Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[N:13]=[C:12]([N:14]2[CH2:22][CH2:21][CH2:20][C@@H:15]2[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=1[CH:34]1[C:47]2[C:46](=[O:48])[CH2:45][C:44]([CH3:50])([CH3:49])[CH2:43][C:42]=2[O:41][C:40]2[CH2:39][C:38]([CH3:52])([CH3:51])[CH2:37][C:36](=[O:53])[C:35]1=2.O>C(COC)OC.O.C(OCC)(=O)C>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:8]2[N:13]=[C:12]([N:14]3[CH2:22][CH2:21][CH2:20][C@@H:15]3[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:10][CH:9]=2)=[CH:27][C:26]=1[CH:34]1[C:35]2[C:36](=[O:53])[CH2:37][C:38]([CH3:51])([CH3:52])[CH2:39][C:40]=2[O:41][C:42]2[CH2:43][C:44]([CH3:50])([CH3:49])[CH2:45][C:46](=[O:48])[C:47]1=2
Reactant: COc1ccc(B(O)O)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: COC(=O)[C@H]1CCCN1c1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H]1CCCN1c1cccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
Sodium carbonate (238 mg, 2.24 mmol) and tetrakistriphenylphosphine palladium(0) (86.3 mg, 74.7μμmol) were added to a solution of the methyl 1-(6-bromopyridin-2-yl)-D-prolinate (213 mg, 747 μmol) obtained in Example 15-1 and the [4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]boronic acid (317 mg, 747 μmol) obtained in Example 1-1 in dimethoxyethane/water (3:1, v/v) (4 mL) at room temperature. The mixture thus obtained was stirred at 80° C. for 4 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate three times. The organic layer thus obtained was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=8:2 to 1:3, v/v) to obtain the title compound (190 mg, yield: 44%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]1([CH2:19][CH2:20][C@H:21]([O:45]C2CCCCO2)/[CH:22]=[CH:23]/[C@@H:24]2[C@@H:36]3[C@@H:27]([O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35]3)[CH2:26][C@H:25]2[O:38]C2CCCCO2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[OH:38][C@@H:25]1[CH2:26][C@@H:27]2[O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][C@@H:36]2[C@H:24]1/[CH:23]=[CH:22]/[C@@H:21]([OH:45])[CH2:20][CH2:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](O)C[C@@H]2O1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Solvent: O
Solvent: CO
Product: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](O)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Toluenesulfonic acid monohydrate (0.16 g, 0.84 mmol) was added to a stirred solution of (6Z,8aR,9R,10R,11aS)-4,5,8,8a,9,10,11,11a-octahydro-9-((S,E)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pent-1-enyl)-10-(tetrahydro-2H-pyran-2-yloxy)cyclopenta[b]oxecin-2(3H)-one (9.0 g, 16.7 mmol) in methanol (90 mL). The mixture was stirred for 2 hr at room temperature (TLC monitoring). Then, the reaction mixture was washed with saturated aqueous solution of sodium bicarbonate (100 mL). The organic layer was separated and the water layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 9.0 g of crude product. The crude product was purified by column chromatography providing 3.5 g of the title compound (56.5% yield).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][C@@H:12]([O:14][CH2:15][C:16]([O:18]C)=O)[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.O([Sn](CCCC)(CCCC)CCCC)[Sn](CCCC)(CCCC)CCCC.[SiH2](C1C=CC=CC=1)C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)Cl.CCOCC.Cl.CCO>[Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]2[O:14][CH2:15][C@H:16]([OH:18])[C@H:11]2[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)CO[C@H]1C=C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)C[AlH]CC(C)C
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: CCO
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H]2[C@@H](O)CO[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A solution of methyl ester 10 (87.2 mg, 0.304 mmol) in dry CH2Cl2 (8 mL) was cooled to −78° C. under argon. DIBAL-H (1M sol. in hexanes, 0.40 mL) was added slowly and the reaction mixture was stirred for 1 h at this temperature. The reaction was quenched by addition of MeOH (100 μL) and the mixture was warmed to rt. A pH 7 phosphate buffer (0.5M solution, 2 mL) was added. The aqueous phase was extracted with CH2Cl2 (3×) and the combined organic phase washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo. The crude aldehyde solution was passed through a short plug of silica gel, initially deactivated with 1% Et3N, using hexanes/EtOAc (5:1) as the eluent. After evaporation, the crude product was directly submitted to the next step. The residue was re-dissolved in dry benzene (degassed, 2 mL) under argon and the solution transferred into a sealable tube. (nBu3Sn)2O (22.5 μL, 26.3 mg, 44 μmol), Ph2SiH2 (42 μL, 41.6 mg, 0.22 mmol), EtOH (45 μL), and AIBN (10 mg) were successively added. The sealed tube was placed with stirring in an oil bath at 80° C. for 6 h. After cooling to room temperature, the reaction mixture was diluted with Et2O (2 mL) and aqueous 0.5M HCl solution (2 mL) was added. After stirring at room temperature for 15 min, the aqueous phase was extracted with Et2O (3×). The combined organic phase was washed with saturated aqueous NaHCO3 solution, brine, dried (MgSO4), filtered, and evaporated. The residue was purified by flash chromatography on silica gel using hexanes/EtOAc (6:1 to 2:1) to afford the (R)-alcohol 11 (50 mg, 64% over 2 steps) as a white solid; 5 mg of the other 3-(S)-diastereoisomer was also isolated and only traces of 1,2 reduction product were observed. TLC: Rf=0.46 (hexanes/EtOAc=3:1); [α]D20+22.3° (c 0.67, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 4.69 (dt, J=3.8, 7.2 Hz, 1H), 4.19-4.02 (m, 3H), 3.72 (d, J=9.8 Hz, 1H), 2.48 (q, J=7.5 Hz, 1H), 2.13-1.96 (m, 2H), 1.70-1.55 (m, 2H), 1.47-1.25 (m, 1H), 0.86 (s, 9H), 0.03 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 82.2, 78.3, 73.1, 72.7, 50.9, 42.4, 39.0, 25.8, 17.5, −4.8, −4.9.
Reaction SMILES: [C:1]1([OH:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:10](=O)([O-])[O-].[K+].[K+].CN(C=O)C.IC>O>[CH3:10][O:9][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
3,5-xylenol (10 g, 0.082 mol) and anhydrous potassium carbonate (34 g, 0.25 mol) were added into DMF (150 mL) and then iodomethane (12.8 g, 0.090 mol) was dropped under an ice bath. The mixture was stirred overnight at room temperature. At the end of reaction, the reaction system was added with water and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, then dried and evaporated in vacuum to obtain 10 g of the product (90%) by column chromatography.
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:4]2[S:5][C:6](=[CH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[C:28]([F:31])([F:29])[F:30])[N:15]=[CH:14]4)[C:7](=[O:9])[N:8]=2)[CH2:41][C@@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(O)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
(2R)2-Hydroxymethyl-4-{5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one and (2R)2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: Br[C:2]1[C:3]2[NH:10][CH:9]=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[NH4+].[OH-].[CH3:13][N:14](C=O)C>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.[C-]#N.[C-]#N.[Zn+2]>[N:10]1[C:3]2[C:2]([C:13]#[N:14])=[CH:7][N:6]=[CH:5][C:4]=2[NH:8][CH:9]=1
Reactant: Brc1cncc2nc[nH]c12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [NH4+]
Product: N#Cc1cncc2[nH]cnc12
Yield: 67 %

Procedure:
To a solution of 7-bromo-1H-imidazo[4,5-c]pyridine (3 g, 15.6 mmol) in DMF (10 mL) was added Pd(PPh3)4 (1.0 g) and Zn(CN)2 (1.2 g, 10 mmol). The reaction mixture was irradiated in a microwave at 100° C. for 2 h under Ar. The reaction mixture was poured into aqueous NH4OH and extracted with DCM. The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography to afford 1.5 g (67%) of 3H-imidazo[4,5-c]pyridine-7-carbonitrile as a white solid; MS (ESI)/v/z: 145.0 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([Mg]Br)=[CH:6]2.Cl[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClCc1cccnc1
Reactant: COc1ccc2[nH]c([Mg]Br)cc2c1
Product: COc1ccc2[nH]cc(Cc3cccnc3)c2c1

Procedure:
The above mentioned compound was prepared analogously to the procedure described in J. Het. Chem. 3, 67 (1966) from 5-methoxy-indolyl-magnesium bromide and 3-chloromethylpyridine. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol/ammonia (98:2:0,1), the desired compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([B-](F)(F)F)=[CH2:12].[K+].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.Cl[Pd]Cl>[CH:11]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)=[CH2:12]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-1H-indole (2.5 g, 12.82 mmol), potassium vinyltrifluoroborate (2.57 g, 19.2 mmol), Cs2CO3 (12.53 g, 38.46 mmol) and triphenylphosphine (201 mg, 0.769 mmol) in THF/water (9:1, 75 ml) was degassed with argon for 20 min, then charged with PdCl2 (45.3 mg, 0.256 mmol). The reaction mixture was heated to reflux for 16 h, then cooled to ambient temperature, filtered through celite bed and washed with ethyl acetate. The filtrate was again extracted with ethyl acetate, and the combined organic layer washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (1.5 g, 83%): 1H NMR (400 MHz, CDCl3) δ 8.20 (br, 1H), 7.68 (s, 1H), 7.45 (s, 2H), 7.21 (m, 1H), 6.90 (dd, J=16.0, 10.8 Hz, 1H), 6.55 (m, 1H), 5.75 (d, J=10.5 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H); ESIMS m/z 142.05 ([M−H]−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCOC(C)=O.O>C(Cl)Cl>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[O:13][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[S:9]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]([CH3:30])[CH3:22])[CH2:25][CH2:26]1)(=[O:11])=[O:10]
Reactant: CN(C)C1CCNCC1
Reactant: N#Cc1ccc(Oc2cc(F)ccc2F)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C1CCN(S(=O)(=O)c2cc(C#N)ccc2Oc2cc(F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 840.3 %

Procedure:
To a solution of compound 23 (0.080 g, 0.24 mmol) in DCM (10.00 mL) was added 4-dimethylaminopiperidine (0.040 g, 0.31 mmol) and TEA (0.043 g, 0.31 mmol). The reaction was monitored with TLC (25% EtOAc in hexanes, Rf=0.0). The reaction was complete after stirring at room temperature for 30 min, as indicated by the absence of the starting material (TLC). Water was then added and extracted twice with DCM. Combined organic extracts were washed sequentially with water and brine, dried over MgSO4, filtered, and evaporated in vacuo to form a yellow oil. The oil was triturated with DCM and hexanes, and filtered to yield compound 59 as a white powder (0.85 g, 97.4% HPLC purity, 84% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.27 (d, J=2 Hz, 1H), 8.08 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.56 (m, 1H), 7.40 (m, 1H), 7.26 (m, 1H), 7.19 (d, J=9 Hz, 1H), 3.71 (d, J=13 Hz, 2H), 2.77 (t, J=13 Hz, 2H), 2.18 (m, 1H), 2.12 (s, 3H), 1.76 (d, J=11 Hz, 2H), 1.35 (m, 2H); MS (ESI, EI+): m/z=422 (MH+); melting point: 154-157° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:30][C:31]1[C:39]([OH:40])=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2>CC(N(C)C)=O>[Br:30][C:31]1[C:39]([O:40][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1ccc2[nH]ccc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3Br)ncnc2cc1OCCCN1CCCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (380 mg, 1.13 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (469 mg, 3.4 mmol), 4-bromo-5-hydroxyindole (240 mg, 1.13 mmol) and DMA (4.0 ml) were stirred at 90° C. for 3 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated under vacuum. The residue was purified by column chromatography eluting with dichloromethane/methanolic ammonia (7M) (95/5) to give an oil. This oil was further purified by column chromatography eluting with dichloromethane/methanol (60/40) to give 4-(4-bromoindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (256 mg, 44%).
Reaction SMILES: C(N(CC)CC)C.C1C(=O)OCC1=[O:10].[CH:15]([N:18]=[C:19]=[N:20][CH:21]([CH3:23])[CH3:22])([CH3:17])[CH3:16]>ClCCl>[CH:15]([NH:18][C:19]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:10])([CH3:17])[CH3:16]
Reactant: O=C1COC(=O)C1
Reactant: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)NC(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.75 mL, 5.5 mmol) was added to a suspension of tetronic acid (500 mg, 5.00 mmol) in dichloromethane (25 mL) to obtain a homogeneous solution. The solution was cooled to 0° C., mixed with 4-N,N-dimethylaminopyridine (200 mg, 1.7 mmol), 3-cyclohexne-1-carboxylic acid (0.65 mL, 5.6 mmol), and then, diisopropylcarbodiimide (1.0 mL, 6.3 mmol), followed by stirring for 30 min. The resulting mixture was removed from the ice bath, stirred for 14 hours at room temperature, and filtered to remove thus-produced insoluble diisopropyl urea; the reaction solution was washed twice with 5% hydrochloric acid (20 mL) and the water layer was extracted twice with dichloromethane (10 mL). The organic layers were combined, dried over sodium sulfate anhydride, and concentrated; the thus-obtained residue was purified by silica gel column chromatography (silica gel, ethyl acetate:methanol=15:1). The resultant was arranged to be a sodium salt by adding an excess amount of sodium hydrogencarbonate and distilled water (100 mL), and then washed with dichloromethane; the water layer was acidified by adding 5% hydrochloric acid and extracted four times with dichloromethane (20 mL). The resultant was dried over sodium sulfate anhydride and concentrated to give pale yellow crystals (394 mg, 38%).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:33]([O-])=O)[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C@@H:17]([O:21][C:22](=[O:24])[CH3:23])[C@H:16]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].O.CC(O)=O>CCOC(C)=O.[Fe]>[C:22]([O:21][C@@H:17]1[C@@H:18]([CH3:20])[CH2:19][N:14]([C:13]2[C:12]([NH2:33])=[CH:11][N:10]=[C:9]3[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][C:8]=23)[CH2:15][C@H:16]1[NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])(=[O:24])[CH3:23]
Reactant: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@H](C)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.7 %

Procedure:
A mixture of 4-{(3R,4R,5S)-4-(acetyloxy)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (0.086 g, 0.17 mmol), water (0.10 mL), AcOH (3.0 mL) and iron powder (0.200 g, 3.58 mmol) was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (10 mL), then filtered. The filtrate was concentrated under reduced pressure. EtOAc (20 mL) and aq. Na2CO3 (10 mL) were added to the residue and the mixture was stirred at room temperature for 30 min. The organic layer was separated, dried over Na2SO4, then filtered and concentrated under reduced pressure to give the sub-title compound (80 mg, 92%) as a brown foamy powder. LCMS calc. for C23H35N4O6 (M+H)+: m/z=463.3. Found: 463.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]([O:11]C)=[O:10])[O:6][N:5]=1)[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[O:6][N:5]=1)[CH3:2]
Reactant: CCOc1cc(C(=O)OC)on1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(C(=O)O)on1
Temperature: 25 °C

Procedure:
A stirred solution of methyl 3-ethoxy-5-isoxazolecarboxylate, prepared according to Example 78, (3.00 g, 17.53 mmole) in 75 ml of 2N sodium hydroxide was stirred at room temperature for ten minutes, cooled in an icebath and acidified to pH 3 with concentrated hydrochloric acid. The precipitated solid was collected by filtration. The remaining desired product was isolated by saturating the aqueous filtrate with solid sodium chloride and extracting with ethyl acetate (3×100 ml). A total of 2.46 g (89% yield) of title compound was obtained in this way. The sample was recrystallized from acetonitrile, m.p. 210-13° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:22]2[C:21]3[CH:20]=[C:19]([OH:23])[C:18]([O:24][CH3:25])=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]([CH3:26])[C:11]1=[O:27])[C:5]#[N:6].C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.[CH3:47][Si:48]([CH3:64])([CH3:63])[CH2:49][CH2:50][O:51][C:52](=[O:62])[NH:53][CH2:54][CH:55](O)[C:56]1[S:57][CH:58]=[CH:59][CH:60]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([N:10]2[C:22]3[C:21]4[CH:20]=[C:19]([O:23][CH:55]([C:56]5[S:57][CH:58]=[CH:59][CH:60]=5)[CH2:54][NH:53][C:52](=[O:62])[O:51][CH2:50][CH2:49][Si:48]([CH3:64])([CH3:47])[CH3:63])[C:18]([O:24][CH3:25])=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:12]([CH3:26])[C:11]2=[O:27])=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: C[Si](C)(C)CCOC(=O)NCC(O)c1cccs1
Reactant: COc1cc2ncc3c(c2cc1O)n(-c1ccc(C#N)cc1F)c(=O)n3C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2ncc3c(c2cc1OC(CNC(=O)OCC[Si](C)(C)C)c1cccs1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
3-Fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (350 mg, 961 μmol) and diphenyl-2-pyridylphosphine (1.46 g, 5.39 mmol) were dissolved in tetrahydrofuran (105 ml). 2-Trimethylsilanylethyl(2-hydroxy-2-thiophen-2-ylethyl)carbamate (787 mg, 2.74 mmol) and diisopropyl azodicarboxylate (788 μl, 4.01 mmol) were subsequently added. The reaction mixture was stirred at room temperature for 15 min. When the reaction was complete (HPLC-MS), it was added to ethyl acetate (50 ml) and saturated sodium chloride solution (50 ml) and extracted. The aqueous phase was extracted with further ethyl acetate (25 ml). The combined organic phases were washed with water (25 ml), dried over Na2SO4 and filtered. The filtrate was evaporated to dryness in vacuo, and the residue was chromatographed over flash silica gel (solvent gradient ethyl acetate/0-7% by vol. of ethanol), giving 2-trimethylsilanylethyl {2-[1-(4-cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yloxy]-2-thiophen-2-ylethyl}carbamate (253 mg, 399 μmol) as solid. MS: 634.2 (M+H+), TLC (HPTLC): Rf=0.34 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)([OH:13])[CH2:9]1)C1C=CC=CC=1.C([SiH](CC)CC)C>[Pd].CO>[F:21][C:16]1[CH:15]=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: OC1(c2cc(F)cc(F)c2)CCNC1

Procedure:
Preparation according to Preparation 18: (+)-1-benzyl-3-(3,5-difluorophenyl)pyrrolidin-3-ol (2.89 g, 10 mmol), methanol (20 mL), palladium on carbon (500 mg), triethyl silane (15.97 mL, 100 mmol). Yield 0.92 g. MS m/z (relative intensity, 70 eV) 199 (M+, bp), 141, (61), 127 (72), 114 (57), 113 (84).