Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:30])[C:22]=3[C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]([F:42])([F:41])[CH:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:14][C:11]1([CH3:15])[O:12][CH2:13][C:8]([NH:7][C:6](=[O:31])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:30][CH:37]4[CH2:38][CH2:39][CH:34]([C:33]([F:42])([F:41])[F:32])[CH2:35][CH2:36]4)[C:22]=3[C:26]([F:27])([F:28])[F:29])[CH:17]=2)[CH2:9][O:10]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3c(C(F)(F)F)c(O)ccc3c2)COC(C)(C)OC1
Reactant: OC1CCC(C(F)(F)F)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc3c(C(F)(F)F)c(OC4CCC(C(F)(F)F)CC4)ccc3c2)COC(C)(C)OC1
Temperature: 0 °C
Yield: 64.1 %

Procedure:
[5-(6-Hydroxy-5-trifluoromethyl-naphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester (1 g, 0.003 mol), 4-Trifluoromethyl-cyclohexanol (0.50 g, 0.0029 mol), and triphenylphosphine (0.84 g, 0.0032 mol) were combined in dry toluene (15 mL, 0.14 mol) and stirred under nitrogen. The solution cooled to 0° C. on an ice bath and diisopropyl azodicarboxylate (0.65 g, 0.0032 mol) was added slowly (dropwise) over 30 min. Once all DIAD was added the mixture was stirred on an icebath for 30 minutes. The ice bath was then removed and the mixture was allowed to warm to room temperature while stirring under nitrogen for 16 hours. The mixture was then washed with 1.0 N HCl, and washed with Sat. Na2CO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude reaction was then dissolved in methylene chloride, absorbed onto 10 g silica and purified (dry load) via column chromatography 0-50% EtoAC/Hexanes using a 125 g column to give 1.1 g the desired product as a white solid. Material was carried forward without additional purification. ESI-MS: 592 (M+H)+
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1>CO.O>[OH:17][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=2)=[CH:10][CH:11]=1)[CH3:16]
Reactant: CC(=O)c1ccc(C2=CCCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1ccc(C2=CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7 g of sodium borohydride in 300 ml of methanol and 80 ml of water is cooled to 5°C and 50 g of p-(1-cyclohexenyl)-acetophenone are stirred in portionwise. The batch is stirred on for 2 hours at room temperature, the solution is concentrated to half its volume in a rotary evaporator, mixed with 1 litre of water and extracted with 3 × 500 ml of methylenechloride. The methylenechloride residue is recrystallized from petroleum ether and furnishes 1-hydroxy-1-[p-(1-cyclohexenyl)-phenyl]-ethane melting at 60°-62°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[C:4]([OH:11])[CH:3]=1.[Cl-].O[NH3+:14].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]([CH3:9])=[N:14][O:11][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cc1noc2cc(F)ccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A mixture of 1-(4-fluoro-2-hydroxyphenyl)ethanone (20 g), hydroxyammonium chloride (18.1 g), sodium acetate (16 g) and methanol (500 mL) was stirred at 60° C. for 1 hr. The reaction mixture was added to ice water, and the obtained crystallized product was collected by filtration and dissolved in tetrahydrofuran (400 mL). N,N′-carbonyldiimidazole (22.5 g) and then a solution of triethylamine (22.3 mL) in tetrahydrofuran (100 mL) were added, and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was diluted with diethyl ether, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as colorless crystals (13.7 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C:16]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][CH:13]1C(O)=O)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].CC(C)[C@H](NC(OC)=O)C(N1C([C:45]([NH:47][CH2:48][C:49]([C:51]2[CH:56]=[CH:55][C:54]([C:57]3[CH:62]=[CH:61][C:60]([C:63]4[N:64]=[C:65]([C@@H:68]5[CH2:72][CH2:71][CH2:70][N:69]5[C:73](=[O:83])[C@@H:74]([NH:78][C:79]([O:81][CH3:82])=[O:80])[CH:75]([CH3:77])[CH3:76])[NH:66][CH:67]=4)=[CH:59][CH:58]=3)=[CH:53][CH:52]=2)=[O:50])=[O:46])CC2(CN(C(OC(C)(C)C)=O)C2)C1)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH3:76][CH:75]([CH3:77])[C@H:74]([NH:78][C:79](=[O:80])[O:81][CH3:82])[C:73]([N:69]1[CH2:70][CH2:71][CH2:72][C@H:68]1[C:65]1[NH:66][CH:67]=[C:63]([C:60]2[CH:59]=[CH:58][C:57]([C:54]3[CH:55]=[CH:56][C:51]([C:49](=[O:50])[CH2:48][NH:47][C:45]([CH:13]4[CH2:14][CH2:15][C:16]5([CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[N:12]4[C:10](=[O:11])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([CH3:9])[CH3:8])=[O:46])=[CH:52][CH:53]=3)=[CH:62][CH:61]=2)[N:64]=1)=[O:83]
Reactant: COC(=O)N[C@H](C(=O)N1C(C(=O)O)CCC12CCOCC2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CC1C(=O)NCC(=O)c1ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc1)CN(C(=O)OC(C)(C)C)C2)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)CNC(=O)C4CCC5(CCOCC5)N4C(=O)[C@@H](NC(=O)OC)C(C)C)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of 1-{N-[(methyloxy)carbonyl]-L-valyl}-8-oxa-1-azaspiro[4.5]decane-2-carboxylic acid (168) (52 mg, 1.5 mmol) and methyl {(1S)-1-[((2S)-2-{4-[4′-(aminoacetyl)-4-biphenylyl]-1H-imidazol-2-yl}-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate dihydrochloride (1) (88 mg, 0.15 mmol) and HATU (58 mg, 0.15 mmol) in anhydrous dichloromethane (1.2 mL) was added Hunig's base (0.12 mL, 0.68 mmol) and the reaction stirred at room temperature for 1 h. The reaction was concentrated in vacuo and purified by HPLC eluting with 10-90% water/acetonitrile/0.2% NH4OH to afford the title compound as an off-white solid (73 mg, 58% yield).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH4+:5].[C:6]([O:10][C:11]([CH2:13][CH:14]([O:16][N:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])[CH3:15])=[O:12])([CH3:9])([CH3:8])[CH3:7]>CO>[C:1]([O-:4])(=[O:3])[CH3:2].[C:6]([O:10][C:11]([CH2:13][CH:14]([O:16][N:17]=[C:18]([C:19]#[N:20])[C:21]([NH2:5])=[NH2+:22])[CH3:15])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: [NH4+]
Reactant: CC(CC(=O)OC(C)(C)C)ON=C(C#N)C#N
Agent: CC(=O)[O-]
Solvent: CO
Product: CC(CC(=O)OC(C)(C)C)ON=C(C#N)C(N)=[NH2+]
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To ammonium acetate (18.5 g) dissolved in methanol (100 ml) was added 2-(tert-butoxycarbonylprop-2-oxyimino)malononitrile (19 g). After stirred for 2 hours, the mixture was standed overnight at room temperature. The reaction mixture was concentrated, and water (500 ml) was added therein. The obtained mixture was extracted with ethylacetate (500 ml). After the extract was dehydrated, filtered, and concentrated, ethylether was added therein, and stirred for 30 minutes. The precipitates were filtered to give the above-indicated compound (15 g) in pale yellow.
Reaction SMILES: [Cu][C:2]#N.C[Mg]Br.[CH3:7][O:8][C:9](=[O:22])[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19](Cl)=[O:20]>C1COCC1>[CH3:7][O:8][C:9](=[O:22])[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19](=[O:20])[CH3:2]
Reactant: N#C[Cu]
Reactant: COC(=O)c1c(C(=O)Cl)cccc1[N+](=O)[O-]
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)c1c(C(C)=O)cccc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a suspension of copper(I)cyanide (5.70 g, 63.6 mmol) in 200 mL of anhydrous THF at −78° C. was added methyl magnesium bromide (1.4 M in toluene and THF, 43 mL, 59.3 mmol). The mixture was stirred at −20° C. for 20 min, then cooled to −78° C. A solution of 2-chlorocarbonyl-6-nitro-benzoic acid methyl ester (11.6 g, 47.8 mmol, Step B) in 30 mL of THF was added. The mixture was cooled at −10° C., and slowly warmed to RT, quenched with NH4Cl(aq), and extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, condensed, and purified by flash column chromatography, to provide the titled compound as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[F:36][CH:37]([F:52])[N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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>[F:36][CH:37]([F:52])[N:38]1[CH:42]=[C:41]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH:40]=[N:39]1
Reactant: CC1(C)OB(c2cnn(C(F)F)c2)OC1(C)C
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
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: COCCOC
Solvent: O
Product: COc1cn(-c2ccc(-c3cnn(C(F)F)c3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (230 mg, 0.45 mmol), 1-(difluoromethyl)-1H-pyrazole-4-boronic acid pinacol ester (122 mg, 0.50 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), Na2CO3 (106 mg, 1.0 mmol), DME (4 mL), and H2O (1 mL) was refluxed for 3 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title compound (183 mg, 85% yield) as a white solid: mp 185-187° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.92 (3H, s), 6.41 (1H, t, J=8.3 Hz), 7.03-7.48 (10H, m), 7.79 (1H, d, J=1.9 Hz), 7.83 (1H, d, J=2.3 Hz), 7.91 (1H, d, J=0.8 Hz). LC-MS (ESI) m/z 479 [M+H]+. Anal. Calcd for C24H17F3N6O2: C, 60.25; H, 3.58; N, 17.57. Found: C, 60.19; H, 3.48; N, 17.52.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6](O)[CH:5]=1.P(Cl)(Cl)([Cl:13])=O>ClCCl>[Cl:13][C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:9]=[CH:8][N:7]=1
Reactant: COCc1cc(O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCc1cc(Cl)ncn1
Reaction time: 18 h
Yield: 76.9 %

Procedure:
6-(Methoxymethyl)pyrimidin-4-ol (1.38 g, 9.85 mmol) was taken up in dichloromethane (14 ml) and phosphorous oxychloride (9 mL, 97 mmol) was added at ambient temperature. The mixture was stirred at ambient for 18 h and concentrated. The residue was taken up in ice-water and the pH was adjusted to 7 with 1N sodium hydroxide. The mixture was extracted with chloroform and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (5-10% ethyl acetate/chloroform) to afford 4-chloro-6-(methoxymethyl)pyrimidine (1.2 g, 7.57 mmol, 77% yield) as a pale yellow oil, which solidified on standing. 1H NMR (400 MHz, CDCl3) δ ppm 8.88 (1 H, d, J=1.01 Hz), 7.52 (1 H, d, J=1.01 Hz), 4.53 (2 H, s), 3.50 (3 H, s). MS (LC/MS) R.T.=0.98; [M+H]+=159.10.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:13][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cccc(F)c2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)cc(F)c2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (109-2; 7 g, 0.0424 mol) in N,N-dimethylformamide (30 mL) was added N-bromosuccinimide (9.06 g, 0.050 mol) portion wise at 0° C. Reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was concentrated and diluted with ice cold water (150 mL) with constant stirring and the solid residue was filtered and dried to obtain the title compound. MS (M+1): 245.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].Br[C:37]1[CH:38]=[N:39][CH:40]=[N:41][CH:42]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:37]2[CH:38]=[N:39][CH:40]=[N:41][CH:42]=2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:20])([F:22])[F:21]
Reactant: Brc1cncnc1
Reactant: CC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: CC(c1ccc(-c2cncnc2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 186, step 2 from 5-{2-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-3-methyl-3H-benzooxazol-2-one (obtained in Example 186, step 1) with 5-bromopyrimidine [CAS Reg. No. 4595-59-9]. MS (m/e)=464.1 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:10](=[O:11])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:3]1.[Br:23]Br>CN(C=O)C>[Br:23][C:3]1[N:2]([CH3:1])[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:15])([F:16])[F:14])[C:10](=[O:11])[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: Cn1cc(-c2ccncc2)c2c(=O)n(CC(F)(F)F)cnc21
Solvent: CN(C)C=O
Product: Cn1c(Br)c(-c2ccncc2)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A solution of 7-methyl-5-(pyridin-4-yl)-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (130 mg, 0.422 mmol) in DMF (6 ml) was cooled to 0° C. Bromine (0.026 ml, 0.506 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 60 min. The reaction mixture was partitioned between ethyl acetate (40 ml) and a mixture of aqueous (3:1:4, water, sodium bicarbonate solution and 20% w/w sodium thiosulfate solution, 40 ml). The organic phase was separated and washed with water (3×30 ml), brine and concentrated to give the title compound (160 mg, 98%). LCMS RT=0.72 min, [M+H+(79Br)]=387.0, [M+H+(81Br)]=389.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Li].Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]([OH:13])[CH3:19])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C(C)O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-benzyloxy-4-methoxybenzaldehyde (33 mmol maximum) in tetrahydrofuran (150 mL) is cooled to −78° C. Methyllithium (Aldrich, 1.6 M solution in diethyl ether, 31 mL, 49 mmol) is added dropwise via syringe. Following completion of the addition, the cooling bath is removed and the reaction mixture is allowed to warm to room temperature. After 90 minutes at that temperature, the mixture is cooled to 0° C. and quenched by the addition of saturated aqueous sodium hydrogen carbonate. The quenched reaction mixture, after warming to room temperature, is acidified with 1 M hydrochloric acid solution to pH 1 and extracted thrice with diethyl ether. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 1-(3-benzyloxy-4-methoxy-phenyl)-ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16](O)=[O:17])=[CH:11][C:10]=1[OH:20].S(Cl)(Cl)=O.[NH3:25]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([NH2:25])=[O:17])=[CH:11][C:10]=1[OH:20]
Reactant: N
Reactant: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)c(O)c1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C(N)=O)c1ccc(-c2ccc(F)cc2F)c(O)c1

Procedure:
A solution of 2-(2',4'-difluoro-2-hydroxy-4-biphenylyl)propionic acid (1.75 g.) and thionyl chloride (1 ml.) in dry benzene (10 ml.) was refluxed for 1 hour and then cooled and added dropwise to stirred cold ammonia (d=0.880 g./ml; 20 ml.). The product was filtered and recrystallised first from aqueous industrial methylated spirits and then light petroleum (b.p. 62°-68° C.) to give 2-(2',4'-difluoro-2-hydroxy-4-biphenylyl)propionamide, m.p. 222°-224° C.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1/[CH:31]=[CH:32]\[C:33](O)=[O:34]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:33](=[O:34])/[CH:32]=[CH:31]\[C:30]1[CH:36]=[CH:37][CH:38]=[CH:39][C:29]=1[O:28][CH3:27])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccccc1/C=C\C(=O)O
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: COc1ccccc1/C=C\C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 32 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with cis-2-methoxycinnamic acid under the conditions described in example 86 to yield 32% of the desired product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[C:26]([C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32])([CH3:29])([CH3:28])[CH3:27]>O1CCOCC1>[CH3:29][C:26]([C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH:32][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:27])[CH3:28]
Reactant: CCOC(=O)c1cnc2cc(-c3c(C)noc3C)c(OC)cc2c1Cl
Reactant: CC(C)(C)c1ccccc1N
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(-c3c(C)noc3C)c(OC)cc2c1Nc1ccccc1C(C)(C)C
Yield: 27.7 %

Procedure:
A mixture of ethyl 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxylate (for a preparation see Intermediate 42 (3.3 g, 9.2 mmol) and 2-tert-butylaniline (2.7 ml, 18.4 mmol) in dioxane (50 ml) was refluxed for 2 days. After cooling, the reaction mixture was evaporated under reduced pressure and the precipitate was purified by chromatography on silica gel eluting with DCM/MeOH (95/5) to give the title compound as a solid (1.2 g, 27.7%).
Reaction SMILES: [CH3:1][C:2]12[C:9](=[O:10])[O:8][C:6](=[O:7])[CH:3]1[CH2:4][CH2:5]2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([N:15]=[C:9]([C:2]2([CH3:1])[CH2:5][CH2:4][CH:3]2[C:6]([OH:8])=[O:7])[OH:10])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: CC12CCC1C(=O)OC2=O
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Product: CC1(C(O)=Nc2cc(Cl)cc(Cl)c2)CCC1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
10 g (0.07 mol) of 1-methyl-cyclobutane-1,2-dicarboxylic acid anhydride are dissolved in 50 ml of toluene, and 11.6 g (0.07 mol) of 3,5-dichloroaniline are added. After 24 hours' stirring at room temperature, the amide acid (m.p. 106°-108° C.) which has precipitated is separated. This amidocarboxylic acid is suspended in 40 ml of acetic anhydride, and the suspension is stirred for 24 hours at room temperature, in the course of which everything goes into solution. The acetic anhydride is evaporated off in a water-jet vacuum, and the pulverulent residue is recrystallised from dichloromethane/n-hexane to yield 15 g (73% of theory) of 1-methyl-cyclobutane-1,2-dicarboxylic acid-(3,5-dichlorophenyl)-imide, m.p. 110°-111° C. NMR Spectrum (100 MHz) δ in ppm: 1.55 (s, 3H, CH3), 2.0-3.2 (m, 5H, --CH2CH2 --CH--), 7.2-7.5 (m, 3H, aromat.). Compound No. 7.
Reaction SMILES: [NH3:1].[F:2][C:3]([F:26])([F:25])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][N:18]3[C:22](=[O:23])[CH2:21][O:20][C:19]3=[O:24])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.O1CCCC1>CO>[F:25][C:3]([F:26])([F:2])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][NH:18][C:19](=[O:24])[O:20][CH2:21][C:22]([NH2:1])=[O:23])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: N
Reactant: O=C1COC(=O)N1CCC1CCN(c2cccc(C(F)(F)F)c2)CC1
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)COC(=O)NCCC1CCN(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 24 h

Procedure:
9.3 ml (64.82 mmol) of a solution of aqueous ammonia (7N) in methanol are added to a solution of 0.77 g (2.16 mmol) of 3-(2-{1-[3-(trifluoromethyl)phenyl]-4-piperidyl}ethyl)-1,3-oxazolidine-2,4-dione, obtained in step 3.3, in 10 ml of a 1/1 mixture of methanol and tetrahydrofuran. Stirring is continued at room temperature for 24 hours.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[C:21]([C:27]1[O:28][C:29]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:30]=2[C:31](=[O:33])[CH:32]=1)([O:23][CH2:24][CH2:25][CH3:26])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O>[C:21]([C:27]1[O:28][C:29]2[CH:37]=[CH:36][C:35]([O:38][CH2:2][C:3]3[CH:20]=[CH:19][CH:18]=[C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:4]=3)=[CH:34][C:30]=2[C:31](=[O:33])[CH:32]=1)([O:23][CH2:24][CH2:25][CH3:26])=[O:22]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CCCOC(=O)c1cc(=O)c2cc(O)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCOC(=O)c1cc(=O)c2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2o1
Yield: 28.2 %

Procedure:
A mixture of 3.47g of 2-((3-chloromethylphenoxy)methyl)quinoline, 3.04g of 2-carbopropoxy-6-hydroxy-4-oxo-4H-1-benzopyran, 1.69g of potassium carbonate and 1 ml of dimethylformamide is refluxed in 50 ml of acetone for 41 hours. The mixture is concentrated in vacuo and the residue is dissolved in water. This solution is neutralized with diluted hydrochloric acid and the resulting solid is filtered off and purified by flash silica gel chromatography in propanol-dimethylformamide to give 1.71 g of 2-carbopropoxy-6-(3-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran as a white solid having an m.p. of 109°-10° C.