Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6](O)=[O:7].CC[N:18]=C=NCCCN(C)C.Cl.[OH-].[NH4+]>C(Cl)Cl>[F:1][C:2]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([NH2:18])=[O:7]
Reactant: CC(C)(Oc1ccc(F)cc1F)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(Oc1ccc(F)cc1F)C(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2,4-difluorophenoxy)-2-methylpropanoic acid (10.0 g, 46.3 mmol, Chembridge) in methylene chloride (200 mL) were added 1-hydroxybenzotriaole hydrate (8.5 g, 55.5 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (10.6 g, 55.5 mmol, Aldrich) and ammonium hydroxide (54.0 g, 463 mmol). The reaction mixture was stirred at room temperature for 16 hours and then quenched with water (100 mL). The aqueous layer was extracted with methylene chloride (3×100 mL). The combined organic extracts were washed with brine, 5% citric acid, and brine (100 mL each), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the titled compound. MS (ESI+) m/z 233 (M+NH4)+.
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:15][C:14]([CH3:16])=[CH:13][C:5]=2[NH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2].[Br:17]N1C(=O)CCC1=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:17][C:13]1[C:5]2[NH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:3]([C:1]#[N:2])[C:4]=2[S:15][C:14]=1[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1[nH]c2cc(C)sc2c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1[nH]c2c(Br)c(C)sc2c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
Ethyl 6-cyano-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (0.3 g), N-Bromosuccinimide (0.24 g) and acetic acid (2.5 mL) were dissolved in chloroform (5.0 mL) and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and concentrated under reduced pressure. The obtained residue was washed with diethyl ether, and dried under reduced pressure to give the title compound (0.20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([Cl:37])[CH:36]=1)[CH2:5][N:6]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:11]=1)(=[O:9])=[O:8].[Cl:38][C:39]1[C:40]([OH:50])=[C:41]([S:46](Cl)(=[O:48])=[O:47])[CH:42]=[C:43]([Cl:45])[CH:44]=1.CCN(CC)CC.S(Cl)(Cl)(=O)=O>C1COCC1>[Cl:38][C:39]1[C:40]([OH:50])=[C:41]([S:46]([N:17]([CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([S:7](=[O:8])(=[O:9])[N:6]([CH2:5][C:4]3[CH:3]=[C:2]([Cl:1])[CH:36]=[C:35]([Cl:37])[CH:34]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:11]=2)[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)(=[O:48])=[O:47])[CH:42]=[C:43]([Cl:45])[CH:44]=1
Reactant: O=S(=O)(c1cccc(CNCc2ccc(F)cc2)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.8 %

Procedure:
To a solution of N-(3,5-dichlorobenzyl)-N-(4-fluorobenzyl)-3-((4-fluorobenzylamino)methyl)benzenesulfonamide (75 mg, 0.13 mmol) in THF (4 mL) at rt was added 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (38 mg, 0.15 mmol) and Et3N (0.06 mL, 0.40 mmol) and it was stirred at rt for 1.5 h. Additional sulfonyl chloride (15 mg) and Et3N (0.05 mL) were added to the reaction mixture, and it was continued to stir for 2 h. The mixture was concentrated and the residue was purified by preparative HPLC (Condition: solvent A: 10% MeOH-90% H2O-0.1% TFA; Solvent B: 90% MeOH-10% H2O-0.1% TFA. Column 3: YMC S5 ODS 20×100 mm; 45% B to final 100% B, gradient time: 10 minutes, flow rate: 20 ml/min) to give the desired product as a white solid (56 mg, 53%). 1H NMR (CD3OD): δ 7.72 (d, J=7.2 Hz, 1H), 7.70 (d, J=2.8 Hz, 1H), 7.64 (s, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.50-7.46 (m, 2H), 7.20-7.10 (m, 5H), 6.93-6.90 (m, 6H), 4.61 (s, 2H), 4.46 (s, 2H), 4.26 (s, 2H), 4.21 (s, 21-1); MS (ESI): [M−H]−=784.9.
Reaction SMILES: [I-].[K+].[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]([C:20]1[O:21][C:22]([CH3:27])=[C:23]([CH2:25]Cl)[CH:24]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:16][O:17][C:18]([C:20]1[O:21][C:22]([CH3:27])=[C:23]([CH2:25][NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][CH:7]=2)[CH:24]=1)=[O:19]
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cc(CCl)c(C)o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(CNc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
Potassium iodide (32 mg) and a solution of biphenyl-4-ylamine (74 mg, 0.438 mmoles) in tetrahydrofuran (1 ml) was added to a mixture of 4-chloromethyl-5-methyl-furan-2-carboxylic acid methyl ester (159) (75 mg, 0.398 mmoles) and potassium carbonate (83 mg) in tetrahydrofuran (1 ml). The mixture was stirred at room temperature under an argon atmosphere for 16 hours, and then refluxed with the exclusion of light for 16 hours. After cooling, the mixture was concentrated and the residue was purified by flash chromatography, using a gradient elution of petrol/diethyl ether 9:1 v/v to 4:1 v/v, to afford compound 158 (91 mg). LC/MS System A; Rt=3.93 mins, m/z (ES+)=322 (M+H for C20H19NO3).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:15])([CH3:16])[N:12]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=1
Reactant: Cc1cc(C[C@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-((2-methylpyridin-4-yl)methyl)oxazolidine-3-carboxylate (0.083 g, 0.18 mmol) was dissolved in THF (2 mL) and cooled to 0° C. Next, TBAF (0.28 ml, 0.28 mmol) was added dropwise and the reaction was stirred 1 hr. and then quenched with saturated ammonium chloride and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated. Purification by column chromatography (19:1 DCM/MeOH) afforded the title compound, MS m/z: 337.2 (100%, M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:21]4[N:20]([C@@H:22]5[O:43][C@H:42]([CH2:44]O)[CH2:41][C@H:32]([O:33][CH2:34][C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C@H:23]5[O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:19]5[C:14](=[CH:15][C:16]([F:46])=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:47](=[O:51])[NH:48][C:49](=[O:50])[C:11]=4[C:10]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Na+].[I-:65]>ClCCl.CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:21]4[N:20]([C@@H:22]5[O:43][C@H:42]([CH2:44][I:65])[CH2:41][C@H:32]([O:33][CH2:34][C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C@H:23]5[O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:19]5[C:14](=[CH:15][C:16]([F:46])=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:47](=[O:51])[NH:48][C:49](=[O:50])[C:11]=4[C:10]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c1c3cc(F)ccc3[nH]c1c1c2c2cc(F)ccc2n1[C@@H]1O[C@H](CO)C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NC(=O)c2c1c1c3cc(F)ccc3[nH]c1c1c2c2cc(F)ccc2n1[C@@H]1O[C@H](CI)C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
A mixture of 3,9-difluoro-12-(2,3-di-O-benzyl-4-deoxy-β-D-glucopyranosyl)-6,7,12,13-tetrahydro-(5H)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (0.312 g, 0.45 mmol) and freshly activated, pulverized 4A molecular sieves (0.5 g) in 15 mL of dichloromethane was cooled at 5° C. under Ar and then triethylamine (0.095 mL, 0.68 mmol) and methanesulfonyl chloride (0.039 mL, 0.50 mmol) were added sequentially. The mixture was stirred at the same temperature for 3 h and then the mixture was quenched with 10% saturated aqueous NaHCO3, diluted with ethyl acetate and then filtered. The filtrate was washed (H2O, brine), dried (Na2SO4) and evaporated to give a yellow glass. This material was taken up in 15 mL of acetone, NaI (0.675 g, 4.50 mmol) was added and the mixture was heated to reflux under Ar for 17 h. The cooled mixture was then evaporated to dryness and the residue was taken up in ethyl acetate, washed (H2O, brine) dried (Na2SO4) and evaporated. The resulting solid was chromatographed (SiO2/ethyl acetate-hexane, 1:1) to give 3,9-difluoro-12-(2,3-di-O-benzyl-4,6-dideoxy-6-iodo-β-D-glucopyranosyl)-6,7,12,13-tetrahydro(5H)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (0.276 g, 77% overall) as a yellow glass. To an ice-cold solution of this iodide in 10 mL of dry THF was added DBU (0.157 mL, 1.05 mmol) and the solution was then kept at room temperature for 5 days. The resulting mixture was quenched with saturated aqueous NH4Cl, diluted with ethyl acetate and then washed (H2O, brine), dried (Na2SO4) and evaporated to give the product (0.232 g, 99%) as a yellow glass. To a solution of this material in dry THF was added 20% Pd(OH)2/C and the mixture was hydrogenated (balloon pressure) until the reaction was complete by tlc. The mixture was then filtered (Celite) and the flitrate evaporated to give a yellow glass. Column chromatography (Sephadex LH-20/methanol) afforded the pure title compound as a yellow solid:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([NH:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)C(N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C(NCc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
to a mixture of benzaldehyde (3.06 ml, 30.3 mmol) and methyl 2-amino-2-phenylacetate 1a (4.552 g, 27.6 mmol) in 50 mL 1,2-dichloroethane was added sodium triacetoxyborohydride (14.6 g, 68.9 mmol) all at once. The reaction mixture was stirred at room temperature for several hours then poured into 100 mL saturated aqueous sodium bicarbonate solution. The biphase was vigorously stirred for 15 minutes then the organic separation dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless oil. The product was purified by chromatography on silica gel eluting with 10-40% ethyl acetate in hexane. ESI+ m/z=256.1 [MH]+.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=O)[CH:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[NH2:23][OH:24].N1C=CC=CC=1>CCO>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=[N:23][OH:24])[CH:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(C=O)cnc32)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C=NO)cnc32)cc1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
To a solution of 1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.58 g, 1.93 mmol) in EtOH (5 mL) was added hydroxylamine hydrochloride (0.7 g, 9.6 mmol) and pyridine (0.5 mL). The reaction mixture was heated at 70° C. for 18 h and then the solvent was removed under reduced pressure to afford 0.6 g (98%) of 1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde oxime as white solid which was used in the next step without further purification. MS (ESI) m/z: 316.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.OC1C=NC=CC=1.[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([CH:34]=1)[C:30](=[O:33])[CH2:31]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH2:31][C:30]([C:29]2[CH:34]=[C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:26]=[CH:27][C:28]=2[O:35][CH3:36])=[O:33])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(O)c1
Reactant: COc1ccc(OCc2ccccc2)cc1C(=O)CBr
Agent: Oc1cccnc1
Product: COc1cccc(OCC(=O)c2cc(OCc3ccccc3)ccc2OC)c1

Procedure:
By the method of Example 1, substituting a molar equivalent of 3-methoxyphenol for 3-hydroxypyridine, 5-benzyloxy-2-methoxyphenacyl bromide was converted to present title product; mp 76°-77° C.; IR (KBr) 1680 cm-1 ; MS 378 (M+); Anal. C 73.05, H 5.74, calcd. C 73.00, H 5.86.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:11].[CH3:12]C1C2C(=CC=CC=2)NC=1>>[CH3:12][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:11])[CH:10]=[C:2]1[CH3:1]
Reactant: Cc1c[nH]c2ccccc12
Reactant: Cc1cc2cccc(C)c2[nH]1
Product: Cc1cccc2cc(C)n(C)c12
Yield: 87 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 2,7-dimethylindole for the 3-methylindole, the title compound (960 mg, 87%) was obtained as an oil: MS (ES) m/e 160.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:20]([N:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[C:17]4[C:21]([OH:23])=O)=[N:12]3)=[C:7]2[CH:6]=[CH:5][CH:4]=1.[C:24](N1C=CN=C1)([N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1)=O.CN(C)CCN>CN(C)C=O>[CH3:24][N:26]([CH3:27])[CH2:30][CH2:29][NH:28][C:21]([C:17]1[C:18]2[C:13](=[N:12][C:11]3[C:20]([N:19]=2)=[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]2=[CH:9][CH:10]=3)[CH:14]=[CH:15][CH:16]=1)=[O:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cccc2c1ccc1nc3cccc(C(=O)O)c3nc12
Agent: CN(C)CCN
Solvent: CN(C)C=O
Product: COc1cccc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
A mixture of 4-methoxy-benzo[a]phenazine-11-carboxylic acid (II.1) (129 mg) and 1,1′-carbonyldiimidazole (138 mg) was stirred in dry N,N-dimethylformamide (8 mL) at room temperature for 4 hours. To this mixture was added N,N-dimethylethylenediamine (commercially available)(0.5 mL) and the reaction mixture was stirred at room temperature for a further 30 minutes. The volatiles were then removed in vacuo. The residue was dissolved in dichloromethane, washed with water, dried (MgSO4) and the solvent removed in vacuo to provide crude product. This was purified using flash chromatography (5% methanol in dichloromethane) to yield the title compound as a bright yellow solid (120 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2ccccc2N1
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=C(C)C(=O)N1c2ccccc2CC1C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The starting material is prepared as follows: To the mixture of 3.0 g of indoline-2-carboxylic acid ethyl ester, 4.3 g of powdered potassium carbonate and 30 ml of methylene chloride is added 1.64 g of methacryloyl chloride in 5 ml of methylene chloride during 1 minute. After stirring at room temperature for 3 hours the mixture is partitioned between 50 ml of water and 100 ml of diethyl ether. The organic layer is washed with 30 ml of 1N hydrochloric acid and 25 ml of saturated sodium chloride, dried and evaporated, to yield the 1-methacryloylindoline-2-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:12][CH:13]=[O:14])/[CH:5]=[C:6](/[CH2:10]Br)\[CH2:7][CH:8]=[CH2:9].[P:16]([O:23]CC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:12][CH:13]=[O:14])/[CH:5]=[C:6](/[CH2:10][P:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:23])\[CH2:7][CH:8]=[CH2:9]
Reactant: C=CC/C(=C\C(NC=O)C(=O)OC)CBr
Reactant: CCOP(OCC)OCC
Product: C=CC/C(=C\C(NC=O)C(=O)OC)CP(=O)(OCC)OCC

Procedure:
3.7 g of E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid methyl ester are dissolved in 37 ml of triethyl phosphite, and the mixture is heated at75° for 8 hours. Excess triethyl phosphite is then distilled off under a high vacuum. Purification by column chromatography (silica gel, methanol/ethyl acetate 1:10) yields E-2-formylamino-4-diethylphosphonomethyl-3,6-heptadienoic acid methyl ester in the form of a colourless oil, 1H-NMR (CDCl3): 2.54 (d,2H, P--CH2); 3.10 (m, 2H, C(5)--H); 5.10 (m, 2H, C(7)--H); 5.37 (d, 1 H, C(2)--H); 5.74 (m, 1 H, C(6)--H).
Reaction SMILES: [OH-].[Na+].OO.C1C[O:8]CC1.[F:10][C:11]([F:44])([F:43])[C:12]([OH:42])([CH2:17][CH2:18][CH2:19][C@H:20]([C@@H:22]1[C@:39]2([CH3:40])[C@H:25]([C@H:26]3[C@H:36]([CH2:37][CH2:38]2)[C@:34]2([CH3:35])[C:29](=[CH:30][C:31](=[O:41])[CH:32]=[CH:33]2)[CH:28]=[CH:27]3)[CH2:24][CH2:23]1)[CH3:21])[C:13]([F:16])([F:15])[F:14]>CO.[Cl-].[Na+].O>[F:10][C:11]([F:43])([F:44])[C:12]([OH:42])([CH2:17][CH2:18][CH2:19][C@H:20]([C@@H:22]1[C@:39]2([CH3:40])[C@H:25]([C@H:26]3[C@H:36]([CH2:37][CH2:38]2)[C@:34]2([CH3:35])[C:29](=[CH:30][C:31](=[O:41])[C@@H:32]4[O:8][C@@H:33]42)[CH:28]=[CH:27]3)[CH2:24][CH2:23]1)[CH3:21])[C:13]([F:15])([F:14])[F:16]
Reactant: C1CCOC1
Reactant: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
To a solution of 27 ml of NaOH and 1 ml of 30% H2O2 in degassed MeOH (20 ml) was added a THF solution (10 ml) of 497 mg of the trienone (3) and then the reaction mixture was stirred for 20 hr at room temperature. The reaction mixture was diluted with brine and extracted with ether. The etheral extract was submitted to silica gel column chromatography (AcOEt-n-hexane, 1:4) to give 499 mg (97%) of the epoxide (4): mp 181°-184° C. (from AcOEt-cyclohexane), MS m/e 520(M+), 505, 503; NMR(CDCl3)δ0.70(s, 18-H3), 0.95(d, J=6 Hz, 21-H3), 1.00(s, 19-H3), 3.45 (1H, m, 2-H), 3.62(1H, d, J=6 Hz, 1-H), 4.10(1H, s, OH), 5.62(1H, bs, 4 -H), 6.04(2H, s, 6- and 7-H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)=[O:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18](=[O:20])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)=[O:12])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)NS(=O)(=O)c1ccc(Cl)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)Nc2ccccc2)cc1)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 28 h
Yield: 34.8 %

Procedure:
To a solution of 4-({[(5-chloro-2-thienyl)sulfonyl]amino}carbonylamino)benzoic acid (69 mg) in DMF (0.7 mL) was added aniline (21 uL, 0.23 mmol), DIEA (3 eq.) then PyBOP (85 mg, 0.16 mmol). The reaction mixture was stirred at room temp for 28 hr, acidified and HPLC purified to give {[(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(N-phenylcarbamoyl)phenyl]carboxamide (29 mg, 45%). ES-MS (M+H)+=436, 438 (Cl).
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH2:12]([O:19][C:20]1[N:29]=[C:28](OCC2C=CC=CC=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:38][CH3:39])[CH:26]=2)[N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O>[CH2:12]([O:19][C:20]1[N:29]=[C:28]([NH:11][CH2:1][C:2]2[CH:3]=[C:4]3[O:5][CH2:6][O:7][C:8]3=[CH:9][CH:10]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:38][CH3:39])[CH:26]=2)[N:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CS(C)=O
Product: COc1ccc2nc(OCc3ccccc3)nc(NCc3ccc4c(c3)OCO4)c2c1
Reaction time: 1 h
Yield: 17.9 %

Procedure:
1.25 g (8.27 mmol) of piperonylamine was added to a solution of 1.00 g (2.69 mmol) of the 2,4-bisbenzyloxy-6-methoxyquinazoline prepared in Example 90 in dimethyl sulfoxide (10 ml). The obtained mixture was stirred at 160° to 180° C. After one hour, the reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 0.20 g of the title compound as a colorless needle.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][C:16]=1[O:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:22](=[O:23])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([OH:14])=[C:16]([O:25][CH3:26])[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: COc1ccc(CCN)cc1OC
Product: COc1cc(CC(=O)NCCc2ccc(OC)c(OC)c2)ccc1O

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine and 4-hydroxy-3-methoxy-phenylacetic acid.
Reaction SMILES: [CH3:1][C:2](=[CH2:14])[CH2:3][C:4]([O:10]CCC)(OCCC)[CH3:5].[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18]O.C1CCCCC1>C(O)=O>[CH3:5][C:4]([CH2:10][CH2:18][CH:17]=[C:16]([CH3:20])[CH3:15])=[CH:3][C:2](=[O:14])[CH3:1]
Reactant: C=C(C)CC(C)(OCCC)OCCC
Reactant: CC(C)=CCO
Solvent: O=CO
Solvent: C1CCCCC1
Product: CC(=O)C=C(C)CCC=C(C)C
Yield: 89 %

Procedure:
In an autoclave, a mixture of 120 parts of 4-methyl-2,2-di-n-propoxy-4-pentene, 50 parts of prenol and 170 parts of cyclohexane is heated with 3.4 parts of formic acid for 4 hours at 160°C. Fractional distillation gives 57.5 parts of 4,8-dimethyl-3,7-nonadien-2-one, equivalent to a yield of 89% and a conversion of 67% based on prenol.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2].CO.[C:14]([O-])([O-])=O.[Cs+].[Cs+].IC>O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:14])=[O:7])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: [Cs+]
Solvent: O
Solvent: CO
Solvent: CI
Product: COC(=O)c1cccc(C=O)c1
Reaction time: 18 h
Yield: 164.6 %

Procedure:
3-Formylbenzoic acid (3.11 g, 20.7 mmol, Aldrich) in 10:1 methanol:water (110 mL) was treated with Cs2CO3 (3.11 g, 10.4 mmol). After stirring 18 hours, the solvent was evaporated under reduced pressure and the residue was dried under reduced pressure at 60° C. The residue was suspended in DMF (40 mL) and treated with iodomethane (2.58 mL, 41.4 mmol). After stirring at ambient temperature 2 hours, the mixture was poured into water and extracted with diethyl ether. The ether extracts were combined, washed with water, saturated NaHCO3, dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound as a white solid (2.81 g).