Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]([F:15])([F:14])[O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>CCO>[OH:2][N:1]=[C:8]([C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[O:5][C:4]([F:3])([F:14])[F:15])[NH2:9]
Reactant: N#Cc1ccccc1OC(F)(F)F
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccccc1OC(F)(F)F
Temperature: 60 °C
Reaction time: 10 h
Yield: 93.5 %

Procedure:
Hydroxylamine (Fluka 55458; 50% in water; 4.81 mL; 80.16 mmol; 5 eq.) was added to a solution of 2-(trifluoromethoxy)benzonitrile (Apollo PC7438E; 3 g; 16.03 mmol; 1 eq.) in EtOH (20 mL) and the reaction mixture was stirred at 60° C. for 10 hours. Evaporation in vacuo gave a white solid, which was further dried under high vacuum to afford the title compound (3.30 g, 94%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10](O)(=[O:14])[CH:11]([CH3:13])[CH3:12].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CCOCC
Product: CC(C)C(=O)NNc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a solution of 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 2.08 g, 16.4 mmol), isobutyric acid (1.82 mL, 19.6 mmol), and HOBt hydrate (251 mg, 1.64 mmol) in DCM (50 mL), EDC (3.76 g, 19.6 mmol) was added, and the resulting orange solution was stirred at room temperature for 18 h. Sat. aq. NaHCO3 (50 mL) was added, and the mixture was stirred vigorously for 15 min. The organics were washed with sat. aq. NaHCO3 (50 mL), passed through a hydrophobic frit, and concentrated under vacuum to leave a pale brown solid. The solid was suspended in Et2O (50 mL) and filtered, washing with Et2O (25 mL), to leave a white solid (1.48 g, 46%). The ethereal washings were concentrated under vacuum and the residue suspended in Et2O (10 mL), filtered, washed with Et2O (2×2 mL), to leave a white solid (330 mg, 10%). The solids were combined (1.81 g, 56%). 1H NMR (400 MHz, CDCl3): 1.23 (6H, d), 2.50 (1H, sept), 6.65 (1H, dd), 6.80 (1H, d), 7.29 (1H, ddd), 7.77 (1H, br s), 8.01 (1H, d).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[C:45]1[CH:46]=[CH:47][C:48]2[S:52][C:51]([S:53]([NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([C:63]4[NH:67][N:66]=[N:65][N:64]=4)[CH:58]=3)(=[O:55])=[O:54])=[C:50]([CH3:68])[C:49]=2[CH:69]=1.Cl.[OH-].[Na+]>C1COCC1>[CH3:68][C:50]1[C:49]2[CH:69]=[C:45]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:46]=[CH:47][C:48]=2[S:52][C:51]=1[S:53]([NH:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([C:63]2[NH:64][N:65]=[N:66][N:67]=2)[CH:58]=1)(=[O:55])=[O:54]
Reactant: C1CCNC1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2ccc(Br)cc12
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2ccc(N3CCCC3)cc12
Temperature: 130 °C
Reaction time: 0.08 h
Yield: 4.3 %

Procedure:
A micro-tube was charged with tris(benzylideneacetone)dipalladium (Pd2(dba)3) (0.5 mg, 0.0005 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.5 mg, 0.0012 mmol) and pyrrolidine (9 mg, 0.12 mmol). The tube was sealed and flushed with nitrogen. LiHMDS (1M in THF, 120 μL, 0.12 mmol) and a solution of 5-bromo-3-methyl-N-[3-(1H-tetrazol-5-yl)phenyl]-1-benzothiophene-2-sulfonamide (Example 34) (45 mg, 0.1 mmol) in dry THF were added to the reaction mixture via syringes. The reaction mixture was heated in a microwave reactor at 130° C. for 1000 s. Aqueous HCl (1 M) was added and the mixture was stirred at room temperature for 5 min. The solution was then neutralized by addition of aqueous NaOH. The crude product was purified by preparative HPLC (ACE C8, 5 μm 21×50 mm, flow 25 ml/min, 50 mM NH4OAc in water/CH3CN) to give 1.9 mg (4%) of the title compound. MS (ESI+) calcd for C20H20N6O2S2 440.108915, found 440.108815.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([N:9]1[CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:12][CH2:11][CH2:10]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1cccc2c1CNCCS2
Agent: Cl
Product: CC(=O)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.6 g, prepared in a similar manner to its hydrochloride, Example 1 above) in acetic anhydride (15 ml) was stirred at room temperature for one hour. The reaction mixture was poured into ice and extracted with dichloromethane. The organic layer was dried and the solvent was removed by evaporation to give 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 1.68 g (m.p. 79°-81° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([N:19]4[CH2:22][CH:21]([N:23]5[CH2:28][CH2:27][N:26]([C:29]([C:31]6[S:32][CH:33]=[CH:34][N:35]=6)=[O:30])[CH2:25][CH2:24]5)[CH2:20]4)=[O:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:43])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:43][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:17]([N:19]3[CH2:20][CH:21]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([C:31]5[S:32][CH:33]=[CH:34][N:35]=5)=[O:30])[CH2:25][CH2:24]4)[CH2:22]3)=[O:18])[CH:12]=2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(c1ccc2c(ccn2-c2ccc(F)cc2)c1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)c(Cl)cn2-c1ccc(F)cc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Cpd 487 (0.2 mmol, 100 mg) in CCl4 (4 mL) and CH2Cl2 (4 mL) was added NCS (0.25 mmol, 33 mg). The reaction mixture was stirred at room temperature for 4 h. It was then diluted with CH2Cl2 and washed with 1N aqueous NaOH and H2O, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave 51 mg of Cpd 1365. MS m/z (M+H+) 524.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[I:13](O)(=O)=O.II>C(O)C>[I:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: [O-][I+2]([O-])O
Agent: II
Solvent: CCO
Product: COc1cc(OC)c(I)c(OC)c1
Temperature: 50 °C
Yield: 171.6 %

Procedure:
1,3,5-Trimethoxybenzene (14.5 g, 0.086 mol) was dissolved in 10 mL of ethanol at rt before warming to 50° C. in a waterbath after which, an aqueous solution of iodic acid (7.6 g, 0.043 mol) was added. Solid iodine (21.88 g, 0.086 mol) was dissolved in 20 mL of ethanol and the resultant solution was added portion-wise over 60 min to the reaction mixture. Stirring was continued at 50° C. until the color of I faded and a white precipitate appeared. The reaction mixture2 was stirred at room temperature for 18 h. The precipitate that formed was isolated via vacuum filtration, washed with ethanol and crystallized from methanol to yield 6 (21.7 g, 86%) as white crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.I[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>O1CCCC1.C(OCC)C.[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: c1cocn1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ncco2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C., stirred solution of oxazole (190 μL, 3.8 mmol) in tetrahydrofuran (10 mL) is added n-butyl lithium (2.6 mL of a 1.6 M solution in hexanes, 4.2 mmol). After 30 min, zinc chloride (11.5 mL of a 1.0 M solution in diethyl ether, 11.5 mmol) is added. The reaction mixture is warmed to 0° C. and methyl 4-iodobenzoate (1 g, 3.8 mmol) and palladium(0) tetrakis(triphenylphosphine) (530 mg, 0.4 mmol) are added. The reaction mixture is heated at 70° C. for 20 h under argon, cooled to room temperature, and then partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (3:1 hexanes/ethyl acetate) yields the title compound. 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 4H), 8.07–8.05 (m, 1H), 7.36–7.35 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[CH2:12][N:13]([CH:33]([CH3:35])[CH3:34])[C:14]([C:16]1[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[N:18][C:19](S(C)(=O)=O)=[N:20][CH:21]=1)=[O:15]>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[CH2:12][N:13]([CH:33]([CH3:35])[CH3:34])[C:14]([C:16]1[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[N:18][C:19]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:20][CH:21]=1)=[O:15]
Reactant: C1CCNCC1
Reactant: COc1cccc(CN(C(=O)c2cnc(S(C)(=O)=O)nc2-c2ccccc2F)C(C)C)c1
Solvent: C1CCOC1
Product: COc1cccc(CN(C(=O)c2cnc(N3CCCCC3)nc2-c2ccccc2F)C(C)C)c1
Temperature: 80 °C

Procedure:
Piperidine (0.0054 g, 0.064 mmol) was added to a stirred solution of N-(3-methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.015 g, 0.032 mmol) in THF (1 mL) and the mixture was heated at 80° C. for 1 h. The solvent was removed under reduced pressure, and the product was purified by preparative HPLC (5-80% CH3CN/0.05% TFA gradient over 15 min) to give N-(3-methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2-(piperidin-1-yl)pyrimidine-5-carboxamide Compound No. 20 (0.012 g, 81%).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[C:19]([NH2:27])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:27]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:26][CH:15]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Reactant: NC(=O)c1ccccc1
Product: O=C(O)COc1ccc(Br)cc1-c1coc(-c2ccccc2)n1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and benzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.6 min, m/z 374/376 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([NH:7][S:8]([C:11]1[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1)(=[O:10])=[O:9])=[O:6])[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)Cl>[CH3:3][CH:2]([NH:4][C:5]([NH:7][S:8]([C:11]1[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[N:13][C:14]([S:17]([CH3:18])=[O:32])=[N:15][CH:16]=1)(=[O:10])=[O:9])=[O:6])[CH3:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc(S(=O)(=O)NC(=O)NC(C)C)c(Nc2cccc(C)c2)n1
Solvent: ClCCl
Product: Cc1cccc(Nc2nc(S(C)=O)ncc2S(=O)(=O)NC(=O)NC(C)C)c1
Yield: 80.8 %

Procedure:
N-[[(1-Methylethyl)amino]carbonyl]-4-[(3-methylphenyl)amino]-2-(methylthio)-5-pyrimidinesulfonamide (4.46 g, 11.29 mmol) was suspended in methylene chloride (250 mL) and m-chloroperoxybenzoic acid (2.44 g, 11.29 mml) was added as a solid. The mixture was then stirred until it became homogeneous. The methylene chloride was removed under reduced pressure and the residue was triturated with hot tert-butyl methyl ether (100 mL). The beige solid was filtered, washed with tert-butyl methyl ether and dried in a vacuum oven at 65° C. for three hours to yield 3.75 g (9.12 mmol, 81%) of pure product as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14]>>[CH3:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: COCCCCCl
Reactant: O=C1CCNCC1
Product: COCCCCN1CCC(=O)CC1

Procedure:
1-(4-Methoxybutyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-4-methoxybutane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[N:2].C(N(CC)CC)C.ClC(OCC)=O.O.[NH2:26][NH2:27]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:26][NH2:27])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: NN
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)NN)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
A solution of 3-cyanobenzoic acid (1.0 g, 6.80 mmol) in tetrahydrofuran (10 mL) at 0° C. was treated with triethylamine (2.84 mL, 20.4 mmol) and ethyl chloroformate (0.78 mL, 8.16 mmol) and stirred at 0° C. for 1 h. The resulting white precipitate was removed by filtration and the filtrate cooled back to 0° C. Hydrazine monohydrate (1.00 mL, 20.4 mmol) was added and the mixture stirred at ambient temperature for 3.5 hours. The reaction mixture was then concentrated to dryness in vacuo and the residue was dissolved in dichloromethane (150 mL). The organic phase was sequentially washed with water (100 mL), 1 N sodium hydroxide (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography using 3% methanol in dichloromethane afforded 0.32 g (30%) of 3-cyanobenzhydrazide.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: O=[N+]([O-])c1ccc(O)c(I)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1I
Yield: 63.6 %

Procedure:
A solution of 2-iodo-4-nitrophenol (2.2 g, 8.3 mmol), tert-butyl bromoacetate (1.6 mL, 11 mmol), and potassium carbonate (2.3 g, 17 mmol) in N,N-dimethylformamide (20 mL) was stirred at 20° C. for 60 h. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (500 mL). The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. This material was purified by flash column chromatography to give the desired product (2.0 g, 60%).
Reaction SMILES: [CH2:1]([N:8]1[CH:11]([C:12]#[CH:13])[CH:10]([CH:14]([OH:16])[CH3:15])[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNC1(NC)C=CN=CC1.[CH2:28]([O:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH:11]([C:12]#[CH:13])[CH:10]([CH:14]([O:16][C:36]([O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])[CH3:15])[C:9]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C#CC1C(C(C)O)C(=O)N1Cc1ccccc1
Agent: CNC1(NC)C=CN=CC1
Solvent: ClCCl
Product: C#CC1C(C(C)OC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 0 °C
Yield: 68.8 %

Procedure:
To a solution of 36 mg (0.16 mmol) of 1-benzyl-4-ethynyl-3-(1-hydroxyethyl)-2-azetidinone in 2 ml of methylene chloride, 30 mg (0.25 mmol) of 4,4-dimethylaminopyridine and 0.04 ml (0.25 mmol) of benzyloxycarbonyl chloride were added at -10° C. and the mixture was stirred for a night. Ice water was added to the reaction solution and the resultant was extracted three times with methylene chloride. The extract was washed with a saturated solution of NaCl, dried with anhydrous magnesium sulfate, concentrated and purified with 5 g of silica-gel column (hexane:ether 2:3) to give 40 mg of 1-benzyl-3-(1-benzyloxycarbonyloxyethyl)-4-ethynyl-2-azetidinone (yield: 69%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([O:16]C)=[O:15])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[CH3:23][Si:24]([CH2:27][CH2:28][O:29][CH2:30]Cl)([CH3:26])[CH3:25]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([OH:16])=[O:15])[CH:9]=2)[N:4]([CH2:30][O:29][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1cccc(-c2cnc3[nH]nc(I)c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2cc(-c3cccc(C(=O)O)c3)cnc21
Temperature: 25 °C
Yield: 15.5 %

Procedure:
To a solution of methyl 3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoate (988 mg, 2.61 mmol) in DMF was added sodium hydride (60% in mineral oil, 525 mg, 13.03 mmol) at −40° C. The mixture was stirred for 60 minutes before SEMCl (920 μl, 5.22 mmol) was added. The reaction was warmed to room temperature and quenched with methanol and water. Acetic acid was then used to adjust the pH to 4-5. The mixture was then extracted with ethyl acetate (3×) and the organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography purification of the resulting crude product afforded 3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoic acid (200 mg, 15% yield) as solids. MS: m/z 517.9 (M+Na+).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:10]=2[CH2:11][N:12]2[C@@H:16]([CH3:17])[C@@H:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[O:14][C:13]2=[O:32])[S:7][CH:8]=1)(=[O:3])[CH3:2].[CH3:41][Mg+].[Br-]>CCOCC>[F:31][C:28]([F:29])([F:30])[C:20]1[CH:19]=[C:18]([C@H:15]2[O:14][C:13](=[O:32])[N:12]([CH2:11][C:10]3[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:9]=3[C:6]3[S:7][CH:8]=[C:4]([C:1]([OH:3])([CH3:41])[CH3:2])[N:5]=3)[C@H:16]2[CH3:17])[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=1
Reactant: C[Mg+]
Reactant: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: [Br-]
Solvent: CCOCC
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(C(C)(C)O)cs1

Procedure:
To a −40° C. solution of (4S,5R)-3-[2-(4-acetyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Example 135) (38.1 mg, 0.064 mmol) in THF/heptanes (1:1, 8 mL) was added MeMgBr (21 μL of a 3M solution in Et2O, 0.07 mmol). The temperature was maintained between −40° C. and −20° C. and the reaction was monitored closely by TLC; additional MeMgBr was added dropwise until nearly all starting ketone was consumed. At this point, the reaction was quenched by pouring it into saturated NH4Cl (15 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (10 to 60% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.20 (40% EtOAc/hexanes). LCMS=613 (M+1)+. 1H NMR (CD2Cl2, 500 MHz) δ 7.90 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.77 (s, 3H), 7.71 (d, J=8.3 Hz, 1H), 7.32 (s, 1H), 5.59 (d, J=8.0 Hz, 1H), 5.28 (d, J=15.8 Hz, 1H), 4.74 (d, J=15.8 Hz, 1H), 3.89 (m, 1H), 3.01 (bs, 1H), 1.63 (s, 3H), 1.62 (s, 3H), 0.64 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][OH:5].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].CCOCC>C1COCC1.O.CCCCCC>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][O:5][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: COc1ccc(Br)c(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
Under a nitrogen atmosphere, 23.0 g (0.11 mol) of 2-bromo-5-methoxybenzyl alcohol (13) was dissolved in 100 mL of anhydrous THF. 14.43 g (0.21 mol) of imidazole was added, followed by 17.6 g (0.12 mol) of t-butyl dimethylsilylchloride. The reaction mixture was allowed to stir overnight at ambient temperature. Ether was added and the reaction was diluted with water (200 mL). The aqueous layer was separated and extracted with ether (2×300 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude product. The crude product was loaded onto a 4 inch×6 inch silica gel column. Using 40% ether in hexane as an eluant afforded 33.63 g (96%) of (2-bromo-5-methoxy-benzyloxy)-tert-butyl-dimethyl-silane (14).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].[F:24][C:25]1[C:30](O)=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[F:24][C:25]1[C:30]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]([O:9][CH2:10][C:11]2[C:23]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:8])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C([O-])CCCC(=O)OCc1cccc2c1Cc1ccccc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CCCC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1cccc2c1Cc1ccccc1-2
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Fluorenylmethyl glutarate (2.5 kg) (prepared as described in Step 4) and pentafluorophenol (1.63 kg) were dissolved in ethyl acetate (25 L). The solution was treated with a solution of dicyclohexylcarbodiimide (1.83 kg) in ethyl acetate (7.5 L) and the mixture was stirred at 20° C. overnight. The resulting slurry was filtered and the solids were washed through with ethyl acetate (10 L). The filtrate was evaporated at atmospheric pressure to a volume of 7.5 L and diluted with hexane (75 L). The slurry was filtered at 60-65° C. then allowed to cool to room temperature and stirred overnight. The slurry was cooled to 0° C. for 1 hour, the solid collected by filtration and washed with 10:1 hexane/ethyl acetate (15 L). The solid was dried in vacuo at 45° C. to afford the title compound as a white crystalline solid.