Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2[NH:6][C:7](=[O:27])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=4)[CH:12]=3)=[C:9]([OH:10])[C:4]=2[C:3]=1[CH3:29].[H][H]>C(O)C.[Pt]=O>[Cl:1][C:2]1[S:28][C:5]2[NH:6][C:7](=[O:27])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=4)[CH:12]=3)=[C:9]([OH:10])[C:4]=2[C:3]=1[CH3:29]
Reactant: [H][H]
Reactant: Cc1c(Cl)sc2[nH]c(=O)c(-c3cccc(Oc4cccc([N+](=O)[O-])c4)c3)c(O)c12
Agent: O=[Pt]
Solvent: CCO
Product: Cc1c(Cl)sc2[nH]c(=O)c(-c3cccc(Oc4cccc(N)c4)c3)c(O)c12

Procedure:
20 mg of platinum oxide are added to a solution of 4.28 g of 2-chloro-3-methyl-4-hydroxy-5-(3-m-nitro-phenoxyphenyl)-6,7-dihydrothieno[2,3-b]pyridin-6-one in 50 ml of 95% ethanol. Hydrogen is passed through the solution until three molar equivalents have been absorbed. The platinum is filtered off and the alcohol is distilled off. 2-Chloro-3-methyl-4-hydroxy-5-(3-m-aminophenoxyphenyl)-6,7-dihydrothieno[2,3-b]pyridin-6-one is obtained.
Reaction SMILES: N1CCCCC1.[CH3:7][C:8]1([CH3:24])[O:12][CH:11]([CH2:13][O:14][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][O:9]1.[Cl:25][C:26]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O>CC(O)C>[Cl:25][C:26]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[C:17]([C:16]([CH2:15][O:14][CH2:13][CH:11]1[CH2:10][O:9][C:8]([CH3:7])([CH3:24])[O:12]1)=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CC(=O)COCC1COC(C)(C)O1
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CCOC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)COCC1COC(C)(C)O1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
Piperidine (1.0 g) was added dropwise over 5 minutes to a stirred, ice-cooled solution of ethyl 4-{(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy}acetoacetate (26.0 g) (see Preparation 5) and 2,3-dichlorobenzaldehyde (17.5 g) in 2-propanol (200 ml) and the mixture was stirred with ice-cooling for 2 hours and at room temperature for 14 hours. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on silica (150 g) using toluene plus 0-40% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give essentially pure ethyl 2-(2,3-dichlorobenzylidene)-4-{(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy}acetoacetate (17.3 g) as an oil. A solution of this oil in 2-propanol (150 ml) was treated with methyl 3-aminocrotonate (5.0 g) and the mixture stirred at room temperature for 24 hours. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on SiO2 (110 g) using toluene plus 0-10% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give the title compound (2.75 g), m.p. 135°-137° C.
Reaction SMILES: C1C2C(CO[C:16]([N:18]([CH2:34][C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH2:19][CH2:20][NH:21][C@@H:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C.C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)OC1C=CC([N+]([O-])=O)=CC=1>CN(C)C=O.ClCCCl>[CH3:31][C:30]([CH3:32])([CH3:33])[C@H:22]([N:21]1[CH2:20][CH2:19][N:18]([CH2:34][C:35]2[N:39]([CH3:40])[C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[N:36]=2)[C:16]1=[O:17])[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24]
Reactant: Cn1c(CN(CCN[C@H](C(=O)OC(C)(C)C)C(C)(C)C)C(=O)OCC2c3ccccc3-c3ccccc32)nc2ccccc21
Agent: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1c(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.7 %

Procedure:
A solution of the product of Example 59D (0.19 g) in N,N-dimethylformamide (3.5 mL) was treated with diethylamine (0.35 mL), stirred at 25° C. for 1.5 hours and concentrated. A solution of the residue in 1,2-dichloroethane (7 mL) was treated with bis-(p-nitrophenyl) carbonate (0.128 g, 1.2 eq.), stirred at 60° C. for 16 hours and concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate:dichloromethane (3:2) to give 80 mg (64% yield) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)CC)C.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[NH:29][CH:28]=[C:27]2[S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[NH:29][CH:28]=[C:27]2[S:35]([N:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:3]([CH2:2][OH:1])[CH2:8]1)(=[O:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Reactant: O=c1[nH]cc(S(=O)(=O)Cl)c2cc(Br)ccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c[nH]c(=O)c3ccc(Br)cc23)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
To a solution of tert-butyl (2R)-2-(hydroxymethyl)piperazine-1-carboxylate (0.479 g) and triethylamine (0.618 mL) in THF (6 mL) was added dropwise a solution of 6-bromo-1-oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (Example 46a, 0.715 g) in THF (10 mL). The reaction was stirred at room temperature for 20 min. The resulting solution was concentrated under reduced pressure before adding water and extracting into ethyl acetate. The combined organics were dried (MgSO4), filtered and evaporated under reduced pressure. Trituration with ethyl acetate gave the subtitle compound (0.855 g).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([OH:17])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[H-].[Na+].I[CH3:21]>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([O:17][CH3:21])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2[nH]nc(CC)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC)c2[nH]nc(CC)c2c1
Reaction time: 1 h
Yield: 100.5 %

Procedure:
A solution of ethyl 3-ethyl-7-hydroxy-1H-indazole-5-carboxylate (2.47 g, 10.5 mmo) in DMF (40 mL) was cooled to 0° C. To this mixture was added 60% NaH (0.42 g, 10.5 mmol) and stirred for 1 hour. To this was added a 0° C. solution of iodomethane (1.50 g, 0.66 mL, 10.5 mmol) in DMF (10 mL). The mixture was kept at 0° C. for several hours before stirring at room temperature overnight. The mixture was diluted with EtOAc, washed with a mixture of saturated aqueous NaHCO3 and saturated aqueous NaCl followed by saturated aqueous NaCl. The organic extract was dried over Na2SO4, filtered and concentrated. Purify by CombiFlash (80 g column, 0-30% EtOAc/hexanes gradient) to provide ethyl 3-ethyl-7-methoxy-1H-indazole-5-carboxylate (2.62 g, 40%).
Reaction SMILES: O[C@H:2]([C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C@@H:3]([NH:5][C:6](=[O:15])[O:7]CC1C=CC=CC=1)[CH3:4].Cl>[OH-].[K+].CO.C1COCC1>[CH3:4][C@H:3]1[C@@H:2]([C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)[O:7][C:6](=[O:15])[NH:5]1
Reactant: Cc1csc([C@@H](O)[C@H](C)NC(=O)OCc2ccccc2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1csc([C@H]2OC(=O)N[C@H]2C)n1

Procedure:
A solution of benzyl [(1S,2S)-2-hydroxy-1-methyl-2-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate (53.4 mg, 0.174 mmol) in 7.5 N aqueous KOH (1 mL), MeOH, (2 mL) and THF (4 mL) was stirred at room temperature overnight. The reaction mixture was acidified with 3N HCl and extracted with EtOAc (3×20 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford the product. LCMS calc.=199.1; found=199.1 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 6.92 (s, 1H), 6.82 (s, 1H), 5.91 (d, J=8.2 Hz, 1H), 4.39-4.35 (m, 1H), 2.44 (s, 3H), 0.95 (d, J=6.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:23]([O:26][CH3:27])=[N:24][CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[C:23]([O:26][CH3:27])=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1ncc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ncc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 31.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxypyridin-3-yl) methanesulfonamide (70 mg, 0.108 mmol) was hydrolyzed with lithium hydroxide (14 mg, 0.324 mmol) in THF/methanol/water (3.5/3.5/0.5 mL) to yield 17 mg (31.8% yield) after purification by preparative TLC (Silicagel-1000 micron) using 5% methanol in chloroform as eluent. 1H NMR (CD3OD, 300 MHz): δ 8.42 (s, 1H), 8.34-8.33 (s, 1H), 8.288-8.280 (d, 1H), 8.22 (s, 1H), 8.04-8.03 (d, 1H), 7.934-7.931 (d, 1H), 8.04-8.03 (d, 1H), 7.934-7.931 (d, 1H), 7.65 (s, 1H), 7.38-7.35 (q, 1H), 7.12-7.09 (d, 1H), 7.03-6.99 (m, 2H), 5.42 (s, 2H), 4.06 (s, 3H), 3.03 (s, 3H). MS: m/z=492.8 (M+1), HPLC: 96.33% in method B.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[Br:13]Br>C(O)(=O)C>[Br:13][CH:6]1[C:5](=[O:12])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[O:8][CH2:7]1
Reactant: O=C1CCOc2ccc(F)cc21
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1c2cc(F)ccc2OCC1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 6-fluorochroman-4-one (21.0 g, 126 mmol) in acetic acid (105 ml) is added bromine (6.5 ml, 126 mmol) at such a rate as to not raise the temperature above 25° C. After the addition is complete, the reaction is allowed to stir for 2 hours before pouring into 1 liter of ice. The resulting mixture is stirred overnight. The precipitate which formed is filtered and placed in drying oven to produce 21 g of 3-bromo-6-fluorochroman-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([N:11]2[C:15]([CH3:16])=[C:14](I)[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:12]2)=[CH:5][N:4]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CCCCCC.CCOC(C)=O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]([OH:29])[C:14]2[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:12][N:11]([C:6]3[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=3)[C:15]=2[CH3:16])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.3 using ethyl 1-(2,4-dimethoxypyrimidin-5-yl)-4-iodo-5-methyl-1H-pyrazole-3-carboxylate (Step 55.2) and 4-chlorobenzaldehyde at RT for 30 min. tR: 4.92 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.24 (Hexane/EtOAc 1:1).
Reaction SMILES: [ClH:1].[I:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl>C(O)C(F)(F)F>[ClH:1].[I:2][C:3]1[C:4]2[NH:9][C:16]3[CH2:17][CH2:18][NH:13][CH2:14][C:15]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccccc1I
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: O
Product: Ic1cccc2c3c([nH]c12)CCNC3
Reaction time: 3 h
Yield: 84.8 %

Procedure:
1-(2-iodophenyl)hydrazine hydrochloride (1.67 g, 6.2 mmol) and 4-piperidone monohydrate hydrochloride (0.952 g, 6.2 mmol) were dissolved in trifluoroethanol (15 mL) and concentrated hydrochloric acid (5 mL) and heated at 87° C. and stirred for 3 h. The solid was filtered, washed with cold isopropyl alcohol (50 mL), and dried to give 6-iodo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (1.76 g, 85%) as a tan solid. 1H NMR (CD3OD, 300 MHz) δ 7.49 (d, 1H, J=7.7 Hz), 7.43 (d, 1H, J=8 Hz), 6.82 (t, 1H, J=7.7 Hz), 4.40 (s, 2H), 3.60 (t, 2H, J=6.25 Hz), 3.18 (t, 2H, J=5.85 Hz) ppm.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]#[N:26])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:27])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[OH-:29].[K+]>C(O)(C)(C)C.O>[O:28]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([NH2:26])=[O:29])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:27])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(CCC#N)c2c1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(CCC(N)=O)c2c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-propionitrile (150 mg, 0.38 mmol), and powdered potassium hydroxide (172 mg, 3.07 mmol) in tert-butanol (8 mL) was heated with stirring under reflux for 1.5 hours. After being cooled to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (eluting with 5% methanol in dichloromethane) to afford 125 mg of the product as a white solid.
Reaction SMILES: [C:1]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CS(C)=O.O>[C:1]([S:14]([N:17]([CH2:23][CH:22]=[CH2:21])[CH3:18])(=[O:15])=[O:16])([C:4]([C:7]([C:10]([F:13])([F:11])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: C=CCBr
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A 250 mL three-neck round-bottom flask equipped with thermometer, magnetic stirring, and addition funnel was charged with a solution of 75 g of C4F9SO2NHCH3 in 80 g of dimethyl sulfoxide. The solution was stirred while a solution of 17.1 g potassium hydroxide in 20 g of water was added in 2 mL aliquots via pipette. The solution turned cloudy during the addition, then cleared with additional stirring. Allyl bromide (31.9 g) was charged to the addition funnel, and added dropwise to the reaction mixture. A rise in temperature of the reaction mixture to 75° C. was noted during the addition. The reaction mixture turned cloudy shortly after the addition was begun, and stirring was continued overnight at room temperature. The reaction mixture was poured into a separatory funnel and allowed to stand until the liquid layers had separated. A few mL water were added to the mixture to facilitate phase separation. The lower layer was drawn off, washed with water and brine, and dried over anhydrous magnesium sulfate, leaving 76.0 g of a clear, colorless crude liquid product which was vacuum distilled to yield 68.7 g C4F9SO2N(CH3)CH2CH═CH2, b.p. 97-101° C. at 19 torr (2.5 kPa).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][CH2:6][C:7](Br)=[O:8].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1>C(Cl)Cl>[Br:5][CH2:6][C:7]([C:13]1[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[O:11][CH3:10])=[O:8].[Br:5][CH2:6][C:7]([C:15]1[C:16]([CH3:18])=[CH:17][C:12]([O:11][CH3:10])=[CH:13][C:14]=1[CH3:19])=[O:8]
Reactant: O=C(Br)CBr
Reactant: COc1cc(C)cc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)CBr)c(C)c1
Product: COc1cc(C)cc(C)c1C(=O)CBr
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 31.7 %
Yield: 6.6 %

Procedure:
To a mixture of AlCl3 (2.0 g, 14.7 mmol) in CH2Cl2 (12 mL) was added a solution of 2-bromoacetyl bromide (3.0 g, 14.9 mmol) in CH2Cl2 (2 mL) at 0° C. Then, a solution of 1-methoxy-3,5-dimethylbenzene (2.0 g, 14.7 mmol) in CH2Cl2 (2 mL) was added dropwise. The whole mixture was stirred for 1.5 h at 0 to 5° C. After that, the mixture was poured into ice water (100 g). The mixture was extracted with CH2Cl2 (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4. After filtration, the solvent was removed in vacuo and the residue was purified by silica gel column (hexane/EtOAc=40/1 to 25/1) to afford 2-bromo-1-(2-methoxy-4,6-dimethylphenyl)ethanone (1.20 g, 31.7%) and 2-bromo-1-(4-methoxy-2,6-dimethylphenyl) ethanone (250 mg, 6.6%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C@H:16]([CH3:22])[CH2:17][C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:52]=[N+:53]=[N-:54])(=O)=O)(C)C.C(O)(=O)C.C([O-])(=O)C.[K+]>C1COCC1.CCOC(C)=O>[N:52]([C@@H:15]([C@H:16]([CH3:22])[CH2:17][C:18]([F:19])([F:20])[F:21])[C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:23])=[N+:53]=[N-:54]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: C[C@@H](CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)CC(F)(F)F
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@H](CC(F)(F)F)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
A solution of (4S)-4-benzyl-3-[(3S)-5,5,5-trifluoro-3-methylpentanoyl]-1,3-oxazolidin-2-one (8.2 g, 24.90 mmol) in THF (100 mL) was cooled to −78° C. and KHMDS (potassium hexamethyldisilazane—59.7 mL, 29.88 mmol) was added dropwise over a period of 10 min. After stirring at −78° C. for 1 h, a pre-cooled (−78° C., 50 min) solution of 2,4,6-triisopropylbenzenesulfonyl azide (10.1 g, 32.37 mmol) was added via cannula over a period of 10 min. After an additional 10 min at −78° C., glacial acetic acid (6.7 mL, 112.05 mmol) was added all at once through a funnel. After 5 min at −78° C. anhydrous potassium acetate (9.77 g, 99.6 mmol) was added. The −78° C. bath was lowered and the reaction mixture was allowed to warm to 25° C. overnight (19 h). The reaction mixture was diluted with EtOAc (200 mL) and the organic phase was washed with saturated aqueous potassium phosphate monobasic (2×100 mL) and saturated aqueous NaCl (100 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a yellow oil (9.5 g). The crude product was purified by flash chromatography, eluent: 1:4 EtOAc-hexane, to furnish (S)-3-[(2S,3R)-2-azido-5,5,5-trifluoro-3-methylpentanol]-4-benzyl-1,3-oxazolidin-2-one as a colorless oil (7.2 g, 73.7%). Mass Spectrum (−ESI): 342 (M−N2)−.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][S:3]1.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[CH2:25]1[C@H:32]([N:33]2C(=O)C3C(=CC=CC=3)C2=O)[C:30](=[O:31])[O:29][C:27](=[O:28])[CH2:26]1.C(NN)(=O)C1C(=CC=CC=1)C(NN)=O>CC#N.CCN(CC)CC.O>[NH2:33][C@H:32]([C:30]([OH:31])=[O:29])[CH2:25][CH2:26][C:27]([N:6]1[C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][S:3][CH:2]1[CH3:1])=[O:28]
Reactant: O=C1CC[C@H](N2C(=O)c3ccccc3C2=O)C(=O)O1
Reactant: CC1N[C@H](C(=O)O)CS1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: NNC(=O)c1ccccc1C(=O)NN
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC1SC[C@@H](C(=O)O)N1C(=O)CC[C@H](N)C(=O)O
Temperature: 25 °C

Procedure:
To a stirred suspension of 2(R,S)-methylthiazolidine-4(R)-carboxylic acid (8.51 g, 57.9 mmol) prepared according to Nagasawa et al., J. Med. Chem., 27, 591 (1984), which is incorporated herein by reference, in dry CH3CN (100 mL) under a N2 atmosphere was added bis-(trimethylsilyl)trifluoroacetamide (17.0 mL, 17.7 g, 68.7 mmol, obtained from Sigma Chemical Co., "BSTFA") and the mixture was heated under reflux for 1.25 hours. The solids dissolved within 10 minutes of heating. After cooling to room temperature, N-phthaloyl-L-glutamic anhydride (15.0 g, 58.0 mmol) prepared according to Elbefling et al., Org. Prep. Proceed. Int., 11, 67 (1979), which is incorporated herein by reference, was added, followed by dry CH3CN (25 mL). After 5 days at room temperature the solvent was evaporated in vacuo. To the resultant pale yellow thick oil (41.1 g) were added with stirring under a N2 atmosphere, 1.0M Et3N in CH3OH (220 mL) and 2.0M NH2NH2.H2O in 50% aqueous CH3OH (73 mL). After 2 days of stirring the solvent was evaporated in vacuo. The resultant thick, white, semisolid (51.8 g) was suspended in H2O (150 mL) and the solvent evaporated again to give 49.7 g of a thick, white oil. This was poured into warm H2O (350 mL) with swirling. The resultant precipitate of phthalhydrazide was removed by filtration and the filter cake was rinsed with H2O (approximately 100 mL). The combined filtrate was acidified to pH 3.5 with 1.0N HCl, whereupon more phthalhydrazide precipitated. This was removed by filtration, and the filtrate was evaporated in vacuo, keeping the temperature under 40° C., to give 35.8 g of a thick, pale yellow oil whose NMR spectrum showed the presence of much Et3N and some phthalhydrazide in addition to the desired product. The oil was, therefore, resuspended in H2O (75 mL), the mixture was stirred, and the additional solids that precipitated were removed by filtration. The filtrate was evaporated to incipient dryness in vacuo to give a thick oil (24.6 g).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[C:33](OC2C=CC([N+]([O-])=O)=CC=2)=[O:34])=[C:7]([S:45]([CH3:48])(=[O:47])=[O:46])[CH:6]=1)#[N:4]>C(#N)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:13](=[O:32])[N:12]2[C:33]([NH:2][CH3:1])=[O:34])=[C:7]([S:45]([CH3:48])(=[O:46])=[O:47])[CH:6]=1)#[N:4]
Reactant: CN
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Methylamine (2.0 M in tetrahydrofuran, 69 μL, 138 μmol) is added to a solution of 4-nitrophenyl 4-(4-cyano-2-(methylsulfonyl)phenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 38, 30 mg, 46 μmol) in acetonitrile (1 mL). The mixture is stirred at room temperature for 20 min and purified by reversed phase HPLC (Agilent ZORBAX™ SB-C18, gradient of acetonitrile in water, 0.15% formic acid). Yield: 22 mg; ESI mass spectrum M+H]+=547, Retention time HPLC: 1.01 min (Z017_S04).