Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([O:19][C:20](=[O:22])[CH3:21])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[S:7][CH:8]=1)(=O)[CH3:2].[NH:23]([C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([N+:36]([O-:38])=[O:37])[CH:28]=1)=[O:26])[NH2:24].Cl.O>CN(C=O)C>[C:20]([O:19][C:5]1[C:4]([C:1](=[N:24][NH:23][C:25]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([N+:36]([O-:38])=[O:37])[CH:28]=2)=[O:26])[CH3:2])=[CH:8][S:7][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1)(=[O:22])[CH3:21]
Reactant: NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CC(=O)Oc1c(C(C)=O)csc1-c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C(C)=NNC(=O)c2ccc(C(=O)O)c([N+](=O)[O-])c2)csc1-c1ccc(C(C)(C)C)cc1
Reaction time: 8 h
Yield: 27.8 %

Procedure:
To a solution of acetic acid 4-acetyl-2-(4-tert-butylphenyl)thiophen-3-yl ester (63.3 mg, 0.2 mmol) and 4-hydrazinocarbonyl-2-nitrobenzoic acid (54.0 mg, 0.24 mmol) in DMF (1 mL) was added 12 M aqueous HCl solution (16.7 μL, 0.2 mmol). The reaction mixture was stirred overnight, and then water was added. The precipitated solid was collected by filtration and washed with water and CHCl3 to give product as a pale yellow solid (29.1 mg, yield 28%).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([CH3:20])=[C:11]([CH3:19])[C:12]2[O:16][CH2:15][S:14][C:13]=2[C:17]=1[CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:1]([O:8][C:9]1[C:10]([CH3:20])=[C:11]([CH3:19])[C:12]2[O:16][CH2:15][S:14](=[O:29])[C:13]=2[C:17]=1[CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)S(=O)CO2
Reaction time: 1 h

Procedure:
The whole of the 5-t-butyldimethylsilyloxy-4,6,7-trimethyl-1,3-benzoxathiole obtained as described in Example 92 was dissolved in 100 ml of methylene chloride, and 0.99 g of m-chloroperbenzoic acid was added, with ice cooling, to the resulting solution. The reaction mixture was then stirred for 1 hour at the same temperature, after which it was poured into a saturated aqueous solution of sodium bicarbonate, extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off, whereupon the residue crystallized. The crystals were washed with carbon tetrachloride, yielding 1.30 g of the title compound, melting at 100°-101° C.
Reaction SMILES: [F:1][C:2]([F:32])([C:28]([F:31])([F:30])[F:29])[C:3]([F:27])([F:26])[C:4]([F:25])([F:24])[O:5][C:6]([F:23])([F:22])[C:7]([F:21])([F:20])[O:8][C:9]([F:19])([F:18])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[CH2:33]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C)C=O>[CH2:33]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:21])([F:20])[C:6]([F:23])([F:22])[O:5][C:4]([F:25])([F:24])[C:3]([F:27])([F:26])[C:2]([F:32])([F:1])[C:28]([F:31])([F:30])[F:29])([F:19])[F:18])=[CH:53][CH:54]=2)=[N:47][CH:48]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: FC(F)(COCCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
Using essentially the procedure of Comparative Example A, the title compound was prepared by combining 5-(2-(2 -(nonafluorobutoxy)tetrafluoroethoxy)-2,2 -difluoroethoxy)-l-bromopentane (4.4 g, 7.6 mmol), 5 -decyl-2-(4-hydroxyphenyl)pyrimidine (2.0 g, 6.4 mmol), potassium carbonate (0.5 g, 10 mmol), acetonitrile (20 mL), and dimethyl formamide (20 mL). The resulting crude product was isolated and purified essentially as in Comparative Example A to yield 4.98 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([F:31])[C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1)[CH2:5][CH2:6][O:7][C:8]1[NH:9][CH:10]=[C:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=1.[CH3:32]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[F:31][C:18]1[CH:17]=[C:4]([CH:3]=[C:2]([F:1])[C:19]=1[O:20][C:21]1[CH:26]=[N:25][C:24]([C:27]([F:29])([F:30])[F:28])=[N:23][CH:22]=1)[CH2:5][CH2:6][O:7][C:8]1[N:9]([CH3:32])[CH:10]=[C:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1c[nH]c(OCCc2cc(F)c(Oc3cnc(C(F)(F)F)nc3)c(F)c2)nc1=O
Solvent: ClCCl
Solvent: CI
Product: CCc1cn(C)c(OCCc2cc(F)c(Oc3cnc(C(F)(F)F)nc3)c(F)c2)nc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To the solution of 2-(3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenethoxy)-5-ethylpyrimidin-4(1H)-one (30 mg, 0.068 mmol) and DIPEA (0.03 ml, 0.172 mmol) in DCM (1.5 ml) was added MeI (0.025 ml, 0.407 mmol). The solution was stirred at room temperature overnight. Purification via reverse phase flash chromatography then afforded the title compound (12 mg, 0.026 mmol, 38.8% yield). LCMS: rt=3.10 min, [M+H]=457
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH:19]=[O:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg]I>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH:19]([OH:20])[CH3:22])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]I
Reactant: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-formyl-5-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.31 g, 1 mmol) in THF (10 mL) was added MeMgI (1 mL, 3 mmol) in Et2O at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with H2O and brine. After drying over Na2SO4, the solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3].[CH3:9][C:10]([CH3:14])=[CH:11]CO.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCCCCCC)CCCCCCC.C([O-])(=O)CCCCCCCCCCC>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][CH:9]=[C:10]([CH3:14])[CH3:11])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3]
Reactant: CC(C)=CCO
Reactant: C/C=C(/C)C(=O)OC
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCCCCCC[Sn+2]CCCCCCCC
Solvent: Cc1ccccc1
Product: C/C=C(/C)C(=O)OCC=C(C)C

Procedure:
A mixture of 19.6 g. of methyl angelate, 22.2 g. of 3-methyl-2-butenyl alcohol, 100 ml. of toluene and 1.6 g. of dioctyltin laurate was placed in a glass flask which was equipped with a Soxhlet extractor filled with molecular sieve 4A on the top and a reflux cooler. The mixture was heated under reflux while returning the refluxed liquid through the molecular sieve 4A to the flask. The mixture obtained from the heating for a total of 26 hours was subjected to single distillation to give 24.24 g. of a distillate boiling at 102°-105° C. (25 mmHg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[C:11]([OH:15])(=[O:14])[CH:12]=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][O:10][CH:12]2[C:11]([OH:15])=[O:14]
Reactant: OCCc1ccccc1Br
Reactant: O=CC(=O)O
Product: O=C(O)C1OCCc2c(Br)cccc21

Procedure:
A solution of 2-(2-bromophenyl)ethanol (40 g, 0.2 mol) and glyoxylic acid (16 g, 0.22 mol) in 100 mL of trifluoacetic acid was refluxed overnight. The solvent was concentrated. Water and ammonium hydroxide was added to the residue to adjust the pH of the solution over 7. The solution was extracted with diethyl ether, and the aqueous layer was adjusted to about 3 with 1M HCl, and then the solution was extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was without purification to give 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylic acid. 1H-NMR (400 MHz, CDCl3) δ 7.52 (d, J=7.6 Hz, 1H), 7.12 (t, J=7.8 Hz, 2 H), 5.33 (s, 1H), 4.27˜4.33 (m, 1H), 3.99˜4.06 (m, 1H), 2.87˜2.89 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C@:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH3:9])=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:11][CH2:12][C@@:13]([OH:19])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][C:15]([OH:17])([CH3:18])[CH3:16])[C:27](=[O:28])[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H](NCC[C@](O)(CC(C)(C)O)c1ccccc1)c1ccc(Br)cc1
Product: C[C@@H](c1ccc(Br)cc1)N(CC[C@](O)(CC(C)(C)O)c1ccccc1)C(=O)Oc1ccccc1
Temperature: 10 °C
Reaction time: 10 h

Procedure:
Preparation 2: Using a procedure similar to that described in Preparation 1 above, the reaction mixture from Step 4 above is cooled to about 10° C. and treated drop-wise with phenyl chloroformate (5.2 mL, 41.3 mmol). The reaction mixture is stirred at 20-25° C. for 2-18 hours, extracted with EtOAc, and the organic extract washed with 3N aqueous HCl. The combined organic phases are distilled to remove EtOAc and DME. The resultant solution is treated with heptane (30 mL), cooled to about 5° C., seeded with 5 (obtained from Preparation 1 immediately above), and held at about 5° C. for 3 hours. The resultant solids are collected by filtration, washed with heptane, and dried under vacuum at 25° C. for 18 hours to provide 5 as an off-white solid. Yield: 14.61 g, 78.3%; 97.2% purity by weight. Melting point: 129-131° C. LC-MS: 507.6/509.6 (95%, 100%); [M−H2O]+; calculated exact mass for M−H2O: 507.1.
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:9][N:8]=[CH:7]1.C(Br)(Br)(Br)[Br:29]>CCCCCC.C1COCC1>[Br:29][C:7]1[S:6][C:10]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:9][N:8]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cncs3)ncnc21
Reactant: BrC(Br)(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnc(Br)s3)ncnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
2.5 M n-Butyllithium in hexane (0.860 mL) was added dropwise to a −78° C. solution of 4-(1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (550 mg, 0.0016 mol) in THF (20 mL). The mixture was stirred for 30 minutes at −78° C., followed by the slow addition of carbon tetrabromide (658 mg, 0.00198 mol) as a solution in THF (10 mL). After 30 minutes, the mixture was quenched with a small amount of saturated ammonium chloride, diluted with ether, and dried over sodium sulfate. The residue obtained after filtration and concentration was purified by flash column chromatography (ethyl acetate/hexanes) to afford the desired product (387 mg, 57%).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[N:12]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#N)[CH:20]=2)=[O:10])[CH2:6][C@H:5]2[CH2:27][C@@H:3]1[C:4]2([CH3:29])[CH3:28].O.P(P([O-])([O-])=O)([O-])([O-])=[O:32].[Na+].[Na+].[Na+].[Na+]>N1C=CC=CC=1CC(O)=O.O.[Ni]>[CH3:1][C@@H:2]1[C@@H:7]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[N:12]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[O:32])[CH:20]=2)=[O:10])[CH2:6][C@H:5]2[CH2:27][C@@H:3]1[C:4]2([CH3:29])[CH3:28]
Reactant: O=P([O-])([O-])P(=O)([O-])[O-]
Reactant: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(C#N)c2)C[C@H]2C[C@@H]1C2(C)C
Agent: [Ni]
Agent: O=C(O)Cc1ccccn1
Agent: [Na+]
Solvent: O
Product: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(C=O)c2)C[C@H]2C[C@@H]1C2(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
To a stirred solution of 2-(3-cyano-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (0.200 g, 0.48 mmol) in a mixture of pyridine-acetic acid-water (2:1:1; 7.2 mL) was added sodium hypophosphate hydrate (0.400 g, 3.77 mmol) at room temperature. The reaction mixture was cooled to 0° C. and Raney Nickel (0.200 g) was added under an argon atmosphere. After stirring at 0° C. for 10 min, the temperature was raised to 40-45° C. and the reaction mixture was stirred for an additional 2.5 h at the same temperature (with monitoring by silica TLC). The reaction mixture was cooled, filtered through a pad of celite and the residue was washed with methanol (5 mL). The combined filtrates were concentrated to provide the crude material, which was purified by silica gel column chromatography (100-200 mesh) using a gradient of 50-60% ethyl acetate/hexanes to give 2-(3-formyl-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (0.100 g, 49%).
Reaction SMILES: [CH2:1](Br)[CH2:2][OH:3].[C:5]1([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:19]1([CH:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH2:1][CH2:2][OH:3])[CH2:17][CH2:18]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OCCBr
Reactant: c1ccc(C(CN2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(CC(c2ccccc2)c2ccccc2)CC1

Procedure:
Ethylene bromohydrin (4.03 g) was added dropwise to a mixture of 1-(2,2-diphenylethyl)piperazine (4.30 g), potassium carbonate (6.7 g) and N,N-dimethylformamide (20 ml) with stirring. The mixture was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over Na2SO4. The solvent was then distilled off and the residue was subjected to silica gel chromatography. Elution with ethyl ether-ethyl acetate-methanol (10:2:1, v/v) gave 4-(2,2-diphenylethyl)-1-piperazineethanol as an oil. Yield 4.24 g.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=2)[CH2:7]1.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:26][N:25]=[C:16]([C:13]1[S:12][C:11]([N:8]2[CH2:9][CH2:10][CH:6]([O:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[C:2]([F:23])([F:1])[F:22])[CH2:7]2)=[N:15][CH:14]=1)[NH2:17]
Reactant: N#Cc1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Temperature: 80 °C

Procedure:
A mixture of 2-{3-[2-(trifluoromethyl)phenoxy]pyrrolidin-1-yl}-1,3-thiazole-5-carbonitrile (370 mg, 1.1 mmol), hydroxylamine hydrochloride (303 mg, 4.4 mmol) and sodium carbonate (231 mg, 2.2 mmol) in EtOH—H2O (4:1, 20 mL) was heated at 80° C. for 2 h. Solvent was evaporated in vacuo. The residue was diluted with H2O, extracted three times with EtOAc, dried (Na2SO4) and concentrated. Trituration with hexanes:Et2O (1:1) gave the title compound as white powder. 1H NMR (400 MHz, acetone-d6): δ 8.73 (s, 1 H), 7.66 (m, 2 H), 7.52 (s, 1 H), 7.38 (d, 1 H), 7.16 (t, 1 H), 5.46 (m, 3 H), 3.94-3.88 (m, 1 H), 3.75-3.59 (m, 3 H), 2.56-2.30 (m, 2 H).
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:5][C:4]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>ClCCCl>[OH:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:5][C:4]=1[NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1Nc1ccccc1
Solvent: ClCCCl
Solvent: O
Product: O=C(Nc1ccccc1)c1ccc(O)c(Nc2ccccc2)c1
Reaction time: 1.5 h
Yield: 35.2 %

Procedure:
Boron tribromide-dimethyl sulfide complex (3.1 g, 9.9 mmol) was added to a stirred suspension of 4-methoxy-3-phenylamino-N-phenyl-benzamide from Example 28 (0.9 g, 2.8 mmol) in 1,2-dichloroethane (50 mL) under an inert atmosphere, and the mixture heated to reflux. After 1.5 hours, the mixture was allowed to cool and was poured into water (125 mL) and extracted with dichloromethane (2×75 mL). The combined extracts were washed with water, then saturated brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate and filtered through a short column of silica gel. The filtrate was stripped of solvent and the residue recrystallized from toluene to afford the product (0.3 g); m.p. 158-159° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1.Cl[CH:17]([F:19])[F:18]>O>[F:18][CH:17]([F:19])[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)Oc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
100 g (0.4.55 mol) of 4-iodophenol and 54.6 g (1.365 mol) of sodium hydroxide are added to a mixture of 300 ml of THF and 30 ml of water. After stirring for about 1/2 hour, the mixture is evaporated in a rotary evaporator; this is repeated after the addition of 200 ml of toluene. The residue is taken up in 400 ml of THF. The mixture is cooled to 0° C., 47.1 g (0.545 mol) of chlorodifluoromethane are introduced, and the mixture is then stirred for 1 hour. It is then stirred at about +5° C. for 18 hours. The solution above the resulting slurry-like precipitate was decanted off. It was evaporated in a rotary evaporator, and the residue was chromatographed through a silica gel column, using petroleum ether as eluent.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O.[OH-].[Li+].O.[O:21]=[C:22]1[O:26][C@H:25]2[CH2:27][C@@H:28]([O:32][C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:34])[C@H:29]([CH:30]=O)[C@H:24]2[CH2:23]1>COC(C)(C)C>[F:15][C:9]([F:14])([CH2:10][CH2:11][CH2:12][CH3:13])[C:8](=[O:16])/[CH:7]=[CH:30]/[C@@H:29]1[C@@H:24]2[C@@H:25]([O:26][C:22](=[O:21])[CH2:23]2)[CH2:27][C@H:28]1[O:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (0.378 g, 1.50 mmol) in t-butyl methyl ether (5 ml), lithium hydroxide monohydrate (60.8 mg, 1.45 mmol) was added and the mixture was stirred for one hour at room temperature. Water (0.15 ml) and (3aR,4R,5R,6aS)-2-oxo-5-phenylcarbonyloxyhexahydro cyclopenta[b]furan-4-carbaldehyde (10) (0.274 g, 1.00 mmol) were added thereto and the mixed solution was stirred for approximately 3 hours at room temperature. The reaction mixture was added to water and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with water, saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 100 g; ethyl acetate:hexane =1:2), to give (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan (11) (0.201 g; 0.495 mmol; yield: 49.5%) as a colorless oil.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.O[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:32][CH:31]([CH2:33][O:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)[CH2:30][C:29]2=[O:45])=[CH:24][CH:23]=1>C(Cl)Cl>[C:1]([O:5][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:32][CH:31]([CH2:33][O:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=3)[CH2:30][C:29]2=[O:45])=[CH:26][CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(O)cc3)C2)cc1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OC(C)(C)C)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.5 %

Procedure:
tert-Butanol (1.58 g), dicyclohexylcarbodiimide (4.04 g) and cuprous chloride (35 mg) are suspended in methylene chloride (5 ml) and the mixture is stirred at room temperature under shading for 4 days. Thereto is added a suspension of methyl 4-[1-(4-hydroxyphenyl)-2-pyrrolidon-4-yl]methoxybenzoate (1.52 g) in methylene chloride (30 ml) and the mixture is further stirred for 14 hours. The reaction mixture is concentrated under reduced pressure and thereto is added chloroform. The insoluble material is removed by filtration and the filtrate is subjected to silica gel column chromatography and eluted with chloroform to give the desired product (0.93 g), m.p. 126°-127.5° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])=[C:2]=[S:3].[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH3:30][CH:29]([CH3:31])[C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:2]([NH:1][C:4]3[C:5]([CH3:10])=[CH:6][CH:7]=[CH:8][CH:9]=3)=[S:3])[CH2:20][CH2:19]2)[CH:22]=1)=[O:32]
Reactant: Cc1ccccc1N=C=S
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: Cc1ccccc1NC(=S)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure P and Scheme AB using 1-isothiocyanato-2-methylbenzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 453.2 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>CO.O>[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:25][CH3:26])[CH2:21][CH2:22]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3
Reactant: Nc1c(Cl)cc2c3c(cccc13)C(=O)N(C1CCNCC1)C2=O
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN1CCC(N2C(=O)c3cccc4c(N)c(Cl)cc(c34)C2=O)CC1
Reaction time: 2 h

Procedure:
To a solution of 6-amino-5-chloro-2,3-dihydro-2-(piperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione hydrochloride (0.9 g; 2.46 mmol), prepared as in Example 10, in methanol (30 mL) and water (5 mL), was added acetaldehyde (2 mL) and sodium cyanoborohydride (approximately 0.5 g) and the reaction mixture stirred for two hours. Additional sodium cyanoborohydride (0.4 g) was added and the mixture stirred for an additional 2 hours. The solution was concentrated to a small volume, acidified with concentrated hydrochloric acid, and then digested for 16 hours. Solid potassium carbonate was added and the solution was extracted twice with methylene chloride. The extracts were combined, dried over potassium carbonate, and concentrated. Purification by column chromatography (silica gel; 3% methanol in CH2Cl2 and approximately 1% NH4OH) gave 6-amino-5-chloro-2-(1-ethylpiperidin-4-yl)-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione (0.6 g; 1.68 mmol).