Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].[OH-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:37](=[O:39])[CH3:38])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 41 %

Procedure:
N-(4-Fluorophenyl)-N′-[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]malonamide (20.6 mg) was dissolved in N,N-dimethylformamide (0.5 ml), and then triethylamine (0.043 ml) and acetyl chloride (0.011 ml) were added dropwise thereto under a nitrogen atmosphere at room temperature, followed by stirring overnight. To the reaction mixture was added a 1 N aqueous solution of sodium hydroxide (1.5 ml), followed by stirring and extracting with ethyl acetate. The organic layer was concentrated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then dried in vacuum to provide the titled compound (9.3 mg, 41%) as white powder.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:12][CH:11]=[CH:10][CH2:9][N:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:7]1[C:24]([OH:26])=O)(=[O:3])[CH3:2].C([Si](C)(C)[O:32][NH2:33])(C)(C)C.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(OCC)(=O)C>[OH:32][NH:33][C:24]([CH:7]1[CH:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:12][CH:11]=[CH:10][CH2:9][N:8]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:26]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(COC(C)=O)C2C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CC=CCC(COC(C)=O)C2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 31.4 %

Procedure:
To a solution of 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid (101 mg, 0.263 mmoL) in 3 mL dimethylformamide at -20° C. under an argon blanket was added O-(tert-Butyldimethyl-silyl)hydroxylamine (50 mg, 0.342 mmoL) followed by N,N-Diisopropylethylamine (0.069 mL, 0.342 mmoL). (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (110 mg, 0.289 mmoL) was added in and the temperature was kept at -20° C. for 40 minutes before allowing to warm to ambient temperature. The reaction was allowed to stir for 19 hours at which time it was diluted with ethyl acetate. 10% citric acid was added in and stirred for 30 minutes, the reaction was then washed sequentially with water, 0.5N HCL, dilute sodium bibarbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by column chromatography (silica: 0.5% to 3% methanol in dichloromethane) to yield (33 mg, 31%) of Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepin-3-ylmethyl ester; MS: (M+H)+ =399, (M+NH4)+ =416.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][N:9]([C:12]3[S:13][C:14]([C:18]([NH:20][CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[O:19])=[C:15]([CH3:17])[N:16]=3)[C:8]2=[O:28])=[CH:4][CH:3]=1.[CH2:31]([Zn]CC)C.ICI.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]3[CH:10]([CH2:31]3)[N:9]([C:12]3[S:13][C:14]([C:18]([NH:20][CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[O:19])=[C:15]([CH3:17])[N:16]=3)[C:8]2=[O:28])=[CH:29][CH:30]=1
Reactant: CC[Zn]CC
Reactant: Cc1nc(-n2ccn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ICI
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C3CC32)sc1C(=O)NCc1cccnc1
Yield: 7 %

Procedure:
To a 25-mL two-neck round bottom flask under argon was charged with 2-(3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.10 g, 0.24 mmol) and tetrahydrofuran (5 mL). Diethylzinc in hexanes (0.35 mL of 1 M solution, 0.35 mmol) was added slowly with a syringe. The solution was stirred and maintained at ambient temperature while diiodomethane (0.10 g, 0.35 mmol) was added slowly with a syringe. The reaction mixture was stirred at 60° C. for 8 hours and cooled in an ice-water bath, followed by the addition of saturated aqueous ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (80 mL) and washed with saturated aqueous ammonium chloride (2×8 mL), water (3×8 mL), dried over sodium sulfate and filtered. The filtrate was concentrated and purified by preparative thin layer chromatography eluted with dichloromethane/methanol (20/1) to afford the title compound in 7% yield (7 mg). 1H NMR (300 MHz, CDCl3) δ 8.57 (br, 2H), 7.66-7.63 (m, 1H), 7.35-7.26 (m, 2H), 7.20-7.18 (m, 1H), 7.06-7.00 (m, 2H), 6.31-6.29 (m, 1H), 4.87 (br s, 2H), 4.74 (br s, 2H), 3.00 (br s, 2H), 2.39 (s, 3H), 0.92-0.81 (m, 2H); MS (ES+) m/z 437.9 (M+1).
Reaction SMILES: O.[C:2]([C:4]1[CH:5]=[C:6]([N:10]2[C:16](=[O:17])[CH2:15][C:14](=[O:18])[NH:13][C:12]3[C:19]4[C:24]([CH:25]=[CH:26][C:11]2=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:7]=[CH:8][CH:9]=1)#[N:3].[H-].[Na+].I[CH3:30]>CS(C)=O.CCCCCC>[C:2]([C:4]1[CH:5]=[C:6]([N:10]2[C:16](=[O:17])[CH2:15][C:14](=[O:18])[N:13]([CH3:30])[C:12]3[C:19]4[C:24]([CH:25]=[CH:26][C:11]2=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:7]=[CH:8][CH:9]=1)#[N:3]
Reactant: CI
Reactant: N#Cc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCCCCC
Product: CN1C(=O)CC(=O)N(c2cccc(C#N)c2)c2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a water-cooled solution of 5-(3-cyanophenyl)-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione (98 mg, 0.30 mmol) in DMSO (1 mL) was added 50-72% sodium hydride (12 mg). The mixture was stirred at room temperature for 1 hour, to which was added iodomethane (0.06 mL, 1 mmol). The mixture was stirred for 4 hours at room temperature, to which was added 50-72% sodium hydride (6 mg) and iodomethane (0.03 mL, 0.5 mmol). The mixture was stirred at room temperature for 18 hour, treated with cold water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was washed with ethyl acetate, then with hexane, to give 5-(3-cyanophenyl)-1-methyl-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione as a pale yellow crystal (28 mg, yield 27%). Then the solvent of washings was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1), to give 5-(3-cyanophenyl)-1,3-dimethyl-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione as a pale yellow oil (9 mg, yield 8%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1.CI.Cl>O1CCCC1.CCCCCC>[O:13]1[CH2:18][CH2:17][CH:16]([CH:19]([CH3:1])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)CC1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C1CCOCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
Diisopropylamine (2.8 g) was dissolved in tetrahydrofuran (20 ml). A solution of n-butyllithium in hexane (2.64 N, 11 ml) was added dropwise under nitrogen atmosphere under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was cooled to −78° C. A solution of ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate (4.0 g) in tetrahydrofuran (15 ml) was added dropwise and the mixture was stirred at the same temperature for 15 minutes. Methyl iodide (2.2 ml) was subsequently added dropwise. The mixture was stirred at the same temperature for 10 minutes, and then warmed to room temperature and stirred for 3 hours. A 1 N aqueous hydrochloric acid solution was added under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (4.0 g) as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)=[CH2:2].[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>C1(C)C=CC=CC=1>[N:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=[CH:12][C:3]=1[CH:1]1[CH2:2][CH:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc2c(n1)CCCC2
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1ccc2c(n1)CCCC2

Procedure:
A solution of 2 (1.6 g, 10 mmol) in toluene (50 ml) was treated with ethyl diazoacetate (1.7 g, 15 mmol) and stirred at reflux overnight. The mixture was concentrated and the residue was purified by gradient elution on silica gel (0 to 10% EtOAc in hexanes) to afford the title compound as a pale yellow oil. LRMS m/z (M+H) 246.2 found, 246.2 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH:14]=O)[N:4]=1.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[CH2:23][O:24][NH2:25]>CO>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[CH2:23][O:24][N:25]=[CH:14][C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[O:11][C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=1
Reactant: NOCc1ccc(Cl)cc1Cl
Reactant: COc1cc(OC)nc(Oc2ccccc2C=O)n1
Solvent: CO
Product: COc1cc(OC)nc(Oc2ccccc2C=NOCc2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
5.2 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldehyde and 3.8 g of 2,4-dichlorobenzyloxyamine were dissolved in 100 ml of methanol and the solution was stirred at room temperature for 2 hours. After the methanol was distilled out under reduced pressure, the resulting residue was recrystallized from isopropyl ether to obtain 8.1 g of O-(2,4-dichlorobenzyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime.
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[C:25]1([S:22]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][C:11]4[CH2:10][CH2:9][NH:8][CH2:21][CH2:20][C:19]=4[C:18]=3[CH:17]=2)(=[O:24])=[O:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2[nH]c3c(c2c1)CCN(Cc1ccccc1)CC3
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1ccc2[nH]c3c(c2c1)CCNCC3

Procedure:
A mixture of 3-benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (VIII, Step II, 453 mg, 1.09 mmol) in methanol (50 mL) is treated with palladium hydroxide (118 mg) and hydrogenated at 30 psi for 5 days. The mixture is filtered, rinsing with methanol and methylene chloride, and the filtrate concentrated under reduced pressure to give an amorphous solid. The material is purified by flash chromatography (Biotage 40M; methanol/methylene chloride, 5/95; methanol/methylene chloride/ammonium hydroxide, 20/79/1) to give the title compound. Analytical data for the hydrochloride salt, mp=290–291.5°; IR (drift) 3382, 2751, 2698, 2689, 2646, 2438, 1297, 1150, 1131, 1095, 801, 759, 722, 684 and 616 cm−1; NMR (300 MHz, DMSO-d6) 11.65, 7.35, 8.05–8.15, 7.85–7.95, 7.40–7.65, 3.20–3.40 and 3.10–3.25 δ; MS (EI) m/z 326 (M+), 298, 297, 286, 285, 284, 143 and 77; HRMS (FAB) calculated for C18H19N2O2S=327.1167, found 327.1165.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][Cl:6])C.[F:10][C:11]1[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=1[CH2:13][O:14][C:15]([CH3:20])([CH2:18][OH:19])[CH2:16][OH:17].[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:6][CH2:5][CH2:4][CH:25]1[O:19][CH2:18][C:15]([O:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[F:10])([CH3:20])[CH2:16][O:17]1
Reactant: CC(CO)(CO)OCc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(CCl)OCC
Product: CC1(OCc2ccccc2F)COC(CCCl)OC1

Procedure:
According to the procedure of Example 47, 8.5 g of chloroacetaldehyde diethyl acetal and 11.0 g of 2-(2-fluorobenzyloxy)-2-methyl-1,3-propanediol were reacted in the presence of 0.02 g of p-toluenesulfonic acid to give, after separation by column chromatography, 5.1 g of t-2-(2-chloroethyl)-r-5-(2-fluorobenzyloxy)-5-methyl-1,3-dioxane, b.p. 130°/0.005 mm, nD25 1.5026; and 4.3 g of c-2-(2-chloroethyl)-r-5-(2-fluorobenzyloxy)-5-methyl-1,3-dioxane, b.p. 120°/0.01 mm; nD25 1.5050. The ir and nmr spectra were consistent with the assigned structures.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C(N(C(C)C)CC)(C)C>CCO>[Br:8][C:6]1[N:7]=[C:2]([NH:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[NH:10][CH:11]=[CH:12]3)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1ncc(Br)nc1Nc1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 42 %

Procedure:
To a stirred suspension of 3,5-dibromopyrazin-2-amine (3.48 g, 13.7 mmol) and 1H-indol-5-amine (2.00 g, 15.0 mmol) in EtOH (3.5 mL) was added diisopropylethylamine [DIEA] (2.60 mL, 15.0 mmol). The resulting mixture was stirred for 48 hr at 80° C., after which it was partitioned between EtOAc and H2O. The organic layer was separated, after which it was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo to yield a residue that was purified via silica gel chromatography eluting with 1:1 EtOAc:hexanes to yield the title compound (1.75 g, 42%) as a red/brown solid. 1H NMR (DMSO-d6, 300 MHz): δ 10.98 (s, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 7.31-7.28 (m, 3H), 7.19 (d, J=8.7 Hz, 1H), 6.43 (s, 2H), 6.36 (s, 1H); HPLC retention time: 2.07 minutes; MS ESI (m/z): 304.2/306.2 (M+1)+, calc. 303.
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=O>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=[N:2][OH:3]
Reactant: NO
Reactant: O=C(c1ccncc1)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccncc1)c1ccc(F)cc1F
Yield: 94.5 %

Procedure:
62.6 g (0.900 mole) of hydroxylamine hydrochloride and 133.6 g (0.982 mole) of sodium acetate trihydrate were added to a suspension of 179.4 g (0.818 mole) of the compound of Example 1 in 1L of ethanol and the mixture was refluxed for 1 hour. The solvent was removed under low pressure evaporation, 1L of water was added to the residue and it was filtered. After drying for 3 hours at 45° C., 181 g (94% yield) of the title compound (mixture of sin- and anti-isomers) were obtained, as a white solid.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O1CCCC1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=1>CN(C)C=O.O>[CH2:1]([S:8][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cccc(Br)n1
Reactant: SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(SCc2ccccc2)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of benzyl mercaptan (0.22 mL, 1.87 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (1.87 mL, 1.87 mmol) dropwise over 2 minutes. To the resulting suspension was added 2-bromo-6-tert-butylpyridine (0.20 g, 0.93 mmol), and the resulting mixture was stirred at 50° C. for 16 hours. The cooled mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL), and the ethyl acetate layer was dried over Na2SO4, filtered and concentrated in vacuo to give a crude product. Purification by column chromatography on silica gel using hexanes gave the titled compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (s, 9H), 4.50 (s, 2H), 6.93-7.03 (m, 2H), 7.17-7.45 (m, 6H); MS (APCI) m/z 258.3 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH:10]([NH2:12])[CH3:11].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH:10]([NH:12][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH3:11]
Reactant: COC(OC)C(C)N
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)NC(C)C(OC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 g (0.73 mol) of ethyl chloroformate are added dropwise to 86.2 g (0.72 mol) of 2-aminopropionaldehyde dimethyl acetal in 350 ml of toluene and 32 g (0.8 mol) of NaOH in 300 ml of water. The mixture is stirred at room temperature for a further 2 hours, the organic phase is separated off, the aqueous phase is extracted with toluene and the toluene solutions are dried over K2CO3. The solution is concentrated and the residue is distilled.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:23]1[C:24]2[N:31]=[CH:30][N:29]([CH:32]([CH3:34])[CH3:33])[C:25]=2[N:26]=[N:27][CH:28]=1.P([O-])([O-])[O-].[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.O>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([C:23]3[C:24]4[N:31]=[CH:30][N:29]([CH:32]([CH3:34])[CH3:33])[C:25]=4[N:26]=[N:27][CH:28]=3)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CC(C)n1cnc2c(Cl)cnnc21
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B(O)O)ccc2F)cc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [K+]
Agent: [O-]P([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(-c3cnnc4c3ncn4C(C)C)ccc2F)cc1
Temperature: 100 °C
Yield: 27 %

Procedure:
A stirred solution of 4′-ethylsulfonyl-6-fluorobiphenyl-3-yl-boronic acid (Preparation 65, 30 mg, 0.097 mmol), 4-chloro-7-isopropyl-7H-imidazo[4,5-c]pyridazine (Preparation 6, 15 mg, 0.077 mmol) and potassium phosphite (33 mg, 0.154 mmol) in dioxane (3 mL) and water (0.7 mL) was degassed with argon for 10 minutes followed by the addition of tricyclohexylphosphine (1.72 mg, 0.006 mmol) and tris(dibenzylideneacetone)palladium(0) (2.82 mg, 0.003 mmol). The resulting mixture was heated at 100° C. for 16 hours. The reaction mixture was filtered to remove inorganics and the filtrate was concentrated in vacuo to remove the volatiles. Purification of the crude residue by preparative TLC eluting with 2% MeOH in DCM afforded the title compound as off white solid in 27% yield, 9 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([OH:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[K].CCN([CH2:17][CH3:18])CC.[CH2:19](Cl)Cl>CC(O)C.O.CCOCC>[CH2:19]=[C:17]([C:2]1[CH:3]=[C:4]([C@@H:8]([OH:10])[CH3:9])[CH:5]=[N:6][CH:7]=1)[CH3:18]
Reactant: CCN(CC)CC
Reactant: C[C@H](O)c1cncc(Br)c1
Reactant: ClCCl
Agent: [K]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: O
Product: C=C(C)c1cncc([C@H](C)O)c1
Temperature: 25 °C
Yield: 1327.5 %

Procedure:
A stirred solution of (S)-1-(5-bromopyridin-3-yl)ethanol (950 mg, 4.7 mmol), potassium isopopenyltrifluoroborate (730 mg, 4.94 mmol), and Et3N (1.95 mL, 14.1 mmol) in iPrOH (30 mL) and H2O (15 mL) was degassed with argon for 10 min and then PdCl2 (dppf).CH2Cl2 (192 mg, 0.24 mmol) was added and the reaction mixture was heated to reflux for 4 h. The solution was cooled to room temperature and diluted with Ether and H2O. The layers were separated and the aqueous layer was extracted with Ether (2×50 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (60% EtOAc in hexanes) to provide 520 mg of (S)-1-(5-(prop-1-en-2-yl)pyridin-3-yl)ethanol.
Reaction SMILES: [N+:1]([N:4]([CH3:7])[CH2:5][OH:6])([O-:3])=[O:2].[C:8](Cl)(=[O:10])[CH3:9]>ClCCl>[C:8]([O:6][CH2:5][N:4]([N+:1]([O-:3])=[O:2])[CH3:7])(=[O:10])[CH3:9]
Reactant: CN(CO)[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)OCN(C)[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To a stirred mixture of 10.6 g of 2-nitro-2-aza-1-propanol and 25 ml of dichloromethane under a nitrogen atmosphere was added dropwise and with ice-cooling 12 g of acetyl chloride. The cooling bath was removed and the mixture was slowly heated to reflux. After 3 hours the solution was allowed to cool and was then triturated with 50 ml of ice water. The organic phase was separated, dried (MgSO4), and distilled. The product 2-nitro-2-azapropyl acetate had b.p. 56°-57° C. at 0.07 mm Hg.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](ON=C(C1C=CC=CC=1)C#N)=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:26][C@@:27]1([C:47]([OH:49])=[O:48])[C@H:32]([CH2:33][S:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=2)[C@@H:31]([OH:43])[C@@H:30]2[C@H:28]1[C@H:29]2[C:44]([OH:46])=[O:45]>O1CCOCC1.O>[C:8]([O:12][C:13]([NH:26][C@@:27]1([C:47]([OH:49])=[O:48])[C@H:32]([CH2:33][S:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=2)[C@@H:31]([OH:43])[C@@H:30]2[C@H:28]1[C@H:29]2[C:44]([OH:46])=[O:45])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1CSc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1CSc1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
Triethylamine (407.27 mL, 2.92 mol) and [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile] (308.39 g, 1.25 mol) are added to a suspension of (1S,2R,3S,4S,5R,6R)-2-amino-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid (300.00 g, 834.84 mmol) in 1,4-dioxane (500.9 mL) and water (500.9 mL) at 25° C. The mixture is warmed to 50° C. After 12 hours, the reaction is cooled to 25° C., diluted with water (2.5 L), and washed with methyl tert-butyl ether (6×1 L). Basify the aqueous phase with a solution of aqueous. 1N HCl until pH=2, and extract with ethyl acetate (3×2 L). The combined ethyl acetate extracts are washed with brine, dried over MgSO4, and concentrated in vacuo to yield the title compound (250 g, 65% yield). MS (m/z): 360 (M+-Boc).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=[O:24])[NH2:22]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=[O:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Yield: 78.1 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (642 mg, prepared following a procedure analogous to Reference Example 5 and Reference Example 6), 552.7 mg of the title compound was afforded (yield 78.1%).