Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:20]([O:22]C)=[O:21])[CH:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][N:19]=3)[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CO.O>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:20]([OH:22])=[O:21])[CH:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][N:19]=3)[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCOc2c(-c3ncco3)cc(C(=O)OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCN1CCOc2c(-c3ncco3)cc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a stirred solution of Methyl 4-butyl-8-(1,3-oxazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (474 mg) in methanol (20 mL) was added potassium hydroxide (15 mL of a 1.0 M solution in water). The mixture was stirred at room temperature overnight then concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid and extracted with chloroform (4×100 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under reduced pressure to give 450 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 11.60, 8.08, 7.74, 7.46, 7.37, 4.46, 3.43, 3.34, 1.62, 1.41, 0.98.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:25]([C:24]1[CH:23]=[C:22]([CH:29]=[CH:28][CH:27]=1)[O:21][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)#[N:26]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: N#Cc1cccc(O)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(C#N)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 3-hydroxy-benzonitrile via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]1)[NH:20][C:19]2=[O:29]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1ccccc1F
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccccc4F)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 2-fluorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11FN4O3, 350.1; m/z found, 351.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.02 (br s, 1H), 12.95 (br s, 1H), 8.99 (s, 1H), 8.28 (s, 2H), 8.05 (d, J=8.5 Hz, 1H), 7.81 (s, 1H), 7.67 (t, J=7.9, 1H), 7.49 (tdd, J=7.1, 5.1, 1.7, 1H), 7.40-7.34 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4](=NN)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].[OH-].[K+]>C(O)COCCO>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:2]=1[NH2:1]
Reactant: NN=C(c1cc(Cl)ccc1N)c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc(Cl)cc1Cc1ccccc1F

Procedure:
In the manner given in Preparation 11, 2-amino-2'-fluoro-5-chlorobenzophenone hydrazone is refluxed with potassium hydroxide in diethylene glycol to give 2-(o-fluorobenzyl)-4-chloroaniline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[N:13][C:12](F)=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(OC(C1C=NC2C(C=1O)=CN=C([Cl:34])C=2)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:10]([C:15]=1[Cl:16])=[CH:11][CH:12]=[N:13][C:14]=2[Cl:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(Cl)ncc2c1O
Reactant: CCOC(=O)c1cnc2ccc(F)nc2c1Cl
Product: CCOC(=O)c1cnc2c(Cl)nccc2c1Cl

Procedure:
The title compound was prepared following the procedure described for 4a using 8-chloro-4-hydroxy-[1,7]naphthyridine-3-carboxylic acid ethyl ester (11). 1H-NMR (CDCl3) δ (ppm): 1.47 (3H, t, J=7.14 Hz), 4.53 (2H, q, J=7.14 Hz), 8.13 (1H, d, J=5.8 Hz), 8.55 (1H, d, J=5.8 Hz), 9.35 (1H, s). m/z 271.0 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][N:3]1C(=O)C.Cl>C(O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: CC(=O)N1CCc2sccc2C1=O
Agent: Cl
Solvent: CCO
Product: O=C1NCCc2sccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
An initially heterogeneous mixture of 4-oxo-5-acetyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (13.6 g; 0.069 mole) from Example 5, ethanol (50 ml) and 6 N hydrochloric acid (50 ml) is stirred for 4 hours at room temperature. The reaction mixture is concentrated in vacuo, the residue is made slightly basic by addition of sodium hydroxide and is then extracted with methylene chloride. The organic extracts are washed with water, dried over sodium sulfate and evaporated to dryness. The resulting residue is recrystallized from isopropanol-diisopropyl ether, to give white crystals, M.p.=94° C. Yield: 70%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CN(C)CCO
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-nitro-4-tert-butylphenol (2 g) and N,N-dimethylethanolamine (1.3 g) and PPh2 (4 g) in THF (50 ml) was added DEAD (2.6 ml). The reaction was stirred at RT for 1 h, diluted with EtOAc (50 ml) and washed with 1 N HCl twice. The aqueous layer was basified with NaHCO3, extracted with EtOAc twice and washed with H2O and brine. The organic layer was dried over Na2SO4 and evaporated to give {2-[4-(tert-butyl)-2-nitrophenoxy]-ethyl}dimethylamine, was used in next step without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][C:18](=[O:23])[C:17]([C:24]([OH:26])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:53]1[C:54]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)=[CH:55][N:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=12>CN(C=O)C>[N:53]1[C:54]([C:62]2[CH:63]=[C:64]([NH:68][C:24]([C:17]3[C:18](=[O:23])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][C:13]([O:12][C:11]([F:10])([F:28])[F:27])=[CH:22][CH:21]=4)=[O:26])[CH:65]=[CH:66][CH:67]=2)=[CH:55][N:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cc(OC(F)(F)F)ccc2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(OC(F)(F)F)ccc2oc1=O
Temperature: 25 °C
Yield: 36.4 %

Procedure:
DIEA (34.9 μL, 0.20 mmol) was added to 6-trifluoromethoxy-3-carboxy-coumarin (50.0 mg, 0.18 mmol) and HATU (76.3 g, 0.20 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (38.2 mg, 0.18 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 30.5 mg of product in 36% yield: LCMS (ESI) m/z 466 (MH+).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:25][CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:23]1([CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:26][CH2:25]1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(C2(CN3CC3)CCOCC2)ccc1OCCCN1CCCC1
Temperature: 70 °C
Yield: 10 %

Procedure:
A mixture of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (482 mg, 1.50 mmol), 1,2-dibromoethane (0.13 ml, 1.50 mmol) and K2CO3 (420 mg, 3.0 mmol) in acetonitrile (50 ml) was heated to 70° C. for 3 days. The mixture was concentrated in vacuo and purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (93:7:1 to 91:9:1) to provide the title compound as a clear colourless oil (51 mg, 0.15 mmol, 10%). 1H NMR (400 MHz, CDCl3) δ 0.71 (m, 2H), 1.48 (m, 2H), 1.78 (m, 4H), 2.00 (m, 4H), 2.19 (m, 2H), 2.30 (s, 2H), 2.54 (m, 4H), 2.63 (t, 2H), 3.54 (m, 2H), 3.78 (m, 2H), 4.01 (t, 2H), 6.86 (d, 2H), 7.21 (d, 2H). HRMS ESI+ m/z 345.2534 [MH]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[C:18]([C:20]([O-])=[O:21])[S:19][C:12]=12.[Li+]>>[N:1]1([CH2:7][CH2:8][NH:9][C:20]([C:18]2[S:19][C:12]3[C:13](=[N:14][CH:15]=[CH:16][C:11]=3[Cl:10])[CH:17]=2)=[O:21])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NCCN1CCOCC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(NCCN1CCOCC1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-morpholine-4-yl-ethylamine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 326/328 (MH+); HPLC Rf: 3.45 min.; HPLC purity 94%.
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:8]\[C:9]1[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[C:12]([O:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:11][CH:10]=1)/[C:5]([OH:7])=[O:6])[CH3:2]>C(O)C>[CH2:1]([O:3][CH:4]([CH2:8][C:9]1[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[C:12]([O:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2sccc12)C(=O)O
Solvent: CCO
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2sccc12)C(=O)O
Yield: 94.8 %

Procedure:
0.175 g (0.39 mmol) 2Z-Ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-acrylic acid (example 103) were hydrogenated with racemic Ru(OAc)2[3,5-xyl-MeOBIPHEP] catalyst in ethanol at 60° C. and a pressure of 60 bar to give 0.167 g [rac]-2-ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionic acid as light grey solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:13]([CH2:15][CH3:16])=[N:14][C:6]1=[N:5]2.[O-]CC.[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.O1CCCC1>[CH2:22]([N:12]1[C:7]2=[N:8][C:9]3[C:4]([N:5]=[C:6]2[N:14]=[C:13]1[CH2:15][CH3:16])=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=3)[CH:21]=[CH2:20]
Reactant: CCc1nc2nc3cc(Cl)ccc3nc2[nH]1
Reactant: C=CCBr
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCn1c(CC)nc2nc3cc(Cl)ccc3nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 75 parts of 6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline, 85 parts of thallous ethoxide, and 600 parts of 2:1 anhydrous dimethylformamide-tetrahydrofuran was stirred at room temperature for 1 hour. Allyl bromide (50 parts) was added in one portion, and the mixture was stirred for an additional hour, followed by heating for 30 minutes on a steam bath. The mixture was filtered, and the filtrate was diluted with 2000 parts of water. The filtrate was extracted with three 500 -part portions of chloroform, and the combined extracts dried (potassium carbonate) and evaporated in vacuo. The residue was dissolved in 500 parts of benzene and decolorized (silica gel). The benzene was removed in vacuo and the crude product recrystallized from 95:5 ether-ethanol to yield 24 parts of 1-allyl-6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline, m.p. 117°-121°.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Cl:18][C:19]1[C:26]([F:27])=[CH:25][C:22]([C:23]#[N:24])=[C:21](F)[CH:20]=1>CN(C)C=O>[Cl:18][C:19]1[C:26]([F:27])=[CH:25][C:22]([C:23]#[N:24])=[C:21]([CH:20]=1)[O:17][CH:12]([C:13]([F:14])([F:15])[F:16])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(CCC(O)C(F)(F)F)C(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)c(Cl)cc1F
Solvent: CN(C)C=O
Product: CN(CCC(Oc1cc(Cl)c(F)cc1C#N)C(F)(F)F)C(=O)OC(C)(C)C

Procedure:
The subtitle compound was prepared according to the method of Example 3 step (b) using methyl-(4,4,4-trifluoro-3-hydroxybutyl)carbamic acid, 1,1-dimethylethyl ester and 4-chloro-2,5-difluorobenzonitrile in N,N-dimethylformamide.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:8])[O:5]CC)[CH3:2].[Na+].[I-]>N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:5])[OH:8])[CH3:2]
Reactant: CCOP(=O)(CCNC(=O)OCc1ccccc1)OCC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOP(=O)(O)CCNC(=O)OCc1ccccc1
Temperature: 115 °C
Yield: 89 %

Procedure:
(2-Benzyloxycarbonylamino-ethyl)-phosphonic acid diethyl ester (5.77 g, 18.3 mmol) was dissolved in pyridine (61 mL). To this solution was added NaI (13.7 g, 92 mmol). The mixture was heated at 115° C. overnight. The next day the reaction was determined, by LC/MS, to be largely complete. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in H2O and extracted with Et2O. The water was then cooled in an ice bath and the adjusted to pH 2 with 2N HCl. The water was then extracted with CH2Cl2 and the combined organic layers were washed with brine and dried over Na2SO4. The drying agent was removed by vacuum filtration and the filtrate was concentrated to yield (2-benzyloxycarbonylamino-ethyl)-phosphonic acid monoethyl ester (4.68 g, 89%) as an oil that turned to a waxy solid under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13]=[N:14][OH:15].[CH:16]1([N:22]=[C:23]=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>CN(C)C=O>[CH:16]1([NH:22][C:23](=[O:15])[OH:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13]=[N:14][OH:15]
Reactant: O=C=NC1CCCCC1
Agent: ON=Cc1c(Cl)ccc2cc(Cl)cnc12
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)NC1CCCCC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
24 g of 3,7-dichloroquinoline-8-aldoxime were dissolved in 250 ml of dimethylformamide, 12.5 g of cyclohexyl isocyanate were added dropwise at room temperature and the solution was then stirred at 50° C. for 5 hours. In the course of the reaction period, a further 12 g of cyclohexyl isocyanate were slowly added dropwise. 2 liters of water were added to the reaction solution, and the solid was filtered off under suction, suspended in a little methanol, again filtered off under suction and recrystallized from toluene with active carbon to give 26 g (72% of theory) of 3,7-dichloroquinoline-8-aldoxime cyclohexylcarbamate of melting point 152° C.
Reaction SMILES: [C:1]([OH:7])(=O)[CH:2]([CH2:4][OH:5])[OH:3].CO[C:10](OC)([CH3:12])[CH3:11].C(O)[C@H](O)C(O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CO>[CH3:11][C:10]1([CH3:12])[O:3][CH:2]([CH2:4][OH:5])[CH2:1][O:7]1
Reactant: COC(C)(C)OC
Reactant: O=C(O)C(O)CO
Agent: O=C(O)[C@@H](O)CO
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Product: CC1(C)OCC(CO)O1

Procedure:
Alternatively, the glyceric acid can be reacted with the 2,2-dimethoxypropane without methanol to prepare 2,3-O-isopropylidene D- or L-glyceric acid which is then reacted with lithium aluminum hydride to produce the solketal.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35](Cl)=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.O1CCOCC1>O>[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=3)=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(C(=O)O)c([N+](=O)[O-])c1)OCC1c2ccccc2-c2ccccc21
Reaction time: 20 h
Yield: 67.2 %

Procedure:
To a solution of 11.4 g 4-amino-2-nitro-benzoic acid in 228 ml of water containing 6.63 g of sodium carbonate were added 17.0 g of 9-fluorenylmethyl-chloroformate and dropwise 20 ml of dioxane. After stirring for 20 hours under nitrogen, the mixture was filtered and the filtrate was washed five times with methyl-tert.-butylether. Residual methyl-tert.-butylether was removed from the aqueous phase by evaporation under vacuum. To the aqueous phase were added 456 g of 0° C. cold water. The mixture was adjusted to pH=3 by addition of 31 ml of 2M aqueous hydrochloric acid. The precipitate was sucked off, washed with 513 ml of water, dried at 40° C. in vacuum to give 17.0 g of 4-(((9H-fluorene-9-yl)methoxy)carbonylamino)-2-nitrobenzoic acid as off-white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:19])[CH2:3][C:2]2([CH3:20])[CH3:1])(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC(=O)c1ccccc1-c1ccc2c(c1)C(C)(C)CC2=O

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 2-acetylphenyl boronic acid according to the procedure described in example 21. MS (ESI) m/z 279; HRMS: calcd for C19H18O2+H+, 279.13796; found (ESI, [M+H]+), 279.1383.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].[CH3:11][O:12][CH:13](OC)[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([Cl:22])[CH:15]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:11][O:12][CH:13]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([Cl:22])[CH:15]=1)[P:1]([O:2][CH2:3][CH3:4])(=[O:5])[O:8][CH2:9][CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: COc1cc(Cl)cc(C(OC)OC)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(OC)c1cc(Cl)cc(OC)c1
Yield: 77 %

Procedure:
Triethyl phosphite (3.2 ml, 19 mmol) was added dropwise to a solution of acetal 7 (4.0 g, 18.5 mmol), boron trifluoride etherate (2.3 ml, 19 mmol) and CH2Cl2 (20 ml) at 0° C. After slowly warming the reaction to room temperature (30 min), the solution was partitioned with dilute NaHCO3, dried over Na2SO4, evaporated and purified on silica gel (40%-100% EtOAc/hexanes) to give 4.6 g (77.5%) of phosphonate 8 as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>CN(C=O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:5][C@@H:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[N:12][CH:13]=1)([O-:19])=[O:18]
Reactant: C[C@H](O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc([N+](=O)[O-])cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 4-neck flask, commercially available 2-chloro-5-nitropyridine (71.9 g) and (S)-1,1,1-trifluoropropan-2-ol (54.3 g) were dissolved in DMF (610 ml) and sodium hydride (20 g, 55%) was added at a temperature of 16 to 18° C. (ice cooling). Following addition, the mixture was allowed to stir for 1 hour. The mixture was poured into ice and was allowed to hydrolyze. The suspension was warmed to RT over a period of 12 hours and the solid was filtered and washed with additional water and then with a small amount of hexanes (50 mL). The brown solid was further dried in vacuo to provide the title compound. (81.9 g). 1H-NMR (δ, CDCl3): 9.06 (m, 1H), 8.43 (dd, 1H), 6.93 (d, 1H), 5.87 (m, 1H); 1.54 (m, 3H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:31]2[CH2:35][CH2:34][O:33][C:32]2=[O:36])(O)[C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[C:31]2\[C:32](=[O:36])[O:33][CH2:34][CH2:35]\2)/[C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=2)=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ccc(C(O)(c2ccc(F)cc2)C2CCOC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2ccc(F)cc2)cc1
Yield: 43.6 %

Procedure:
A few mg of toluene-4-sulphonic acid are added to a solution of 7 g of 3-[1-(4-fluorophenyl)-1-hydroxy-1-(4-methanesulphonylphenyl)methyl]dihydrofuran-2-one, prepared in Example 3, in 100 ml of toluene and the mixture is refluxed for 10 hours in a Dean-Stark apparatus. The solvent is then evaporated off to dryness under vacuum and the residue is chromatographed using a 9/1 dichloromethanel/acetone mixture as the eluent to give an oil, which is chromatographed using t-butyl methyl ether as the eluent to give 2.9 g of (E)-3-[1-(4-fluorophenyl)-1-(4-methanesulphonylphenyl)methylidene]dihydrofuran-2-one (second product eluted) in the form of crystals melting at 187-9° C. 1.5 g of (Z)-3-[1-(4-fluorophenyl)-1-(4-methanesulphonylphenyl)methylidene]dihydrofuran-2-one (first product eluted) are recovered in the form of crystals melting at 157-158° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[C:16]([C:18]([C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]([CH3:33])([C:31]#[N:32])[CH3:30])[CH:28]=1)[CH2:24]Br)([CH3:20])[CH3:19])#[N:17]>>[C:31]([C:29]([C:27]1[CH:26]=[C:23]([CH:22]=[C:21]([C:18]([CH3:20])([C:16]#[N:17])[CH3:19])[CH:28]=1)[CH2:24][N:9]([C:10]1[CH:15]=[N:14][CH:13]=[N:12][CH:11]=1)[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:30])[CH3:33])#[N:32]
Reactant: CC(C)(C#N)c1cc(CBr)cc(C(C)(C)C#N)c1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: CC(C)(C#N)c1cc(CN(c2ccc(C#N)cc2)c2cncnc2)cc(C(C)(C)C#N)c1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 3,5-bis(1-cyano-1-methylethyl)benzyl bromide
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH3:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[Cl:10]OC(C)(C)C>CO>[Cl:10][N:7]1[C:3]([CH2:2][Cl:1])([CH3:9])[CH2:4][CH2:5][C:6]1=[O:8]
Reactant: CC(C)(C)OCl
Reactant: CC1(CCl)CCC(=O)N1
Solvent: CO
Product: CC1(CCl)CCC(=O)N1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A solution of 5-(chloromethyl)-5-methylpyrrolidin-2-one (302 mg, 2.05 mmol) in methanol (20 mL) was cooled in ice water for 10 min, before neat tert-butyl hypochlorite (0.46 mL, 4.1 mmol, 2 equiv.) was added in one portion. Additional tert-butyl hypochlorite (0.46 mL, 4.1 mmol, 2 equiv.) was added after 45 min. After 1 h, the mixture was concentrated in vacuo and the residue absorbed on silica. Chromatography on silica (0-2.5% MeOH/DCM) afforded the N-chloro-pyrrolidinone as a colorless oil (292 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 3.74 (d, J=11.9 Hz, 1H), 3.50 (J=11.9 Hz, 1H), 2.66-2.57 (m, 1H), 2.54-2.40 (m, 2H), 2.10-2.01 (m, 1H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ171.6 (C), 65.4 (C), 49.1 (CH2), 28.9 (CH2), 27.8 (CH2), 23.1 (CH3); LRMS (ESI/APCI): 182 [M+H]+.