Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[N:11](OCCC(C)C)=[O:12].C[O-].[Na+]>CO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[N:11][OH:12])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CC(C)CCON=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(C=NO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
19.9 g of 4-bromoacetophenone are placed in 150 ml of methanol under nitrogen, and 14.7 ml of isopentyl nitrite are added. To the resulting solution there are then added dropwise, at 17-23° C., 22.2 ml of a 5.4M solution of sodium methanolate in methanol. After 70 hours' stirring at room temperature the orange suspension is concentrated using a rotary evaporator. 300 ml of water are added to the residue, and the mixture is rendered acidic with 60 ml of 2N hydrochloric acid. The resulting yellow suspension is filtered and washed with water; the filter cake is taken up in ethyl acetate and washed with water. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is recrystallised from ethyl acetate/toluene. In this way (4-bromophenyl)-oxoacetaldehyde oxime is obtained in the form of a colourless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][NH:25][CH:26]=4)[N:19](S(C4C=CC=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H-].[Na+].CS(O[CH:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1)(=O)=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][N:25]([CH:43]5[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]5)[CH:26]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(CCc2cnc3c(cc(-c4cn[nH]c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: CN1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(C5CCN(C)CC5)c4)cc3n2)cc(OC)c1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 4.8 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-6-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (from Example 35, Step 1, 50.0 mg, 0.102 mmol) in N,N-dimethylformamide (2.0 mL), sodium hydride (6.13 mg, 0.153 mmol) was added at 0° C. After 15 minutes, a solution of 1-methylpiperidin-4-yl methanesulfonate (23.7 mg, 0.122 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was then warmed up to 55° C. After 2 hours, the reaction was quenched with water, and extracted with methylene chloride. The combined organic layers were dried over MgSO4, then filtered and concentrated. The crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (2.2 mg) as its TFA salt. LCMS calculated for C25H31N6O2 (M+H)+: m/z=447.3. Found: 447.3.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:24]([CH3:35])[C:25](=[O:34])[C:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)[CH2:21][CH2:22][CH3:23].[Br:36]C(Br)(Br)Br>C(Cl)Cl>[Br:36][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:25]([N:24]([CH2:20][CH2:21][CH2:22][CH3:23])[CH3:35])=[O:34]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCN(C)C(=O)C#CCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)C#CCCCCCBr
Temperature: -10 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
1.205 g of triphenyl phosphine were added to a solution of 855 mg of the product of Step D in 4 ml of methylene chloride and the mixture was cooled to -10° C. 1.522 g of tetrabromomethane were added, and after stirring for one hour at -5° C., the reaction mixture was chromatographed on silica (eluant: cyclohexane-ethyl acetate 35-65) to obtain 0.98 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C:43]1([CH3:50])[O:47][C@@H:46]([CH2:48]O)[CH2:45][O:44]1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C(OCC)(=O)C.C1COCC1>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[C:19]([O:21][CH2:48][C@H:46]5[CH2:45][O:44][C:43]([CH3:50])([CH3:42])[O:47]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Reactant: CC1(C)OC[C@H](CO)O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
Under nitrogen atmosphere, 3-bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ2, 356 mg, 1.00 mmol) and triphenylphosphine (317 mg, 1.2 eq.) were added with THF (3 ml), followed by dropwise addition of ((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (148 μl, 1.2 eq.) and diisopropyl azodicarboxylic acid (252 μl, 1.3 eq.). The mixture was then stirred at 50° C. for 2 hr. After cooling, the reaction solution was added with ethyl acetate, washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting residues were purified by silica gel column chromatography (ethyl acetate/dichloromethane) to yield the solid, which was then washed with dichloromethane to obtain the title compound (white powder, 241.6 mg, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[N:17]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:29][CH:28]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Nc1ccc(CN2CCCCC2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CN2CCCCC2)cc1
Temperature: 115 °C
Yield: 84.6 %

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (100 mg, 0.350 mmol) and 4-piperidin-1-ylmethyl-phenylamine (67 mg, 0.35 mmol) are suspended in 5 ml of dimethylformamide. Mixture is heated at 115° C. for 2 hours forming a homogeneous mixture. Mixture is cooled to room temperature and concentrated on high vacuum to yield an orange oil. Residue is taken up in ethyl ether causing an orange solid to form. Mixture is filtered, and residue washed with 50 ml of ethyl ether to afford the product as an orange solid (130 mg, 0.296 mmol, 85%); 1H NMR (DMSO-d6) δ 1.37-1.52 (m, 6H), 2.25-2.36 (m, 4H), 3.40 (s, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.39 (dd, J=1.6, 8.4 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.4 Hz, 1H), 8.44 (d, J=1.6 Hz, 1H), 8.92 (d, J=12.8 Hz, 1H), 11.39 (s, 1H), 12.50 (d, J=12.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:37]1[C:33](=[O:43])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36]1=[O:38])=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CCl)c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 95.2 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-4-(2-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone (4.27 g, 9.5 mmol) and potassium phthalimide (2.65 g, 14.3 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-[[6-benzyloxy-4-(2fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (5.07 g, 95.3%) as an amorphous.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(N(CC)C(C)C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[C:3]([F:9])[CH:4]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1ccc(N)cc1F
Temperature: 110 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
4-Bromo-3-fluoroaniline (5.0 g) was dissolved in a mixed solvent of DMF (18 ml) and N,N-diisopropylethylamine (18 ml). Ethyl acrylate (3.9 ml), palladium acetate (295 mg), and tris(2-methylphenyl) phosphine (3.2 g) were added to the obtained mixture in a nitrogen atmosphere, and the mixture was stirred at 110° C. for 5 hours. The reaction mixture was filtered through Celite and separated with ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (14-25% ethyl acetate/n-hexane). The purified material was crystallized with n-hexane to obtain Compound 2a (4.2 g, 76%) as a yellow solid.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](O)([CH3:32])[CH3:31])=[CH:29][C:24]=2[O:23][CH2:22]1>C1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]([S:1][CH2:2][C:3]([OH:5])=[O:4])([CH3:32])[CH3:31])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: O=C(O)CS
Reactant: CC(C)(O)c1ccc2c(c1)OCO2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Product: CC(C)(SCC(=O)O)c1ccc2c(c1)OCO2
Yield: 45.8 %

Procedure:
600 ml of benzene, 59.5 g of mercaptoacetic acid and a catalytic amount of D-10-camphorsulfonic acid were added to 97 g of 2-(1,3-benzodioxol-5-yl)-2-propanol. The obtained mixture was heated under reflux for 4 hours and distilled to remove the solvent. The pH of the residue was adjusted to 10 with a 1N aqueous solution of sodium hydroxide. The resulting mixture was washed with ethyl acetate. 4N hydrochloric acid was added to the mixture under cooling with ice to acidify the aqueous layer. The resulting mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain a crude crystal. This crude crystal was recrystallized from diisopropyl ether to obtain 62.70 g of the title compound as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[CH:32]([O:31][C:29]([N:25]1[CH2:24][CH2:23][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])[N:13]=[CH:14][C:15]=23)[CH2:27][CH2:26]1)=[O:30])([CH3:34])[CH3:33]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 mL round-bottom flask was placed 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (80 mg, 0.2 mmol) and triethylamine(200 μl). DMF (3 mL) was added to completely dissolve the solid material. The reaction flask was immersed in an ice-bath. Isopropyl chloroformate (1.0M in toluene, 0.22 mL) was added to the solution and the mixture was stirred 2 h under N2 at 0° C. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was then concentrated under vacuum and purified by preparative HPLC to give 4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (Compound A129). 1H NMR (CDCl3, 400 MHz) δ 1.27 (d, 6H), 1.9 (m, 2H), 2.12 (m, 2H), 3.13 (s, 3H), 3.40 (m, 2H), 3.91 (m, 2H), 4.97 (m, 1H), 5.63 (m, 1H), 7.95 (m, 3H), 8.34 (s, 1H), 8.63 (s, 1H). Exact mass calculated for C21H24FN5O5S: 477.15, found 478.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH2:24][OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=2)[C:11]([CH3:27])([CH3:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH:24]=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=2)[C:11]([CH3:26])([CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(CO)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCC(C=O)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.1 %

Procedure:
A solution of 7-(1-hydroxymethyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (1.27 g, 3.38 mmole) in 10 mL of dichloromethane was added to a suspension of 1.1 g of pyridinium chlorochromate in 15 mL of dichloromethane. The reaction mixture was stirred at room temperature for 6 hours, diluted with 50 mL of ether and filtered through a pad of Celite. The volatiles were removed in vacuo to give a brown oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to yield 0.91 g of 7-(l-formyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-])=O>C(OCC)(=O)C.[Pd].C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1N
Reaction time: 3 h

Procedure:
A mixture of methyl 2-(2-nitro-4-trifluoromethylphenoxy)benzoate (12.7 g, 0.0373 mol) was dissolved in ethyl acetate (200 ml) and 10% palladium on carbon was added under argon. The mixture was hydrogenated in a parr bottle at 55 psi for three hours. The mixture was diluted with chloroform, filtered through Celite® and the filtrate evaporated. The residue was flash chromatographed (silica gel, ethyl acetate/hexane) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35](O)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C>ClCCl>[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:18][CH:19]=1)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(COC(=O)c2ccc(O)cc2)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(COC(=O)c2ccc(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)cc2)cc1

Procedure:
4-Methoxybenzyl 4hydroxybenzoate was acylated with N-benzyloxycarbonyl-L-valine by the method described in Example A-I-1, step b. The title compound (2.71 g) was obtained after silica gel column chromatography (0, 1% ethanol in dichloromethane). Rf (2%MeOH/CHCl3) 0.70.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:18]2[CH:19]=[CH:20][C:21]([C:2]3[C:3]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=3)=[CH:22][C:17]=2[F:16])=[CH:33][N:34]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: NS(=O)(=O)c1cc(C(F)(F)F)ccc1Br
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3S(N)(=O)=O)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-bromo-5-(trifluoromethyl)benzenesulfonamide and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C17H12F4N4O2S, 412.06; m/z found, 413.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.56-8.53 (d, J=1.4, 2H), 8.43-8.40 (m, 1H), 7.98-7.92 (d, J=7.7, 1H), 7.63-7.58 (d, J=8.0, 1H), 7.58-7.52 (m, 1H), 7.37-7.35 (m, 1H), 7.35-7.32 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C([C@@]23C(C)(C)[C@@](C)(CC2)C(=O)O3)=O)=[C:4]([C@@:22]([OH:32])([C:27]#[C:28][CH:29]2[CH2:31][CH2:30]2)[C:23]([F:26])([F:25])[F:24])[CH:3]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C@@:22]([OH:32])([C:27]#[C:28][CH:29]2[CH2:31][CH2:30]2)[C:23]([F:25])([F:26])[F:24])[CH:3]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F
Temperature: 92.5 °C
Reaction time: 20 h

Procedure:
A suspension of (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10, 1 g, 2.13 mmol) and 40% NaOH aqueous solution (20 mL) was stirred at 90-95° C. for 20 hours. Toluene (20 mL) was added and the layers were separated. The organic layer was washed with water (20 mL) and evaporated to dryness to give (S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)aniline (8). 1H NMR (CDCl3) δ 7.54 (s, 1H), 7.12 (dd, J=8.5, 1.5 Hz, 1H), 6.62 (d, J=8.6 Hz, 1H), 4.47 (br. s, 3H), 1.44-1.35 (m, 1H), 0.93-0.88 (m, 2H), 0.83-0.80 (m, 2H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](/[CH:19]=[CH:20]/OC)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C.BrN1C(=O)CCC1=O.[CH3:31][O:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([NH2:42])[CH:37]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[CH3:31][O:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][N:39]2[C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[CH:20][N:42]=[C:38]2[CH:37]=1
Reactant: COCCOc1ccnc(N)c1
Reactant: CO/C=C/c1ccc2cccc(O[Si](C)(C)C(C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1CCC(=O)N1Br
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
(E)-8-(tert-butyldimethylsilyloxy)-2-(2-methoxyvinyl)quinoline (1.90 g, 6.02 mmol) was dissolved in a solution of THF (20 mL) and water (3 mL). N-bromosuccinimide (1.13, 6.32 mmol) was added to the reaction mixture. After the reaction was judged to be complete (monitored by MS), 4-(2-methoxyethoxy)pyridin-2-amine 1.01 g, 6.02 mmol) was added. The reaction was then heated to reflux for 5 hours and then cooled to ambient temperature. To the reaction mixture was added 10 ml of 1.0 M tetrabutylammonium fluoride in THF. The reaction mixture was stirred at ambient temperature for 1 hour and then diluted with water. The mixture was extracted with 1:4 isopropyl acetate:dichloromethane. The combined organic phase was dried (sodium sulfate), filtered and condensed under reduced pressures. The residue was purified by flash chromatography, eluting with gradient from 100% EtOAc to 10% MeOH (w/6% NH4OH)/EtOAc to obtain 700 mg of the desired product as a red solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cccc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepared according to the method described in Example 24a) from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 4-hydrochloride (0.764 g), 4-dimethylaminopyridine (0.488 g), morpholine (0.35 ml) and a solution of 3-bromophenylacetic acid (0.43 g) in dichloromethane (10 ml). The mixture was stirred overnight at room temperature. The reaction mixture was washed with 2M hydrochloric acid (3×100 ml), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The sub-title compound was obtained as a solid (0.550 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23]Br)[CH:7]=1)[CH3:2].[CH3:26][C:27]([SH:30])([CH3:29])[CH3:28]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][S:30][C:27]([CH3:29])([CH3:28])[CH3:26])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Reactant: CC(C)(C)S
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CSC(C)(C)C)c1

Procedure:
As described for Example 21, [3-(2-bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and 2-methyl-2-propanethiol were reacted to provide [3-(2-tert-butylsulfanylmethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-tert-butylsulfanylmethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester. The amine was treated with trimethylacetyl chloride to provide {3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-chloro-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided the acid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([NH:20][C:21](=[O:32])[NH:22][C:23]1[CH:24]=[C:25]([C:29]([OH:31])=O)[S:26][C:27]=1[CH3:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:40][C:29]([C:25]1[S:26][C:27]([CH3:28])=[C:23]([NH:22][C:21]([NH:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:32])[CH:24]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1sc(C(=O)O)cc1NC(=O)NCc1ccccc1
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1sc(C(=O)NCc2ccccc2)cc1NC(=O)NCc1ccccc1
Yield: 96.6 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (0.24 g, 1.7 mmol), 4-(3-benzyl-ureido)-5-methyl-thiophene-2-carboxylic acid from Step 3 (0.27 g, 0.9 mmol), and benzyl amine (0.1 g, 0.9 mmol) to afford 0.33 g of 4-(3-benzyl-ureido)-5-methyl-thiophene-2-carboxylic acid benzylamide. A sample of the crude product was stirred in 2 M aqueous KHCO3 for several hours, filtered off, rinsed with water, dried, and recrystallized from methanol to give product with a mp 180-181° C.