Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1[NH:21][C:22](=[O:24])[CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][O:28][CH3:29]>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1[N:21]([CH2:26][CH2:27][O:28][CH3:29])[C:22](=[O:24])[CH3:23])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COCCBr
Reactant: CC(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN(C(C)=O)c1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.1 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 1.78 g, 44.5 mmol) in N,N-dimethylformamide (100 mL) was added dropwise a solution of N-[2-(benzyloxy)-4-bromo-6-nitrophenyl]acetamide (13.5 g, 37.1 mmol, Step 1) in N,N-dimethylformamide at 0° C. over 10 minutes. After stirring at 0° C. for 20 minutes, 1-bromo-2-methoxyethane (7.21 g, 51.9 mmol) was added, and the mixture was stirred at 50° C. for 2 hours. After cooling to room temperature, the mixture was poured onto water, and the aqueous layer was extracted with ethyl acetate/toluene (3:1). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3:1) to afford the title compound as a gray solid (12.1 g, 77%).
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[O:7]=[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].S(=O)(=O)(O)O>>[C:1]([O:5][O:6][C:8]1([O:7][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)(C)OO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCCC1(OOC(C)(C)C)OOC(C)(C)C
Temperature: -10 °C

Procedure:
Ethyl 2,2-di(tertiary-butylperoxy)-1-cyclopentanecarboxylate was prepared by the addition of 92.28% TBHP (tertiary butyl hydroperoxide) (24.41 g, 0.2500 moles) to 95% ethyl 2-oxo-cyclopentanecarboxylate (16.44 g, 0.1000 mol) in a three necked 250-mL round bottomed flask equipped with a thermometer and mechanical stirrer at room temperature. The solution was cooled to −10° C. via a dry ice-acetone bath and 70% sulfuric acid (16.81 g, 0.1200 mol) was added dropwise to the solution with temperature at −10° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for three hours with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.5 or greater. The organic layer was then dried over MgSO4, filtered through a Buchner funnel and analyzed for purity by gas chromatography (87.98% by area). Purification by chromatography (silica gel, 90:10 petroleum ether/diethyl ether) afforded a liquid product: 13C NMR (75 MHz, CDCl3) δ 171.8 (C═O), 116.8 (O—C—O, cyclic), 79.6 (C(CH3)3, 79.2 (C(CH3)3, 59.8 (O—CH2CH3), 49.5 (CH, cyclic), 32.9 (CH2, cyclic), 27.7 (CH2, cyclic) 26.2 ((CH3)3), 26.1 ((CH3)3), 22.1 (CH2, cyclic) 13.8 (CH2CH3); IR (neat) ν 1735, 1364, 1198, 878 cm−1; Analysis calculated for C16H30O6; C, 60.36, H, 9.50; O, 30.15; found: C, 60.36; H, 9.58; O, 29.11.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]=[C:6]([CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:7].C=CC=CC.[C:17]1([CH3:23])[CH:22]=CC=[CH:19][CH:18]=1>>[CH3:7][C:6]([CH:8]1[C:17]([CH3:23])([CH3:22])[CH2:18][CH:19]=[CH:10][CH:9]1[CH3:11])=[O:5]
Reactant: Cc1ccccc1
Reactant: CC(=O)C=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C=CC=CC
Product: CC(=O)C1C(C)C=CCC1(C)C
Reaction time: 3 h

Procedure:
In a 3-liter four-necked flask equipped with a dropping funnel, thermometer, condenser and a stirrer, placed were aluminum chloride (70 g) and toluene (300 ml) under ice cooling in a nitrogen gas stream. Under stirring, a solution of mesityl oxide (120 g) in toluene (300 ml) was added drop by drop during 1 hour at 2 to 5° C. After the addition, a solution of 1,3-pentadiene (450 g) in toluene (1,200 ml) was added drop by drop at 0 to −5° C. during 4 hours. After the addition, the mixture was stirred at the same temperature for 3 hours. After 3 hours at 30 to 40° C., the reaction was completed. The reaction mixture was cooled, followed by decomposition, washing with water (1,200 ml). After further washing with water (1,200 ml), the reaction mixture was washed with a 5% aqueous solution (500 ml) of sodium carbonate. Final washing with saturated salt solution (500 ml) gave a toluene solution of the product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].Br.Br[CH2:19][CH2:20][CH2:21][NH2:22].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:7][N:8]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:9][CH2:10]1)=[O:4]
Reactant: NCCCBr
Reactant: COC(=O)C1(c2ccccc2)CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)C1(c2ccccc2)CCN(CCCN)CC1
Yield: 72.4 %

Procedure:
A mixture of 4-methoxycarbonyl-4-phenylpiperidine (8.5 g, 0.039 mol), 3-bromopropylamine hydrobromide (12.7 g, 0.058 mol), potassium carbonate (13.475 g, 0.0957 mole), and KI (3.24 g, 0.0195 mol) in 1,4-dioxane (200 mL) was stirred and refluxed for 24 hours. Dioxane was evaporated at reduced pressure, the residue was treated with ice-cold 6 N NaOH (400 mL) and extracted with CH2Cl2 (4×120 mL). Solvent was evaporated from the combined dried (K2CO3) extracts and the residue was purified by column chromatography on silica gel using CHCl3/MeOH/2 M NH3 in MeOH (20:2:1) as the eluent to afford the product as a viscous oil (7.8 g, 72%).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[CH:11]=2)[N:4]=1.Br[C:28]1[CH:29]=[N:30][N:31]([CH:33]([C:35]([CH3:37])=[CH2:36])[CH3:34])[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:26][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([C:28]3[CH:29]=[N:30][N:31]([CH:33]([C:35]([CH3:37])=[CH2:36])[CH3:34])[CH:32]=3)[CH:13]=[C:12]([CH3:25])[CH:11]=2)[N:4]=1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C=C(C)C(C)n1cc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C=C(C)C(C)n1cc(-c2cc(C)cc(Nc3nccc(C(F)F)n3)c2)cn1
Temperature: 90 °C

Procedure:
4-(Difluoromethyl)-N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine (400 mg, 1.11 mmol) and 4-bromo-1-(3-methylbut-3-en-2-yl)-1H-pyrazole (238 mg, 1.11 mmol) were dissolved in dioxane (4 ml) and degassed with nitrogen for 5 minutes. PdCl2(dppf)-CH2Cl2 (90 mg, 0.11 mmol) and sodium carbonate (2.0 M in water, 1.1 ml, 2.2 mmol) were added and the reaction was sealed and heated to 90° C. for 12 hours. The reaction was cooled, diluted with water (10 mL), and the product was extracted with ethyl acetate (2×20 mL). The extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica two times utilizing (10-50% ethyl acetate/hexanes) and (0-5% acetone/dichloromethane) to afford 4-(difluoromethyl)-N-(3-methyl-5-(1-(3-methylbut-3-en-2-yl)-1H-pyrazol-4-yl)phenyl)pyrimidin-2-amine. MS ESI calcd. for C20H22F2N5 [M+H]+ 370. found 370.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(Br)ccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 106.1 %

Procedure:
To a pre-stirred solution of 4-bromo-2-fluorobenzaldehyde (1.82 g, 9.0 mmol) and piperidine (0.97 mL, 9.9 mmol) in DCM (40 mL) at 0° C. was added sodium triacetoxyborohydride (2.85 g, 13.4 mmol) in portions. The reaction mixture was allowed to warm to ambient temperature and stirred for an additional 14 h. The reaction was quenched by the addition of water (30 mL) and extracted with ethyl acetate (75 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (2.6 g, 84%) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 7.33-7.17 (m, 3H), 3.49 (d, J=1.6 Hz, 2H), 2.43-2.33 (m, 4H), 1.61-1.53 (m, 4H), 1.46-1.38 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1nn(-c2ccccc2)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nn(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
Intermediate c (9 g, 0.042 mol) was added to DMF (80 mL) under an ice bath. To the mixture was added NaH (1.3 g, 0.054 mol) in batch under an ice bath. After stirring for 30 min, benzyl bromide (3.1 mL, 0.042 mol) was added dropwise. After the dropwise addition, the reaction was conducted at 50° C. for 4 h. After completion of the reaction, the reaction solution was poured into water (300 mL). A great deal of solid separated out and was filtered by suction. The filtered cake was washed with water and dried to produce Intermediate j (8.1 g) in a yield of 81%.
Reaction SMILES: [Si]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[C:22]([C:23]([F:26])([F:25])[F:24])=[C:21]([C:27]([N:29]([CH2:39][C:40]([C:42]3[C:47]([Cl:48])=[CH:46][N:45]=[CH:44][C:43]=3[Cl:49])=[O:41])[CH2:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=3)=[O:28])[CH:20]=[N:19]2)[CH2:14][CH2:13]1)=[O:11])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:49][C:43]1[CH:44]=[N:45][CH:46]=[C:47]([Cl:48])[C:42]=1[C:40](=[O:41])[CH2:39][N:29]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[C:27]([C:21]1[CH:20]=[N:19][N:18]([C@H:15]2[CH2:14][CH2:13][C@H:12]([C:10](=[O:11])[NH:9][OH:8])[CH2:17][CH2:16]2)[C:22]=1[C:23]([F:26])([F:24])[F:25])=[O:28]
Reactant: CC(C)(C)[Si](C)(C)ONC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cncc3Cl)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(CN(Cc1cc(F)cc(F)c1)C(=O)c1cnn([C@H]2CC[C@H](C(=O)NO)CC2)c1C(F)(F)F)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of compound 5-5 (100 mg, 0.13 mmol) in THF (8 mL) was added TBAF (1 M in THF, 0.20 mL, 0.20 mmol) dropwise and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with MeOH (2 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 7% MeOH/DCM as eluent) to provide the compound of example 5 (19 mg, 22%) as a white solid. 1H NMR (CDCl3) rotamers present δ 8.54 and 8.48 (2H, 2×s); 7.64 and 7.60 (1H, 2×s); 6.84-6.68 (3H, m); 4.82-4.25 (5H, m); 2.23-2.04 (7H, m); 1.83-1.73 (2H, m); LCMS (APCI): 634 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]=1)([O-])=O>C(OCC)(=O)C.[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]=1
Reactant: O=c1oc(-c2ccccc2[N+](=O)[O-])nc2ccccc12
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Nc1ccccc1-c1nc2ccccc2c(=O)o1
Reaction time: 3 h

Procedure:
2-(2-Nitrophenyl)-3,1-benzoxazin-4-one (1.1 g, 4.10 mmole) was suspended in 40 ml of ethyl acetate, with platinum oxide (100 mg) being added, and the resulting reaction mixture was hydrogenated at atmospheric pressure with vigorous stirring. After 3 hours, the catalyst was removed and the solvent was rotoevaporated. The residual yellow oil was subjected to flash chromatography to give a homogeneous product. Recrystallization from acetone provided the analytical sample, m.p. 163°-165° C. (lit.* 162° C.).
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([F:16])([F:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])C.Cl>[OH-].[Na+]>[F:15][C:5]([F:16])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(F)(F)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(F)(F)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
According to the above-described scheme, 2,2-difluoro-2-(2-nitrophenyl)acetic acid ethyl ester (Compound 2c; 1.01 g, 4.1 mmol) and 1N NaOH solution (10 mL) were put into an eggplant flask, and the mixture was stirred at room temperature for 19 hours. After the reaction, the reaction mixture was neutralized with 5% HCl solution, extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2,2-difluoro-2-(2-nitrophenyl)acetic acid (Compound 4c) was obtained with a yield of 85%.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[N:45]1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>CS(C)=O.O>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:45])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: c1ccncc1
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.5 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) in DMSO (5 mL) was added Boc anhydride (69 mg, 0.31 mmol) followed by pyridine (24 mg, 0.26 mmol) and stirred at room temperature for 5 min. Ammonium bicarbonate (62 mg, 0.78 mmol) was added and stirred for additional 1 h. Reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 59 mg (59%) of the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]1([O:18][CH2:17]1)[CH3:16]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]([CH3:17])([OH:18])[CH3:16])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CO1
Reactant: Clc1ccc(N2CCNCC2)cn1
Solvent: CO
Product: CC(C)(O)CN1CCN(c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To 1-(6-chloropyridin-3-yl)piperazine (0.600 g, 3.04 mmol) in methanol (1.5 mL) was added dropwise isobutylene oxide (0.274 mL, 3.04 mmol). The reaction was left to stir at room temperature overnight. An additional 0.15 equivalents of isobutylene oxide were added and the reaction was placed in a 55° C. oil bath overnight. Solvent was removed in vacuo. Silica gel chromatography (gradient elution 2 to 10% methanol in DCM) afforded compound 251 (0.450 g, 55.0% yield). 1H NMR (400 MHz, CDCl3) δ 0.95-1.50 (m, 7 H) 2.23-3.61 (m, 9 H) 7.12-7.24 (m, 2 H) 8.03 (br. s., 1 H) ppm.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH2:9]1)=O)(C)(C)C.C(O)([C:23]([F:26])([F:25])[F:24])=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:24][C:23]([F:26])([F:25])[C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH2:9]1)=[O:5]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccccc1CC1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccccc1CC1CN(C(=O)C(F)(F)F)C1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of 3-(2-methoxy-benzyl)-azetidine-1-carboxylic acid tert-butyl ester (370 mg, 1.3 mmol) in DCM (10 mL) was added TFA (3 mL). After stirring for 16 h, TLC analysis indicated complete consumption of the starting material. To quench the reaction, saturated NaHCO3 solution and EtOAc were added. The aqueous portion was extracted twice with EtOAc and the combined organic extracts were dried (Na2SO4) and concentrated. To a solution of this material in DCM (20 mL) was added triethylamine (370 μL, 2.60 mmol) followed by trifluoroacetic anhydride (204 μL, 1.50 mmol). After 1 h, saturated NaHCO3 solution and EtOAc were added. The aqueous portion was extracted twice with EtOAc and the combined organic extracts were dried (Na2SO4) and concentrated to provide the title compound (274 mg, 75%). MS (ESI): mass calcd. for C13H14F3NO2, 273.1; m/z found, 274.2 [M+H]+. 1H NMR (CDCl3): 7.26-7.20 (m, 1H), 7.07 (dd, J=7.4, 1.6 Hz, 1H), 6.94-6.82 (m, 2H), 4.41 (dd, J=9.6, 8.4 Hz, 1H), 4.23-4.14 (m, 1H), 4.12-4.08 (m, 1H), 3.93-3.84 (m, 1H), 3.82 (s, 3H), 3.18-3.00 (m, 1H), 2.95-2.91 (m, 2H).
Reaction SMILES: O.[C:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1C[CH2:12][CH2:11][CH2:10]1.C(Br)C=C>C1(C)C=CC=CC=1>[CH2:12]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:8])[CH:11]=[CH2:10]
Reactant: O=C1CCCCC1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: C=CCBr
Solvent: O
Product: C=CCC1CCCCC1=O

Procedure:
Into a 2 liter round bottom flask, equipped with Dean-Stark water separator, cyclohexanone (186 g, 1.90 moles, Aldrich) was dissolved in 1 liter toluene, and then pyrrolidine (292 g, 4.1 moles) was added. The mixture was brought to reflux overnight, during which 55 mL of water was collected. After switching to a distillation head, excess pyrrolindine and toluene were distilled off (1.2 liter). When most of the volatiles had been removed, aspirator vacuum was applied to assist in removal of residual toluene. In the same flask, the residue was dissolved in 1.2 liter of acetonitrile. Allyl bromide (305 g, 2.5 moles) was added dropwise. The mixture was heated slowly to gentle reflux overnight. After distilling off most of the acetonitrile and cooling, 1.2 liter of water was added and heated to reflux for 30 minutes. Extracted with ether after the mixture was cooled (200 mL×3). Combined ether layer was dried over sodium sulfate. The crude product, after removing the solvent, was purified by vacuum distillation: 73-78° C., 6.7 mmHg, Yield: 156 grams (59% for two steps). See also, Stork et al., J. American Chem. Soc., 85:207-222 (1963), and Johnson et al., J. American Chem. Soc., 88:149-159 (1966).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([OH:13])=O)[CH:6]=1)=[O:4].C(Cl)(=O)C([Cl:17])=O>ClCCl>[Cl:17][C:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][N:8]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:13]
Reactant: COC(=O)c1ccnc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccnc(C(=O)Cl)c1

Procedure:
To 4-(methoxycarbonyl)picolinic acid (150 g, 1.62 mol) in dichloromethane (500 mL) was added oxalyl chloride (400 mL) keeping the temperature at 25-30° C. for 3 days. The reaction was evaporated in vacuo to afford methyl 2-(chlorocarbonyl)isonicotinate as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14](OCC)=[O:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][OH:15])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)c1cnoc1-c1cc(Cl)cc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.4 %

Procedure:
To a solution of ethyl 5-(3,5-dichlorophenyl)isoxazole-4-carboxylate (10.82 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 100 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(3,5-dichlorophenyl)-4-isoxazolylmethanol (10.28 g, yield 94%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 104–105° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[Cl:40][C:41]1[C:42]([F:50])=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[NH2:32][C:4]1[S:3][C:2]([C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([Cl:40])[C:42]=2[F:50])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1cccc(Cl)c1F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(Cl)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-chloro-2-fluorophenyl)boronic acid gave 338. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.47-8.06 (m, 1H), 7.86 (s, 1H), 7.66-7.55 (m, 1H), 7.52 (s, 2H), 7.30 (t, J=8.1 Hz, 1H), 4.83 (dd, J=10.5, 3.6 Hz, 1H), 4.58-4.37 (m, 1H), 4.36-4.22 (m, 1H), 4.18-3.97 (m, 1H), 3.76 (s, 3H), 2.10-2.00 (m, 1H), 1.89-1.60 (m, 4H). LCMS (ES+) m/z 483 (M+1).