Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=O)=[CH:17]1>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:16][CH:17]=1)(=[O:5])=[O:4]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1c[nH]c3ccccc13)C(=O)N2

Procedure:
5-Methylaminosulfonyl-2-oxindole was condensed with indole-3-carboxaldehyde to give the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClC1C=CC([CH2:35][C:36]#[N:37])=CC=1.Cl>CN(C=O)C>[CH2:7]([O:14][C:15]1[C:16]([C:24]([F:25])([F:26])[F:27])=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[C:19]([CH2:35][C:36]#[N:37])[CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cc(OCc2ccccc2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Potassium tert-butoxide (3.94 g, 35.4 mmol) was dissolved in anhydrous DMF (15 ml) and a mixture of 2-benzyloxy-5-nitro-trifluoromethylbenzene (3.5 g, 16.1 mmol) and 4-chlorophenylacetonitrile (2.96 g, 17.7 mmol) in DMF (20 ml) was added over 30 minutes keeping the temperature at −15° C. The mixture was stirred at −10° C. for 1 hour, then poured into 1M hydrochloric acid (150 ml) and the product extracted with dichloromethane (2×100 ml). The organic extracts were dried (MgSO4) and purified by silica column chromatography eluting with dichloromethane/hexane (1/1) to give 5-benzyloxy-2-nitro-4-(trifluoromethyl)phenylacetonitrile (5.2 g, 77%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]3[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[F:32])[CH2:6]1)=[O:4].[CH3:33][NH:34][CH3:35]>C(O)C>[Cl:31][C:27]1[C:26]([F:32])=[C:25]([CH:30]=[CH:29][CH:28]=1)[NH:24][C:15]1[C:14]2[C:19](=[CH:20][C:21]([O:22][CH3:23])=[C:12]([O:11][CH:7]3[CH2:8][CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:34]([CH3:35])[CH3:33])[CH2:6]3)[CH:13]=2)[N:18]=[CH:17][N:16]=1
Reactant: CNC
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CCl)C1
Solvent: CCO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CN(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline (470 mg, 0.98 mmol) was treated with a 33% solution of dimethylamine in ethanol (20 ml) and stirred at room temperature for 3 hours. The solvent was evaporated under vacuum and the residue purified by column chromatography eluting with methylene chloride/methanol (9/1). The fractions containing the expected product were combined and evaporated under vacuum. The residue was re-columned eluting with methylene chloride/methanol (saturated with ammonia) (92/8). The fractions containing the expected product were combined and evaporated to give the title product (185 mg, 39%); 1H NMR Spectrum: (DMSO d6 at 100° C.) 1.40-1.65 (m, 1H); 1.75-1.95 (m, 2H); 2.00-2.30 (m, 7H); 3.05 (dd, 2H); 3.40-3.62 (m, 2H); 3.62-3.75 (m, 1H); 3.88 (dd, 1H); 3.95 (s, 3H); 4.45-4.65 (m, 1H); 7.15-7.30 (m, 2H); 7.30-7.47 (m, 1H); 7.50-7.7 (m, 1H); 7.88 (s, 1H); 8.40 (s, 1H); 9.25 (s, 1H); Mass Spectrum: (M+H)+ 488.
Reaction SMILES: [OH:1][CH:2]([CH3:10])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:19]([Si:16]([CH3:18])([CH3:17])[O:1][CH:2]([CH3:10])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(O)C(=O)N1CCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)C(=O)N1CCCC1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 2-hydroxy-1-pyrrolidin-1-yl-propan-1-one (47.0 mmol, 6.72 g) in DMF (25 mL) was added imidazole (70.5 mmol, 4.8 g), N,N-dimethyl-4-aminopyridine (4.7 mmol, 0.57 g) at room temperature. Tert-butyl-dimethylsilyl chloride (48.5 mmol, 7.31 g) was then added while stirring. Some exotherm was observed. The initial pale yellow solution turned brwn-red in color and some precipitate was observed after 30 min. The reaction mixture was allowed to stir overnight and then filtered through a sintered glass funnel. The solid was washed with some Et2O. The filtrate was diluted with water (150 mL) and it was extracted with Et2O (2×100 mL). The organic extrats were combined and washed successively with water (100 mL), sat. NH4Cl solution and the organic layer was separated. It was dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain 2-(tert-butyl-dimethyl-silanyloxy)-1-pyrrolidin-1-yl-propan-1-one as a golden yellow oil (10.4 g, 86% yield). The product was judged to be >95% pure by NMR and was used in next step without any purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[CH:7]=1.BrC1C=NC2N(C=C(CC3C=C4C(=CC=3)N=CC=C4)N=2)C=1.C([Sn](CCCC)(CCCC)[C:48]([O:50]CC)=[CH2:49])CCC>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][C:8]3[N:6]4[CH:7]=[C:2]([C:48](=[O:50])[CH3:49])[CH:3]=[N:4][C:5]4=[N:10][CH:9]=3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc2ncc(Cc3ccc4ncccc4c3)n2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Brc1cnc2nc(Cc3ccc4ncccc4c3)cn2c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1cnc2ncc(Cc3ccc4ncccc4c3)n2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-((6-bromoimidazo[1,2-a]pyrimidin-3-yl)methyl)quinoline and 6-(6-bromo-imidazo[1,2-a]pyrimidin-2-ylmethyl)quinoline (mixture, 250 mg, 0.737 mmol), PdCl2(PPh3)2 (51.7 mg, 0.074 mmol) and tributyl(1-ethoxyvinyl)stannane (399 mg, 1.106 mmol) in 5 mL of 1,4-dioxane was heated at 80° C. for 12 h under N2. The reaction mixture was diluted with EtOAc, washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in HOAc and 3 N HCl and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in CH2Cl2, washed with sat. aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel eluting with a EtOAc/MeOH gradient to afford the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.97 (d, 1H), 8.84 (d, 1H), 8.67 (d, 1H), 8.04-7.99 (m, 2H), 7.74 (s, 1H), 7.53-7.51 (m, 1H), 7.34 (dd, 1H), 7.19 (s, 1H), 4.44 (s, 2H), 2.49 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]I.[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:3][CH:2]([F:5])[F:1])=[CH:9][CH:8]=1
Reactant: FC(F)CI
Reactant: NCc1ccc(Cl)nc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: FC(F)CNCc1ccc(Cl)nc1
Temperature: 100 °C
Yield: 80.2 %

Procedure:
26.3 g (0.135 mol) of 2,2-difluoro-1-iodoethane, 10 g (0.067 mol) of 1-(6-chloropyridin-3-yl)methanamine and 8.2 g of triethylamine are initially charged with 31 g of N-methylpyrrolidone. The mixture is heated to 100° C. for 50 minutes and then cooled again to 80° C. The N-methylpyrrolidone is distilled off at 80° C. under reduced pressure and the reaction mixture is poured onto 50 ml of water. 3 ml of 45% sodium hydroxide solution are used to adjust the pH to 12, and the mixture is then extracted twice with 30 ml of toluene. The product is subsequently finely distilled under reduced pressure. This gives 11.1 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine (corresponds to 79.5% yield).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(P(=O)(OCC)OCC)#N.CN1CCOCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[C:36]=2[S:35][N:34]=1>C(Cl)Cl>[C:46]([NH:45][S:42]([C:41]1[C:36]2[S:35][N:34]=[C:33]([NH:32][CH2:31][CH2:30][CH2:29][NH:28][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)[C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:43])=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c(NCCCN)nsc12
Agent: CCOP(=O)(C#N)OCC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cccc2c(NCCCNC(=O)c3ccc(I)cc3)nsc12
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
To a solution of 4-iodobenzoic acid (270 mg, 0.8 mmol) in methylene chloride (2 mL), diethyl cyanophosphonate (130 μL, 0.9 mmol) and 4-methylmorpholine (182 μL, 1.7 mmol) were added at room temperature and allowed to stir for 15 min. A solution of 3-(3-aminopropylamino)-N-t-butylbenzo[d]isothiazole-7-sulfonamide (270 mg, 0.8 mmol) in methylene chloride (4 mL) was then added and the resulting reaction mixture was allowed to stir overnight. The reaction mixture with diluted with methylene chloride (20 mL), washed with 10% HCl aqueous solution and brine, dried anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 6:4 ethyl acetate:hexanes provided N-(3-(7-(N-tert-butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4-iodobenzamide (355 mg). 1H NMR (300 MHz, CDCl3): 8.01 (dd, 1H), 7.96 (d, 1H), 7.78 (d, 2H), 7.59 (d, 2H), 7.53 (t, 1H), 7.44 (t, 1H), 6.15 (t, 1H), 5.09 (s, 1H), 3.70 (dd, 2H), 3.57 (dd, 2H), 1.90-1.99 (m, 2H), 1.24 ppm (s, 9H). MS (m/z): 573 (M+H)+ confirmed by LC-MS, tr=13.92 min (Method Y) MW=572 confirmed by LC-MS, tr=13.92 min (Method Y) MH+=573.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[N:3]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[C:12]([NH:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[N:3]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1nc(Cl)c2ccnc-2[nH]1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2ccnc-2[nH]1
Yield: 73.8 %

Procedure:
A solution of 2-amino-4-chloro-pyrrolo[2,3-d]pyrimidine (20 g, 118 mmol) and pivaloyl chloride (14.3 g, 118 mmol) in pyridine (150 mL) was stirred for 18 hours at ambient temperature. The resulting dark red solution was evaporated to an amber solid which was co-evaporated with water (20 mL, 3×). The resulting solid was filtered, washed with cold water and then dried over KOH in vacuo to yield 22 g (83%) of 2-pivaloylamino-4-chloro-pyrrolo[2,3-d]pyrimidine as a reddish solid. 1H-NMR (DMSO-d6): δ 12.35 (bs, 1, N (7)-H); 10.07 (s,1, N (2)-H); 7.56 (m,1, H-6); 6.58 (m,1, H-5); 1.24 (s, 9, pivaloyl methyls). mp>210° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[Cl:8][CH2:9][C:10](=O)[CH2:11][C:12](OCC)=[O:13].C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>>[Cl:8][CH2:9][C:10]1[N:1]=[C:2]2[S:3][C:4]([CH3:7])=[CH:5][N:6]2[C:12](=[O:13])[CH:11]=1
Reactant: Cc1cnc(N)s1
Reactant: CCOC(=O)CC(=O)CCl
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Product: Cc1cn2c(=O)cc(CCl)nc2s1
Yield: 63.9 %

Procedure:
This compound was synthesized from 2-amino-5-methyl thiazole (5.0 g, 43.710 mmol) and ethyl chloroacetoacetate (9.893 g, 59.561 mmol) in polyphosphoric acid (40.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 6.0 g of the desired compound as a black solid; 1H NMR (300 MHz, DMSO-d6) δ 2.43 (s, 3H), 4.58 (s, 2H), 6.39 (s, 1H), 7.87 (s, 1H); ESI-MS (m/z) 215.37 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([O:12][C:13]1[C:22]3[C:17](=[CH:18][C:19]([OH:25])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=1)=[CH:6][CH:5]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([O:12][C:13]1[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:46][CH2:47][N:48]4[CH2:52][CH2:51][CH2:50][CH2:49]4)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=1)=[CH:6][CH:5]=2
Reactant: OCCN1CCCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a suspension of 4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (124 mg, 0.32 mmol) in methylene chloride (2.5 ml) was added triphenylphosphine (179 mg, 0.628 mmol), 1-(2-hydroxyethyl)pyrrolidine (75 mg, 0.65 mmol) followed by diisopropyl azodicarboxylate (134 μl, 0.68 mmol) in portions. After stirring overnight at ambient temperature the mixture was poured onto a column of silica and eluted with ethyl acetate/methylene chloride (1/1) followed by ethyl acetate/methylene chloride/methanol (4/5/1) followed by methylene chloride/methanol (9/1). After removal of the solvent, the solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (51 mg, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[F-].[K+].Br[CH2:15]Br.O>CN(C=O)C>[Br:1][C:2]1[C:9]2[O:10][CH2:15][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: BrCBr
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)c2c(c1)OCO2
Temperature: 140 °C
Yield: 60.5 %

Procedure:
To a solution of 3-bromo-4,5-dihydroxy-benzaldehyde (1.52 g, 7.02 mmol) in DMF (20 mL), were added KF (4.077 g, 70.18 mmol) followed by dibromomethane (1 mL, 14.04 mmol) and the mixture heated at 140° C. for 4 hours. The solution was cooled to room temperature, water was added and the mixture extracted with ether. The organic layer was further washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and evaporated to give 973 mg of 7-bromo-benzo[1,3]dioxole-5-carbaldehyde. 1H NMR (300 MHz; CDCl3): δ 6.16 (s, 2H), 7.26 (s, 1H), 7.54 (s, 1H), 9.76
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9](=[O:22])[N:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:29]OS(O)(=O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].O>C(O)(=O)C>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][S:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:29])[C:9](=[O:22])[N:8]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C(CCSc2ccccc2)C(=O)N(c2ccccc2)N1c1ccccc1
Reactant: O=S(=O)(O)OO
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C(CCS(=O)c2ccccc2)C(=O)N(c2ccccc2)N1c1ccccc1

Procedure:
Oxidation of 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione with the above solution of Caro's acid gives 1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione. With respect to 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione, about 1.0 to 2.0 molar equivalents, preferably 1.3 to 1.5 molar equivalents, of Caro's acid is required. These amounts of Caro's acid are based upon the potassium persulfate used to make up the Caro's acid. When performing the oxidation, a solvent is used to dissolve the starting material, 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione. Suitable solvents are inert water miscible solvents; for example, lower alkanols containing up to four carbon atoms and lower alkanoic acids containing two to four carbon atoms, or mixtures thereof. A useful solvent is acetic acid which can be used in amounts ranging from about 100 to 200 molar equivalents of acetic acid with respect to the starting material. The starting material is first dissolved in the glacial acetic acid and then the Caro's acid is added. The solution of 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione, aqueous Caro's acid and acetic acid is allowed to react until the oxidation is complete and 1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione is formed. Usually, the solution is maintained at about 0° to 30° C., preferably 5° to 25° C., for about 10 to 30 hours. From the solution, 1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl] -3,5-pyrazolidinedione is isolated in a conventional manner, for example, decomposition of excess Caro's acid, extraction and crystallization.
Reaction SMILES: N1CCCC1.C(=O)([O-])N.[CH2:10]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([N:34]4[CH2:39]C[CH:37](N5CCCC5)[CH2:36][CH2:35]4)=[O:33])[CH:26]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=[O:14])[CH3:11]>CN(C)C=O>[CH2:10]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([N:34]4[CH2:39][CH2:37][CH2:36][CH2:35]4)=[O:33])[CH:26]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=[O:14])[CH3:11]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Agent: NC(=O)[O-]
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCCC4)c3)ccc21
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (5 ml) and pyrrolidine (0.36 ml, 4.3 mmol) were added to a mixture (0.461 g) of phenyl N-(4-(1-(ethylamino)carbonyl)-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate obtained in Example 77; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated to yield the title compound as crystals (245 mg, 0.623 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:12](=[O:11])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][NH:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c[nH]c2cc(Cl)ccc2c1=O
Yield: 131.8 %

Procedure:
3-Chloroaniline (5.0 g) and diethyl ethoxymethylenemalonate (10.2 g) were reacted in the same manner as in Experimental Example 1 to obtain 7-chloro-3-ethoxycarbonyl-4(1H)-quinolone (13.0 g). This compound (5.0 g) was hydrolyzed in the same manner as in Experimental Example 2 to obtain a carboxylic acid (4.2 g). This acid derivative (4.2 g) was dissolved in pyridine (40 ml), piperazine (5.2 g) was added to the solution, and the mixture was heated under reflux for 48 hours. The solvent was removed by distillation, and the residue was purified by column chromatography (Wako Gel C-200, 100 g). Elution with a mixed solvent of chloroform (90 parts) and methanol (10 parts) gave 7-piperazinyl-4(1H)-quinolone (compound 67, 3.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:22])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>>[Cl:1][C:2]1[C:3]([CH:8]([NH:22][C:26]([CH:23]2[CH2:25][CH2:24]2)=[O:27])[C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 120.4 %

Procedure:
In a 10 mL flask were added C-(3-chloropyrazin-2-yl)-C-(4-phenoxyphenyl)-methylamine (110 mg, 0.00035 mol), cyclopropanecarboxylic acid (0.056 mL, 0.00070 mol), DIEA (0.55 mL, 0.0032 mol), TBTU (0.17 g, 0.00053 mol) and DMF (5 mL, 0.07 mol). The reaction mixture was stirred at rt for 10 min. Reaction was left to stir over weekend. The reaction mixture was concentrated in vacuo, dissolved in DCM and washed with sat aq NaHCO3 followed by brine. The organics were collected and concentrated in vacuo to give 160 mg of the compound as a yellow solid. Purification by prep TLC in 60% EtOAc: hexanes afforded 55 mg of the title compound as a yellow solid. The compound was carried on to the next step. MS (ES+): m/z 380.08 (20)[MH+]. HPLC: tR=3.56 min (Open lynx polar—5 min).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6](O)[N:5]2[N:10]=[CH:11][CH:12]=[C:4]2[C:3]=1[C:13]#[N:14].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:6]1[N:5]2[N:10]=[CH:11][CH:12]=[C:4]2[C:3]([C:13]#[N:14])=[C:2]([OH:1])[C:7]=1[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(O)c(C#N)c2ccnn2c1O
Solvent: CN(C)c1ccccc1
Product: Cc1c(O)c(C#N)c2ccnn2c1Cl
Temperature: 25 °C

Procedure:
To the crude product (378 mg) of 5,7-dihydroxy-6-methylpyrazolo[1,5-a]pyridine-4-carbonitrile (5), N,N-dimethylaniline (380 μL) was added and this mixture was suspended in phosphoryl chloride (20 mL). This suspension was stirred under reflux with heating for 3 h. After the reaction solution was cooled to room temperature, excessive phosphoryl chloride was removed under reduced pressure. The residue was diluted with ethyl acetate and water, and two layers were separated. The organic layer was reversely extracted with saturated aqueous sodium hydrogen carbonate solution, and the aqueous extract was combined with the aqueous layer. The pH of combined aqueous layers were adjusted to 10 with 2 mol/L aqueous sodium hydroxide solution, and the solution was stirred for 4 days. This mixture was acidified to pH 2 with 1 mol/L hydrochloric acid and extracted with ethyl acetate three times. The combined organic layers were washed with a mixture of brine and 1 mol/L hydrochloric acid (5:1) and dried over sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound (13) (211 mg), a part of which was purified with preparative HPLC and the NMR spectrum was recorded.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:12][CH2:13][CH:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]([CH3:17])[CH3:16].O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:12][CH2:13][CH:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:15]([CH3:17])[CH3:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)C(CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(NC(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
4-Methylbenzenesulfonyl chloride (0.2222 mol) was added portionwise at 10° C. to a mixture of 1,1-dimethylethyl [1-(hydroxymethyl)-2-methylpropyl]carbamoate (0.202 mol) in pyridine (65 ml). The mixture was stirred at 10° C. for 2 hours. H2O (75 ml) was added at 10° C. The precipitate was filtered off, washed with H2O and taken up in CH2Cl2. The organic solution was washed with H2O, dried, filtered and the solvent was evaporated, yielding 49 g of (±)-1,1-dimethylethyl [1-[[[(4-methylphenyl)-sulfonyl]oxy]methyl]-2-methylpropyl]carbamate (68%) (interm. 13).