Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:4]1)(=[O:20])=[O:19]
Reactant: CC(C)(C)OC(=O)NC1CCCC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCCC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 3-(hydroxymethyl)cyclohexylcarbamate (7.9 mmol), methanesulfonyl chloride (23.7 mmol) and triethylamine (119 mmol) in DCM (100 ml) was stirred at rt overnight. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[CH:4][C:3]=1[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1cc(O)ccc1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc(Br)c(C(C)(C)C)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-tert-butylphenol (Intermediate 104, 1.17 g, 5.10 mmols) and imidazole (520.0 mg, 7.65 mmols) in 10 mL DMF was added chloro-triisopropylsilane (1.18 g, 6.10 mmols). After stirring overnight at room temperature the solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 1.80 g (92%), was isolated by column chromatography (0-1.5% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([CH2:17][CH2:18][CH3:19])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[C:11]([CH2:17][CH2:18][CH3:19])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCCc1cc(O[Si](C)(C)C(C)(C)C)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1cc(O[Si](C)(C)C(C)(C)C)ccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a solution of 0.386 g (1.32 mmol) of the product of Step D dissolved in 4.0 mL of ethanol was added 0.025 g (0.66 mmol) of sodium borohydride and the reaction mixture was stirred at room temperature for 30 minutes. The excess reducing agent was then quenched with 10% aqueous NaHSO4 and the methanol was removed in vacuo. The residue was partitioned between EtOAc and water and extracted, the organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 15% EtOAc-hexane. Evaporation of the purified fractions and solvent removal in vacuo afforded 0.246 g (63%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[O-:11][Mn](=O)(=O)=O.[K+].[OH2:17]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])=[O:17])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(C)ccc1Cl
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Product: COc1cc(C(=O)O)ccc1Cl

Procedure:
2-chloro-5-methylanisole (31.2 g, 1 equiv) and Bu4NCl (2 g, cat.) in 500 mL of water was treated with 95 g of KMnO4 at reflux for 3 hours. The mixture was then filtered through celite, acidified with conc. HCl and the white solid was collected after filtration and air dry to give 4-chloro-3-methoxybenzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:18]=[C:19]([N:20]3[CH2:24][CH2:23][N:22]([CH3:25])[C:21]3=[O:26])[C:12]2=[N:11][C:10]=1[C:33](=[S:35])[NH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36](N(C(C)C)CC)(C)C.CI>C1COCC1>[CH3:36][S:35][C:33]([C:10]1[N:11]=[C:12]2[C:19]([N:20]3[CH2:24][CH2:23][N:22]([CH3:25])[C:21]3=[O:26])=[CH:18][C:17]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][N:13]2[C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[NH:34]
Reactant: CN1CCN(c2cc(N3CCOCC3)cn3c(=O)c(OCc4ccccc4)c(C(N)=S)nc23)C1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CSC(=N)c1nc2c(N3CCN(C)C3=O)cc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
To a solution of the product of example 74 (250 mg, 0.5 mmol) in THF (20 ml) was added diisopropyl ethylamine (65 mg, 0.5 mmol) and methyl iodide (140 mg, 1 mmol), and the mixture was stirred at 60° C. for 1.5 h. The reaction mixture was added ice water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give title product (190 mg, 74%).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>N1C=CC=CC=1.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:19][C:18]([NH:20][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:25][CH:26]=4)=[N:17][N:16]=3)=[CH:13][CH:14]=2)[CH:3]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1ccc(OC(F)(F)F)cc1
Reaction time: 6 h
Yield: 40.2 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. 4-Trifluoromethoxybenzoyl chloride (167.2 mg, 117 uL, 0.75 mmol) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of precipitate. It was left to stir for 6 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (89.0 mg). Yield 40.2%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O>CO.[Pd]>[N:14]1([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3.01 g (7.46 mmol) of benzyl 4-(1-tert-butoxycarbonylpiperidin-4-yl)piperazine-1-carboxylate and 300 mg of Pd—C (5%) in 100 ml of methanol was mixed with 4 ml of formic acid and stirred under a hydrogen atmosphere (1 bar) at room temperature overnight. The reaction mixture was filtered through Celite, the residue on the filter was washed with methanol, and the solvent was then removed in vacuo. The residue was used without further purification in the next reaction step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28]O)=[C:22]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:42]C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(F)(=O)=O.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][F:42])=[C:22]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCO)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCF)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 37.4 %

Procedure:
To a stirred solution of 64 mg (0.11 mmol) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-[3-tert-butoxy-4-(2-hydroxyethoxy)benzyl]-L-glutamate in 0.5 ml THF was added 102.7 mg (0.34 mmol) nonafluoro 1-butanesulphonic acid fluoride, 54.8 mg (0.34 mmol) triethylamine trihydrofluoride and 102 mg (1.01 mmol) triethyl amine. The reaction mixture is stirred for 3 days. Further 34 mg (0.11 mmol) nonafluoro 1-butanesulphonic acid fluoride, 18 mg (0.11 mmol) triethylamine trihydrofluoride and 34 mg (0.33 mmol) triethyl amine were added. The reaction mixture is stirred for 3 hours and is concentrated in vacuo. The crude product is purified by column chromatography (silica gel, hexane/ethylacetate gradient: 12:1→1:1). The desired product was obtained in 37.4% yield (64.2 mg, 0.04 mmol).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.[CH3:20][S:21]([NH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:9]1([CH3:13])[O:8][C:6]2[N:7]=[C:2]([C:29]3[CH:30]=[C:25]([NH:24][S:21]([CH3:20])(=[O:22])=[O:23])[CH:26]=[CH:27][CH:28]=3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[O:11][CH2:10]1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)COc2c(nc(-c3cccc(NS(C)(=O)=O)c3)nc2N2CCOCC2)O1
Temperature: 120 °C
Yield: 14.5 %

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), 3-(methanesulfonylamino)phenylboronic acid (57 mg, 0.27 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then evacuated and back filled with nitrogen before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 114 as a white solid (11 mg, 15%). LCMS: RT=4.22 min, [M+H]+=421. 1H NMR (400 MHz, CDCl3): δ 8.19-8.12 (1H, m), 8.05-8.02 (1H, m), 7.44-7.37 (2H, m), 6.34 (1H, broad s), 3.92 (2H, s), 3.88-3.79 (8H, m), 3.00 (3H, s), 1.47 (6H, s)
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:10]([N:12]1[C@H:21]([C:22](=[O:34])[NH:23][C@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)[CH2:20][C:19]2[C:14](=[CH:15][C:16]([C:35]([O:37][CH3:38])=[O:36])=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:10]([N:12]1[C@H:21]([C:22](=[O:34])[NH:23][C@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)[CH2:20][C:19]2[C:14](=[CH:15][C:16]([C:35]([O:37][CH3:38])=[O:36])=[CH:17][CH:18]=2)[CH2:13]1)=[O:11]
Reactant: COC(=O)c1ccc2c(c1)CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CN(C(=O)[C@@H](N)C(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Reaction time: 0.67 h
Yield: 96.7 %

Procedure:
A solution of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (1.21 g, 2.09 mmol) in CH2Cl2 (13.9 mL) was charged with TFA (3.49 mL) at room temperature. After 40 min, the reaction mixture was quenched carefully with sat. NaHCO3 and then extracted with EtOAc (3×). The combined extracts were washed with sat. NaCl, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (0.97 g, 2.02 mmol, 97%) as a light yellow foam, which was used without further purification. MS (ESI+) m/z 478.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(Cl)nc2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Oc2ccc(Cl)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-((6-chloropyridin-3-yl)oxy)-3-fluorobenzaldehyde (2.80 g, 11.1 mmol) in methanol (25 mL) was added portionwise solid NaBH4 (0.842 g, 22.3 mmol) at room temperature. The reaction mixture was stirred at 25° C. for 2 h, concentrated to remove solvent, dissolved in water (50 mL) and extracted with ethyl acetate (50 mL×2). Combined organic parts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude was used into next step without purification (2.8 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13](F)=[CH:12][N:11]3[C:17]=2[CH2:18][C:19]2[N:23]=[C:22]([C:24]([NH:26][OH:27])=[O:25])[O:21][N:20]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N=C3C=CC=CN3C=2CC2N=C(C(OCC)=O)ON=2)=CC=1.Cl.NO>>[OH:27][NH:26][C:24]([C:22]1[O:21][N:20]=[C:19]([CH2:18][C:17]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[N:23]=1)=[O:25]
Reactant: O=C(NO)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1
Agent: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Agent: Cl
Agent: NO
Product: O=C(NO)c1nc(Cc2c(-c3ccccc3)nc3ccccn23)no1

Procedure:
The title compound was prepared in the same fashion as that for compound 222 from ethyl 3-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate and hydroxylamine hydrochloride. m/e+=370 (M+H+). 1H NMR (400 MHz, in DMSO-d6): δ 8.43-8.41 (1H, D, d, J=7.2 Hz, ArH), δ 8.31 (1H, D, s, ArH), δ 7.88-7.86 (2H, D, d, J=8.4 Hz, ArH), δ 7.65-7.62 (1H, D, d, J=9.2 Hz, ArH), δ 7.57-7.54 (1H, D, d, J=8.4 Hz, ArH), δ 7.35-7.31 (1H, D, t, J=8.0, ArH), δ 7.04-7.00 (1H, D, t, J=8.0, ArH), and δ 4.62 (2H, D, s, CH2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:9][C@@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27](B(O)O)[CH:26]=1>>[CH3:17][CH:16]([CH3:18])[CH2:15][C@H:10]([O:9][C@H:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]1[CH:6]=[CH:7][C:2]([C:27]2[CH:26]=[N:25][C:34]3[C:29]([CH:28]=2)=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:3][CH:4]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CC(C)C)O[C@H](c1ccccc1)c1ccc(Br)cc1
Reactant: OB(O)c1cnc2ccccc2c1
Product: COC(=O)[C@H](CC(C)C)O[C@H](c1ccccc1)c1ccc(-c2cnc3ccccc3c2)cc1

Procedure:
Using the same procedure as described for example 36 step 2, methyl (2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoate (2.05 g, 5.25 mmol) and 3-quinolineboronic acid (1.0 g, 5.78 mmol) were coupled to give the title compound as an oil.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][CH2:12][CH2:13][Cl:14])=[O:10]>O.C(O)=O>[CH2:7]([NH:8][C:9]([N:11]([N:1]=[O:3])[CH2:12][CH2:13][Cl:14])=[O:10])[CH2:6][Cl:5]
Reactant: O=N[O-]
Reactant: O=C(NCCCl)NCCCl
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: O=NN(CCCl)C(=O)NCCCl
Reaction time: 2 h

Procedure:
A cold solution of 0.2346 g (3.4 mmole) sodium nitrite in 2 ml water was slowly added to a stirred solution of 0.2727 g (1.47 mmole) 1,3-bis(2-chloroethyl)urea in 2 ml 88% formic acid at 0°. After 2 hours at 0°, 0.1449 g (46.0%) of an oil solid phase was removed. The ir spectrum of this fraction failed to agree with that of BCNU. After 2 days a small amount of crystalline BCNU slowly formed in this oil phase. A methylene dichloride extract of the aqueous phase yielded 0.0943 g (30.0%) of an amber oil whose ir spectrum agreed with that of a known sample of BCNU. Treatment of this oil with 5 ml hexane and cooling to 0° gave crystalline BCNU which formed an oil on warming to ambient temperature.
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]2[N:13]=[CH:14][NH:15][C:11]=2[CH:10]=1.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH:21]=O.[Si](C#N)(C)(C)C.[N:34]1([C:39](N2C=CN=C2)=[O:40])C=CN=[CH:35]1>>[NH:13]1[C:12]2[CH:16]=[CH:17][C:9]([N:8]3[CH:21]([C:20]4[C:19]([Cl:18])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:27])[CH2:35][NH:34][C:39]3=[O:40])=[CH:10][C:11]=2[N:15]=[CH:14]1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])C(F)(F)F
Product: O=C1NCC(c2c(Cl)cccc2Cl)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized as trifluoroacetate salt starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 2,6-dichloro-benzaldehyde (0.7 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (0.4 mL, 2.8 mmol), di-(imidazol-1-yl)methanone (0.253 g, 1.56 mmol) as described in method 2. The product was purified by means of preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:11])[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.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>[CH3:11][N:6]1[C:5]2[CH:12]=[CH:13][C:2]([C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)=[CH:3][C:4]=2[N:8]([CH3:9])[C:7]1=[O:10]
Reactant: Cn1c(=O)n(C)c2cc(Br)ccc21
Reactant: OB(O)c1cccnc1
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: Cn1c(=O)n(C)c2cc(-c3cccnc3)ccc21
Yield: 31.8 %

Procedure:
A mixture of 5-Bromo-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (121 mg, 0.5 mmol), 3-pyridyl boronic acid (68 mg, 0.55 mmol), polymer-supported Pd(PPh3)4 (0.09 mmol/g, 278 mg, 0.025 mmol) and Na2CO3 (2 M in water, 0.55 mL, 1.1 mmol) in DME (3.3 mL) was heated to reflux for 1 hr. After filtration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-7.5%) and yielded the title compound (38 mg). MS (ESI) m/z 240.0 (M+H), retention time 1.00 min. 1H NMR (400 MHz, CD2Cl2) δ ppm 3.47 (s, 3H), 3.49 (s, 3H), 7.13 (d, J=8.1 Hz, 1H), 7.25 (s, 1H), 7.38-7.40 (m, 1H), 7.41-7.44 (m, 1H), 7.95-7.98 (m, 1H), 8.60 (m, 1H), 8.90 (s, 1H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:37])[C:21]([CH3:36])=[C:22]([C:24]3[CH:35]=[CH:34][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])=[CH:26][N:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:37])[C:21]([CH3:36])=[C:22]([C:24]3[N+:25]([O-:9])=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])=[CH:34][CH:35]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: CCCNC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCNC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)[n+]([O-])c1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-propyl-nicotinamide (Intermediate 31, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-propyl-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:49][C@@H:50]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:51]([NH2:53])=[O:52]>CN(C=O)C>[C:51]([C@@H:50]([NH:49][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)(=[O:52])[NH2:53]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)[C@@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.5 %

Procedure:
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) was suspended in DMF (3 mL). TBTU (224.14 mg, 0.85 mmol), DIEA (0.31 mL, 2.24 mmol) and (αS)-α-amino-benzeneacetamide (CAN 6485-52-5, 51.2 mg, 0.51 mmol) were added and the reaction mixture was stirred at room temperature for 12 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Xbridge-C18, 5 μ, 19×250 mm/acetonitrile/0.1% ammonia in water) to give the desired product (15 mg, 9.58%) as white solid; LC-MS (UV peak area, ESI) 93.20%, 367.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:26][S:27][C:28]1[S:29][C:30]2[CH:36]=[C:35]([CH:37]=O)[CH:34]=[CH:33][C:31]=2[N:32]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH:7][CH2:37][C:35]1[CH:34]=[CH:33][C:31]2[N:32]=[C:28]([S:27][CH3:26])[S:29][C:30]=2[CH:36]=1
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CSc1nc2ccc(C=O)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccc(CNc3cc(Br)ccc3[N+](=O)[O-])cc2s1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a stirred mixture of 5-bromo-2-nitroaniline (714 mg, 4.0 mmol) in TFA (7 mL) at −15° C. under argon, was added NaBH(OAc)3 (1.2 g, 5.4 mmol) in small portions. The mixture was stirred for 15 min, then a solution of 2-(methylthio)benzo[d]thiazole-6-carbaldehyde in CH2Cl2 (2 mL) was added dropwise. The mixture was stirred for 30 min then concentrated under reduced pressure to give a red oil. The oil was partitioned between EtOAc (200 mL) and saturated aq NaHCO3 (100 mL). The organic layer was separated and washed with brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 50% hexanes in EtOAc to afford 5-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (1.1 g, 73%) as a yellow solid. LCMS (ESI) m/z 409, 411 (M+H)+.