Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].O.[C:16]([O:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>C(O)C.O>[C:16]([O:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][S:1][C:2]3[N:3]([CH3:12])[C:4](=[O:11])[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:32][CH:33]=2)=[O:25])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: Cn1c(S)nc2ccsc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)Oc1ccc(C(=O)c2ccc(CSc3nc4ccsc4c(=O)n3C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 2-mercapto-3-methylthieno[3,2-d]-pyrimidin-4(3H)-one (1.98 g) and 1N-sodium hydroxide/water (10 ml) in ethanol (30 ml) was added 4-(4-acetoxybenzoyl)benzyl bromide (3.95 g) and the mixture was stirred at 60° C. for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water, and recrystallized from ethyl acetate to provide the title compound as colorless solid (3.87 g).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-octenyl)pyridine (Example 33) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.14 (m, 4 H), 4.33 (d, J=5.5 Hz, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.23 (sept, J=6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J=6.6 Hz, 6 H), 1.30 (d, J=6.6 Hz, 6 H), 1.25 (m, 3 H), 1.15 (m, 10 H), 0.87 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C26H38FNO) 399, found 400 (M+H). Anal. Calcd for C26H38FNO: C, 78.15; H, 9.59; N, 3.51. Found: C, 78.27; H, 9.81; N, 3.43. Gummy oil; Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: C(#N)C.Br[CH2:5][C:6]([NH:8][CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:7].[O:20]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[O:20]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([CH2:5][C:6]([NH:8][CH:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[O:13][CH2:12][CH2:11][CH2:10]3)=[O:7])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(CBr)NC1CCCOc2ccccc21
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1)NC1CCCOc2ccccc21
Temperature: 0 °C
Yield: 98 %

Procedure:
To a 5 ml acetonitrile solution of 190 mg of the compound (8) synthesized in Reference Example 8 were added 184 mg of the compound (4) synthesized in Reference Example 4 and 0.14 ml of triethylamine. This was heated at reflux for 3 hours. To the reaction was added 10 ml of ice water, then extraction was performed with ethyl acetate. The extract was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=25:1) to obtain the above-identified compound (28) in an amount of 300 mg (yield of 98%).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.N1C=CC=CC=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=2)[CH:3]=1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc(Cl)n2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a 20 mL scintillation vial was added 7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J, 0.207 g, 1.131 mmol) and pyridine (2.84 ml, 35.1 mmol) and the solution was cooled to 0° C. To the yellow solution was added 4-(trifluoromethoxy)benzoyl chloride (0.508 g, 2.262 mmol) to give an orange suspension. The reaction mixture was stirred for one hour, quenched by the addition of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure in the presence of silica gel. The silica-adsorbed material was then purified by silica gel chromatography (25-75% ethyl acetate/hexanes gradient) to afford the desired compound N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(trifluoromethoxy)benzamide 14A as an orange solid (215 mg, 51% yield); ESI-MS: m/z 370.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9]C(=O)[C:7]2=[O:12].[OH-:15].[Na+].[Na+].[Cl-].OO>O.C(Cl)Cl>[NH2:9][C:10]1[C:2]([Cl:1])=[C:3]([O:13][CH3:14])[CH:4]=[CH:5][C:6]=1[C:7]([OH:12])=[O:15]
Reactant: COc1ccc2c(c1Cl)NC(=O)C2=O
Reactant: [OH-]
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)O)c(N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A suspension of compound 103d (6.03 g, 28.52 mmol), NaOH (1.25 g, 31.37 mmol), and NaCl (3.49 g, 59.89 mmol) in water (60 mL) was stirred at room temperature for 30 min and was then ice-cooled. H2O2 was added dropwise. The mixture was stirred at 0° C. for 20 min and at room temperature for 3 hrs. The reaction mixture was quenched with glacial AcOH, filtered, and washed with water. The solid obtained was dissolved in DCM, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (DCM/MeOH) to yield compound 104d as an orange solid in 36% yield.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][N:16]1[CH2:21][C@H:20]([CH3:22])[NH:19][C@@H:18]([CH3:23])[C:17]1=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:23][C@H:18]1[C:17](=[O:24])[N:16]([CH3:15])[CH2:21][C@H:20]([CH3:22])[N:19]1[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: C[C@@H]1N[C@@H](C)CN(C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2oc(N3[C@@H](C)CN(C)C(=O)[C@@H]3C)nc12
Yield: 19.1 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (342 mg, 1.62 mmol), (3S,5S)-1,3,5-trimethylpiperazin-2-one (230 mg, 1.62 mmol) and potassium carbonate (670 mg, 4.85 mmol), in DMF (10 mL), was stirred at ambient temperature for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with 0.5 N HCl (10 mL), H2O (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and the solids were removed by filtration. The filtrate was concentrated and purified by column chromatography (silica gel, 10% CH2Cl2 in EtOAc to 100% EtOAc) to give methyl 2-((2S,6S)-2,4,6-trimethyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (98 mg, 19%): 1H NMR consistent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.[CH:24](O)=[O:25].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH:24]=[O:25])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Reaction time: 18 h
Yield: 54.3 %

Procedure:
The 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (160 mg, 0.387 mmol) obtained in Example 2 was dissolved in N,N′-dimethylformamide (4.0 mL). Thereafter, formic acid (22.0 μL, 0.581 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 mg, 0.774 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred for 18 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain the captioned compound (92.8 mg, 54%) in the form of a white solid.
Reaction SMILES: [O:1]1[C:20]([CH3:23])([CH2:21][CH3:22])[CH:2]1[CH2:3][CH2:4][C:5]([CH3:19])=[CH:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][O:16]2)=[CH:11][CH:10]=1.[H][H]>[Pt]=O.C(OCC)(=O)C>[O:1]1[C:20]([CH3:23])([CH2:21][CH3:22])[CH:2]1[CH2:3][CH2:4][CH:5]([CH3:19])[CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][O:16]2)=[CH:11][CH:10]=1
Reactant: CCC1(C)OC1CCC(C)=CCOc1ccc2c(c1)OCCC2
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCC1(C)OC1CCC(C)CCOc1ccc2c(c1)OCCC2

Procedure:
2.6 g. of 7-(6,7-epoxy-3,7-dimethyl-2-nonenyloxy)-chromane are dissolved in 26 ml. of ethyl acetate and hydrogenated in the presence of 130 mg. of platinum oxide until the theoretical amount of hydrogen has been made up. The mixture is then filtered off from the catalyst, evaporated and chromatographed on silica gel with hexane/ether (7:3). There is obtained pure 7-(6,7-epoxy-3,7-dimethyl-nonyloxy)-chromane, nD20 = 1.5159.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([OH:9])[C:4]=1[Cl:10].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([O:23][CH3:24])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:12][C:2]([F:1])([F:11])[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([O:9][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([O:23][CH3:24])[CH:15]=2)[C:4]=1[Cl:10]
Reactant: Cn1nc(O)c(Cl)c1C(F)(F)F
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(Oc2nn(C)c(C(F)(F)F)c2Cl)ccc1[N+](=O)[O-]
Yield: 93.1 %

Procedure:
8.02 g (0.04 mol) of 5-trifluoromethyl-4- chloro-3-hydroxy-1-methylpyrazole and 6.85 g (0.04 mol) of 4-fluoro-2-methoxynitrobenzene were mixed together with 6.22 g (0.045 mol) of potassium carbonate in 50 ml of DMSO for 4 hours at a temperature of 72° C. and overnight at a temperature of 85° C. The product was isolated in accordance with Example 2(c) to give 13.1 g (93% yield) of a yellow solid, m.p. 71°-73.5° C.
Reaction SMILES: [S-:1][CH2:2][CH3:3].[Na+].[C:5]([C:9]1[C:14]2[O:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:13]=2[CH:12]=[C:11]([C:20](=[O:23])[CH2:21]Cl)[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([C:9]1[C:14]2[O:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:13]=2[CH:12]=[C:11]([C:20](=[O:23])[CH2:21][S:1][CH2:2][CH3:3])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1cc(C(=O)CCl)cc2c1OCC2(C)C
Reactant: CC[S-]
Agent: [Na+]
Solvent: CO
Product: CCSCC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reaction time: 2.5 h
Yield: 58.7 %

Procedure:
Sodium thioethoxide (0.54 g, 6.4 mmol) is added in portions to a solution of 1 -(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-2-chloroethan-1-one (1.12 g, 4.0 mmol) in 30 mL of methanol at room temperature. The reaction is stirred for 2.5 h, and concentrated in vacuo. The residue is dissolved in ether, washed with water and with brine, dried over anhydrous magnesium sulfate, and concentrated to give 1.12 g of the crude product. Purification by flash column chromatography on silica gel (5% ethyl acetate-hexane) afforded 0.72 g of the title compound as a light yellow oil.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:10]1([CH2:16][CH2:17][CH:18]([C:24]([CH3:26])=O)[C:19](OCC)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:24]([CH3:26])=[C:18]([CH2:17][CH2:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:19](=[O:20])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: CCOC(=O)C(CCc1ccccc1)C(C)=O
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: Cc1c(CCc2ccccc2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (0.87 g) and ethyl 2-(2-phenylethyl)-acetoacetate (1.62 g) in ethanol (30 ml) was treated with dry HCl as described in example 1a. Yield: 1.77 g (87%). Melting point 248-252° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:10]=1[CH:11](OCC)OCC)=O)C.O.[NH2:26][NH2:27].Cl>C(O)(=O)C.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:9]2[C:10]3=[CH:11][N:26]=[N:27][C:4]([OH:3])=[C:6]3[CH:7]=[N:8]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1C(OCC)OCC
Reactant: NN
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Oc1nncc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-diethoxymethyl-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5.70 g, 16.9 mmol) in acetic acid (100 mL) is added hydrazine monohydrate (5.0 mL, 6.1 mmol) and 12 N aqueous hydrochloric acid (200 μL). The reaction mixture is warmed at reflux. After 2 hours, the mixture is cooled to room temperature and diluted with water. The solid is collected by filtration, washed with water and air dried to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyridazin-4-ol.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH:15]([F:17])[F:16])[C:10]=1[CH:18]=[O:19]>C(O)C.[Pd]>[CH3:14][N:13]1[CH:9]=[C:10]([CH:18]=[O:19])[C:11]([CH:15]([F:16])[F:17])=[N:12]1
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1cc(C=O)c(C(F)F)n1
Temperature: 30 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
In an autoclave, 10 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde were dissolved in 150 ml of ethanol, and 10.4 g of triethylamine and 500 mg of 5% palladium on calcium carbonate were added. The autoclave was flushed with nitrogen and subsequently pressurised to 5 bar hydrogen. The reaction mixture was then stirred at 30° C. for 4 h. After filtration of the catalyst, the solvent was removed under reduced pressure and the product was obtained as a solid (7.4 g) having a melting point of 46-47° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:17]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=[O:21])=[O:27])=[CH:7][C:6]=3[C:5]2([CH3:16])[CH3:15])=[CH:13][CH:14]=1
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)c2cc(Br)ccc2-c2ccc(C(=O)c3ccccc3C(=O)O)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.9 %

Procedure:
2-bromo-9,9-dimethyl-9H-fluorene (40 g, 0.146 mol) and phthalic anhydride (23.8 g, 0.161 mol) were placed in a reaction vessel and dichloromethane (1 l) was added thereto. Then, aluminum chloride (29.2 g, 0.219 mol) was gradually added at 0° C., and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was terminated, distilled water was gradually added, and the reaction solution was extracted with dichloromethane and 3 times washed with distilled water. After solvent removal, the resultant solid was placed in a hexane(2 l)-containing vessel, washed, filtered and dried to give 2-(7-bromo-9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (50.4 g, yield 82%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:15](OCC)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33])[CH3:28]>>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH:33]/[C:15](=[C:6]1\[C:5](=[O:25])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:26]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)ccc21)c1ccccc1
Product: COc1ccc2c(c1)NC(=O)/C2=C(\Nc1cccc(CN(C)C)c1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-2-indolinone and 3-(dimethylaminomethyl)-aniline
Reaction SMILES: [F:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([C:20]([OH:22])=O)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:55]([O:59][CH2:60][CH2:61][O:62][NH2:63])([CH3:58])([CH3:57])[CH3:56]>CN(C=O)C>[C:55]([O:59][CH2:60][CH2:61][O:62][NH:63][C:20]([C:9]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:2]([F:1])[C:3](=[O:23])[N:4]2[C:8]=1[CH2:7][CH2:6][CH2:5]2)=[O:22])([CH3:58])([CH3:57])[CH3:56]
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Reactant: CC(C)(C)OCCON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OCCONC(=O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Temperature: 70 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
Example 1 (656 mg, 1.52 mmol), HATU (870 mg, 2.28 mmol) and N-Methylmorpholine (835 μL, 7.59 mmol) were stirred in DMF (7.6 mL) at r.t. for 10 min. O-(2-tert-Butoxy-ethyl)-hydroxylamine (303 mg, 2.28 mmol) was added, and the reaction stirred at 70° C. for 16 h. Purification by prep-HPLC gave 730 mg (73%) of compound 4a as a beige solid. MS (ES) [m+H] calc'd for C21H24F2IN3O4, 548. found 548.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Br
Reactant: NCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Br)c(CNCCCO)c1
Reaction time: 4 h

Procedure:
To a stirring solution of 2-bromo-5-nitrobenzaldehyde (1 eq) in methylene chloride (0.1 M) at room temperature was added 3-amino-1-propanol (2 eq). After stirring for 4 hr, sodium triacetoxyborohydride (2 eq) and acetic acid (5 eq) was added. The reaction mixture was stirred for 3 hr and carefully quenched with methanol. The organic phase was washed with saturated sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (10% EtOAc/Hexane). EI-MS m/z 289 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[NH:7]2.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:25][CH2:14][CH:13]1[O:1][C:2]2=[C:3]3[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]2[CH2:12]1)[NH:7][C:6](=[O:16])[CH:5]=[CH:4]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc(C)c2[nH]c(=O)ccc2c1O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CO)C2
Temperature: 50 °C
Reaction time: 17 h
Yield: 37.9 %

Procedure:
Chloroform (1.5 ml) was added to a mixture of 5-hydroxy-6-allyl-8-methylcarbostyril (50.6 mg) and m-chloroperbenzoic acid (61.5 mg). The obtained mixture was stirred at 50° C. for 17 hours. Excessive aqueous sodium sulfite solution was added thereto, and stirring was continued at room temperature for 30 minutes, followed by extracting with a solvent mixture of chloroform and methanol (4:1). The organic phase was dried over sodium sulfate, and condensed. The resultant residue was purified by thin layer chromatography (solvent=chloroform:methanol=10:1), obtaining 20.6 mg of 2-hydroxymethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (37.9%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:16][CH:11](OC(=O)C)[C@@H:10]1[O:28][C:29](=[O:31])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:32]>C(O)(=O)C.COC>[CH2:1]([O:8][C@H:9]1[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:16][CH:11]([Br:32])[C@@H:10]1[O:28][C:29](=[O:31])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OCc2ccccc2)[C@@H]1OC(C)=O
Reactant: Br
Agent: COC
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1OC(Br)[C@H](OC(C)=O)[C@@H](OCc2ccccc2)[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
To 16 g of compound 4 in 35 mL of acetic acid precooled to 10° C., a solution of hydrogen bromide in acetic acid (50% w/v; 16 mL)-was added slowly. The solution was stirred at 5°-10° C. for 3 hours, diluted with alcohol-free chloroform (250 mL) then washed sequentially with ice water, aqueous sodium hydrogen carbonate, and water, and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave a syrup which was taken up in methyl ether and adsorbed on silica gel (300 g). Elution with light petroleum ether gave 2.5 g of benzyl bromide, and further elution with ether gave a syrup of 3-O-benzyl-2,4,6-tri-O-acetyl-D-glucopyranosyl bromide (5)-which crystallized on cooling. Recrystallization from dry ether gave 12.2 g of needles with m.p. 79° C. and [α]D25 +145 (c=1 in chloroform).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9]([SH:12])([CH3:11])[CH3:10].[CH3:16][O-].[Na+].CI>CO>[CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9]([S:12][CH3:16])([CH3:10])[CH3:11]
Reactant: COC(CC(C)CCCC(C)(C)S)OC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COC(CC(C)CCCC(C)(C)SC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 10 g. of 1,1-dimethoxy-7-mercapto-3,7-dimethyloctane, one equiv. of sodium methoxide and 100 ml. of methanol is added 1.5 equivalents of methyl iodide. The mixture is stirred for 2 hours at room temperature and then refluxed for 2 hours. After cooling to room temperature, solvent is removed by evaporation and the residue taken up in ether. The ether solution is washed with water, dried and evaporated under reduced pressure to give 1,1-dimethoxy-7-methylthio-3,7-dimethyloctane which can be purified by chromatography or distillation.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:11]([O:12][CH3:13])[CH2:10][C:9]2[C:8](=[NH:14])[NH:7][C:6](=N)[C:5]=2[CH2:4]1.Cl.[C:17]1([CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][CH2:29][C:30](=[NH:32])[N:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[NH:14]=[C:8]1[C:9]2[CH2:10][CH:11]([O:12][CH3:13])[CH:3]([O:2][CH3:1])[CH2:4][C:5]=2[C:6](=[C:29]2[S:28][C:27]([NH:26][CH2:25][CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:31][C:30]2=[NH:32])[NH:7]1
Reactant: COC1CC2=C(CC1OC)C(=N)NC2=N
Reactant: N=C1CSC(NCCCc2ccccc2)=N1
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: COC1CC2=C(CC1OC)C(=C1SC(NCCCc3ccccc3)=NC1=N)NC2=N

Procedure:
When equivalent amounts of 5,6-dimethoxy-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(3-phenylpropylamino)-4-imino-2-thiazoline hydrochloride are substituted for the 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride respectively, in the procedure described in Example 10, part A above, there is obtained as the product 1-imino-5,6-di-methoxy-4,5,6,7-tetrahydro-3-[2-(3-phenylpropylamino)-4-imino-2-thiazolin-5-ylidene]isoindoline.