Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](/B(O)O)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1CCOCC1.Br[C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:1](/[C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:21][CH:20]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: OB(O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 18.3 %

Procedure:
To a solution of (E)-styrylboronic acid (289 mg, 1.95 mmol) in mixed solution of dioxane and water (4:1, 15 mL) were added tert-butyl 4-bromobenzoate (500 mg, 1.95 mmol), tetrakis(triphenylphosphine)palladium (225 mg, 0.2 mmol) and sodium carbonate (622 mg, 5.9 mmol). The mixture was stirred at 90° C. under nitrogen atmosphere for 18 hours. Once start material has been consumed, the mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=25:1) to give (E)-tert-butyl 4-styrylbenzoate (0.1 g, 18%). The product was used for the next step directly without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:13]3[C:14]([C:26]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:32][CH:31]=4)=[C:27]([CH2:28][CH3:29])[C:12]3=[CH:11][CH:10]=1)=[C:15]([C:22]([O:24]C)=[O:23])[C:16]=2[C:18]([O:20]C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O.Cl>CO>[CH2:1]([O:8][C:9]1[C:17]2[N:13]3[C:14]([C:26]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:34][CH:35]=4)=[C:27]([CH2:28][CH3:29])[C:12]3=[CH:11][CH:10]=1)=[C:15]([C:22]([OH:24])=[O:23])[C:16]=2[C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)OC)c(C(=O)OC)c3c(OCc4ccccc4)ccc1n32
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)O)c(C(=O)O)c3c(OCc4ccccc4)ccc1n32
Temperature: 25 °C

Procedure:
Dimethyl 7-Benzyloxy-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate (1.0 g, 1.7 mmol) was dissolved in 100 ml of methanol. Potassium hydroxide (3.37 g, 60 mmol) and 2 ml of water was added and the mixture was heated to reflux for 4 days. The reaction mixture was allowed to cool to room temperature and acidified with concentrated hydrochloric acid until pH=1. The resulting precipitate was filtered off, and washed with water and ethanol. This gave 0.89 g (96%) of 7-benzyloxy-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid as yellow crystals. M.p. 151-161° C. MS(SP): m/z 545 (M+). 1H-NMR (DMSO-d6, 200 MHz) δ: 1.32 (t, 3H); 3.02 (q, 2H); 5.18 (s, 2H); 5.52 (s, 2H); 7.15 (d, 2H); 7.29-7.56 (m, 10H); 7.61-7.71 (m, 3H); 8.18 (d, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([NH:31][C:32]([NH:34][C@@H:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@H:38]([O:45][C:46]3[CH:47]=[CH:48][C:49]4[N:50]([C:52]([N:55]5[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]5)=[N:53][N:54]=4)[CH:51]=3)[CH2:37][CH2:36]2)=[O:33])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][O:24]C3CCCCO3)[CH:16]=2)[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([C:10]1[CH:11]=[C:12]([NH:31][C:32]([NH:34][C@@H:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@H:38]([O:45][C:46]3[CH:47]=[CH:48][C:49]4[N:50]([C:52]([N:55]5[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]5)=[N:53][N:54]=4)[CH:51]=3)[CH2:37][CH2:36]2)=[O:33])[N:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:22][CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cccc(OCCOS(C)(=O)=O)c2)n1
Temperature: 0 °C
Yield: 100 %

Procedure:
Methane sulfonylchloride (46.0 μL, 0.59 mmol) was added to an ice cold solution of Example 39 (187 mg, 0.28 mmol) and DIPEA (122 μl, 0.70 mmol) in DCM (3.0 mL). After 2.5 h the reaction was partitioned between DCM and water. The aqueous layer was then extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound (208 mg, 99%). LCMS (Method 2): Rt 3.38 min, m/z 743 [MH+].
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:32]=[CH:31][C:20]2[N:21]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:22]([CH3:24])=[N:23][C:19]=2[CH:18]=1)=O)(C)(C)C>Cl>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:32]=[CH:31][C:20]2[N:21]([CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[C:22]([CH3:24])=[N:23][C:19]=2[CH:18]=1
Reactant: Cc1nc2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)ccc2n1C1CCOCC1
Agent: Cl
Product: Cc1nc2cc(-c3cc4ccccc4[nH]3)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(N-t-butoxycarbonylindol-2-yl)-2-methyl-1-(tetrahydropyran-4-yl)benzimidazole (see Synthesis Example 37 (200 mg, 0.463 mmol) was added to a 1N aqueous hydrochloric acid solution (10 mL), and this was stirred at room temperature for 3 hours. After the reaction was complete, this was allowed to stand for 3 days and the precipitated crystals were filtered off, and to this was added saturated aqueous sodium hydrogen carbonate (5 mL) and this was stirred for 30 minutes. The precipitated crystals were filtered off, washed with water and dried to yield the title compound (155 mg, quant.) as light brown crystals.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([F:22])=[C:7]([O:12][C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[N:14]=2)[C:8]([Cl:11])=[CH:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[C:6]([F:22])=[C:7]([O:12][C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[N:14]=2)[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CN)c2F)c1
Yield: 43.4 %

Procedure:
2-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (0.402 g, 1.189 mmol) dissolved in THF (10 mL) was treated successively with triphenylphosphine (0.468 g, 1.783 mmol) and water (0.107 mL, 5.94 mmol) at 25° C. for 16 h with stirring. The reaction mixture was concentrated to dryness and purified on 40 g silica gel eluted successively with EtOAc (to remove tripheylphosphine oxide) followed by 0 to 10% CH3OH/DCM to give 2-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (0.161 g, 0.516 mmol, 43.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (s, 1H), 7.93 (s, 1H), 7.44-7.55 (m, 2H), 3.77 (s, 2H), 1.94 (br. s., 2H). LC-MS (ES+) m/z 312.29, 314.28 [M+H].
Reaction SMILES: [NH:1]([C:3](=[O:23])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5])[NH2:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]=[C:39]=S)=[CH:34][CH:33]=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]3[O:23][C:3]([C:4]([NH:6][C:7]4[CH:8]=[CH:9][C:10]([N:13]5[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]5)=[N:11][CH:12]=4)=[O:5])=[N:1][N:2]=3)=[CH:34][CH:33]=2)=[CH:27][CH:26]=1
Reactant: S=C=Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: COC(=O)C1CCN(c2ccc(NC(=O)C(=O)NN)cn2)CC1
Product: COC(=O)C1CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(Oc5ccc(Cl)cc5)cc4)o3)cn2)CC1

Procedure:
Prepared using the procedures described above for Example 631 except starting from methyl 1-(5-{[hydrazino(oxo)acetyl]amino}pyridin-2-yl)piperidine-4-carboxylate (Intermediate 83) and 1-chloro-4-(4-isothiocyanatophenoxy)benzene. 1H NMR δ 1.51-1.61 (m, 2H), 1.86-1.91 (m, 2H), 2.59-2.66 (m, 1H), 2.91-2.98 (m, 2H), 3.63 (s, 3H), 4.14-4.19 (m, 2H), 6.87 (d, 1H), 7.00 (d, 2H), 7.13 (d, 2H), 7.41 (d, 2H), 7.64 (d, 2H), 7.90 (d, 1H), 8.47 (s, 1H), 10.88 (s, 1H), 10.97 (s, 1H); MS m/e MH+ 549.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH2:11]([P:18]([O:22][CH3:23])(=[O:21])[O:19][CH3:20])[P:12]([O:16][CH3:17])(=[O:15])[O:13][CH3:14]>>[CH3:10][O:9][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:11]([P:12]([O:13][CH3:14])(=[O:15])[O:16][CH3:17])[P:18]([O:22][CH3:23])(=[O:21])[O:19][CH3:20])=[O:8]
Reactant: COP(=O)(CP(=O)(OC)OC)OC
Reactant: COC(=O)CCCCCCl
Product: COC(=O)CCCCCC(P(=O)(OC)OC)P(=O)(OC)OC

Procedure:
Following the General Synthetic Procedure B, methyl 6-chlorohexanoate is reacted with tetramethyl methanebisphosphonate to produce tetramethyl 5-methoxycarbonylpentyl-methanebisphosphonate that is then hydrolyzed to yield 5-carboxypentyl-methanebisphosphonic acid, and then hydrogenated to reduce the carboxy group to a hydroxymethylene group. The resulting 6-hydroxyhexyl-methanebisphosphonic acid is then methacrylated with methacryloyl chloride to afford 6-methacryloxyhexyl-methanebisphosphonic acid.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]2[N:28]=[C:29]([CH2:31][OH:32])[O:30][C:24]=2[CH2:23]1)=[O:21])[CH3:18].[C:33]1(O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]2[N:28]=[C:29]([CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:24]=2[CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)N1CCc2nc(CO)oc2C1
Reactant: Oc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2nc(COc3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 114.4 %

Procedure:
Di-tert-butyl azodicarboxylate (2.20 g, 9.5 mmol) was added portionwise to a stirred solution of 6,7-dihydro-2-(hydroxymethyl)-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester (1.80 g, 7.95 mmol), phenol (0.90 g, 9.5 mmol) and triphenylphosphine (2.5 g, 9.5 mmol) in THF (40 mL) at 0° C. The mixture was stirred at room temperature for 20 minutes. The solvent was evaporated in vacuo and the crude product purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and evaporated in vacuo. The crude product was dissolved with AcOEt and washed with a 10% solution of NaOH. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 6,7-dihydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester (2.75 g, quantitative yield) that was used in the next step without further purification. C16H18N2O4 LCMS: Rt 2.43, m/z 303 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][NH2:44])[CH:38]=1>>[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][NH:44][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:24]=[CH:25][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:27][CH:28]=2)=[O:10])[CH:38]=1
Reactant: NCc1cccnc1
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)NCc4cccnc4)cc32)cc1

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and (3-pyridyl)methylamine according to Procedure K: mp 211-215° C.; Anal. Calcd for C21H18N6O4S.H2O: C, 53.84; H, 4.30; N, 17.94. Found: C, 54.29; H, 4.03; N, 17.82.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19](O)([CH3:20])[C:18]3[C:13](=[C:14]([N+:22]([O-])=O)[CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:22][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:25])[N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=1)[CH:19]2[CH3:20]
Reactant: CC(C)(C)c1ccc(N2C(=O)c3c([N+](=O)[O-])cccc3C2(C)O)cc1
Agent: [Pd]
Solvent: CO
Product: CC1c2cccc(N)c2C(=O)N1c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
The mixture of 2-(4-tert-butyl-phenyl)-3-hydroxy-3-methyl-7-nitro-2,3-dihydro-isoindol-1-one (170 mg, Step F) and Pd/C (10 wt %, 35 mg) in 10 mL of MeOH was placed under H2 and stirred at RT for 19 h. The mixture was filtered through Celite®, condensed, and the titled compound was obtained as a colorless oil after flash column chromatography (5 to 35% of EtOAc in hexanes). MS (ES+): 295.1 (M+H)+. Calc'd for C19H22N2O-294.39.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][CH3:21])[N:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=3)([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][CH3:21])[N:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: COc1cc(C2C(=O)Nc3cc(Cl)ccc32)nc(OC)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)nc(OC)n1
Temperature: 80 °C

Procedure:
A mixture of rac-6-chloro-3-(2,6-dimethoxy-pyrimidin-4-yl)-1,3-dihydro-indol-2-one (0.23 g, 0.75 mmol) (from Example 29a supra), 3-chlorobenzyl bromide (0.19 g, 0.9 mmol) (Aldrich), potassium iodide (0.15 g, 0.9 mmol) and potassium carbonate (0.23 g, 1.66 mmol) in acetone (20 mL) was heated at 80° C. for 30 minutes. After cooling, mixture was diluted with ethyl acetate and washed with water and brine. Aqueous layers were back washed with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate-hexanes, 1:6, V/V) to give rac-6-chloro-3-(3-chloro-benzyl)-3-(2,6-dimethoxy-pyrimidin-4-yl)-1,3-dihydro-indol-2-one as an orange solid. (Yield 0.21 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@H:20]([S:33][CH2:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37]([OH:39])=[O:38])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+:43]>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@H:20]([S:33][CH2:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37]([O-:39])=[O:38])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:30])[CH3:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[Na+:43]
Reactant: CC(C)(CS[C@H](CCc1ccccc1C(C)(C)O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(CS[C@H](CCc1ccccc1C(C)(C)O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)CC(=O)[O-]

Procedure:
To a solution of the acid of Step 11 in ethanol was added 1.0 equiv of 1N NaOH. The solvent was evaporated and the remaining oil was dissolved in water and freeze-dried to yield the title compound.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:38][C:39]1[N:43]2[C:44](=[O:55])[N:45]([CH2:47][CH2:48][CH:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[CH2:46][C:42]2=[CH:41][N:40]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:13][C:10]([CH3:11])([CH3:12])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:14]([N:52]1[CH2:53][CH2:54][CH:49]([CH2:48][CH2:47][N:45]2[CH2:46][C:42]3=[CH:41][N:40]=[C:39]([CH3:38])[N:43]3[C:44]2=[O:55])[CH2:50][CH2:51]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: Cc1ncc2n1C(=O)N(CCC1CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc2n1C(=O)N(CCC1CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC1)C2
Yield: 69.1 %

Procedure:
To a solution of Boc-D-tert-leucine (0.69 g) in methylene chloride (15 ml) were added HOBt (0.61 g), WSC (0.86 g) and triethylamine (0.84 ml) under ice-cooling. The reaction mixture was mixed at 0° C. for 2.5 hours. Then, 5-methyl-2-(2-(4-piperidinyl)ethyl)-1,2-dihydroimidazo[1,5-c]imidazol-3-one (0.74 g) obtained in Example 96b) was added thereto, and further mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate/methanol=20/1) to obtain the title compound as colorless powder (0.95 g, 69%).
Reaction SMILES: [F:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10]>ClCCl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: OCc1cccc(I)c1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc(I)c1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
Manganese (IV) oxide (15.40 g, 177 mmol) was added portionwise to a stirred solution of (2-fluoro-3-iodophenyl)methanol (preparation 22c, 4.03 g, 16 mmol) in dichloromethane (140 mL) and the mixture was stirred at 50° C. After 3 hours, the mixture was filtered through Celite® and the solvent was evaporated to give the title compound (2.10 g, 53%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:18])([CH3:17])[C@@H:12]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:26](O)[C:27]#[C:28][CH2:29][OH:30]>>[OH:30][CH2:29][C:28]#[C:27][CH2:26][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:17])([CH3:18])[C@@H:12]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: OCC#CCO
Product: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCO)cc2)CCSC1(C)C
Yield: 48.3 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 2.5 g (6.46 mmoL) of tert-butyl (3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.667 g (7.752 mmol) of 2-butyne-1,4-diol gave 1.42 g of tert-butyl (3S)-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxylate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20].C(OCC)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:25][C:24]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:9][C:19](=[O:20])[C:18]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH3:10]
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: COc1ccc2c(O)c(-c3ccccc3OC)c(=O)[nH]c2c1
Temperature: 280 °C
Yield: 90.7 %

Procedure:
A mixture of 2.7 g of m-anisidine and 5.32 g of diethyl 2-methoxyphenylmalonate in 20 ml of diphenyl ether was placed in a flask equipped with an air condenser, and heated at 270-290° C. for 2.5 hours. After cooling, to the reaction mixture there was added 80 ml of diethyl ether. The precipitates were collected by filtration, and washed with diethyl ether to obtain 5.39 g of 4-hydroxy-7-methoxy-3-(2-methoxyphenyl)-2-quinolone (yield: 90.7%).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([C@@:1]2([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cn([C@@]2(C(=O)c3ccc([N+](=O)[O-])cc3)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 58 %

Procedure:
Thymidine (2.42 g; 10 mmol) is dried by coevaporation in pyridine, then taken up in 200 ml of anhydrous pyridine and cooled to 4° C. p-Nitrobenzoyl chloride (2.04 g; 11 mmol) is added. The temperature is allowed to rise and the reaction is left overnight at room temperature. The reaction is stopped with 5 ml of saturated sodium bicarbonate. The reaction mixture is concentrated and then taken up in 500 ml of chloroform. The organic solution obtained is washed with 2×500 ml of 0.5 M NaHCO3 and then with 250 ml of saturated NaCl. The aqueous phases are counter-extracted with 100 ml of CHCl3. The organic phases are evaporated. The pure product is obtained by column chromatography on silica. It is eluted with 5% of methanol in chloroform. Yield=58%.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:20]=[CH:21][CH:22]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:28]([C:24]2[N:25]=[CH:26][O:27][C:23]=2[C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=2)=[O:29])[CH:9]=[N:8]1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(CCCCC(C)(F)F)c2)c1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=405.24.