Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Mg].[CH3:13][C:14]1([CH3:21])[CH2:18][C:17](=[O:19])[O:16][C:15]1=[O:20].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17](=[O:19])[CH2:18][C:14]([CH3:21])([CH3:13])[C:15]([OH:20])=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: COc1ccc(Br)cc1OC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(C)(C)C(=O)O)cc1OC
Temperature: 25 °C

Procedure:
Under an atmosphere of dry nitrogen a grignard solution, prepared from 43.4 g 3,4-dimethoxybromobenzene and 6.1 g magnesium in 200 ml of tetrahydrofuran, is added dropwise to a solution of 20.5 g 3,3-dimethyl-dihydro-furan-2,5-dione in 200 ml of tetrahydrofuran cooled in an ice-bath. The reaction mixture is stirred for an additional hour at RT. 100 ml of a 20% ammonium chloride solution is added and the water layer is extracted twice with 75 ml of ethyl acetate. The combined organic layers are washed twice with 100 ml of half saturated brine and extracted with 3×100 ml 1 M sodium hydroxide solution. The aqueous layers are washed with 75 ml of ethyl acetate, acidified with concentrated hydrochloric acid and extracted 3 times with 100 ml of dichloromethane. The organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo. The oily residue is crystallized from ethyl acetate/petroleum ether (60-80° C.). M. p. 114-116° C.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][N:8]([CH3:20])[CH2:9][CH2:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>O.CO>[CH3:7][N:8]([CH3:20])[CH2:9][CH2:10][S:11]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)=[O:2]
Reactant: CN(C)CCSc1ccc(C=O)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)CCS(=O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 7 h
Yield: 53 %

Procedure:
Sodium periodate (512 mg, 2.39 mmol) was dissolved in water (10 ml) and cooled to 0° C. 4-(2-Dimethylaminoethylthio)benzaldehyde (0.5 g, 2.39 mmol), prepared as described in Reference Example 2, was then added in methanol (2 ml) and the reaction mixture stirred at room temperature and then later warmed to 35° C. After 7 hours the reaction mixture was basified using sodium carbonate and exhaustively extracted with dichloromethane, dried over magnesium sulphate and the solvent removed in vacuo to yield the title compound as an oil in a yield of 53%.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28]([OH:30])=[O:29].C(=O)([O-])[O-].[K+].[K+].Cl>C1(C)C=CC=CC=1.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.C(O)C>[F:34][C:33]1[C:32]([C:16]2[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: OB(O)c1ccccc1-c1ccccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(F)c(-c2ccccc2-c2ccccc2OCc2ccccc2)c1
Temperature: 90 °C

Procedure:
{2′-[(phenylmethyl)oxy]-2-biphenylyl}boronic acid (60 mg, 0.19 mmol) and 3-bromo-4-fluorobenzoic acid (69 mg, 0.31 mmol) were dissolved in 1:1 toluene:ethanol (6 ml) under nitrogen. Potassium carbonate (290 mg, 2.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.019 mmol) were added and the mixture heated at 90° C. for 1 h. After cooling, the reaction mixture was poured into water, acidified with 1M HCl solution and extracted with ethyl acetate (15×2 ml), the combined organic layer were dried and evaporated. The residue was then purified on an SPE column using 40% of ethyl acetate in iso-hexane to give the title compound as white solid.
Reaction SMILES: C(O[C:6](=[O:35])[NH:7][CH:8]([CH3:34])[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:33])[NH:18][CH:19]1[CH2:23][C:22](=[O:24])[O:21][CH:20]1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:10])(C)(C)C.[C:36]([NH:39][C:40]1[CH:48]=[CH:47][C:43](C(O)=O)=[CH:42][C:41]=1[Cl:49])(=[O:38])[CH3:37].O=C1OC(OCCC2C=CC=CC=2)C(NC(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)C1>>[CH2:26]([O:25][CH:20]1[CH:19]([NH:18][C:17]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][N:11]2[C:9](=[O:10])[CH:8]([NH:7][C:6](=[O:35])[C:43]2[CH:47]=[CH:48][C:40]([NH:39][C:36](=[O:38])[CH3:37])=[C:41]([Cl:49])[CH:42]=2)[CH3:34])=[O:33])[CH2:23][C:22](=[O:24])[O:21]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1Cl
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(=O)Nc1ccc(C(=O)NC(C)C(=O)N2CCCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1Cl
Yield: 47 %

Procedure:
Prepared from {2-[2-(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-piperidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert butyl ester and 4-acetylamino-3-chlorobenzoic acid by the procedure used in the preparation of 98a to give the title compound (71 mg, 47% yield). 1H-NMR (500 MHz, CDCl3) δ 1.10-1.97 (m, 10H), 2.10-2.68 (m, 5H), 2.73-3.24 (m, 2H), 3.62-3.92 (m, 1H), 4.24-5.27 (m, 5H), 5.48-5.59 (m, 0.5H), 5.75-5.85 (m, 0.5H), 6.51-6.61 (d, 1H), 7.05-7.45 (m, 4H), 7.52-8.12 (m, 4H). Analytical HPLC 8.30 min. LC-MS (ES+) m/e=585.3 (MH+).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][N:14]=1>C1COCC1>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[CH2:8][O:18]2)=[CH:15][N:14]=1
Reactant: C[S+](C)C
Reactant: Cc1ccc(C=O)cn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccc(C2CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 137.9 %

Procedure:
DMSO (4 mL) was added to NaH 60% dispersion in oil (0.314 g, 7.8 mmol, 1.3 eq.) and heated it to 65° C. for 1 h. THF (10 mL) was added at the same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1.2 g, 5.9 mmol, 1 eq.) was added and stirred for 10 min and solution of 6-methylnicotinaldehyde (0.720 g, 5.9 mmol, 1 eqv) in THF was added dropwise. After complete of addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get product 2-methyl-5-(oxiran-2-yl)pyridine (1.1 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([N:37]3[CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)N3CCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=O)N3CCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-pyrrolidinocarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14](I)=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+]>CN(C)C=O.O>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([C:20]#[N:21])=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(I)nc2sc(SCc3ccccc3)nn12
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(=O)n2nc(SCc3ccccc3)sc2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
In 120 ml of dimethylformamide, 9 g of 90% pure 2-benzylthio-7-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved, and 3.05 g of cuprous cyanide and 1.57 g of sodium cyanide were added thereto. The reaction mixture was heated to 100° C. and stirred at that temperature for 1 hour. After the reaction was finished, the reaction mixture was cooled, diluted with water and extracted with chloroform. The organic layer was washed with water, and the chloroform was distilled off. Water was added to the residue and the mixture was extracted with toluene. The organic layer was washed with water and dried over anhydrous sodium sulfate. Florisil® was added to the dried organic layer, and the organic layer was shaken well. After the Florisil® was separated, the solvent was distilled off, and thus 3.0 g of 2-benzylthio-7-cyano-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 50%. (Florisil® (a registered trademark of Floridin Company) is a highly selective magnesium silicate absorbent.)
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[OH:1][CH:2]([CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC(O)CN1CCCC1
Temperature: 70 °C
Yield: 36.3 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.27 mmol), (prepared as described for the starting material in Example 162), and pyrrolidine (67 μl, 0.8 mmol) in DMF (4 ml) was heated at 70° C. for 24 hours. The solvent was removed by evaporation and the residue purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1). The relevant fractions were evaporated to dryness then the residue treated with a little dichloromethane and dried under high vacuum to give 7-(2-hydroxy-3-pyrrolidin-1-ylpropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (44 mg, 37%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([NH2:27])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=1.[O:28]=[C:29]1[NH:33][CH2:32][C@@H:31]([C:34](O)=[O:35])[CH2:30]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([NH:27][C:34]([C@H:31]3[CH2:30][C:29](=[O:28])[NH:33][CH2:32]3)=[O:35])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: C[C@@H](OCc1cc(Cl)cc(-c2cc(N)nn2-c2ccccc2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H](OCc1cc(Cl)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccccc2)c1)C(F)(F)F
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of 5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine (79 mg) in N,N-dimethylacetamide (1.0 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (31 mg) prepared according to the same procedures as Preparation 14 and WSC.HCl (47 mg) at room temperature, and the mixture was stirred overnight. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. This solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration and was dried under reduced pressure to give the titled compound (60 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:7]([C:8]([O:10]C)=[O:9])[C:6](=[O:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[S:3]1(=[O:18])=[O:17].[OH-].[Na+].Cl>O>[CH3:1][N:2]1[CH:7]([C:8]([OH:10])=[O:9])[C:6](=[O:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[S:3]1(=[O:17])=[O:18]
Reactant: COC(=O)C1C(=O)c2ccccc2S(=O)(=O)N1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1C(C(=O)O)C(=O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (50 g.) is added to a solution of sodium hydroxide (160 g.) in water (500 ml.) at 70° C. The resulting lemon-yellow slurry is then heated at 90°-95° C. for 45 minutes and then cooled to room temperature is an ice-water bath. The pH of the reaction mixture is adjusted to 1-1.5 by gradual addition of concentrated hydrochloric acid (350 ml.). Ice chips are added as necessary to keep the temperature below 35° C. The acid product precipitates and is granulated by stirring at 10°-15° C. for 15 minutes. It is recovered by suction filtration, washed with water (100 ml.) and reslurried in water (250 ml.) for a half hour to remove excess hydrochloric acid. It is again filtered with suction and washed with water (100 ml.). Twenty-five grams of the wet filter cake (total wet filter cake is 25.5 g.) is dissolved in warm methanol (150 ml.), the solution filtered and water (50 ml.) added to the filtrate. The addition of seed crystals causes immediate precipitation of product. The slurry is granulated by stirring at about 10° C. for a half hour. The white crystalline product is separated by filtration, washed with water and air-dried. Yield = 13.2 g., M.p. 144°-146° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:24][CH2:25][N:26]([S:48]([C:42]3[C:43]([Cl:47])=[CH:44][CH:45]=[CH:46][C:41]=3[Cl:40])(=[O:50])=[O:49])[CH2:27][CH2:28]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3c(Cl)cccc3Cl)CC2)c1C
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 77.2 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 102 mg, 0.237 mmol) and N,N-diisopropylethylamine (124 μL, 0.711 mmol) in methylene chloride (6.0 mL) was added 2,6-dichlorobenzenesulfonyl chloride (116 mg, 0.47 mmol). After stirring for ˜25 minutes at 0° C., the light yellow reaction mixture was allowed to warm to room temperature and then was stirred for 6.5 hours at room temperature under nitrogen. During this time, some solvent had evaporated. Methylene chloride (˜10 mL) and water (˜25 mL) were added and the mixture was extracted with methylene chloride (2×25 mL). The combined extracts were washed with brine solution, dried over anhydrous MgSO4, filtered, concentrated, and purified by silica gel chromatography (eluting with 25% ethyl acetate/hexanes) to give {4-[1-(2,6-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (96 mg, 77%) as a light yellow product. MS cald. for C25H25Cl2FNO4S [(M+H)+]: 524, obsd. 524.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=[O:28])([O-])[O-:26].[Na+].[Na+]>O.O1CCCC1.ClC(OCC1C=CC=CC=1)=O.C(OCC)(=O)C>[CH2:14]([O:26][C:25]([N:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1)[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:28])[C:15]1[CH:24]=[CH:23][CH:18]=[CH:17][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(CNCCCCNC(=O)OC(C)(C)C)cc1
Agent: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(CCCCNC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 204.8 %

Procedure:
To a solution of the compound 3 (810 mg) and sodium carbonate (383 mg) in water (5 mL) and tetrahydrofuran (2 mL), benzyl chloroformate (413 μl) was added at 0° C. The reaction mixture was stirred at 0° C. for one hour. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:1) to obtain the title compound (1.16 g) having the following physical properties.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Br[C:16]1[CH:17]=[C:18]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH2:33][CH:32]([CH3:34])[O:31][CH:30]([CH3:35])[CH2:29]2)=[CH:26][CH:27]=1)=[O:20].C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O.O.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>[CH3:34][C@H:32]1[CH2:33][N:28]([C:25]2[N:24]=[CH:23][C:22]([NH:21][C:19]([C:18]3[C:17]([CH3:16])=[C:39]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)[CH:38]=[CH:37][CH:36]=3)=[O:20])=[CH:27][CH:26]=2)[CH2:29][C@@H:30]([CH3:35])[O:31]1
Reactant: Cc1ccc(C(=O)Nc2ccc(N3CC(C)OC(C)C3)nc2)cc1Br
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1c(C(=O)Nc2ccc(N3C[C@@H](C)O[C@@H](C)C3)nc2)cccc1-c1ccc(OC(F)(F)F)cc1
Temperature: 130 °C
Yield: 61 %

Procedure:
A mixture of 4-(trifluoromethoxy)phenylboronic acid (254 mg, 1.24 mmol), 3-bromo-N-[6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-4-methyl-benzamide 5 (250 mg, 0.62 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol), Na2CO3 (2.0M aqueous solution, 1.23 mL, 2.4 mmol) and DME (4.5 mL) in a sealed tube was heated at 130° C. overnight. The reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine and concentrated to give the crude product which was then purified by preparative mass triggered HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4′-(trifluoromethoxy)biphenyl-3-carboxamide (183.5 mg, 61.1% yield). LC-MS m/z: 486.2 (M+1).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12])=[O:5])C.[OH-].[Na+].Cl>CO.O>[CH3:12][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1CCCCN1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCCCC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-piperidine-2-carboxylic acid ethyl ester (5.1 g) was dissolved in a mixture of 100 ml methanol and 10 ml water. NaOH (8 g) was added and the reaction mixture was stirred at room temperature overnight. The solution was then neutralized with hydrochloric acid, evaporated to dryness, and evaporated four times with toluene. The resulting powdery residue was used directly in the next step.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([O-:7])=[O:6].[OH-].[Na+]>C(O)C>[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:3][CH2:2][Br:1])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: BrCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(OCCBr)cc1
Yield: 50.8 %

Procedure:
1,2-Dibromoethane (24.4 g, 0.13 mol) and 4-nitrophenol (6 g, 0.044 mol) were dissolved in ethyl alcohol (60 ml) and sodium hydroxide (2 g) was added to the solution. The reaction mixture was refluxed for 24 h and thereafter concentrated under vacuum, followed by column chromatography using a 3:1 solvent system of n-hexane and ethyl acetate as an eluent to yield the end compound 1-(4-nitrophenoxy) -2-bromoethane (5.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19](I)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:22]([NH:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([C:19]2[N:18]=[CH:17][N:16]([C:11]3[N:12]=[C:13]([CH3:15])[CH:14]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[N:10]=3)[CH:20]=2)[CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
N-tert-Butyl-3-{1-[6-(3,4-dichloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(3,4-dichloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.74) (0.37 g, 0.86 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.33 g, 1.29 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.23 g) which was subsequently deprotected.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].[ClH:16]>CN(C)C=O>[ClH:16].[N:1]1[CH:2]=[CH:3][C:4]([CH:7]=[C:11]([C:10](=[O:15])[CH3:9])[C:12](=[O:14])[CH3:13])=[CH:5][CH:6]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)C(=Cc1ccncc1)C(C)=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution containing 1.1 g of pyridine-4-carboxaldehyde and 1.0 g of 2,4-pentanedione in 10 ml of N,N-dimethylformamide was saturated with hydrogen chloride gas at 20° C. The solution was stirred for 1 h at 20° C. and then for 2 h at 80° C. The solvent was evaporated in vacuo and the residue was crystallized from ethanol. Yield 0.17 g, mP 175°-186° C.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.CO[NH2:10].[Cl:11][C:12]1[CH:13]=[C:14]([C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16]>CN(C=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:10][C:19]1[C:18]([N+:21]([O-:23])=[O:22])=[C:14]([CH:13]=[C:12]([Cl:11])[CH:20]=1)[C:15]([OH:17])=[O:16]
Reactant: CON
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Cl)cc(C(=O)O)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 60.5 %

Procedure:
To a mixture of potassium tert-butoxide (38.9 g, 0.347 mol) and copper-(II) acetate monohydrate (0.9 g, 4.96 mmol) in DMF (160 ml) was added a solution of O-methylhydroxylamine hydrochloride (8.3 g, 99.3 mmol) and 3-chloro-6-nitrobenzoic acid (69; 10 g, 49.6 mmol) in DMF (160 ml) at 0° C. The resulting reaction mixture was stirred at that temperature for 3 h. It was then quenched with water, acidified with 10% HCl and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was taken up in EtOAc and extracted with 10% aqueous NaOH. The combined aqueous layers were acidified with concentrated HCl to a pH=3 and then extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 3-amino-5-chloro-2-nitrobenzoic acid 70 (6.5 g, 60.5%) as a brown red solid.