C:25]=2[F:27])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(I)c(F)c1
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2F)cc1[N+](=O)[O-]
Yield: 107.8 %

Procedure:
Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example F2) (525 mg, 2.0 mmol) and 2,4-difluoro-1-iodobenzene (0.36 mL, 3 mmol) according to the general procedure F. Obtained as a yellow solid (807 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[OH:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1.Cl>CN(C=O)C>[CH3:23][C:21]1[NH:20][N:19]=[C:18]([O:17][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 182.5 %

Procedure:
Potassium carbonate (0.5 g, 3.6 mmol) and 4-fluoronitrobenzene (1.6 g, 1.0 mmol) were added to a solution of 3-hydroxy-5-methylpyrazole (0.33 g, 3.4 mmol) in DMF (50 ml) at room temperature, and further, the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (100 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7→1/3), to give a white solid of 5-methyl-3-(4-nitrophenyloxy)pyrazole (0.4 g, yield: 63.3%) mp: 124-125° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.33 (s, 3H), 5.75 (s, 1H), 7.20 (dd, J=2.2 and 7.1 Hz, 2H), 8.22 (dd, J=2.2 and 7.1 Hz, 2H), 9.30-9.90 (br s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[O:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(4-nitrophenyl)piperazine (0.5 g) and TEA (0.7 mL) in DCM (15 mL) at rt was added 4-nitrophenyl chloroformate (0.7 g). The reaction mixture was stirred at rt for 18 h and then partitioned between DCM and ice-water. The separated aqueous layer was extracted with DCM thrice and the pooled organic extracts was washed with water and sat'd NaCl, dried over anhyd. Na2SO4, filtered, and conc. in vacuo to give the crude product as a yellow solid which was recrystallized from DCM and diisopropylether to give 4-nitrophenyl 4-(4-nitrophenyl)piperazine-1-carboxylate as a bright yellow powder (Y=0.8 g, 89%).
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:18])([CH3:17])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])(=O)=O.[CH3:21][C:22]1[CH:23]=[C:24]([C-:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1.[Li+]>CCOCC>[CH3:28][C:26]1[CH:25]=[C:24]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]([Si:7]([CH3:17])([CH3:18])[CH:8]3[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]3[CH3:16])[CH:30]=2)[CH:23]=[C:22]([CH3:21])[CH:27]=1
Reactant: CC1=C(C)C([Si](C)(C)OS(=O)(=O)C(F)(F)F)C(C)=C1C
Reactant: Cc1cc(C)cc(-[c-]2ccc3ccccc32)c1
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3cc(C)cc(C)c3)c3ccccc32)C(C)=C1C
Reaction time: 19 h

Procedure:
To a solution of dimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silyl trifluoromethanesulfonate (Compound C, 7.50 g, 22.8 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium (1-(3,5-dimethylphenyl)indenide) (5.53 g, 24.4 mmol, 1.07 eq.). The reaction was stirred for 19 hours, and was then evaporated under vacuum. The residue was extracted with pentane (40 mL, then 2×20 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a sticky solid. Yield 9.65 g (106%). 1H NMR(C6D6): δ 7.87 (d, 1H), 7.40 (s, 2H), 7.25 (m, 2H), 6.88 (s, 1H), 6.64 (s, 1H), 3.73, (s, 1H), 2.93 (br s, 1H), 2.23 (s, 6H), 1.93 (s, 3H), 1.92 (s, 3H), 1.84 (s, 3H), 1.82 (s, 3H), −0.07 (s, 3H), −0.36 (s, 3H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].C(O)(C)C>C1COCC1>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCOc1ccccc1
Reactant: O=C1CCCCC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C1CCCCC1(CCCCCOc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 5 phenoxy pentyl bromide (122.0 g, 0.5 mol) and 2-phenylcyclohexanone (104.4 g, 0.6 mol) in 1.5 L THF, NaH (0.55 mol, 24.0 g) was added portionwise, keeping the temperature between 25° to 30° C. After most of the H2 evolution had ceased, the reaction mixture was heated to reflux for 16 hours under a N2 atmosphere. After cooling to room temperature, 50 mL isopropanol was added and the mixture was concentrated in vacuo to half its volume. This residue was diluted with 2 L ether and 1 L H2O. The layers were separated and the aqueous layer was washed one time with 500 mL ether. The combined organic layers were washed two times each with 500 mL H2O, dried (MgSO4), and concentrated in vacuo to give a solid. Recrystallization from petroleum ether yielded 27.5 g (16.4%), mp 69°-72° C., of the desired product.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1

Procedure:
The preparation of compound 9 is outlined in Scheme 1. Commercially available tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (compound 1) is treated with methanesulfonyl chloride to give tert-butyl (R)-3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (compound 2), which then is reacted with diethylmalonate and a suitable base (e.g., potassium tert-butoxide or sodium ethoxide) to give diethyl (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)malonate (compound 3) with inverted stereochemistry around the chiral carbon.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=2)[CH:8]=[CH:9][C:10]=1[C@@H:11]1[C@@H:14]([CH2:15][CH2:16][C@H:17]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:13](=[O:33])[N:12]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)C.O.C(N(CC)CC)C.C1(C)C=CC=CC=1>CO>[Si:26]([O:25][C@H:17]([C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH2:16][CH2:15][C@@H:14]1[C@@H:11]([C:10]2[CH:9]=[CH:8][C:7]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=3)=[CH:6][C:5]=2[OH:4])[N:12]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:13]1=[O:33])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(=O)Oc1cc(-c2cccc(O)c2)ccc1[C@@H]1[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N1c1ccccc1
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC[C@H]1C(=O)N(c2ccccc2)[C@@H]1c1ccc(-c2cccc(O)c2)cc1O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
4-{(2S,3R)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl acetate (70 mg, 0.11 mmol) was dissolved in methanol (2.45 mL). Water (0.73 mL) was added dropwise followed by triethylamine (2.2 mL) and the reaction stirred at room temperature for 1 h. Toluene (3 mL) and methanol (5 mL) were added and the reaction was concentrated to give 69 mg of crude (3R,4S)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3,3′-dihydroxybiphenyl-4-yl)-1-phenylazetidin-2-one which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:11]([OH:28])[C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[N:15][N:16]=1)[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]([CH2:9][CH3:10])[C@@H:11]([C:12]1[O:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=2)=[N:15][N:16]=1)[OH:28]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(N)[C@H](O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Reaction time: 4 h
Yield: 95.7 %

Procedure:
((S)-1-{hydroxy-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-methyl}-propyl)-carbamic acid tert-butyl ester (0.54 mmol, 0.225 g) is dissolved in dichloromethane (9 mL) and treated with trifluoroacetic acid (1 mL). The reaction mixture is stirred for four hours. The solvents are evaporated under reduced pressure. The residue is re-dissolved in dichloromethane (20 mL) and Silicycle Triamine (5.4 mmol, 1.47 g) is added. The reaction mixture is stirred for 60 h (over the weekend). The reaction mixtures are filtered under suction and the solvents evaporated to give (S)-2-Amino-1-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-butan-1-ol (0.164 g, 96%). MS: m/z=318 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[N+:4]([O-:10])[C:3]=1[C:11]([O:13][CH3:14])=[O:12].[CH3:15][O-:16].[Na+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:16][CH3:15])=[N+:4]([O-:10])[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(Cl)ccc(CCl)[n+]1[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCc1ccc(Cl)c(C(=O)OC)[n+]1[O-]
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A solution of methyl 3-chloro-6-(chloromethyl)pyridine-2-carboxylate 1-oxide (1.50 g, 6.35 mmol) in methanol (15 mL) was cooled to 0° C. A 25% solution of sodium methoxide in methanol (1.52 mL) was added and the mixture stirred at room temperature for 6 days. The reaction mixture was diluted with ethyl acetate and washed with water. To the aqueous layer was added brine solution and was extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), filtered and concentrated to dryness to give crude methyl 3-chloro-6-(methoxymethyl)pyridine-2-carboxylate 1-oxide (1.14 g, 4.92 mmol) as a yellow oil; 1H NMR (CDCl3): δ 7.50 (d, 1H), 7.40 (d, 1H), 4.60 (s, 2H), 4.10 (s, 3H), 3.50 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1.[Br:24]C1C=C(I)C=CC=1>>[Br:24][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([C:7]1[NH:8][C:9]2[C:5]([C:6]=1[CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)=[O:19]
Reactant: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Reactant: Brc1cccc(I)c1
Product: O=C(O)Cc1c(C(=O)c2cccc(Br)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1) and 3-bromoiodobenzene.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@@H:21]([O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH3:22])[CH2:12][C@@H:11]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO.C[O-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@@H:21]([O:23][CH2:24][C:25]([OH:27])=[O:26])[CH3:22])[CH2:12][C@@H:11]([O:39][Si:40]([C:43]([CH3:44])([CH3:46])[CH3:45])([CH3:41])[CH3:42])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](OCC(=O)OC(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](OCC(=O)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
To a solution of tert-butyl [{1α,3β-bis(tert-butyldimethylsilyloxy)pregna-5,7-dien-20(S)-yl}oxy]acetate (9 mg, 0.013 mmol) in tetrahydrofuran (0.13 ml), a 1M methanol solution of sodium methoxide (0.13 ml) was added and stirred at room temperature for 20 minutes. Water (0.26 ml) was further added and stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium dihydrogenphosphate, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the titled compound (6 mg, 73%) as a colorless solid.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[CH2:25]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:38])[C:30]1=[O:39])[CH:26]([CH3:28])[CH3:27].[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:49](=[O:51])[CH3:50])=[CH:41]1>>[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:49](=[O:51])[CH2:50][C:31]2([OH:38])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:30]2=[O:39])=[CH:41]1
Reactant: CC(C)CN1C(=O)C(=O)c2ccccc21
Reactant: CC(=O)c1c[nH]c2ccccc12
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: CC(C)CN1C(=O)C(O)(CC(=O)c2c[nH]c3ccccc23)c2ccccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 1-isobutylindoline-2,3-dione and commercially available 1-(1H-indol-3-yl)ethanone (purchased from Fisher Scientific). 1H-NMR δ 8.87 (bs, NH), 8.38 (m, 1H), 7.72 (d, 3.1 Hz, 1H), 7.49 (dd, 1H), 7.47 (m, 1H) 7.30 (m, 3H), 7.01 (dd, 1H), 6.86 (d, 7.8, 1H), 3.51 (m, 3H), 3.24 (d, 1H), 2.16 (m, 1H) 0.98 (dd, 6H). Calculated mass for C22H22N2O3, 362.16. Observed 385.3 (M+Na).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[CH2:44][CH2:43][N:35]3[C:36]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[CH:42]=[C:34]3[C:33]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:29]=[C:22]3[CH:23]([CH3:28])[N:24]([CH3:27])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+].C(O)(C)C.C1COCC1>O>[CH3:28][CH:23]1[N:24]([CH3:27])[CH2:25][CH2:26][N:21]2[N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:32]5[CH2:44][CH2:43][N:35]6[C:36]7[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=7[CH:42]=[C:34]6[C:33]5=[O:45])[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:29]=[C:22]12
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4C)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC1c2cc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nn2CCN1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 287j (60 mg, 1.0 eq., 0.098 mmol), lithium hydroxide (12 mg, 5.0 eq., 0.49 mmol), i-propanol/THF (4/4 mL), and water (1 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 287 as a yellow solid (24 mg, 43%). MS-ESI: [M+H]+ 568.9. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J=5.0 Hz, 1H), 7.99 (s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J=5.0 Hz, 1H), 6.91 (s, 1H), 5.74 (s, 1H), 5.04-5.02 (m, 1H), 4.64-4.62 (m, 1H), 4.56-4.54 (m, 1H), 4.39-4.37 (m, 1H), 4.17-3.92 (m, 4H), 3.86-3.84 (m, 1H), 3.72 (s, 3H), 3.45-3.37 (m, 1H), 3.17-3.14 (m, 1H), 2.89-2.81 (m, 1H), 2.64-2.58 (m, 4H), 2.48 (s, 3H), 1.93-1.89 (m, 2H), 1.81-1.80 (m, 2H), 1.46 (d, J=6.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.N1CCCCC1.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]([OH:34])([C:32]#[CH:33])[CH3:31]>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.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:33]#[C:32][C:30]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)([OH:34])[CH3:31])[CH:10]=3)[C:6]([CH3:18])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#CC(C)(O)c1nccs1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3nccs3)ccc12
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 4-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine (5-a) (240 mg, 0.489 mmol) and piperidine (1.2 mL) was added tetrakis(triphenylphosphine)palladium (53.5 mg, 0.049 mmol), copper(I) iodide (9.3 mg, 0.049 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (I-1) (150 mg, 0.978 mmol). The reaction was purged with N2 and stirred at 60° C. for 1.5 hr. The reaction mixture was concentrated in vacuo. EtOAc (2 mL) was added to the residue and concentration in vacuo was repeated. The resultant residue was purified by flash chromatography (Isolute column, 100% DCM to 3% MeOH in DCM) to afford the title compound as a white solid: 1H NMR (250 MHz, DMSO) δ 1.87-1.97 (3H, m), 2.56 (3H, s), 6.91-7.00 (1H, m), 7.01-7.07 (1H, m), 7.10-7.23 (1H, m), 7.29-7.40 (1H, m), 7.65-7.73 (1H, m), 7.74-7.80 (1H, m), 7.81-7.90 (1H, m), 8.19-8.32 (1H, m), 8.76-8.92 (1H, m); LC-MS: m/z=+377.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([S:12][CH:13]1[N:16](/[C:17](=[C:21](\[O:23][CH3:24])/[CH3:22])/[C:18](O)=[O:19])[C:15](=[O:25])[CH:14]1[NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:11])=[O:10].C(Cl)(=O)C([Cl:40])=O>CN(C)C=O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([S:12][CH:13]1[N:16](/[C:17](=[C:21](\[O:23][CH3:24])/[CH3:22])/[C:18]([Cl:40])=[O:19])[C:15](=[O:25])[CH:14]1[NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:11])=[O:10]
Reactant: CO/C(C)=C(/C(=O)O)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CO/C(C)=C(/C(=O)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
One drop of dimethylformamide in dioxane is added to a soltuion of 54 mg (0.1 mM) of 2-[4-(o-methoxybenzensulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid in 0.5 ml of a 10% strength solution of oxalyl chloride in dioxane, whereupon an evolution of gas occurs immediately. The mixture is stirred for 2 hours at room temperature and the solvent and the excess oxalyl chloride are evaporated off in vacuo. The residue is dried in a high vacuum and gives 2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1yl]-3-methoxy-isocrotonic acid chloride in the form of a slightly orange-coloured foam, IR spectrum (CH2Cl2): 5.60, 5.90 and 8.70 μ.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[CH:16]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)[C:15](=O)[C:14]2[C:13]([C:24](OCC)=[O:25])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8]1.O.[NH2:30][NH2:31]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[NH:8][C:9]2[C:14]3[C:15](=[N:30][NH:31][C:24](=[O:25])[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:16]1[C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1nccn1C)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1Nc2cccc3c(=O)[nH]nc(c23)C1c1nccn1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 41 %

Procedure:
A mixture of ethyl 2,3-bis(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg) in 85% hydrazine monohydrate (2 mL) and methanol (3 mL) was stirred at room temperature for 3.5 h. Evaporated the solvent and methanol (1 mL) was added, filtered and washed the cake by methanol (2 mL) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain 8,9-bis(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (45 mg, yield 41%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.46 (s, 3H), 3.49 (s, 3H), 4.78-4.81 (d, J=12.0 Hz, 1H), 5.08-5.11 (d, J=12.0 Hz, 1H), 6.69 (s, 1H), 6.76-6.79 (m, 3H), 6.99-7.02 (d, J=7.6 Hz, 1H), 7.42-7.49 (m, 2H); LC-MS (ESI) m/z: 348 (M+1)+.