Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][CH2:9][NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[C:25]([NH:27][C:28]3[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=3)[CH:24]=[C:23]([CH3:38])[CH:22]=2)=[CH:17][N:16]=1)=[O:12]>C1COCC1>[CH3:38][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:13]3[CH2:8][CH2:9][NH:10][C:11]3=[O:12])=[N:16][CH:17]=2)[CH:26]=[C:25]([NH:27][C:28]2[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=2)[CH:24]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CNC(=O)NCCCl)nc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CN3CCNC3=O)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium tert-butoxide (34.3 mg, 0.305 mmol) was added to a solution of 1-(2-chloroethyl)-3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]methyl}urea (129 mg, 0.277 mmol) in THF (4.62 mL). The reaction mixture was stirred at room temperature overnight under an argon atmosphere. An additional equivalent of potassium tert-butoxide was added to the reaction. The solvent was removed under reduced pressure and the residue was directly purified by reverse phase HPLC (10-75% acetonitrile in water+0.5% TFA). The isolated fractions were partitioned between 10% IPA/chloroform and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]methyl}imidazolidin-2-one. MS APCI calc'd for C21H20F3N6O [M+H]+ 429. found 429. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.05-7.83 (m, 2H), 7.55 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.27 (d, J=4.9 Hz, 1H), 7.18 (s, 1H), 6.47 (s, 1H), 4.36 (s, 2H), 3.38-3.44 (m, 4H), 2.35 (s, 3H).
Reaction SMILES: C(O[C:4](=O)[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1Br)C.C(N(CC)CC)C.[CH3:25][Si:26]([C:29]#C)([CH3:28])[CH3:27].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOCC>[F:13][C:12]([F:15])([F:14])[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:5][C:4]#[C:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:11]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)Nc1cc(C(F)(F)F)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)C#CNc1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Following the procedure described in J. Org. Chem. 1997, 62, 6507, combine N-(2-bromo-5-trifluoromethylphenyl)carbamic acid ethyl ester (34.33 g, 110 mmol), triethylamine (300 mL), dichlorobis (triphenylphosphine)palladium(II) (5.4 g, 7.7 mmol), and copper (I) iodide (1.47 g, 7.7 mmol). Evacuate the dark solution and fill with N2 twice and then quickly add (trimethylsilyl)acetylene (16.21 g, 165 mmol, 23.32 mL) with vigorous stirring. Heat to 80° C. When TLC indicates absence of the starting material, add water and Et2O and filter through celite and evaporate the filtrate in vacuo to give a residue. Dilute residue with water and extract with Et2O, combine the organic layers and remove the evaporate to give a dark brown oil. Absorb the oil onto silica gel and load onto a short column of silica gel equilibrated with 100% hexanes. Wash with 100% hexanes (2 L) and elute the product with 1% EtOAc in hexanes. Pool fractions containing the product and remove in vacuo the solvent to give 5-trifluoromethyl-2-trimethylsilanylethynyl phenylamine as a red/brown oil; MS (IS): m/z 330 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[C:9]([N+:27]([O-])=O)[CH:8]=1)[CH:2]([CH3:4])[CH3:3].Cl.C(OCC)(=O)C>O1CCCC1>[CH2:1]([N:5]([CH2:6][C:7]1[CH:8]=[C:9]([NH2:27])[C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[CH:11][CH:12]=1)[CH2:31][CH:32]([CH3:34])[CH3:33])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)CCc2ccncc2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CN(Cc1ccc(NCCCN(C)CCc2ccncc2)c(N)c1)CC(C)C
Temperature: 0 °C

Procedure:
A molar solution of borane-tetrahydrofuran complex (6.25 ml, 15 eq) is added dropwise to a solution of N,N-diisobutyl-4-({3-[methyl(2-pyridin-4-ylethyl)amino]propyl}amino)-3-nitrobenzamide (200 mg, 1 eq) in tetrahydrofuran (3 ml) cooled down to 0° C. The mixture is heated under reflux for 20 hours then cooled down to 0° C. and hydrolysed with a 6N aqueous solution of hydrochloric acid (12 ml). After 1 hour 30 minutes under reflux, the mixture is cooled down to 0° C. and brought to basic pH by a 6N aqueous solution of soda. After adding ethyl acetate, decanting and extracting, the organic phases are combined, followed by washing with salt water, drying over sodium sulphate and evaporating under reduced pressure. Purification by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 8:2) produces the expected compound in the form of an oil (92 mg, 51% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]=[N:7][C:6]=2[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20](=[O:28])[CH2:21][CH2:22][C:23]([O:25]CC)=[O:24].C(OCC)(=O)CCC(OC1C2C=C(C3C=CC=CC=3)N=NC=2N(C)C(=O)C=1)=O.C([O-])(=O)C.[Na+].[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:1][C:2]1[C:11]2[CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]=[N:7][C:6]=2[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20](=[O:28])[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)CCC(=O)c1c(O)c2cc(-c3ccccc3)nnc2n(C)c1=O
Agent: CC(=O)[O-]
Agent: CCOC(=O)CCC(=O)Oc1cc(=O)n(C)c2nnc(-c3ccccc3)cc12
Agent: [Al+3]
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2cc(-c3ccccc3)nnc21

Procedure:
Ethyl 4-(5-hydroxy-8-methyl-7-oxo-3-phenyl-7,8-dihydropyrido[2,3-c]pyridazin-6-yl)-4-oxobutanoate. The title compounds is prepared by rearrangement of ethyl 8-methyl-7-oxo-3-phenyl-7,8-dihydropyrido[2,3-c]pyridazin-5-yl succinate using sodium acetate according to literature procedures. Alternatively, the title compound is prepared by rearrangement of ethyl 8-methyl-7-oxo-3-phenyl-7,8-dihydropyrido[2,3-c]pyridazin-5-yl succinate using aluminum chloride according to that described in Method 4 (step c).
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].C(=O)([O-])O.[Na+].[Cl:19][C:20]([Cl:27])([Cl:26])[CH2:21][O:22][C:23](Cl)=[O:24]>O>[Cl:19][C:20]([Cl:27])([Cl:26])[CH2:21][O:22][C:23]([NH:5][C@@H:4]1[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@@H:10]([CH2:12][OH:13])[O:11][CH:3]1[OH:2])=[O:24]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)OCC(Cl)(Cl)Cl
Reaction time: 11 h

Procedure:
Thirty grams of D-glucosamine hydrochloride was dissolved in 500 ml of water, and 30.0 g of sodium hydrogen carbonate was added thereto, followed by cooling in an ice bath. To the cooled solution was added 27.5 ml of trichloroethoxycarbonyl chloride, and the mixture was stirred under ice-cooling for 2 hours and then at room temperature for 11 hours. The precipitate was collected by filtration, washed successively with water and diethyl ether, and recrystallized from 95% ethanol to obtain 42.3 g of N-trichloroethoxycarbonyl-D-glucosamine (Compound A) having a melting point of 183° to 184° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([CH3:14])[NH:11][C:10]=2[C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C.C(=O)([O-])O.[Na+]>[CH2:27]([N:13]1[C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:20])=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:10]=2[N:11]=[C:12]1[CH3:14])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCc1ccc2nc(C)[nH]c2c1C(=O)OC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCc1ccc2c(nc(C)n2Cc2ccccc2)c1C(=O)OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
To a solution of methyl 6-(3-methoxy-3-oxopropyl)-2-methyl-1H-benzimidazole-7-carboxylate (417 mg, 1.51 mmol) in acetonitrile (15 mL) were added potassium carbonate (62.6 mg, 0.453 mmol) and benzyl bromide (269 μL, 2.26 mmol), and the mixture was stirred at 80° C. for 3 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (164 mg, yield 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.C(N(CC)CC)C.P(Cl)(Cl)([Cl:22])=O.O>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:22][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: Cc1ccc2nc[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2ncnc(Cl)c2c1
Reaction time: 3 h

Procedure:
6-Methyl-3H-quinazolin-4-one (1.1 g, 6.9 mmol) is dissolved in toluene (70 mL). To the solution is added triethyl amine (1.82 g, 18 mmol) and P(O)Cl3 (1.06 g, 6.9 mmol). The solution is heated to reflux. After 3 h, the solution is poured into water (100 mL). The solution is diluted with EtOAc (200 mL). The layers are separated. The organic layer is washed with water, saturated NaHCO3 (aq.) and saturated NaCl (aq.). The organic layer is dried over MgSO4, filtered and concentrated. The title compound is obtained as an oil (0.75 g, 4.2 mmol).
Reaction SMILES: C[O:2][C:3](=[O:55])[CH2:4][N:5]([C:16](=[O:54])[C@@H:17]([NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:18][C:19]1[N:20]=[CH:21][N:22]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=1)[CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CO.O.[OH-].[Na+]>O1CCCC1>[CH2:47]([O:46][C:44]([NH:43][C@@H:17]([CH2:18][C:19]1[N:20]=[CH:21][N:22]([C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=1)[C:16]([N:5]([CH2:4][C:3]([OH:55])=[O:2])[CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[O:54])=[O:45])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: COC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCN(CC(=O)O)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
The product from Step 2 (1.8 g, 2.4 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL) and water (2 mL). Sodium hydroxide (0.192 g, 4.8 mmol) was added and the mixture stirred overnight at room temperature. The solution was concentrated in vacuo and the residue taken up in 0.1 M NaPO4 buffer (100 mL). The pH was brought to 6 by the addition of 1N HCl. The product was extracted three times with ethyl acetate. The ethyl acetate was washed twice with brine, dried over MgSO4, filtered and concentrated in vacuo to give a white powder; 1.3 g (74% yield). MS-APCI: M+1=732.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N+:11]=2[O-:16])=[N:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:25])C=1.CO>C(Cl)(Cl)Cl>[N+:1]([C:4]1[S:8][C:7]([S:9]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N+:11]=2[O-:16])=[O:25])=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cnc(Sc2cncc[n+]2[O-])s1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnc(S(=O)c2cncc[n+]2[O-])s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a stirred solution of 1.0 g (0.004 mol) of Compound 2 in 50 ml of chloroform was gradually added 2.0 g (0.010 mol) of 85% m-chloroperbenzoic acid. The reaction mixture was stirred overnight at room temperature and then filtered. The filtrate was washed with water, dilute bicarbonate and brine, and dried over MgSO4. Evaporation of the solvent afforded a yellow oil that solidified on standing. This crude product was recrystallized from CHCl3 /hexane and a second crop of crystals was recrystallized from methanol for a total yield of 0.3 g (28% yield) of yellow crystals, m.p. 139°-141° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH2:22][C:23]3([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:26][CH2:25][CH2:24]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=2)=[N:5][CH:4]=1.[N-:34]=[N+:35]=[N-:36].[Na+].CCN(C(C)C)C(C)C.C(OCC)(=O)C>CN(C=O)C>[N:34]([CH2:2][C:3]1[S:7][C:6]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH2:22][C:23]3([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:26][CH2:25][CH2:24]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=2)=[N:5][CH:4]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CCl)s2)nn1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CN=[N+]=[N-])s2)nn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a stirring solution of t-butyl 6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (60.7 g, 124 mmol) in DMF (800 mL) was added sodium azide (22.2 g, 341 mmol) and DIPEA (31.1 mL, 171 mmol). The reaction was heated to 60° C. and stirred for 1 h. The reaction was poured into ethyl acetate (2000 mL), washed with water (3×400 mL), and the combined organic layers were separated, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAC/hexanes) to afford 20.0 g of t-butyl 6-(5-(azidomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(COc2ccc(C(=O)OCC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCOc1ccc(COc2ccc(C(=O)O)cc2)cc1

Procedure:
In 20 ml of benzene were dissolved 2.2 g of 4-heptyloxybenzyl alcohol and 1.7 g of ethyl 4-hydroxybenzoate, 1.8 g of diethyl azodicarboxylate and 2.6 g of triphenylphosphine were added to the solution, and a reaction was carried out with stirring. The reaction liquid was concentrated and the concentrate was separated and purified by the silica gel chromatography to obtain 3.1 g of ethyl 4-(4'-heptyloxybenzyloxy)benzoate. This ester was dissolved in 20 ml of ethanol and 4.2 ml of a 2N aqueous KOH solution was added to the solution to effect the hydrolysis. The reaction mixture was treated by customary procedures to obtain 2.7 g of 4-(4'heptyloxybenzyloxy)benzoic acid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][CH:8]=1
Reactant: CCS(=O)(=O)c1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(CCl)cc1

Procedure:
A mixture of (4-(ethylsulfonyl)phenyl)methanol (200 mg, 1 mmol) and thionyl chloride (3 mL) was stirred at reflux for 4 h. The solvent was removed under reduced pressure to obtain a gum. Dichloromethane (10 mL) was added, and the mixture was stirred for 5 min and then concentrated under vacuum. This process was repeated two more times to ensure complete removal of thionyl chloride. After residual solvent removal under vacuum, 205 mg of the title compound was obtained as a white solid. HPLC/MS: retention time=2.308 min, [M+H]+=219.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[N:13]=[C:12](Cl)[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=2)[N:5]=1>C1COCC1>[Cl:3][C:4]1[NH:13][C:12](=[O:1])[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=2)[N:5]=1
Reactant: [OH-]
Reactant: Clc1ccc2c(Cl)nc(Cl)nc2c1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(Cl)nc2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A 1.0 M aqueous solution of sodium hydroxide (19 mL, 19 mmol) was added to a mixture of 2,4,7-trichloroquinazoline (2.0 g, 8.5 mmol) and THF (30 mL) that had been cooled to 0° C. The reaction mixture was allowed to warm to rt and was stirred vigorously for 2 h. The mixture was concentrated to remove the THF, and the remaining aqueous phase was cooled to 0° C. and acidified by addition of 1.0 M aqueous HCl (25 mL). The resulting mixture was allowed to stand at 0° C. for 20 min, the solid was collected by filtration and dried to provide the titled compound (1.7 g, 92%). The MS and NMR data are in agreement with those that have been previously described: Journal of Medicinal Chemistry, 2007, 50, 2297-2300.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:26]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[ClH:1].[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C@H:3]([NH:2][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:31][CH:32]=2)[C:4]([NH:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5])=[CH:17][CH:16]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (3.85 g, 10.6 mmol, Example 2, Step A) and 4-tert-butylbenzaldehyde (1.72 g, 10.6 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (54 mL). After stirring at ambient temperature under a nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (3.37 g, 15.9 mmol). The resulting reaction mixture was stirred for 30 minutes at 0° C., followed by an additional 12 hours at ambient temperature. Saturated aqueous NaHCO3 solution (77 mL) was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×70 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. Title compound was isolated by flash chromatography (30% EtOAc in hexanes). The free amine was dissolved in 20 mL of ethyl ether and treated with ethereal HCl to afford 1.71 g (34%) of the pure titled compound as a white foam; mp 95-105° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])=[C:4]([O:15][CH3:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]([C:29](O)=[O:30])[NH:27][CH:28]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]([C:29]([NH:1][C:2]3[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][C:9]([OH:11])([CH3:12])[CH3:10])=[C:4]([O:15][CH3:16])[CH:3]=3)=[O:30])[NH:27][CH:28]=2)=[CH:20][CH:19]=1
Reactant: COc1cc(N)ccc1OCCC(C)(C)O
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCC(C)(C)O

Procedure:
Acylation of 4-(4-amino-2-methoxyphenoxy)-2-methylbutan-2-ol from step A with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid to generate the title compound was achieved via the procedure described in step C of Example 1. The crude product was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:56][O:57][C:58]([C:60]1[O:61][C:62]2[CH:68]=[CH:67][C:66]([NH2:69])=[CH:65][C:63]=2[N:64]=1)=[O:59]>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:69][C:66]2[CH:67]=[CH:68][C:62]3[O:61][C:60]([C:58]([O:57][CH3:56])=[O:59])=[N:64][C:63]=3[CH:65]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2cc(N)ccc2o1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2o1
Reaction time: 0.33 h

Procedure:
A solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (59.8 mg, 0.128 mmol) in dichloromethane (3 ml) was treated with DIPEA (66.8 mg, 0.517 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (80.7 mg, 0.341 mmol) and stirred for 20 min under argon. 5-AMINO-BENZOOXAZOLE-2-CARBOXYLIC ACID METHYL ESTER (25.8 mg, 134 μmol, JW PharmLab) was added and stirred 2 hrs. The reaction mixture was diluted with dichloromethane and washed with water, sat'd NaHCO3, water and brine. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylate (73.7 mg., 89.8%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 641.15. found: 641.2.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[ClH:11]>CO.O=[Pt]=O>[ClH:11].[NH2:1][C:2]1[CH:3]([C:4]([OH:6])=[O:5])[CH2:7][CH2:8][CH2:9][N:10]=1
Reactant: Nc1ncccc1C(=O)O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: NC1=NCCCC1C(=O)O
Reaction time: 2 h
Yield: 103.5 %

Procedure:
2-Aminonicotinic acid (0.912 g, 6.6 mmol) was dissolved in 90% methanol (137 ml) and conc. HCl (3.5 ml, 40 mmol) was added. The solution was hydrogenated over PtO2 (200 mg) in a Parr shaker apparatus at room temperature and 29 psig for 2 hours. Filtration and evaporation gave 1.22 g (100%) oily product identified by ir 3300-2500, 1724 cm-1.