Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](B(O)O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:17]2[CH:18]=[C:19]([NH2:20])[CH:21]=[CH:22][CH:23]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2cnn(Cc3ccccc3)c2)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
1-benzyl-1H-pyrazole-4-boronic acid (0.176 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.137 g in 94% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]([F:16])([F:15])[CH2:11][N:12]=[C:13]=[S:14]>C(#N)C>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([NH:1][C:13]([NH:12][CH2:11][C:10]([F:16])([F:15])[F:9])=[S:14])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1cncc(Cl)n1
Solvent: CC#N
Product: FC(F)(F)CNC(=S)Nc1cncc(Cl)n1

Procedure:
To a solution of 2-amino-6-chloropyrazine (6 g.) in acetonitrile (50 ml.) was added 2,2,2-trifluoroethylisothiocyanate (6 ml.) and the mixture heated under reflux on a steam bath for 6 hours. The mixture was allowed to cool, the resulting solid filtered and recrystallised from toluene to give 2-chloro-6-(3-[2,2,2-trifluoroethyl]thioureido)pyrazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](O)([C:19]([F:22])([F:21])[F:20])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH3:18].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:7]=[C:6]1[CH3:18])[C:19]([F:21])([F:20])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(F)cc2)c1=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=C1C(=O)N(c2ccc(F)cc2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 1-(4-fluorophenyl)-2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (171 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[OH-].[Na+].[ClH:14].[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[CH:34]=[CH:33][C:32](Br)=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2>CN(C=O)C.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]>[ClH:14].[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[CH:34]=[CH:33][C:32]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3oc(C(=O)N[C@H]4CN5CCC4CC5)cc3c2)cc1
Temperature: 90 °C

Procedure:
130 mg (0.86 mmol) of 4-(methoxy)phenylboronic acid and 2.15 ml of 1N sodium hydroxide solution are added to a mixture of 250 mg (0.72 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 52 mg (0.07 mmol) of PdCl2(dppf) in 3 ml of DMF. The reaction mixture is heated at 90° C. overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered through kieselguhr. Purification takes place by preparative HPLC. The product fractions are mixed with an excess of 1N hydrochloric acid. The solvent is removed under reduced pressure. Drying under high vacuum results in 127 mg (39% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Mg]([CH2:15][CH2:16][CH2:17][CH2:18][Mg]Br)Br>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]1([OH:6])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(C)cc1Br
Reactant: Br[Mg]CCCC[Mg]Br
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of methyl 2-bromo-4-methylbenzoate (5.0 g, 21.3 mmol) in THF (20 mL) was added dropwise BrMg(CH2)4MgBr (50 mL, 25.5 mmol) at 0° C. under nitrogen and then stirred at rt overnight. The reaction mixture was quenched with aqueous NH4Cl and extracted with EA. The combined organic layer was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4. The solution was concentrated and the residue was purified by column chromatography over silica gel eluted with PE-EA (20:1˜10:1) to provide 1-(2-bromo-4-methylphenyl)-cyclopentanol (4.2 g; yield 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1 H), 7.39 (s, 1 H), 7.10 (d, 1 H), 4.84 (s, 1 H), 2.33 (s, 3 H), 1.89-1.74 (m, 8 H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc(C(F)(F)F)cnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C(F)(F)F)cnc1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-chloro-5-(trifluoromethyl)nicotinamide (as prepared in the previous step, 788 mg, 3.51 mmol) in dry DCM was added TEA (1.1 mL, 7.89 mmol). After cooling to 0° C. under argon, trifluoroacetic anhydride (0.54 mL, 3.88 mmol) was added dropwise. After stirring for 1.5 hours at 0° C., DCM (30 mL) and saturated aqueous sodium bicarbonate were introduced. The organic layer was removed and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, DCM) to afford the product as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][CH2:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][NH:27][C:28](=O)[CH:29]([C:31]2[N:32]=[N:33][C:34](Cl)=[CH:35][CH:36]=2)[CH3:30])=[N:24][CH:25]=1.P(Cl)(Cl)(Cl)=[O:40]>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:28]([CH:29]([C:31]3[CH:36]=[CH:35][C:34]4[N:33]([CH:9]=[C:10]([NH:14][C:15]([CH:16]5[CH2:17][CH2:18]5)=[O:40])[N:11]=4)[N:32]=3)[CH3:30])=[N:27][N:26]=2)[CH:25]=1.[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][CH2:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C(=O)NNc1ccc(Br)cn1)c1ccc(Cl)nn1
Reactant: O=P(Cl)(Cl)Cl
Agent: Clc1ccc(CCc2nnc3ccccn23)nn1
Product: CC(c1ccc2nc(NC(=O)C3CC3)cn2n1)c1nnc2ccc(Br)cn12

Procedure:
6-Bromo-3-((-(6-chloropyridazin-3-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (48D): A solution of N′-(5-bromopyridin-2-yl)-2-(6-chloropyridazin-3-yl)propanehydrazide (13 g, 36.5 mmol) in phosphoryl trichloride (84 ml, 901 mmol) was heated in the microwave at 140° C. for 15 min. The reaction was concentrated via rotary evaporation and the resulting mixture was added drop-wise to a mixture of EtOAc:Saturated Bicarbonate (aq) (4:6, 1 L). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×75 mL). The EtOAc solutions were combined and evaporated to dryness. The resulting residue was purified by MPLC (DCM:MeOH, 97:3) to provide the title compound, 6-Bromo-3-(1-(6-chloropyridazin-3-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (48D, 3.3 g, 26.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (d, J=7.07 Hz, 3 H) 5.27 (d, J=7.33 Hz, 1 H) 7.49 (dd, J=9.60, 1.77 Hz, 1H) 7.78 (dd, J=9.85, 1.01 Hz, 1 H) 7.94 (s, 2 H) 8.79 (s, 1 H). ESI-MS:m/z 339.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[C:9]([C:11]2[C:12]([Cl:28])=[C:13]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=2)[CH:8]=[N:7][CH:6]=1)C.[OH-].[K+].Cl>C(O)C.O>[Cl:28][C:12]1[C:11]([C:9]2[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=2)[C:4]([OH:29])=[O:3])=[CH:16][N:15]=[C:14]2[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:13]=12
Reactant: CCOC(=O)c1cncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)c2Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)c(-c3cncc(C(=O)O)c3)cnc21
Reaction time: 16 h
Yield: 111.3 %

Procedure:
1.070 g (2.48 mmol) of 5-[4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-nicotinic acid ethyl ester was dissolved in 10 mL of ethanol. 2 mL of 50% w/v solution of potassium hydroxide in water and 10 mL of water were added and the resulting solution was left standing at ambient temperature for 16 h. Subsequently the pH was adjusted to approximately 4 by addition of concentrated aqueous hydrochloric acid and the mixture diluted with 100 mL of water. The resulting precipitate was filtered off and dried by suction to afford 1.1153 g (2.76 mmol, quant.) of 5-[4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-nicotinic acid. 1H-NMR [500 MHz, d6-DMSO] δ: 9.13 (d, 1H), 8.94 (d, 1H), 8.393 (m, 1H), 8.388 (m, 1H), 7.89 (d, 1H), 6.70 (d, 1H), 5.69 (s, 2H), 3.55 (t, 2H), 0.84 (t, 2H), 0.08 (s, 9H); MS [MH+] m/z: 404; [M−H−] m/z: 402.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[BH:24]([OH:26])[OH:25]>>[CH2:17]([O:16][C:3]1[CH:2]=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[C:4]=1[B:24]([OH:26])[OH:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: OBO
Product: CCCCCCCOc1ccc2c(c1B(O)O)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to Example 3(a), starting with 10 g (26.2 mmol) of 3-bromo-2-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, 6.1 g (67%) of the expected boronic acid are obtained, with a melting point of 102-3° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11](O)[CH3:12])[C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CC(O)c1cc(Br)cc2c1OCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(Br)cc2c1OCO2
Temperature: -50 °C
Yield: 75.6 %

Procedure:
To a 250-mL flask was added 1-(6-bromo-benzo[1,3]dioxol4-yl)-ethanol (9.3 g, 37.9 mmol) was added. The solid was cooled to −50° C. and trifluoroacetic acid (44 mL, 568 mmol) was added. Followed addition of triethylsilane (60.5 mL, 379 mmol). The mixture was stirred at reflux for 5 hours, and evaporated in vacuo to an oil. The oil was distilled twice, collecting the fraction boiling between 80° C. and 110° C. at 1.5 mm Hg. The oil was chromatographed on 100 g silica gel, eluted with 5:95 ethyl acetate/hexane. Evaporation of the appropriate fractions gave a clear oil, 6.56 g, 75.6% yield. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCOCC4)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and morpholine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.3-4.1 (m, 16H), 3.37 (t, J=7.5 Hz, 4H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](C4C=CN=CC=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].[CH2:39](O)[CH3:40].Cl>O>[N:19]1[CH:40]=[CH:39][CH:16]=[C:17]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:3])=[O:36])=[CH:10][CH:11]=4)[N:19]=3)=[CH:29][CH:28]=2)[CH:18]=1
Reactant: CCO
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccncc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1oc(-c2ccc(-c3cccnc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-pyrid-4-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4-pyrid-3-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 7.99 (2H, d), 7.66 (2H, d), 7.45 (2H, m), 7.53 (1H, m), 7.42 (1H, m), 6.90 (2 h, m), 6.78 (2H, m), 4.17 (2H, t), 2.99 (2H, t) 2.39 (3H, s), 1.53 (6H, s).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1([CH3:47])[CH2:13][N:12]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[C:11](=[O:22])[CH2:10][N:9]1[CH2:23][C@H:24]([NH:34]S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C@@H:25]1[CH2:29][C@@H:28]([CH:30]([CH3:32])[CH3:31])[C:27](=[O:33])[O:26]1.C1(S)C=CC=CC=1.C(=O)(O)[O-].[Na+].[C:60](OC(OC(C)(C)C)=O)([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61].N[C@H]([C@@H]1C[C@@H](C(C)C)C(=O)O1)CN1C(C)(C)CN(C2C=C(F)C=CC=2C)C(=O)C1>[Cl-].[Na+].O.C(OCC)(=O)C.O>[C:63]([O:62][C:60](=[O:61])[NH:34][C@H:24]([C@@H:25]1[CH2:29][C@@H:28]([CH:30]([CH3:32])[CH3:31])[C:27](=[O:33])[O:26]1)[CH2:23][N:9]1[CH2:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:13][C:8]1([CH3:47])[CH3:7])([CH3:66])([CH3:65])[CH3:64]
Reactant: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](N)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Reaction time: 2 h
Yield: 81.1 %

Procedure:
953 mg of cesium carbonate (2.92 mmol) was added to a solution of 1.44 g of N-{(S)-2-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (70e) (2.43 mmol) and 0.52 ml of thiophenol (content: 95%) (4.87 mmol) in acetolitrile (25 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature for two hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1-10/1). 211 mg of sodium bicarbonate (2.51 mmol) and 549 mg of di-t-butyl dicarbonate (2.51 mmol) were added to a solution of 4-{(S)-2-amino-2-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-5,5-dimethyl-1-(5-fluoro-2-methylphenyl)piperazin-2-one obtained above in a mixture of ethyl acetate (11 ml) and water (11 ml), and the mixture was stirred at room temperature for four hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=5/1-3/1) to obtain 996 mg of the title compound (yield: 93%).
Reaction SMILES: [C:1]([O:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[CH2:6][O:7][CH2:8][CH2:9][O:10]C(C)(C)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)C.O>[C:1]([O:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[CH2:6][O:7][CH2:8][CH2:9][OH:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(COCCOC(C)(C)C)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)OC(COCCO)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
40.0 g of 1-acetoxy-1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethane was dissolved in 40 ml of methylene chloride. To the solution was added 80 ml of trifluoroacetic acid with ice cooling. The mixture was stirred for 12 hours at room temperature. After the completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was mixed with 100 ml of toluene. The solvent was further removed by distillation under reduced pressure. The residue thus obtained was dissolved in a mixture of 90 ml of ethanol and 10 ml of water. To the solution was added 10.7 g of sodium hydrogencarbonate at room temperature. The mixture was adjusted to pH 6-7 with a saturated aqueous sodium hydrogencarbonate solution, and then concentrated to about a half volume under reduced pressure. To the concentrate was added 100 ml of ethyl acetate. The organic layer was separated. The aqueous layer was extracted with 50 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=3/1) to obtain 19.4 g of oily 1-acetoxy-1-(3-chlorophenyl)-2-(2-hydroxyethoxy)ethane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10]([O-])(O)=O.[Na+]>C(O)=O.O>[CH3:1][C:2]1[C:3]2[N:9]=[CH:10][NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: Cc1cccc(N)c1N
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Cc1cccc2[nH]cnc12

Procedure:
A solution of 3-methylbenzene-1,2-diamine (170 mg) in formic acid (2 mL) was heated at 140° C. for 5 min in a microwave reactor. The mixture was diluted with water, neutralized with sat. NaHCO3, then extracted with EtOAc. The organic phase was washed with water and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel and concentrated to afford 122 mg of Intermediate 171.1 as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[N:17][C:18]([N+:21]([O-])=O)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])nc2)CC1
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)nc2)CC1
Yield: 122.4 %

Procedure:
By repeating procedures described in Example B, 4-(6-nitro-pyridin-3-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (490 mg, 1.52 mmol) is hydrogenated over Pd—C on an H-cube (Thales) (instead of under an atmosphere of hydrogen) to give 4-(6-amino-pyridin-3-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (544 mg, 98%). MS(ESI) m/z 293 (M+H)+
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F-].[K+]>>[C:12]([C:10]1[S:11][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=1)#[CH:13]
Reactant: CCCCCCc1ccc(C#C[Si](C)(C)C)s1
Agent: [F-]
Agent: [K+]
Product: C#Cc1ccc(CCCCCC)s1

Procedure:
According to the method of S117b, ((5-hexylthiophen-2-yl)ethynyl)trimethylsilane (1 g, 3.7 mmol) was reacted with potassium fluoride (429 mg, 7.4 mmol) to give the title compound as a yellow oil following silica gel purification (hexane) (500 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 7.10 (d, 1H, J=3.6 Hz), 6.64 (d, 1H, J=3.6 Hz), 2.78 (t, 2H, J=7.2 Hz) 1.68-1.55 (m, 2H), 1.36-1.28 (m, 6H), 0.89 (t, 3H, J=6.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([O-:12])=O)[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH2:18][CH2:17]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[O:12])[CH:3]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: COc1cc(Cl)cc(C(=O)[O-])n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1

Procedure:
550 mg (2.93 mmol) 4-chloro-6-methoxy-pyridine-2-carboxylate, 411 mg (3.00 mmol) 5-fluoroindoline, 1.06 g (3.30 mmol) TBTU and 927 μL (6.60 mmol) triethylamine in 5.00 mL DMF were stirred for 3 h at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and evaporated down using the rotary evaporator.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:15][F:16])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH:13]=O)=[CH:12][C:4]1=2.[NH2:17][OH:18].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[F:1][CH2:2][C:3]1([CH2:15][F:16])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11](/[CH:13]=[N:17]/[OH:18])=[CH:12][C:4]1=2
Reactant: O=Cc1ccc2c(c1)C(CF)(CF)OB2O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O/N=C/c1ccc2c(c1)C(CF)(CF)OB2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3,3-bis(fluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (400 mg, 1.77 mmol) and NH2OH.HCl (148 mg, 2.12 mmol) in THF (25 mL) and H2O (5 mL) at rt was added NaOAc (203 mg, 2.48 mmol). The mixture was stirred at rt overnight, diluted with H2O and extracted with EA (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (440 mg) was used directly in the next step without purification.