Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][OH:25])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](Cl)=[O:31]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][O:25][C:30](=[O:31])[CH2:29][C:28]([CH3:34])([CH3:33])[CH3:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 7, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 3,3-dimethylbutyryl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 83% yield.
Reaction SMILES: CCCC.[C:5]1([S:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([NH:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31](I)[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)=[O:36].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C1(C)C=CC=CC=1>[C:5]1([S:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([NH:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([C:40]6[CH:41]=[CH:42][C:37]([CH:35]=[O:36])=[CH:38][CH:39]=6)[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4ccc(I)cc34)ccc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCC
Solvent: N#Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc5c(ccn5S(=O)(=O)c5ccccc5)c4)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of toluene (100 mL) in a 500 mL round-bottom flask equipped with a reflux condenser was added 1,4-bis(diphenyl)phosphino)-butane (4.25 mg, 0.997 mmol) and bis(benzonitrile)dichloro-palladium (385 g, 0.997 mmol). Nitrogen was bubbled through the reaction mixture for 1 minute and the resulting suspension was stirred at room temperature for 30 minutes. THF (125 mL) and EtOH (50 mL) were then added. To the resulting mixture was added (1-benzenesulfonyl-1H-indol-5-yl)-(6-iodo-quinazolin-4-yl)-amine 20 (3.5 g, 6.6 mmol), 4-formylphenylboronic acid (1.99 g, 13.3 mmol) and 2M aq Na2CO3 (6.7 mL). The mixture was heated at reflux under an atmosphere of N2 for 15 hours. The solvent was removed under reduced pressure and the residue was purified using flash chromatography (silica gel, EtOAc/hexanes 1:1) to provide 3.1 g of 4-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzaldehyde 22 in 92% yield. 1H NMR (DMSO-d6; 400 MHz): δ: 9.24 (s, 1H, NH), 8.84 (s, 1H), 8.33 (dd, 1H, J=8.9 Hz and 1.7 Hz), 8.01 (m, 4H), 7.90 (m, 2H), 7.70 (m, 2H), 7.60 (m, 3H), 6.92 (dd, 1H, J=3.7 Hz and 0.6 Hz); MS (Cl) m/e 505.1 (M++1, 100).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])(=[O:3])[CH3:2].[C:16]([CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)#[N:17].N1CCCCC1.O>C(Cl)(Cl)Cl>[OH:10][C:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][C:5](=[O:15])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH2:18][C:16]#[N:17])[CH:21]=1
Reactant: N#CCOc1cccc(C=O)c1
Reactant: CC(=O)c1c(O)c2ccccc2oc1=O
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Solvent: O
Product: N#CCOc1cccc(C=CC(=O)c2c(O)c3ccccc3oc2=O)c1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
In 5 ml of chloroform were dissolved 0.57 g of 3-acetyl-4-hydroxy-2H-1-benzopyran-2-one, 0.45 g of 3-(cyanomethoxy)benzaldehyde and 0.20 g of piperidine, and the solution was heated under refluxing for 1 hour and 30 minutes while water was removed with a Soxhlet's extractor filled with a molecular sieve. After cooling to room temperature, the reaction mixture washed successively with 10% hydrochloric acid and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. Precipitated crystals were washed with a mixture of 10 ml of dioxane and 10 ml of chloroform, and washed with 10 ml of t-butyl methyl ether to obtain 0.56 g of 4-hydroxy-3-[3-[3-(cyanomethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (14d)] as a yellow crystal.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([O:34][CH2:35][CH3:36])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:15]([C:17]2([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][CH:7]=1.[Li+].[OH-]>O1CCCC1>[CH2:35]([O:34][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:15]([C:17]2([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][CH:7]=1)[C:3]([OH:37])=[O:2])[CH3:36]
Reactant: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)OC)cc1)C(=O)C1(c2ccc(C)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)O)cc1)C(=O)C1(c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.7 %

Procedure:
A solution of 2-ethoxy-3-(4-{2-[heptyl-(1-p-tolyl-cyclopropanecarbonyl)-amino]-ethyl}-phenyl)-propionic acid methyl ester (94 mg, 0.185 mmol) and 1 M LiOH (0.60 mmol, 0.60 mL) in tetrahydrofuran (1 mL) was allowed to stir at room temperature for 16 hours. 2 N HCL was then added until the solution had a pH<2. After dilution with twice its volume in water, the aqueous layer was extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (2×), dried over anhydrous sodium sulfate, and concentrated to give 2-ethoxy-3-(4-{2-[heptyl-(1-p-tolyl-cyclopropanecarbonyl)-amino]-ethyl}-phenyl)-propionic acid as a clear oil (60 mg, 66%).
Reaction SMILES: [C:1]([O:4][CH2:5]I)(=[O:3])[CH3:2].[Cl:7][C:8]1[C:9]([F:48])=[C:10]([C@@H:14]2[C@:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])([C:19]#[N:20])[C@H:17]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:16][C@H:15]2[C:34]([NH:36][C:37]2[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][C:38]=2[O:46][CH3:47])=[O:35])[CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][O:43][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:37]([NH:36][C:34]([C@H:15]2[C@H:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[C:9]=3[F:48])[C@:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])([C:19]#[N:20])[C@H:17]([CH2:29][C:30]([CH3:32])([CH3:33])[CH3:31])[NH:16]2)=[O:35])=[C:38]([O:46][CH3:47])[CH:39]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(=O)OCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OCOC(C)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A portion of this iodomethyl acetate (661 mg, 3.31 mmol) was added to a suspension of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200.1 mg, 0.325 mmol) and cesium carbonate (964.4 mg, 2.93 mmol) in dimethylformamide (8 mL) and the reaction was stirred in the dark overnight. It was then taken up in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (hexane/ethyl acetate, 80/20 to 10/90) to give chiral-4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid acetoxymethyl ester as a white solid (42.8 mg, 19% yield). MS (ES+) m/z calcd. for C34H34Cl2F2N3O6: [(M+H)+]: 688, found: 688
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[S:34][CH:35]=[C:36]([CH3:38])[N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:36]1[N:37]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[S:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: Cc1csc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (855 mg; compound B50) is reacted with 2-(chloromethyl)-4-methyl-1,3-thiazole (368 mg; compound D13) in the presence of potassium carbonate (276 mg) in DMF (15 ml). Using WU1 a solid is obtained which is purified by flash chromatography [silica gel, eluation gradient: DCM/MeOH, 100/0 to 95/5 (v/v)] to give the title compound as a solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[C:5]([CH3:12])=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14].O>CN1C(=O)CCC1>[CH3:11][N:8]1[CH:7]=[C:6]2[C:10]([C:2]([C:13]#[N:14])=[CH:3][CH:4]=[C:5]2[CH3:12])=[N:9]1
Reactant: N#C[Cu]
Reactant: Cc1ccc(Br)c2nn(C)cc12
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(C#N)c2nn(C)cc12
Temperature: 130 °C
Yield: 40 %

Procedure:
To a solution of 7-bromo-2,4-dimethyl-2H-indazole (1 eq.) in NMP, was added CuCN (2 equiv.) and heated at 130° C. for 16 h. On completion, water was added to quench the reaction, solid precipitated was filtered and purified by column chromatography to afford the title compound (40-60% yield)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][C:22]([F:37])([CH:34]([F:36])[F:35])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:22]([F:37])([F:21])[CH:34]([F:36])[F:35])=[CH:30][N:29]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)C(F)F)cn1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(OCC(F)(F)C(F)F)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid following procedure I yielded the 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide which, after treatment with hydrochloric acid in dioxane (4N), evaporation and trituration with diethylether, gave the title compound as an off-white solid. MS (ISP): m/z=523.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl[S:21]([OH:24])(=[O:23])=[O:22]>ClCCl>[CH3:16][C:6]1[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([S:21]([OH:24])(=[O:23])=[O:22])[CH:14]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)O)c1
Reaction time: 16 h

Procedure:
A solution of the title B compound, 3,5-dimethyl-4-(4′-hydroxyphenoxy)nitrobenzene (7.86 g, 30.35 mmol) in 150 mL of dichloromethane (CH2Cl2) is treated with chlorosulfonic acid (2.4 mL, 36.42 mmol) at RT. After 16 h, the reaction mixture is concentrated and the residue is dissolved in small amount of CH2Cl2 (ca. 5 mL). The product is precipitated by addition of brine (100 mL), collected by vacuum filtration, washed with water, hexanes and diethyl ether (Et2O) and dried in vacuo to give 5-(2,6-dimethyl-4-nitrophenoxy)-2-hydroxy-benzenesulfonic acid: NMR (DMSO-d6) 2.18 (s, 6H), 6.67-6.83 (m, 3H), 8.1 (s, 2H), 10.07 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:4]([C:5](=[O:7])[CH2:6]1)[CH2:3][C:2]2=[O:10].[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:7]1[CH2:11][CH2:12][O:13][C:5]21[CH2:6][CH:1]1[CH2:9][CH2:8][CH:4]2[CH2:3][C:2]1=[O:10]
Reactant: OCCO
Reactant: O=C1CC2CCC1CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1CC2CCC1CC21OCCO1
Temperature: 25 °C

Procedure:
To 4.0 g of rac-(1R*,4R*)-bicyclo[2.2.2]octane-2,5-dione (intermediate K1A.1), dissolved in 120 mL of toluene, 1.7 mL of ethylene glycol and 0.27 g of TsOH were added and the solution was heated under vigorous stirring to reflux for 3.5 h. The reaction mixture was cooled to rt, quenched with saturated aq. NaHCO3, extracted with Et2O, and the organic phase was evaporated. The crude product was purified by CC with Hex-EtOAc (7:3) to yield 2.41 g of rac-(1R*,4R*)-spiro[bicyclo[2.2.2]octane-2,2′-[1,3]dioxolan]-5-one as yellow oil.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:30][C:31]([CH2:35][CH3:36])([OH:34])[CH2:32][CH3:33])[CH2:12][C@@H:11]([O:37][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:32]([C:31]([OH:34])([CH2:35][CH3:36])[CH2:30][O:29][CH2:28][C:20]1[C@:21]2([CH2:23][CH2:24][C@H:25]3[C:16](=[CH:15][CH:14]=[C:13]4[C@:26]3([CH3:27])[C@@H:9]([OH:8])[CH2:10][C@H:11]([OH:37])[CH2:12]4)[C@@H:17]2[CH2:18][CH:19]=1)[CH3:22])[CH3:33]
Reactant: CCC(O)(CC)COCC1=CC[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: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)COCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 71.6 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-{2-ethyl-2-hydroxybutoxymethyl}androsta-5,7,16-triene (139 mg, 0.216 mmol), a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (1.3 ml, 1.3 mmol) and tetrahydrofuran (3 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (4 hours), worked up and the thus obtained residue was purified by preparative thin layer chromatography (1 sheet (0.5 mm thickness), dichloromethane:ethanol=10:1, developed three times) to give the titled compound (64.4 mg, 72%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18](Cl)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[N:22]1([CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[CH2:26][CH2:25][CH2:24][CH2:23]1.N1C=CC=CC=1>C1COCC1>[OH:31][CH:28]([CH2:27][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:29][O:30][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:21])=[O:19]
Reactant: OCC(O)CN1CCCC1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)CN3CCCC3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol) and 3-pyrrolidin-1-yl-propane-1,2-diol (88 mg, 0.6 mmol) in 3.0 mL of THF was added 80 μl of pyridine dropwise at room temperature. Upon addition, the reaction mixture was stirred at room temperature for 20 min., and filtered. The orange solid was then washed with ethyl acetate and hexane sequentially and dried in a vacuum oven overnight to give 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-pyrrolidin-1-yl-propyl ester as an orange solid. 1HNMR (400 MHz, CDCl3 and 2 drops of DMSO-d6) δ 12.63 (s, br, 1H, NH-1′), 11.77 (s, br, 1H, OH), 7.86–7.88 (m, 1H), 7.51–7.53 (m, 1H), 7.42 (s, 1H, H-vinyl), 7.18–7.25 (m, 2H), 6.06 (d, J=2.3 Hz, 1H, H-4′), 4.65–4.73 (m, 2H), 4.44–4.56 (m, 2H), 3.91–3.93 (m, 1H), 3.33–3.52 (m, 2H), 2.88–3.15 (m, 2H), 2.40 (s, 3H, CH3), 2.36 (s, 3H, CH3), and 2.01–2.32 (m, 4H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][NH2:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[CH2:14][O:13]1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:29]=1[O:30][CH2:31][C:32](Cl)=[O:33]>O1CCCC1>[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][NH:10][C:32]([CH2:31][O:30][C:29]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:28]=2[Cl:27])=[O:33])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[CH2:14][O:13]1
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Reactant: CC1(C)CON(Cc2ccc(NN)cc2Cl)C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CON(Cc2ccc(NNC(=O)COc3ccc(Cl)cc3Cl)cc2Cl)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 2-[(2-chloro-4-hydrazinophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone hydrochloride (1.5 g, 0.0049 mole) and triethylamine (1.4 ml) in tetrahydrofuran (100 ml) was cooled to 10° C. and 2,4-dichlorophenoxyacetyl chloride (0.80 g, 0.0067 mole) was added in one portion. The reaction mixture was stirred overnight at ambient temperature. Triethylamine hydrochloride was removed by filtration, and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 60:40 ethyl acetate:heptane. Appropriate fractions were combined and concentrated under reduced pressure. The residual solid was recrystallized from ethyl acetate:heptane to yield 2-[[2-chloro-4-[(2,4-dichlorophenoxy)methylcarbonylhydrazo]phenyl]methyl]-4,4-dimethyl-3-isoxaolidinone as a yellow solid; m.p. 149°-150° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:17]=3[CH:16]=[C:15]([F:31])[CH:14]=2)[CH:10]=[N:9]1)(C)(C)C.[CH2:33]=[O:34].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.CN(C)[CH:56]=[O:57]>O1CCCC1>[F:31][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[N:9][N:8]([C:7]([CH2:56][OH:57])([CH2:33][OH:34])[C:6]([OH:5])=[O:32])[CH:12]=2)[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:17]=2[CH:16]=1
Reactant: C=O
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Cn1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(O)C(CO)(CO)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of an optically active form (33.3 g) of t-butyl[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetate and paraformaldehyde (18.3 g) in dimethylformamide (100 ml) was added at room temperature a 1M solution (244 ml) of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture was stirred at 90° C. for 4 hr. To the reaction mixture was added 1N hydrochloric acid (400 ml), and the mixture was extracted with ethyl acetate (200 ml). The separated aqueous layer was extracted twice with ethyl acetate (100 ml). The combined organic layer was successively washed once with 1N hydrochloric acid (100 ml), twice with brine (water/saturated brine=100 m1/10 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was azeotroped twice with toluene to give the title compound (28.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:15]3[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:17][CH:9]2[CH2:10]4)[CH2:14]3)=[CH:4][CH:3]=1.F[C:26]1[CH:27]=[CH:28][C:29]([N+:33]([O-:35])=[O:34])=[C:30]([OH:32])[CH:31]=1.[C:36]([O-:39])([O-])=O.[K+].[K+].Cl>O.CN(C=O)C>[OH:32][C:30]1[CH:31]=[C:26]([CH:27]=[CH:28][C:29]=1[N+:33]([O-:35])=[O:34])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:26]4[CH:27]=[CH:28][C:29]([N+:33]([O-:35])=[O:34])=[C:36]([OH:39])[CH:31]=4)=[CH:22][CH:23]=3)[CH:9]3[CH2:17][CH:13]4[CH2:12][CH:11]([CH2:16][CH:15]2[CH2:14]4)[CH2:10]3)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)C3CC4CC(C3)CC2C4)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C3(c4ccc(Oc5ccc([N+](=O)[O-])c(O)c5)cc4)C4CC5CC(C4)CC3C5)cc2)cc1O
Yield: 73.9 %

Procedure:
A mixture of 2.00 g (6.26 mmol) of 2,2-bis(4-hydroxyphenyl)adamantane, 2.00 g (12.7 mmol) of 5-fluoro-2-nitrophenol, 1.70 g (12.3 mmol) of anhydrous K2CO3, and 50 mL of dry DMF was reflux for 12 h under nitrogen. The mixture was allowed to cool and subsequently poured into 500 mL of distilled water. The resulting solution was acidied by concentrated hydrogen chloride to pH=3.5˜4.0. The precipitated product was collected, washed thoroughly with water until neutral, and then dried to give 2.75 g (73.9%) of 2,2-bis(4-(3-hydroxy-4-nitrophenoxy)phenyl)adamantane. mp 248˜250° C.; Elemental Anal. Calcd. for C34H30N2O8: C, 68.69; H, 5.05; N, 4.71. Found: C, 68.58; H, 5.10; N, 4.68. MS (EI) m/z 594 (M+, 100); IR (KBr): 3402, 2896, 2868, 1576, 1322 cm−1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[CH3:17])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[CH3:17])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1nccn1-c1ccc2ncnc(Cl)c2c1
Product: Cc1nccn1-c1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Yield: 10 %

Procedure:
Using an analogous procedure to that described in Example 4, 4-chloro-6-(2-methylimidazol-1-yl)quinazoline was reacted with 3-chloro-4-fluoroaniline to give 4-(3-chloro-4-fluoroanilino)-6-(2-methylimidazol-1-yl)quinazoline in 10% yield: NMR Spectrum: (CD3SOCD3) 2.4 (s, 3H), 7.0 (d, 1H), 7.4 (m, 2H), 7.6 (m, 1H), 7.95 (d, 2H), 8.2 (m, 1H), 8.6 (s, 1H), 8.7 (s, 1H), 9.7 (broad s, 1H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:5]([OH:15])[CH:4]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=O.[C:24]([CH:31]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:4]1[CH:3]([CH:1]=[CH:31][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:5]1[OH:15]
Reactant: O=CC1CC(OC2CCCCO2)C(O)C1CCCCCCCO
Reactant: CCCCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCC(=O)C=CC1CC(OC2CCCCO2)C(O)C1CCCCCCCO
Yield: 57.3 %

Procedure:
A mixture of 3-formyl-2-(7-hydroxyheptyl)-5-(2-tetrahydropyranyloxy)cyclopentanol [5.4 g.; prepared as described above in Example 2(e)] and hexanoylmethylene triphenylphosphorane (5.6g.) in dry tetrahydrofuran (60 ml.) was heated under reflux under nitrogen for 24 hours. The solvent was then removed in vacuo and the resulting residue was chromatographed on silica gel. Elution with diethyl ether gave 2-(7-hydroxyheptyl)-3-(3-oxooct-1-enyl)-5-(2-tetrahydropyranyloxy)cyclopentanol (3.64g.), νmax 3450 cm-1, 1670 cm-1, 1630 cm-1, 985 cm-1.