Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:10][CH3:11])[N:3]=1)[CH:8]=[O:9]
Reactant: COc1cc(CO)cc(Cl)n1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(C=O)cc(Cl)n1

Procedure:
To a solution of (2-chloro-6-methoxypyridin-4-yl)methanol (1.73 g, 9.97 mmole) from the protocol immediately above in CH2Cl2 (40 ML) was added PCC (2.58 g, 11.96 mmole) all at once at RT. After 60 hr the mixture was diluted with Et2O and filtered through a plug of Celite®. The filtrate was concentrated to give the titled compound as a tan-yellow solid which was sufficiently pure for use in the next step. 1H-NMR (500 MHz, CDCl3) δ9.96 (s, 1H), 7.32 (s, 1H), 7.06 (s, 1H), 4.00 (s, 3H).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([N:12]1[CH2:17][CH2:16][CH:15]([C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)(=[O:11])[CH3:10].[Cl-].[NH4+]>C(OCC)C.O1CCCC1.O>[C:9]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:26])[CH2:16][CH2:17]1)(=[O:11])[CH3:10]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A solution (667 ml, 2 mole) phenylmagnesium bromide* (3 molar in ethyl ether) was diluted with 2 liters of anhydrous ethyl ether, cooled to 0°-10° C., and treated with a solution of 148 g (0.6 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 1.5 liters of anhydrous tetrahydrofuran dropwise over a 1.5 hr period. The mixture was stirred at ambient temperature overnight and then poured into a solution of 107 g (2 mole) of ammonium chloride in 2 liters of cold water. The mixture was extracted thrice with 1 liter portions of benzene. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated to give a semi-solid as residue. The semi-solid was triturated with isopropyl ether and the mass crystallized. The solid was collected by filtration and dried to yield 87.8 g (45%) of title compound as a white solid. An analytical sample was recrystallized from 2-propanol, mp 173°-175° C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][C@@H:39]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1)[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:38][C@H:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:47][C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=2)=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 5 h
Yield: 77.1 %

Procedure:
Prepared using General Procedure 7. Into a solution of 4-(tert-butyl)benzoic acid (8.3 g, 46.4 mmol) in DMF (100 mL) were added HATU (19.2 g, 50.6 mmol), TEA (17.6 mL, 126.4 mmol) and (S)-tert-butyl 2-amino-3-(4-hydroxyphenyl)propanoate (10.0 g, 42.1 mmol). After 5 h, the reaction mixture was diluted with EA, washed with saturated aqueous NaHCO3 and brine, then dried (Na2SO4), concentrated, and purified by chromatography (EA/hexanes) to provide 12.9 g (69%) of tert-butyl (4-(tert-butyl)benzoyl)-L-tyrosinate. LCMS-ESI (m/z) calculated for C24H31NO4: 397.5; no m/z observed, tR=3.59 min (Method 1). 1H NMR (400 MHz, CDCl3) δ7.71-7.65 (m, 2H), 7.47-7.39 (m, 2H), 7.04 (t, J=5.7 Hz, 2H), 6.78-6.70 (m, 2H), 6.59 (d, J=7.5 Hz, 1H), 4.91 (dt, J=7.5, 5.6 Hz, 1H), 3.15 (qd, J=14.0, 5.6 Hz, 2H), 1.45 (s, 9H), 1.33 (s, 9H).
Reaction SMILES: [Br-].N[N:3]1[CH2:7][NH+:6]([CH2:8][C:9]2[CH:14]=[C:13]([C:15]([CH3:19])([C:17]#[N:18])[CH3:16])[CH:12]=[C:11]([C:20]([C:23]#[N:24])([CH3:22])[CH3:21])[CH:10]=2)[N:5]=[CH:4]1.Cl.N([O-])=O.[Na+].C1CCCCC1>O>[CH3:22][C:20]([C:11]1[CH:10]=[C:9]([CH2:8][N:6]2[N:5]=[CH:4][N:3]=[CH:7]2)[CH:14]=[C:13]([C:15]([C:17]#[N:18])([CH3:16])[CH3:19])[CH:12]=1)([C:23]#[N:24])[CH3:21]
Reactant: CC(C)(C#N)c1cc(C[NH+]2CN(N)C=N2)cc(C(C)(C)C#N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Br-]
Solvent: C1CCCCC1
Solvent: O
Product: CC(C)(C#N)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1
Temperature: -5 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
4-Amino-1-[3,5-bis-(1-cyano-1-methylethyl)benzyl]-1H-[1,2,4]triazolium bromide (5) (70 g) was dissolved in cone. HCl (280 mL) in a 5 L R.B. flask and cooled to −5° C. A solution of sodium nitrite (15 g) in water (70 mL) was slowly added to the reaction mixture at 0-5° C. in 4 hrs and the reaction mixture was stirred for one hour at 0-5° C. and further at 10-20° C. for next 3 hours. The reaction mixture was quenched by the addition of a solution of urea (4.5 g) in water (15 mL). Toluene (700 mL) was added to the reaction mixture and the heterogeneous solution was further cooled down to 0-5° C. The solution was basified by the addition of liquor ammonia (365 mL) slowly in 4 hours at 5-25° C. Organic layer was separated and further washed with water (200 mL). Aqueous layer was removed and a solution of cone. HCl (140 mL) in water (140 mL) was added to the organic layer slowly in 30 minutes at 25-30° C. and reaction mass was heated at 60-65° C. for 30 minutes. The lower aqueous layer (280-300 mL), containing product was collected in a conical flask maintaining at 50° C. The aqueous part was again washed with toluene (700 mL) at 60-65° C. for 30 minutes. The lower aqueous layer, containing product was charged in a separating funnel and again washed with fresh toluene (700 mL). The aqueous layer, containing product was transferred in a R.B. flask and ethyl acetate (350 mL) was added to it. The heterogeneous solution was cooled to 0-5° C. basified by the slow addition of liquor ammonia (280 mL) in 2-3 hours at 5-25° C. The solution was stirred for one hour at 25-35° C., and the upper organic layer (360-375 mL), containing product was separated and filtered through hyflow super cell bed. Solvent was distilled out below 50° C. under vacuum leaving approximately 100 mL ethyl acetate in the flask. The content of the flask was cooled down to 25-35° C. and cyclohexane (500 mL) was added to the solution slowly in 30 minutes. The precipitated solid product was filtered and washed with fresh cyclohexane (20 mL×2). The product was dried at 45-50° C. to get crude Anastrozole (44 g) with more than 98% HPLC purity contaminated with related substance (6) as 0.36% and with related substance (7) as 0.05%.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:21])[C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37])[C:28](OC)=O>O1CCCC1>[Cl:24][C:25]1[CH:26]=[C:27]([C:28]2[O:1][N:2]=[C:3]([C:4]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:5]=3[CH2:6][CH2:7][N:8]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]4)[N:21]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=N)NO)C1
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Yield: 79.7 %

Procedure:
1,1-dimethylethyl 5-[(hydroxyamino)(imino)methyl]-3,4-dihydro-2(1H)-isoquinoline carboxylate (Preparation 1)(2 g, 6.86 mmol) was dissolved in tetrahydrofuran (THF) (100 mL) and stirred with sodium hydride (60% dispersion, 0.302 g, 7.55 mmol) under argon at room temperature for 30 minutes. Then methyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (Preparation 2)(2.355 g, 10.30 mmol) was added and the reaction heated at reflux temperature for 1.5 hours. The cooled reaction was evaporated and partitioned between DCM (100 mL) and water (100 mL). The water layer was washed with DCM (50 mL) and the combined DCM layers dried (hydrophobic frit) and evaporated. The crude product was purified by chromatography through a small silica pad, eluting with DCM to yield 1,1-dimethylethyl 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinoline carboxylate (2.57 g, 5.47 mmol, 80% yield). 1H NMR (400 MHz, CDCl3) δ 8.23 (1H, s), 8.05 (1H, d), 7.95 (1H, d), 7.34 (1H, t), 7.27 (1H, d), 7.06 (1H, d), 4.76-4.63 (1H, m), 4.66 (2H, br.s), 3.67 (2H, br.t), 3.25 (2H, br.t), 1.51 (9H, s), 1.45 (6H, d); m/z (API-ES) 414, 416 [M+H-56]+.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:32][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:32][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCOc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCOc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 50 °C
Yield: 10 %

Procedure:
A mixture of (2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-ethyl)-dimethyl-amine (200 mg, 0.44 mmol) and 10% palladium on activated carbon (40 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) for 6 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford (2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-ethyl)-dimethyl-amine (20 mg, 10%) as a white solid: LC/MS m/e calcd for C25H33N3O3S [M+H]+ 456.62, observed 456.3; 1H NMR (400 MHz, CD3OD) δ ppm 1.26 (m, 2 H), 1.51 (m, 2H), 1.58-1.90 (m, 5H, H), 2.11 (m, 1H), 2.27 (m, 1H), 2.44 (s, 6H), 2.89 (t, J=5.4 Hz, 2H), 3.10 (s, 3H), 4.19 (t, J=5.4 Hz, 2H), 4.30 (t, J=8.0 Hz, 1H), 6.35 (s, 1H), 7.55 (d, J=2.8 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.9 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:18])[C:8](=[O:17])[N:9]2[CH2:12][C:13]([O:15]C)=[O:14])=[CH:4][C:3]=1[N:19]1[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]1[CH3:25].[OH-].[Li+]>O1CCCC1.O>[C:13]([CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([N:19]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]3[CH3:25])=[C:2]([Cl:1])[CH:11]=2)[NH:6][C:7](=[O:18])[C:8]1=[O:17])([OH:15])=[O:14]
Reactant: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(-n3c(C)ccc3C)c(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)n(CC(=O)O)c2cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
4.0 g (10.6 mmol) of 7-chloro-6-(2,5-dimethyl-1-pyrrolyl)-1-(methoxycarbonylmethyl)-2,3(1H,4H)-quinoxalinedione (Example 44) were dissolved in 100 ml of tetrahydrofuran, and a solution of 0.76 g (31.9 mmol) of lithium hydroxide in 15 ml of water was added. The mixture was stirred at room temperature for 2 h and then the organic solvent was removed under reduced pressure, and the aqueous phase was acidified with 1M hydrochloric acid. The precipitate was filtered off with suction to yield 3.1 g (84%) of the product. Melting point >265° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[NH2:25])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:33][C:34]1[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:35]=1[C:36](Cl)=[O:37].CCOC(C)=O>C1COCC1>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][C:16]=2[NH:25][C:36](=[O:37])[C:35]2[CH:39]=[C:40]([I:43])[CH:41]=[CH:42][C:34]=2[F:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2N)C1
Reactant: O=C(Cl)c1cc(I)ccc1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(I)ccc2F)C1
Reaction time: 48 h

Procedure:
In a vial, (R)-2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)benzenamine (.517 g, 1.4 mmol) was taken up in THF. Triethylamine (0.29 ml, 2.1 mmol) and 2-fluoro-5-iodobenzoyl chloride (0.43 g, 1.5 mmol) were added. The vial was sealed and the reaction stirred for 48 h. The reaction mixture was poured into EtOAc/1N NaOH. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was treated with hexanes and passed through a Redi-Sep® pre-packed silica gel column (40 g) eluting with 0-10% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)—N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluoro-5-iodobenzamide as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[S:23][C:22]([NH:24]CC5C=CC(OC)=CC=5)=[N:21][N:20]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6][CH:5]=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[S:23][C:22]([NH2:24])=[N:21][N:20]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cncc(-c2c[nH]c3ccc(-c4nnc(NCc5ccc(OC)cc5)s4)cc23)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cncc(-c2c[nH]c3ccc(-c4nnc(N)s4)cc23)n1
Temperature: 120 °C
Yield: 37.2 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-ethoxypyrazin-2-yl)-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (68 mg, 0.148 mmol) in TFA (1 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 30 min, then the solvent was removed. The residue was purified with RP-HPLC (10-40% ACN in H2O with 0.1% TFA) and the fractions were combined and MeCN was removed in vacuo. The mixture was treated with sat. NaHCO3 and extracted with CHCl3/iPrOH (4:1). The combined organic layers were dried, filtered and concentrated to give 5-(3-(6-ethoxypyrazin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (18.5 mg, 0.055 mmol, 36.9% for two steps) as a yellow solid. MS (ESI, pos. ion) m/z: 339 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.94 (1H, br. s.), 8.80 (1H, d, J=1.6 Hz), 8.76 (1H, s), 8.37 (1H, d, J=2.5 Hz), 8.00 (1H, s), 7.76 (1H, dd, J=8.5, 1.7 Hz), 7.54 (1H, d, J=8.4 Hz), 7.27 (2H, s), 4.61 (2H, q, J=7.0 Hz), 1.53 (3H, t, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH3:14]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([O:9][CH3:14])=[O:8]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Yield: 57.9 %

Procedure:
3,4-Dichlorocinnamic acid (6.5g) (Ex.Aldrich), dimethylsulphate (3.77 g), potassium carbonate (4.13 g) and anhydrous acetone heated together under reflux. After cooling and filtration the acetone was removed and the residue recrystallised (80:20-hexane: ether) to give methyl 3,4-dichlorocinnamate as a colourless solid (4 g).
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([CH2:14][F:15])[C@:11](OCC2C=CC=CC=2)([OH:16])[C@H:10]([O:25]CC2C=CC=CC=2)[CH2:9]1)C1C=CC=CC=1.[ClH:33]>CCO>[ClH:33].[F:15][CH2:14][C@@H:12]1[CH2:13][NH:8][CH2:9][C@@H:10]([OH:25])[C@@H:11]1[OH:16]
Reactant: O[C@@]1(OCc2ccccc2)[C@H](CF)CN(Cc2ccccc2)C[C@H]1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: O[C@@H]1[C@H](CF)CNC[C@H]1O
Reaction time: 14 h
Yield: 85 %

Procedure:
To a solution of 5 (0.24 g, 0.57 mmol) in EtOH (40 mL) was added 0.5 mL of 6N HCl in 2-PrOH. The solvent was evaporated in vacuo and then co-evaporated 2× more with EtOH. The residue was dissolved in EtOH and hydrogenated at 55 psi using Pd(OH)2 as catalyst. After 14 hrs the starting material could no longer be detected and the solution was filtered and the filtrate was evaporated in vacuo. The residue was triturated with acetone and then filtered to give an off white solid (0.09 g, 85%) as the title compound. 1H NMR (DMSO-d6) 1.95-2.05 (m, 1H), 2.65 (t, 1H), 2.85 (t, 1H) 3.15-3.4 (m, 3H), 3.55 (m, 1H), 4.55 (m, 1H), 4.65 (m, 1H), 5.45-5.6 (dd, 2H), 9.05 (br s, 2H).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=1.O>CN(C)C(=O)C>[I:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][S:3][C:1](=[O:4])[CH3:2])=[CH:9][CH:10]=1
Reactant: CC([O-])=S
Reactant: BrCc1ccc(I)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)SCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following a general procedure (Zheng et al. (1999) Tetrahedron Lett. 40: 603–606), potassium thioacetate (2.20 g, 19.3 mmol) was added to a solution of 4-(bromomethyl)-1-iodobenzene (4.80 g, 16.2 mmol) in anhydrous N,N-dimethylacetamide (15 mL). The mixture was stirred overnight at rt, poured into water, and extracted with CH2Cl2. The combined organic extracts were washed with water, dried (Na2SO4) and evaporated. The resulting brown oil was distilled (90° C., 0.005 mmHg) to obtain a pale-yellow solid which solidified after a few days (4.68 g, 99%). mp 40–41° C.; 1H NMR δ 2.37 (s, 3H), 4.07 (s, 2H), 7.07, 7.64 (AA′BB′, 2×2H); 13C NMR δ 31.09, 33.6, 93.5, 131.6, 138.2, 138.4, 195.5; FAB-MS obsd 291.9425, calcd exact mass 291.9419; Anal. Calcd. for C9H9IOS: C, 37.00; H, 3.11; I, 43.44; S, 10.98; Found: C, 37.39; H, 3.13; 1,43.04; S, 11.26.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][C@H:19]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Reaction time: 1 h

Procedure:
Fmoc-protected dipeptide 72 (500 mg, 1.00 mmol) was treated with a 5% v/v solution of piperidine in DMF (5 mL). After stirring for 1 h, the reaction mixture was concentrated to dryness. The crude material was used for the next step without purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)(=[O:3])[CH3:2].Cl.[N:15](OC(C)(C)C)=[O:16]>C(Cl)Cl.O1CCOCC1>[CH:10]([N:8]1[C:7](=[O:13])[CH:6]=[CH:5][C:4]([C:1](=[O:3])/[CH:2]=[N:15]/[OH:16])=[CH:9]1)([CH3:11])[CH3:12]
Reactant: CC(C)(C)ON=O
Reactant: CC(=O)c1ccc(=O)n(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)/C=N/O)ccc1=O
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
5-Acetyl-1-isopropyl-2(1H)-pyridone was dissolved in CH2Cl2 (300 ml). The solution was cooled to −30˜−25° C. To the cooled solution were added 4N hydrogen chloride in dioxane (55.3 ml) and t-butyl nitrite (10.4 g) at −30˜−25° C. The temperature of the reaction mixture was raised to 20-25° C. The mixture was stirred at the same temperature for 3 hours. The precipitated crystal was collected by filtration, and dried in the air at ambient temperature, to give (1E)-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)(oxo)acetaldehyde oxime (14.0 g).
Reaction SMILES: C1(CO[C:6]([S:8][CH:9]2[N:12]([C:13](=[C:22]([OH:25])CBr)[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[C:11](=[O:26])[CH:10]2[NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=O)CC1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[O:30]([CH2:29][C:28]([NH:27][CH:10]1[C:11](=[O:26])[N:12]2[CH:13]([C:14]([O:16][CH2:17][C:18]([Cl:19])([Cl:21])[Cl:20])=[O:15])[C:22](=[O:25])[CH2:6][S:8][C@H:9]12)=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(O)CBr)C1SC(=O)OCC1CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(=O)CS[C@H]12
Reaction time: 1 h
Yield: 124.7 %

Procedure:
To a stirred solution of 2,2,2-trichloroethyl α[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxo-azetidine-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (330 mg) in methylene chloride (6 ml) is added aluminum chloride (330 mg) at room temperature, and the mixture is stirred for 60 minutes. The reaction mixture is poured into ice cold diluted hydrochloric acid, and is extracted with ethyl acetate. The extract solution is washed with diluted hydrochloric acid and water, dried, and evaporated to give 2,2,2-trichloroethyl 7-phenoxyacetamido-3-oxocepham-4-carboxylate (300 mg). Foam. IR: νmaxCHCL3 3420, 1780, 1685 cm-1. NMR: δCDCl 3.37s2H, 4.53s2H, 4.85s2H, 5.07d(4)1H, 5.20-5.73m2H, 6.8-7.7m6H.
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[CH:15][C:9]([C:10](OCC)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.O.[NH2:18][NH2:19]>CCO>[N:1]1([C:6]2[CH:16]=[CH:15][C:9]([C:10]([NH:18][NH2:19])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1ccc(-n2cccn2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(-n2cccn2)cc1
Reaction time: 144 h

Procedure:
To a solution of ethyl 4-(1H-pyrazol-1-yl)benzoate (711 mg, 3.29 mmol) in absolute EtOH (50 mL) was added hydrazine monohydrate (1.6 mL, 32.9 mmol) at room temperature. The reaction mixture was heated to reflux and stirred for 6 d, then concentrated under reduced pressure. The residue was suspended in H2O (30 mL), filtered, washed with H2O (2×20 mL) and EtOH (2×20 mL) to provide the title compound as an off white solid (101 mg, 15%): 1H NMR (400 MHz, CDCl3, δ in ppm) 9.84 (s, 1H), 8.62-8.59 (m, 1H), 7.98-7.90 (m, 4H), 7.81-7.78 (m, 1H), 6.61-6.57 (m, 1H), 4.51 (br d, J=3.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][Sn:9](Cl)([CH3:11])[CH3:10]>C1COCC1>[F:1][C:2]1[C:7]([Sn:9]([CH3:11])([CH3:10])[CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Fc1ccccn1
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cccnc1F

Procedure:
Metalation of 2-fluoropyridine was performed as described in Estel, Marsais and Queguiner, J. Org. Chem. 53, 2740-2744, 1988. The lithium anion was quenched with 1 eq. of trimethyl tin chloride in THF (1 M) at −78° C. and stirred for 30′, quenched with 1 M sodium bicarbonate and extracted with ethyl acetate. Upon Na2SO4 drying and evaporation under reduced pressure the resulting oil was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:15])C(=O)[NH:7]2.[OH-].[Na+].OO.CC[N:22]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[NH2:7][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([NH2:22])=[O:15]
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: OO
Agent: On1nnc2ccccc21
Product: COc1cc(N)c(C(N)=O)c(OC)c1

Procedure:
2-Amino-4,6-dimethoxybenzamide can be prepared from 4,6-dimethoxyisatoic anhydride. The 4,6-dimethoxyisatoic anhydride may be prepared by a reaction of 4,6-dimethoxyanthranilic acid with phosgene (U.S. Pat. No. 4,191,840 and Org. Synth. 1947, 27, 45). Alternatively, to prepare 2-amino-4,6-dimethoxybenzamide, 3,5-dimethoxyaniline may be converted to its hydrochloride salt, after which the salt is reacted with oxalyl chloride to give 4,6-dimethoxyisatin. The isatin may then be converted to the target compound via an unstable carboxyl intermediate by reaction with sodium hydroxide and hydrogen peroxide followed by an EDCl/HOBt-mediated coupling to form 2-amino-4,6-dimethoxybenzamide (WO2008/92231).