Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>C(Cl)Cl>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[O:22])=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: O=C(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a solution of p-toluidine (0.44 g, 4.1 mmol) in 10 ml of CH2Cl2 (pre-cooled to 0° C.) are added Et3N (1.14 ml, 2 eq.) and 4-chloro-3-trifluoromethyl-benzoyl chloride (1 g, 4.1 mmol) in 5 ml of CH2Cl2. The mixture is slowly warmed to room temperature and continued to stir at room temperature for an hour. The mixture is diluted with 50 ml of CH2Cl2, washed with 1N HCl solution, and brine. The organic layer is separated, dried over MgSO4, filtered, and concentrated. The residue is purified by column chromatography (EtOAc/Hexanes, 2:3) to give 1.25 g (97%) of 4-chloro-N-p-tolyl-3-trifluoromethyl-benzamide.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C@@H:15]2[CH2:19][S:18][C:17]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=4[NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:16]2)[CH2:9]1)(C)(C)C.O1CCOCC1.Cl>ClCCl>[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C@@H:15]2[CH2:19][S:18][C:17]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=4[NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:16]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
[(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-carbamic acid t-butyl ester (150 mg, 0.27 mmol) prepared in Example 169 was dissolved in dichloromethane (30 mL). 4N hydrochloric acid dioxane solution (0.34 mL, 1.35 mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. The residue was recrystallized from DCM/ethylether to give the title compound (92 mg, Yield 75%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O=[C:12]([CH2:16][CH2:17][C:18](O)=[O:19])[C:13]([OH:15])=[O:14]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[N:9]=[C:17]([CH2:16][CH2:12][C:13]([OH:15])=[O:14])[C:18](=[O:19])[NH:10]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)CCC(=O)C(=O)O
Solvent: CCO
Product: O=C(O)CCc1nc2cc(Cl)c(Cl)cc2[nH]c1=O

Procedure:
Following the above procedure, 4,5-dichloro-o-phenylenediamine was reacted with 2-ketoglutaric acid in ethanol to yield 6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxaline propionic acid. Reaction of the free acid with ethanol in the presence of BF3 etherate yielded the corresponding ethyl ester, β-(6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxaline)propionic acid, ethyl ester melting at 183.5-184.5. The free acid had the following analysis.
Reaction SMILES: [NH2:1][C@@:2]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([Br:16])[N:10]=1)([CH3:8])[C:3]([F:7])([F:6])[CH2:4][OH:5].C([O-])(O)=O.[Na+].[N:22]#[C:23]Br>CCO>[Br:16][C:11]1[N:10]=[C:9]([C@:2]2([CH3:8])[C:3]([F:6])([F:7])[CH2:4][O:5][C:23]([NH2:22])=[N:1]2)[C:14]([F:15])=[CH:13][CH:12]=1
Reactant: C[C@@](N)(c1nc(Br)ccc1F)C(F)(F)CO
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@]1(c2nc(Br)ccc2F)N=C(N)OCC1(F)F
Temperature: 85 °C

Procedure:
To a solution of (R)-3-amino-3-(6-bromo-3-fluoro-pyridin-2-yl)-2,2-difluoro-butan-1-ol (9.49 g, 31.7 mmol) in EtOH (256 ml) was added NaHCO3 (1.066 g, 12.69 mmol) and cyanogen bromide (10.08 g, 95 mmol) and the mixture was warmed to 85° C. over night. After cooling to rt the solvent was evaporated and the residue taken up in 1N HCl and TBME, the layers were separated and the organic layer was washed with 1N HCl. The aq. layers were combined, basified by addition of solid Na2CO3 and extracted with TBME (2×). The combined TBME extracts were washed with sat. aq. NaCl, dried with K2CO3 to provide the desired product as yellow resin. This material was used for the next step without further purification.
Reaction SMILES: C(O)(=O)C(O)=O.[CH:7]([NH:10][OH:11])([CH3:9])[CH3:8].[OH-].[Na+].[Br:14][CH:15]([CH2:19]Br)[C:16](Cl)=[O:17].C(Cl)Cl>O>[Br:14][CH:15]1[CH2:19][O:11][N:10]([CH:7]([CH3:9])[CH3:8])[C:16]1=[O:17]
Reactant: CC(C)NO
Reactant: O=C(Cl)C(Br)CBr
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)N1OCC(Br)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a stirred mixture of 6 g (25 mmol) of N-isopropylhydroxylamine oxalate and 1N sodium hydroxide (50 ml) in water (100 ml) cooled to 0° C. there was added 2,3-dibromopropionyl chloride (12.5 g, 50 mmol), followed by the addition of 50 ml of 1N sodium hydroxide. Ten minutes later, 150 ml of methylene chloride and 60 ml of 1N sodium hydroxide were added. The mixture was stirred continuously for one hours following which the organic phase was separated, dried over anhydrous magnesium sulfate and concentrated. The concentrate was chromatographed on silica gel with 40% ethyl acetatehexane to afford 3.3 g of 4-bromo-2-isopropyl-3-isoxazolidinone.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])(=[O:3])[CH3:2].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH:8][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:3])[CH3:2]
Reactant: CCCCCCCCBr
Reactant: CC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCNc1cccc(NC(C)=O)c1

Procedure:
3-Acetylaminoaniline (15 parts) was reacted with n-octyl bromide (19.3 parts) at 90° to 100° C. for 4 hours in the presence of anhydrous potassium carbonate (6.9 parts) to obtain 3-acetylamino-N-octylaniline. Thereafter, reaction was further continued at 120° to 130° C. for 4 hours with addition of n-hexyl bromide (16.5 parts) and anhydrous potassium carbonate (6.9 parts) to obtain 3-acetylamino-N-n-octyl-N-n-hexylaniline (coupling component). In the same manner as in Example 1, 2-cyano-4-nitro-6-chloroaniline was diazotized and coupled with the above coupling component to obtain 45.9 parts of a dye (5).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[S:12]1(=[O:18])(=[O:17])[CH:16]=[CH:15][CH2:14][CH2:13]1>C(O)C>[OH:4][CH2:3][CH2:2][NH:1][CH:14]1[CH2:15][CH2:16][S:12](=[O:18])(=[O:17])[CH2:13]1
Reactant: NCCO
Reactant: O=S1(=O)C=CCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S1(=O)CCC(NCCO)C1
Temperature: 78 °C

Procedure:
A mixture of 2-aminoethanol (310 mg, 5.08 mmol), triethylamine (514 mg, 5.08 mmol) and 2,3-dihydrothiophene 1,1-dioxide (200 mg, 1.693 mmol) in ethanol (3 mL) was heated up at 78° C. for 16 hours. TLC indicated the starting material was consumed and desired product was formed (30% methanol/ethyl acetate). The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography with 0-35% methanol/ethyl acetate to provide the title compound as a colorless oil (260 mg, 86%). 1H NMR (400 MHz, CHLOROFORM-d) δ 3.78-3.56 (m, 3H), 3.38-3.21 (m, 2H), 3.14-3.00 (m, 1H), 2.94 (dd, J=13.3, 6.0 Hz, 1H), 2.85-2.68 (m, 2H), 2.53-2.34 (m, 1H), 2.22-2.03 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])[CH:22]=[CH:23][C:15]1=2)C(=O)OC(C)(C)C.[ClH:32]>CO>[ClH:32].[ClH:32].[OH:1][CH2:2][CH2:3][NH:4][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])[CH:22]=[CH:23][C:15]1=2
Reactant: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Agent: Cl
Solvent: CO
Product: N=C(Nc1ccc2c(c1)SCCN2CCNCCO)c1cccs1
Temperature: 75 °C

Procedure:
To a solution of tert-butyl 2-hydroxyethyl(2-(7-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (130 mg, 0.281 mmol) in MeOH (10 mL) was added 3N HCl (2.81 mL, 8.43 mmol). The yellow solution was heated at 75° C. for 30 minutes. At this time, the reaction was filtered and concentrated to half its volume. The yellow solution was then extracted with 2×50 mL CH2Cl2, and the aqueous layer was concentrated to dryness to give a yellow residue. This residue was dried under reduced (high vacuum) pressure to give compound 16 as yellow powder. 1H-NMR (CD3OD) δ 7.98-7.94 (m, 2H), 7.29 (pseudo t, J=4.2 Hz, 1H), 7.04-6.94 (m, 3H), 3.79 (brt, J=4.8 Hz, 2H), 3.72-3.65 (m, 4H), 3.28 (brs, 2H), 3.16 (brt, J=5.1 Hz, 2H), 3.09-3.06 (m, 2H); ESI-MS (m/z, %): 363 (MH+, free base, 100), 276 (90); ESI-HRMS calculated for C17H23N4O1S2 (MH+, free base): 363.1307, observed: 363.1316; HPLC purity: 96.2% a/a.
Reaction SMILES: P(Cl)(C(C)(C)C)C(C)(C)C.O.Cl[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F-].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[C:20]1([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(Cl)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In the drybox, 1100 mg (6.09 mm) of (Me3C)2P—Cl, 670 mg (2.98 mmol) of Pd(OAc)2 and 100 mL of 1,4-dioxane were loaded into a round-bottomed flask (250 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature for 10 min before the flask was removed from the glove box. The mixture was refluxed under open-to-air condition. The progress of the reaction was monitored by phosphorus-31 NMR spectroscopy. After 2 h, approximately 95% of the reaction had proceeded. The phosphorus-31 NMR spectrum of the reaction mixture showed only the δ123.0 (singlet) resonance, and no unchanged (Me3C)2P—Cl. The reaction mixture was therefore cooled to room temperature and 600 mg (33.3 mmol) of H2O was added. The mixture above was refluxed for a further 15 min. Next, 12.659 g (100.0 mm) of 4-chlorotoluene, 13.41 g (110.0 mm) of PhB(OH)2 and 22.785 g (150.0 mm) of CsF were added into the mixture above. The resulting mixture was refluxed for 18 h. The reaction mixture was then cooled to room temperature, quenched with 200 mL of H2O, and extracted with diethyl ether (2×300 mL). The organic extracts were washed with H2O (2×250 mL), brine (250 mL), and dried over mgSO4, filtered, and the ether and dioxane removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 4-phenyltoluene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7]#[N:8].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1(C)C=CC=CC=1>[C:7]([CH2:6][O:5][C:4]1[CH:3]=[C:2]([NH:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH:11]=[CH:10][CH:9]=1)#[N:8]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCOc1cccc(N)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)Nc1cccc(OCC#N)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of crude (3-aminophenoxy)acetonitrile (ca 12.1 g) in toluene (50 mL) was added pyridine (6.6 mL) and methanesulfonyl chloride (6.3 mL) at 5° C. and the resultant mixture was warmed to ambient temperature. After 2 h, the crude product mixture was partitioned between 1N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (50 mL). The combined organic solution was washed with water, then concentrated with concomitant replacement of solvent with isopropanol. After cooling the resultant mixture to 5° C., the white crystalline product was collected, rinsed with cold isopropanol, and dried to afford 12.14 g (65.1% yield based on cyanomethyl tosylate) of N-(3-cyanomethoxyphenyl)methanesulfonamide (99.8% pure by HPLC). This material could optionally be recrystallized from isopropanol.
Reaction SMILES: [CH2:1]([N:5]([CH:10]=[N:11][C:12]1[N:17]=[C:16]([N:18]=[CH:19][N:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[N:15]=[C:14]2[N:29]([C@@H:32]3[O:37][C@H:36]([CH2:38][OH:39])[C@@H:34]([OH:35])[CH2:33]3)[N:30]=[CH:31][C:13]=12)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Br:40]C1C2C(=NC(N)=NC=2N)N([C@@H]2O[C@H](CO)[C@@H](O)C2)N=1.COC(OC)N(CCCC)CCCC>CO>[CH2:1]([N:5]([CH:10]=[N:11][C:12]1[N:17]=[C:16]([N:18]=[CH:19][N:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[N:15]=[C:14]2[N:29]([C@@H:32]3[O:37][C@H:36]([CH2:38][OH:39])[C@@H:34]([OH:35])[CH2:33]3)[N:30]=[C:31]([Br:40])[C:13]=12)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1nc(N)c2c(Br)nn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Reactant: CCCCN(C=Nc1nc(N=CN(CCCC)CCCC)c2cnn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1)CCCC
Agent: CCCCN(CCCC)C(OC)OC
Solvent: CO
Product: CCCCN(C=Nc1nc(N=CN(CCCC)CCCC)c2c(Br)nn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1)CCCC
Yield: 50 %

Procedure:
As described for 8a, with 2b (350 mg, 1 mmol) and N,N-di-n-butylformamide dimethyl acetal (720 μl, 3.1 mmol) in MeOH (7 ml) for 2 h at 40°. After FC (eluant: A→B) two main products were isolated. The faster migrating zone gave 8b as a foam (310 mg, 50%). TLC(B): Rf 0.3. UV (MeOH): 235 (22500), 275 (14500), 320 (22100). 1H-NMR ((D6)DMSO): 0.94-0.99 (m, CH2CH3); 1.32-1.44 (m, CH2CH3); 1.59-1.73 (m, CH2CH2); 2.21 (m, H—C(2′)); 2.91 (m, H—C(2′)); 3.32-3.78 (2m, H2—C(5′), NCH2); 3.89 (m, H—C(4′)); 4.40 (m, H—C(3)); 4.78 (t, J=5.8, HO—C(5′)); 5.19 (d, J=4.4, HO—C(3′)); 6.81 (‘t’, J=6.5, H—C(1′)); 8.69 (s, N═CH); 8.94 (s, N═CH). Anal. calc. for C28H47BrN8O3 (623.6): C, 53.93; H, 7.60; N, 17.97. found: C, 54.01; H, 7.52; N, 18.05. The slower zone furnished 3-bromo-1-[2-deoxy-β-D-erythro-pentofuranosyl]-N6-((di-n-butylamino)methylene)-1H-pyrazolo[3,4-d]-pyrimidin-4,6-diamine (9b) (75 mg, 16%). TLC(B): Rf 0.3. UV (MeOH): 236 (21600), 276 (14000), 320 (21900). 1H-NMR ((D6)DMSO): 0.90-0.96 (m, CH2CH3); 1.30-1.39 (m, CH2CH3); 1.59-1.73 (m, CH2CH2); 2.23 (m, H—C(2′)); 2.89 (m, H—C(2′)); 3.35-3.78 (2m, H2—C(5′), NCH2); 3.84 (m, H—C(4′)); 4.43 (m, H—C(3′)); 4.80 (t, J=5.7, HO—C(5′)); 5.23 (d, J=4.6, HO—C(3′)); 6.40 (s, NH2); 6.81 J=6.4, H—C(1′)); 8.65 (s, N═CH). Anal. calc. for C19H30BrN7O3 (484.4): C, 47.11; H, 6.24; N, 20.24. found: C, 47.23; H, 6.52; N, 20.35.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.O1C=CC=C1C(O)=O.[Cl-].[Al+3].[Cl-].[Cl-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:8]3[CH:12]=[CH:11][O:10][C:9]=3[C:13](=[O:15])[C:6]=2[CH:7]=1
Reactant: O=C(O)c1occc1-c1ccc(F)cc1
Agent: O=C(O)c1ccco1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1c2cc(F)ccc2-c2ccoc21

Procedure:
Synthetic substrates 8H-indeno[2,1-b]furan-8-one and 8H-indeno[2,1-b]furan and their derivatives are prepared in accordance with the following. Substituted and unsubstituted 3-arylfuran-2-carboxylic acids are prepared according to a general procedure of Burgess, J. Org. Chem., 21, 102 (1956), wherein, 4,5-dimethoxy-1-phenyl-2-butanone and related 2' to 4' substituted phenyl analogs (e.g., 4,4-dimethoxy-1-(4'-fluorophenyl)-2-butanone, prepared according to the general procedure of Royals and Brannoch, J. Amer. Chem. Soc., 75, 2050 (1953)) are converted into 3-phenylfuran-2-carboxylic acid methyl ester (e.g., 3'-(4'-fluorophenylfuran-2-carboxylic acid methyl ester) by the Darzens glycidic ester condensation (Darzens, Compt. Rend., 139, 1214 (1904)). This rearrangement of the glycidic ester yields the furoic ester. The furoic ester can be hydrolyzed in alkaline methanolic solution to yield, for example, 3-(4'-fluorophenyl)-furan-2-carboxylic acid. The furoic acid product can be cyclized via the aroyl chloride in the presence of stannic chloride or aluminum chloride to yield the ketone, e.g., 6-fluoro-8H-indeno [2,1-b]furan-8-one. This ketone can be derivatized in accordance with Method V. Hydantoin derivatization (Method I) yields the spiro-hydantoin, e.g., spiro-(6-fluoro-8H-indeno[2,1-b]furan-8,4'-imidazolidine)-2',5'-dione. Reduction according to methods cited in Method VIII yields the corresponding 8H-indeno[2,1-b]furan derivative which can be derivatized in accordance with Methods II, III and IV into the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide. Furthermore, the spiro-derivatives may be further derivatized according to Method VI.
Reaction SMILES: B.CSC.[C:5]1([C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][C:13](O)=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.B(OC)(OC)OC.Cl>O1CCCC1.O>[C:22]1([C:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:13][OH:14])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: B
Agent: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Solvent: O
Product: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 87.5 %

Procedure:
Borane-methyl sulfide (60 mL, 0.63 mol) was added dropwise to 100 g (0.33 mol) of 3,3,3-triphenylpropanoic acid and 38 mL (0.33 mol) trimethyl borate in 1 liter of anhydrous tetrahydrofuran at room temperature. After 18 hr, the reaction mixture was carefully acidified with 180 mL of conc. hydrochloric acid, stirred for 3 hours and then further diluted with ca. 450 mL of water. The THF layer was collected, the aqueous layer extracted twice with dichloromethane, and the organic layers combined and dried over magnesium sulfate. The organic solution was evaporated to leave a solid, which was recrystallized (two crops) from hexane-dichloromethane to give 83.3 g (87.5%) of the title compound, mp 103°-106° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:16][C:15]1[CH:14]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH:12]=[C:11]([F:29])[C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 73.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (192 mg, 0.33 mmol) prepared in Example 27b, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (106 mg, 74%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=2)[N:19]([CH3:27])[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([NH2:16])=[N:18][N:19]2[CH3:27])=[CH:24][CH:23]=1
Reactant: Cn1nc(N)c2ccc(O)cc21
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(N)nn(C)c4c3)c2cc1OC
Temperature: 25 °C

Procedure:
4-Chloro-6,7-dimethoxyquinoline (2.60 g, 11.7 mmol), 3-amino-1-methyl-1H-indazol-6-ol (Step a, 2.72 g, 16.7 mmol) and cesium carbonate (Aldrich, 16.3 g, 50.1 mmol) in DMSO (16.7 mL, Aldrich) were stirred at 100° C. for 16 h. After cooling to RT, water was added. The aqueous layer was extracted with DCM. The organic phase was washed with water, dried with MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography using 0-100% of a 90:10:1 (CH2Cl2:MeOH:NH4OH) solution as the eluant afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 351.1 (M+1). Mass Calc'd for C19H18N4O3: 350.38.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@@:23]([OH:49])([CH2:43][N:44]1[CH:48]=[N:47][CH:46]=[N:45]1)[C@H:24]([S:26][C@@H:27]1[CH2:32][O:31][C@@H:30]([C:33]2[CH:42]=[CH:41][C:36]([C:37](OC)=[O:38])=[CH:35][CH:34]=2)[O:29][CH2:28]1)[CH3:25]>>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:37](=[O:38])[C:36]2[CH:41]=[CH:42][C:33]([C@H:30]3[O:29][CH2:28][C@H:27]([S:26][C@H:24]([CH3:25])[C@:23]([C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[F:15])([OH:49])[CH2:43][N:44]4[CH:48]=[N:47][CH:46]=[N:45]4)[CH2:32][O:31]3)=[CH:34][CH:35]=2)=[CH:3][CH:4]=1)(=[O:7])[NH2:8]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C(N)=O)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available p-aminobenzamide (162 mg, 1.2 mmol), trimethylaluminium (2.2 ml, 1.07M n-hexane solution, 2.4 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (66 mg, yield 37%) as a white solid which was recrystallized from ethyl acetate-hexane to give pale orange powdery crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C@H:6]([OH:8])[C@@H:5]([NH:9][C@@H](C2C=CC=CC=2)C)[CH2:4][O:3]1.[H][H]>[Pd].CO>[NH2:9][C@H:5]1[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[CH2:7][C@@H:6]1[OH:8]
Reactant: C[C@@H](N[C@H]1COC(C)(C)C[C@@H]1O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)C[C@H](O)[C@@H](N)CO1
Yield: 189.4 %

Procedure:
A suspension mixture of (4S,5S)-2,2-dimethyl-5-((R)-1-phenylethylamino)-tetrahydro-2H-pyran-4-ol (1.0 g, 4.0 mmol) and 10% palladium on carbon (200 mg) in methanol (20 mL) was stirred at room temperature under 1 atm hydrogen atmosphere (hydrogen balloon) overnight. After that, the mixture was filtered through a pad of celite, and the filtrate was concentrated to get the title compound (1.1 g, crude) as a yellow oil, which was used directly for the next step without further purification.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:27](=[CH2:31])[C:28]([OH:30])=[O:29].[CH2:32](O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CCCCCC.C(OCC)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:27](=[CH2:31])[C:28]([O:30][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29]
Reactant: C=C(C(=O)O)c1cc(F)ccc1F
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: C=C(C(=O)OCc1ccccc1)c1cc(F)ccc1F
Reaction time: 17 h

Procedure:
Under a nitrogen atmosphere, dicyclohexyl carbodiimide (206 mg, 1.0 mmol) was added to a methylene chloride solution (10 ml) of 2,5-difluorophenylacrylic acid (184 mg, 1 mmol), benzyl alcohol (104 ml, 1 mmol), and N,N-dimethylaminopyridine (36 mg, 0.3 mmol) at room temperature and the resulting mixture was stirred for 17 hours. After concentration of the reaction mixture under reduced pressure, 10 ml of hexane-diethyl ether (4:1) was added to the residue. The precipitate thus formed was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1), whereby the title compound (242 mg, 88%) was obtained.