Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:26](F)=[C:25]([F:28])[C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([N+:17]([O-:19])=[O:18])=[C:11]([O:20][CH2:21][CH:22]=[CH2:23])[C:10]=2[F:24])=[C:6]([F:29])[C:5]=1[F:30])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+].[OH2:42]>CS(C)=O>[OH:42][C:26]1[C:25]([F:28])=[C:7]([C:6]([F:29])=[C:5]([F:30])[C:4]=1[N+:1]([O-:3])=[O:2])[O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([N+:17]([O-:19])=[O:18])=[C:11]([O:20][CH2:21][CH:22]=[CH2:23])[C:10]=1[F:24]
Reactant: C=CCOc1c(F)c(Oc2c(F)c(F)c([N+](=O)[O-])c(F)c2F)c(F)c(F)c1[N+](=O)[O-]
Reactant: O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOc1c(F)c(Oc2c(F)c(O)c([N+](=O)[O-])c(F)c2F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h

Procedure:
44.2 g of 1-(4-nitro-2,3,5,6-tetrafluorophenoxy)-3-(prop-2-enyloxy)-4-nitro-2,5,6-trifluorobenzene prepared as described in Example 9 (0.1 mol) are dissolved in a mixture of 200 ml of dimethyl sulfoxide and 30 ml of water in a three-neck flask fitted with reflux condenser and stirrer. 15 g of potassium carbonate (0.11 mol) and 10 g of potassium hydrogen carbonate (0.1 mol) are added in portions to the solution, and the mixture is then stirred at 80° C. for 24 hours. The reaction solution is then filtered via a fluted filter, and the crude product is extracted by shaking with 200 ml of ethyl acetate and 400 ml of water. The organic phase is washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. The precipitated reaction product is then recrystallized from a mixture of methylene chloride and petrol ether (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [CH2:1](I)[CH3:2].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([OH:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1>C(OC(C)C)(C)C.[Ag-]=O.[Ag]=O>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@H:12]([O:17][CH2:1][CH3:2])[C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=1
Reactant: COC(=O)[C@@H](O)Cc1ccc(Br)cc1
Reactant: CCI
Agent: O=[Ag-]
Agent: O=[Ag]
Solvent: CC(C)OC(C)C
Product: CCO[C@@H](Cc1ccc(Br)cc1)C(=O)OC
Temperature: 70 °C
Yield: 79 %

Procedure:
11 ml of ethyl iodide are added dropwise to a solution of 23.5 g (91 mmol) of methyl 3-(4-bromophenyl)-2(S)-hydroxypropanoate and 35.6 g (155 mmol) of silver(I) oxide in 120 ml of isopropyl ether. The reaction medium is heated at 70° C. overnight. 10 g (45 mmol) of silver oxide and 3.7 ml (45 mmol) of ethyl iodide are added and the reaction medium is heated for a further 4 hours and then filtered through Celite, the precipitate is rinsed with ethyl acetate and the filtrate is concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 95/5 and then 90/10 heptane/ethyl acetate mixture. 20 g (79%) of methyl 3-(4-bromophenyl)-2(S)-ethoxypropanoate are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[OH:17])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:25][N:26]([CH3:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:25][N:26]([CH3:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31]([O:17][C:5]2[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=[C:7]([NH:10][C:11](=[O:13])[CH3:12])[C:6]=2[N+:14]([O-:16])=[O:15])=[O:32])=[CH:29][CH:28]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(C)=O)c(OC(=O)c2ccc(N(C)C)cc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The imidazole flavonoid was prepared according to scheme 5. To a mixture of N-(4-acetyl-3-hydroxy-2-nitrophenyl)acetamide (1, 1 g, 4.1 mmol, 1.0 eq) and triethylamine (1.5 mL) was added 4-(dimethylamino)benzoyl chloride (2 hydrochloride, 6.3 mmol, 1.5 eq.) in 3 portions at 0° C. Then the mixture was stirred at rt for 3 h. Diluted with DCM (100 mL), washed with 1N HCl (100 mL) and water (50 mL). The organic phase was separated, dried with sodium sulfate, filtered and concentrated to afford gray solid, which was purified by SGC (PE/EA=1/1) to afford (3-acetamido-6-acetyl-2-nitrophenyl 4-(dimethylamino)benzoate (3), 1.2 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.O.[OH:16]S(O)(=O)=O>C(O)(=O)C.C(O)(=O)CC.[O-2].[O-2].[O-2].[Cr+6]>[CH3:14][O:13][C:10]1[CH:9]=[C:8]2[C:3](=[C:2]([Cl:1])[C:11]=1[Cl:12])[C:4](=[O:16])[CH2:5][CH2:6][CH2:7]2
Reactant: O=S(=O)(O)O
Reactant: COc1cc2c(c(Cl)c1Cl)CCCC2
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)CCC2
Temperature: 70 °C
Reaction time: 20 h

Procedure:
Chromium trioxide (28 g., 0.028 mole) in 83% acetic acid (12 ml.) is added slowly at 0° C. to a stirred solution of 5,6-dichloro-7-methoxytetralin (4 g., 0.073 mole) in a mixture of acetic acid (90 ml.) and propionic acid (20 ml.). The resulting dark mixture then is kept for 20 hours at 20°-25° C. The resulting dark green solution is poured into a mixture of water (900 ml.) and 96% H2SO4 (10 ml.). The mixture is heated to 70° C., cooled to 0° C. and the precipitate is collected, washed with water, and dried. The dried product is sublimed twice at 100° C. at ca. 0.5 mm. and then crystallized from methanol to obtain 6-methoxy-7,8-dichloro-1-tetralone (1 g.), melting point 132°-132.5° C. The identity of the product is established by proton magnetic resonance (pmr).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][CH3:20])=[CH:11][C:10]=1[C:21](OC)=[O:22]>C1COCC1>[CH3:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][CH3:20])=[CH:11][C:10]=1[CH2:21][OH:22]
Reactant: COC(=O)c1cc(OC)c2ccccc2c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
According to the procedure by Flader et al.,22 lithium aluminum hydride (0.855 g, 21.4 mmol) was added to a flame-dried 250 mL round bottom flask under argon to which dry THF (150.0 mL) was added at room temperature. Ester 25 (5.05 g, 20.5 mmol) was then dissolved in THF (50.0 mL) and added slowly at room temperature under argon, and the reaction was stirred at room temperature for 8 hours. The reaction was then quenched by adding H2O (1.0 mL) dropwise at 0° C., followed by 2 M NaOH (2.0 mL), and then H2O (3.0 mL). The resulting suspension was then filtered and the filtrated was acidified with dilute HCl, washed with saturated brine, dried over MgSO4, and filtered. The condensed filtrate resulted in a crude solid that could be purified by flash column chromatography (7:13 EtOAc:hexanes) or recrystallization from Et2O/hexanes to afford 26 (4.34 g, 19.9 mmol, 97%) as long white needles.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:3]1=2.[CH:20](O)=[O:21]>>[CH:20]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:3]1=2)=[O:21]
Reactant: O=CO
Reactant: NC1c2ccccc2COc2ccc(C(=O)O)cc21
Product: O=CNC1c2ccccc2COc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add to a mixture of 1.77 gm. (5 mmole) of 6,11-dihydro-11-aminodibenz[b,e]oxepin-2-carboxylic acid in 5 ml. of 90% formic acid, 1.5 gm. of aceticformic anhydride* at 10° C. with stirring. After 1 hour allow the mixture to warm to room temperature and continue stirring for 3 hours. Remove the volatiles by evaporation in vacuo to obtain the title product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2].C(OC(N1CCC(=O)CC1)=O)(C)(C)C.C([N-]C(C)C)(C)C.[Li+].C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CC1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 109.7 %

Procedure:
A solution of 300 mg of (1-tert-butoxycarbonylpiperidin-4-ylidene)acetic acid ethyl ester (which had been prepared by Horner-Wittig reaction of commercially available 1-tert-butoxycarbonyl-4-piperidone and triethyl phosphonoacetate by the method known per se) in 30 ml of tetrahydrofuran was cooled to −78° C., to which 1.3 ml of a tetrahydrofuran solution (1.5 M) of lithium diisopropylamide was added and stirred for 15 minutes. Thereafter 150 μl of acetic acid was added, and the system was warmed up to room temperature, over an hour. The reaction liquid, to which saturated aqueous sodium hydrogencarbonate solution was added, was extracted with chloroform. The chloroform layer was dried over sodium sulfate and the solvent was distilled off therefrom to provide 329 mg of (1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridin-4-yl)acetic acid ethyl ester. This ester was dissolved in 10 ml of tetrahydrofuran, cooled to 0° C., and to which 80 mg of lithium aluminium hydride was added. The reaction liquid was stirred for 15 minutes and to which an excessive amount of sodium sulfate decahydrate was added, followed by 2 hours' stirring at room temperature. The insoluble matter was filtered off, and the filtrate was concentrated to provide 228 mg of 2-(1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridin-4-yl)ethanol.
Reaction SMILES: [F:1][C:2]1([CH2:35][N:36]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[O:34][CH:33]=[CH:32][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:23]=[C:22]4[C:18]([CH:19]=[N:20][N:21]4[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:17][CH:16]=3)[N:13]=2)[CH2:4][CH2:3]1.C(N)(=O)C1C(=CC=CC=1)C(N)=O.ClC1N=C(Cl)C2OC=CC=2N=1.C[Si](C)(C)CCOCN1C2C(=CC=C(N)C=2)C=N1.O.NN>CO>[NH2:36][CH2:35][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[O:34][CH:33]=[CH:32][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:23]=[C:22]4[C:18]([CH:19]=[N:20][N:21]4[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])=[CH:17][CH:16]=3)[N:13]=2)[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2ccc(Nc3nc(N4CCC(F)(CN5C(=O)c6ccccc6C5=O)CC4)c4occc4n3)cc21
Agent: C[Si](C)(C)CCOCn1ncc2ccc(N)cc21
Agent: Clc1nc(Cl)c2occc2n1
Agent: NC(=O)c1ccccc1C(N)=O
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1ncc2ccc(Nc3nc(N4CCC(F)(CN)CC4)c4occc4n3)cc21
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 2-((4-fluoro-1-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methyl)isoindoline-1,3-dione (0.510 g, 0.795 mmol, prepared using W from Preparation #X.1, V, U with phthalamide, G, A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine [WO 2010/027500 Intermediate 21, Step C]) in MeOH (20 mL) was treated with hydrazine hydrate (0.190 mL, 2.50 mmol). The mixture was heated at about 70° C. for about 3 h. The mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in DCM/MeOH (10:1) (30 mL) and stirred for about 30 min. The resulting suspension was filtered and the filtrate was concentrated in vacuo to give 4-(4-(aminomethyl)-4-fluoropiperidin-1-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)furo[3,2-d]pyrimidin-2-amine (0.41 g, 100%). LC/MS (Table 2, Method i) Rt=1.60 min; MS m/z 512 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[C:4]([NH:6][CH3:7])=[O:5])[CH3:2].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[CH2:1]([N:3]([CH2:8][CH3:9])[C:4]([N:6]([CH3:7])[C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18])=[O:5])[CH3:2]
Reactant: O=C=Nc1ccccc1
Reactant: CCN(CC)C(=O)NC
Solvent: ClCCl
Product: CCN(CC)C(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 15 h
Yield: 79 %

Procedure:
In 300 ml of anhydrous dichloromethane, 13.0 g (0.1 mole) of 1,1-diethyl-3-methylurea and 12.0 g (0.1 mole) of phenylisocyanate were dissolved. Under cooling the mixture with stirring, 26.0 g (0.1 mole) of stannic chloride was added dropwise. The reaction was continued at a room temperature for 15 hours and the reaction mixture was treated by a procedure similar to that of mentioned in Example 1, and recrystallized from ethanol-petroleum ether to obtain 19.7 g (yield 79%) of 1,1-diethyl-3-methyl-5-phenylbiuret having a melting point of 88°-89.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:34])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[N+:31]([O-:33])=[O:32])[C:5]2=[CH:4][CH:3]=1.C[Si]([C:39]#[CH:40])(C)C.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:34])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:39]#[CH:40])[CH:27]=[CH:26][C:25]=3[N+:31]([O-:33])=[O:32])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2[N+](=O)[O-])N1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: C#Cc1ccc([N+](=O)[O-])c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 83.7 %

Procedure:
In a manner similar to the method described in example 193, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-iodo-2-nitrophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 201c (0.36 g, 0.59 mmol) was reacted with trimethylsilyl acetylene (120 mg, 1.18 mmol), CuI (0.23 g, 1.18 mmol), triethylamine (120 mg, 1.18 mmol), and dichlorobis(triphenylphosphine)palladium(0) (83 mg, 0.118 mmol) in anhydrous tetrahydrofuran, and then treated with aqueous NaOH in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-ethynyl-2-nitrophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 84%)
Reaction SMILES: [Br-].C([N+]1C=CC=C(O)C=1C1C=CC=CC=1)C1C=CC=CC=1.C(OC(C)(C)C)(=O)C=C.C([O-])(O)=O.[Na+].[CH2:36]([N:43]1[C@@H:48]2[C@H:49]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][C@@:44]1([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:45](=[O:58])[CH:46]=[CH:47]2)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N1[C@@H]2[C@@H](C(OC(C)(C)C)=O)C[C@@]1(C1C=CC=CC=1)C(=O)C=C2)C1C=CC=CC=1>O1CCOCC1.C(N(CC)CC)C>[CH2:36]([N:43]1[C@@H:48]2[CH:49]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][C@@:44]1([C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[C:45](=[O:58])[CH:46]=[CH:47]2)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Agent: C=CC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (255 g, 0.745 mol), tert-butyl acrylate (470 ml), triethylamine (150 ml) and 1,4-dioxane (1 l) was heated at reflux for 15 hours and cooled to room temperature. The reaction mixture was poured onto saturated aqueous NaHCO3 (1 l) and extracted into an 1:1 mixture of iso-hexane:diethyl ether (3×500 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (750 g, iso-hexane:diethyl ether 0-20%) to give a 2:1 mixture of (1R*,5S*,6R*)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one and (1R*,5S*,6S*)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one (205 g, 70%) as a yellow-orange foam. The isomers were separated on silica gel (iso-hexane:diethyl ether) and crystallised from iso-hexane:diethyl ether giving yellow rhombs:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].[O:26]1CCOCC1>O>[NH2:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:26])=[O:1]
Reactant: C1COCCO1
Reactant: COc1cc(Oc2cccc3c2NC(=O)C3)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Oc2cccc(CC(=O)O)c2N)cc(OC)c1OC

Procedure:
A mixture of 2-oxo-7-(3,4,5-trimethoxyphenoxy)indoline (3.2 g.), sodium hydroxide (1 g.), dioxane (20 ml.) and water (20 ml.) was refluxed under heating for 36 hours with stirring. After cooling, the reaction mixture was washed with diethyl ether. Ethyl acetate was added to the aqueous solution and adjusted to pH 4.0 with 5% sulfuric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was pulverized with diethyl ether to give 2-[2-amino-3-(3,4,5-trimethoxyphenoxy)phenyl]acetic acid (2.5 g.).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4](OC)=[O:5].[CH3:10][NH2:11]>>[OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:11][CH3:10])=[O:5]
Reactant: CN
Reactant: COC(=O)C(C)(C)CO
Product: CNC(=O)C(C)(C)CO
Yield: 51 %

Procedure:
Prepared as in Example 215d from methyl 3-hydroxy-2,2-dimethylpropanoate and methylamine in 51% yield. MS 132 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[S:6][C@@H:5]2[CH:7](N)[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(C1C(=O)C(=[O:36])C=C(C(C)(C)C)C=1)(C)(C)C>O1CCCC1>[CH3:1][C:2]1([CH3:21])[S:6][C@@H:5]2[C:7]([C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:36]
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2[C@H]1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)S[C@@H]2C(=O)C(=O)N2[C@H]1C(=O)OCc1ccccc1
Reaction time: 6 h

Procedure:
A solution of 3.06 g. (10 mmol.) of 6-aminopenicillanic acid benzyl ester and 2.20 g. (10 mmol.) of 3,5-di-t-butyl-1,2-benzoquinone in 50 ml. of tetrahydrofuran containing 5 g. of 5A molecular sieves is maintained at 4° for 16 hours. The solution is decanted and treated with 3 g. of oxalic acid in 10 ml. of water. After standing at 4° for 6 hours most of the solvent is removed below ambient temperature and the residue is partitioned between benzene and water. The aqueous phase is extracted with additional benzene and the combined organic phases are dried (MgSO4) and evaporated to dryness to give a residue which is chromatographed on silica gel with benzene-ethyl acetate as eluant to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:21][OH:22])[CH:5]=[C:6]([F:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1.Cl[C:24]1[CH:34]=[C:28]2[N:29]([CH3:33])[CH2:30][CH2:31][CH2:32][N:27]2[C:26](=[O:35])[N:25]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:17])([F:18])[F:19])[CH:10]=1)[CH2:21][O:22][C:24]1[CH:34]=[C:28]2[N:29]([CH3:33])[CH2:30][CH2:31][CH2:32][N:27]2[C:26](=[O:35])[N:25]=1
Reactant: OCc1cc(F)c(Oc2ccc(F)c(C(F)(F)F)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3ccc(F)c(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3,5-difluoro-4-(4-fluoro-3-(trifluoromethyl)phenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]3[C:22]([OH:24])=[O:23])=[O:15])[CH:5]=[CH:4][C:3]1=2.Cl>[Zn].C(O)(=O)C>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([OH:15])[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]3[C:22]([OH:24])=[O:23])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)C3CCCCC3C(=O)O)ccc21
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2cc(C(O)C3CCCCC3C(=O)O)ccc21
Yield: 84.2 %

Procedure:
A suspension of 3.42 g (10 mmoles)of 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) carbonyl]cyclohexane carboxylic acid, described in Example III, and 10 g of powdered zinc (0.15 mole)in 150 cm3 of a 2.5M aqueous soda solution is heated at reflux for 7 hours. After cooling to +5° C., the reaction mixture is neutralized with 60 cm3 of 6N HCl and then acidified to pH of about 3 by the addition of 20 cm3 of glacial acetic acid. The mixture is then extracted with ethyl ether [2×150 cm3). The ether phase is thoroughly washed with water, dried on sodium sulfate and evaporated to dryness. The resulting solid is taken up in 50 cm3 of hexane, filtered, washed again twice with 40 cm3 of hexane and dried under a vacuum at 40° C. 2.9 g of 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) hydroxymethyl]cyclohexane carboxylic acid are obtained in the form of a white solid whose melting point is 186° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:10][O:11][C:12](=[O:25])[CH2:13][C@@H:14]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:15]#[C:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:10][O:11][C:12](=[O:25])[CH2:13][C@@H:14]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[CH3:1])=[CH:22][CH:23]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(O)cc1
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC#C[C@@H](CC(=O)OC)c1ccc(OCc2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Methylbenzyl bromide (0.98 g, 5.3 mmol) and phenol 1 (0.97 g, 4.4 mmol) were dissolved in acetone (9 mL) and treated with Cs2CO3 (1.45 g, 4.4 mmol). The reaction was stirred at room temperature for 16 h then filtered and concentrated to an oil which was purified by radial chromatography (2 mm silica gel plate, 10% ethyl acetate in hexanes). Eluant containing compound 13.1 was concentrated to a colorless oil (1.37 g, 96%). This material was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1% TFA in 95:5 hexanes:2-propanol) and was found to have 94% ee. 1H NMR(500 MHz)(MeOH-d4) δ 7.39 (d, 1H, J=7 Hz); 7.28 (d, 2H, J=8.5 Hz); 7.25-7.15 (m, 3H); 5.05 (s, 2H); 4.02 (m, 1H); 3.64 (s, 3H); 2.68 (m, 2H); 2.36 (s, 3H); 1.80 (d, 3H, J=2.5 Hz). MS ESI (pos.) m/e: 323.0 (M+H); 245.1 (M+Na).
Reaction SMILES: O[C@:2]1([NH:27]OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C@@H:8]([O:9]C(=O)C)[C@@H:7]([O:13]C(=O)C)[C@@H:6]([C:17](=C=O)[O:18]C(=O)C)[O:5][C@@:3]1([CH:24]([NH2:26])[CH3:25])[OH:4].[OH-].[Na+].C(Cl)Cl>CO>[NH2:26][CH:24]([C@:3]1([O:5][C@H:6]([CH2:17][OH:18])[C@H:7]([OH:13])[C@H:8]([OH:9])[C@H:2]1[NH2:27])[OH:4])[CH3:25]
Reactant: CC(=O)OC(=C=O)[C@H]1O[C@](O)(C(C)N)[C@@](O)(NOCC2c3ccccc3-c3ccccc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(N)[C@@]1(O)O[C@H](CO)[C@H](O)[C@H](O)[C@H]1N
Reaction time: 1 h
Yield: 82.4 %

Procedure:
0.1 g (0.17 mmol) of 2-hydroxy-N-9-fluorenylmethoxy-carbonyl-1-aminoethyl-3,4,6-tri-O-acetyl-2-deoxy-2-amino-β-D-galactopyranose (3) as obtained above in step 3) was dissolved in 5 ml of methanol and then 13.6 ml (8 eq.) of a 1N sodium hydroxide solution were added. The reaction mixture was stirred for 1 hour and then neutralized by adding a cation exchange resin sold under the name Dowex 50WX8 by the company Sigma-Aldrich. The resin was then removed by filtration through sintered glass and the filtrate was concentrated under reduced pressure. 0.32 g (0.14 mmol) of compound (4) was then isolated by crystallization from DCM with a yield of 84%.