Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:36])[N:21]([NH:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCCC1.[Pd].[OH-].[OH-].[Pd+2]>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([NH:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C:20](=[O:36])[C:19]=1[C:14]1[NH:13][C:12]2[CH:37]=[CH:38][C:9]([OH:8])=[CH:10][C:11]=2[S:16](=[O:17])(=[O:18])[N:15]=1
Reactant: CC(C)CCNn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Agent: [Pd+2]
Agent: [Pd]
Agent: O=C[O-]
Solvent: C1CCOC1
Product: CC(C)CCNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Yield: 80.7 %

Procedure:
The product of Example 323B (0.037 g, 0.07 mmol) in tetrahyrofuran (8 mL) was reacted with a catalytic amount of palladium hydroxide on carbon, a catalytic amount of 5% palladium on carbon, and ammonium formate (0.018 g, 0.29 mmol) at 60° C. for 30 minutes. The warm reaction mixture was filtered through celite® (diatomaceous earth) and the filtrate was evaporated under reduced pressure to give the title compound (0.025 g, 80%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:29]1[N:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1>>[CH3:35][C:32]1[CH:31]=[N:30][C:29]([N:23]2[CH2:22][CH2:21][C:20]3([CH2:26][C:18]4([O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=6)[CH:12]=[C:13]5[CH2:27]4)[CH2:19]3)[CH2:25][CH2:24]2)=[N:34][CH:33]=1
Reactant: Cc1cnc(Br)nc1
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)cc1
Product: Cc1cnc(N2CCC3(CC2)CC2(Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O2)C3)nc1

Procedure:
The title compound is prepared from 5-(4-methylsulfonyl-phenyl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2-bromo-5-methyl-pyrimidine following a procedure analogous to that described for Example 4. LC (method 1): tR=1.07 min; Mass spectrum (ESI+): m/z=477 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].I[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][CH3:13])[CH3:2]
Reactant: CCOc1ccccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccccc1OCC
Temperature: 80 °C
Reaction time: 30 h

Procedure:
15.0 g of 2-ethoxyphenol, 18.0 ml of iodoethane and 30.0 g of potassium carbonate were suspended in 150 ml dimethylformamide, and the mixture was stirred at 80° C. for 30 hours. Ethyl acetate was added thereto, and the mixture was washed with water for five times and with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound quantitatively as a red-brown oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([C:2]3[N:3]=[C:4]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:13][CH2:14][CH:15]([N:18]([CH3:19])[CH3:20])[CH2:16][CH2:17]5)=[CH:8][C:6]=4[N:7]=3)=[CH:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccnc3cc(Cl)ccc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)C1CCN(Cc2cc3nc(-c4ccnc5cc(Cl)ccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 130 °C
Yield: 42.8 %

Procedure:
A sealable tube was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.150 g, 0.380 mmol), 7-chloroquinoline-4-boronic acid pinacol ester (0.132 g, 0.456 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.013 g, 0.02 mmol), 1 N aqueous sodium carbonate solution (1 mL) and acetonitrile (3 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130° C. for 90 min. The reaction mixture was cooled, concentrated, redissolved in ethyl acetate and filtered through celite. The filtrates were concentrated then purified by chromatography (silica, 10 to 20% methanol in dichloromethane) to give 104 (0.085 g, 43%) as a yellow solid. MS m/e 531 [M+H]+; 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.48-1.67 (m, 2 H) 1.82-1.96 (m, 2 H) 2.07-2.26 (m, 3 H) 2.30 (s, 6 H) 3.07 (d, J=11.7 Hz, 2 H) 3.82-3.91 (m, 6 H) 4.02-4.11 (m, 4 H) 7.36 (s, 1 H) 7.60 (dd, J=9.1, 2.3 Hz, 1 H) 7.95 (d, J=4.5 Hz, 1 H) 8.10 (d, J=2.3 Hz, 1 H) 8.67 (d, J=9.4 Hz, 1 H) 8.98 (d, J=4.9 Hz, 1 H)
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C([N+]1([O-])CC[O:17]CC1)C.CN(C)C=O.S(=O)(=O)(O)O>C(OCC)(=O)C>[CH3:9][C:8](=[CH:7][CH2:6][CH2:5][C:3](=[CH:2][CH:1]=[O:17])[CH3:4])[CH3:10]
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: CC[N+]1([O-])CCOCC1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCCC(C)=CC=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
346 mg (2 mmols) of geranyl chloride and 787 mg (6 mmols) of N-ethylmorpholine N-oxide were placed in a flask, to which was further added 3 ml of N,N-dimethylformamide. The mixture was agitated at room temperature for 1 hour and at 50° C. for 4 hours. To the reaction mixture was added 10 ml of 2.5% sulfuric acid and 10 ml of ethyl acetate for phase separation. The resultant organic phase was washed with 5 ml of 2.5% sulfuric acid, 5 ml of a saturated sodium hydrogen carbonate aqueous solution and 5 ml of a 10% sodium sulfate aqueous solution successively, after which it was dried with magnesium sulfate. After the drying, the solvent was distilled off from the solution and the residue was subjected to distillation by the use of Kugel-rohr distillation apparatus (bath temperature 93° C./3 Torr.) to obtain 268 mg (1.76 mmols) of citral. The yield was 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]#[N:31])=[C:25](Br)[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]1[CH:24]=[CH:25][C:26]([CH2:29][C:30]#[N:31])=[C:27]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[CH:28]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cc(-c3nc4ccccc4o3)ccc2CC#N)c(OC)c1
Temperature: 83 °C

Procedure:
A mixture of 2,4-dimethoxyphenylboronic acid (175 mg, 0.96 mmol), [4-(1,3-benzoxazol-2-yl)-2-bromophenyl]acetonitrile (example 1) (200 mg, 0.64 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.032 mmol), triphenylphosphine (17 mg, 0.064 mmol), and potassium carbonate (177 mg, 1.3 mmol) in degassed DME/H2O (5:1, 12 mL) was heated at 83° C. for 18 h. The mixture was cooled to rt, the two layers were separated and the aqueous layer was extracted with EtOAc (3×). The organics were combined, dried over Na2SO4 and evaporated to dryness to give an orange solid. Purification of the crude by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 40 min: 0 to 20% EtOAc, 40 to 50 min: 50% EtOAc) afforded [5-(1,3-benzoxazol-2-yl)-2′,4′-dimethoxy-1,1′-biphenyl-2-yl]acetonitrile as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.26 (dd, 1H), 8.15 (s, 1H), 7.77 (m, 1H), 7.70 (d, 1H), 7.57 (m, 1H), 7.36 (m, 2H), 7.16 (d, 1H), 6.62 (dd, 1H), 6.57 (s, 1H), 3.88 (s, 3H), 3.78 (s, 3H), 3.64 (q, 2H). MS (ESI) 371 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[C:22](=O)([O:25]C)[O:23][CH3:24]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:18])[C:15](=[O:17])[CH2:16][C:22]([O:23][CH3:24])=[O:25])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)OC
Agent: [Na]
Product: COC(=O)CC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
3-(4-Benzyloxyphenoxy)-2-butanone (5.0 g) was dissolved in 25 ml of dimethyl carbonate and added to a 50 ml, three-necked, round-bottom flask fitted with a thermometer, condenser, magnetic stirrer and nitrogen sweep. The solution was heated to 85° C. in an oil bath, then charged with 0.51 g of sodium over a period of 0.5 hour. The resulting clear yellow solution began off-passing after 15 minutes, and then turned a cloudy yellow. After 1 hour, the condenser was replaced with a Vigreux column and distillation head, and the bath temperature was raised to 130° C. Methanol was distilled off for 45 minutes. After approximately 4.5 hours, the reaction was stopped and the solution let cool to room temperature. The dimethyl carbonate was stripped off, and the residue rediluted with 50 ml of ethyl acetate. The solution was then washed with a solution of 50 ml of ice water and 5 ml of acetic acid and then with 50 ml of water. The organic phase was dried over magnesium sulfate, filtered, and stripped. The crude yield was 6.06 g of an orange oil. This was submitted for analysis and found to contain 82% of the desired product, methyl 4-(4-benzyloxyphenoxy)-3-oxopentanoate.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([O:12][CH2:13][CH3:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:15]([Cl:19])[C:16](=[CH2:18])[CH3:17]>>[CH2:13]([O:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:16]([CH3:18])([CH3:17])[CH2:15][Cl:19])[CH3:14]
Reactant: CCOc1ccccc1
Reactant: C=C(C)CCl
Agent: O=S(=O)(O)O
Product: CCOc1ccccc1C(C)(C)CCl
Temperature: 0 °C
Reaction time: 10 h
Yield: 213.4 %

Procedure:
120 g of 98% sulfuric acid was charged in a 500 ml four-neck flask. 200 g of phenetole was added dropwise thereto while the temperature was kept at 45° C. A mixed solution of 90 g of methallyl chloride and 165 g of phenetole was added dropwise thereto over 10 h while the temperature was kept at 0° to 10° C. The mixture was kept at 25° C. for 15 h and then poured into ice/water. An organic layer was separated out, washed thoroughly with a dilute aqueous sodium hydroxide solution and then water and dried over anhydrous sodium sulfate to obtain 451.2 g of crude 2-(2-ethoxyphenyl)-2-methylpropyl chloride. The crude product was analyzed according to gas chromatography to reveal that it comprised 22% of 2-(4-ethoxyphenyl)-2-methylpropyl chloride and 78% of 2-(2-ethoxyphenyl)-2-methylpropyl chloride (isomer).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2(C3C=CC=CC=3)[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[N:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>CCCCCC.CN(C)C=O.C(OCC)C>[C:3]1([C:9]2[C:13]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C1=C(c2ccccc2)N=NC1(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)CCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 199.8 %

Procedure:
Sodium hydride (1.30 g of 60% dispersion, 32 mmol) was washed twice with hexane and covered with dimethylformamide (DMF) (100 mL). 3,3,5-Triphenyl-3H-pyrazole (8 g, 27 mmol) was added and the mixture stirred at 110° C. uhder an atmosphere of nitrogen for 25 minutes before being cooled to room temperature. Ethyl 6-bromohexanoate (6.6 g, 5.3 mL, 29 mmol) in DMF (2 mL) was added dropwise and the mixture stirred at room temperature. After 15 minutes water was added and the mixture extracted with diethyl ether (4 times). The combined extracts were washed with water (3 times), dried and concentrated in vacuo to give an oil. Chromatography on a column of silica gel using a mixture of hexane and diethyl ether (11:9) as eluent afforded ethyl 3,4,5-triphenyl-1H-pyrazol-1-hexanoate (11.83 g, 100%) as a viscous oil. MS(CI): m/e=439 (MH+)
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH2:15](Cl)[CH2:16]Cl.C1C=CC2N(O)N=NC=2C=1>C(O)C>[CH2:15]([O:13][C:12](=[O:14])[CH:2]([NH2:1])[CH2:3][CH2:4][C:5]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:11])[CH3:16]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCO
Product: CCOC(=O)C(N)CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A dry 250 mL round-bottomed flask was charged with 2.200 g (10.800 mmol) H-Glu(O-t-Bu)-OH (41a) dissolved in 100 mL ethanol. To this was added 4.4 g (22.9 mmol) EDC and 3.2 g (23.7 mmol) HOBt. The reaction mixture was stirred at ambient temperature for 22 h. The reaction mixture was followed to completion according to the LC-MS data. The solvent was removed under reduced pressure and the resulting oil was dissolved in dichloromethane 300 mL and extracted with H2O 300 mL. The H2O-phase was adjusted to pH 9.5. The crude product was extracted into dichloromethane 400 mL, dried over NaSO4, filtrated and evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:13]=2[CH3:14])=[O:17])[CH:20]=[CH:21][C:22]=1[N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH2:29][CH2:28]1)#[N:25]
Reactant: COc1ccc(-n2ncc(C(=O)O)c2C)cc1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: COc1ccc(-n2ncc(C(=O)Nc3ccc(N4CCC(N5CCOCC5)CC4)c(C#N)c3)c2C)cc1
Yield: 62 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-methoxyphenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl) benzonitrile (1.2 g), the title compound (1.3 g) was obtained, melting point: 238° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:14][C:15]([NH:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=2)=[O:16])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)CC(CNS(=O)(=O)c2ccc(C)cc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NCC(CC(=O)Nc2ccc(C(=O)O)cc2)c2ccccc2)cc1
Yield: 85.5 %

Procedure:
A solution of the ester 55 (0.106 g, 0.220 mmol) in methanol (3 ml) and THF (3 ml) was stirred in presence of NaOH (aq, 1M, 1 ml) at room temperature overnight. The solvent was removed under reduced pressure. HCl (aq, 1M, 1.5 ml) was added and the white precipitate was filtered, washed with water (5 ml) and dried under vacuum. Pure 59 was obtained as a white solid (0.085 g, 0.188 mmol, 85%) without further purification, mp 225-227° C. 1H NMR (400 MHz, CD3OD) δ2.39 (3H, s), 2.62 (1H, dd, J 8.4, 14.8 Hz), 2.35 (1H, dd, J 6.6, 14.6 Hz), 3.05 (1H, dd, J 8.0, 13.0 Hz), 3.12 (1H, dd, J 7.2, 12.8 Hz), 7.16-7.19 (3H, m), 7.24-7.27 (2H, m), 7.30 (2H, d, J 7.6 Hz), 7.53 (2H, d, J 8.4 Hz), 7.65 (2H, d, J 8.4 Hz), 7.91 (2H, d, J 9.2 Hz). 13C NMR (100 MHz, DMSO-d3) δ 21.61, 40.65, 42.32, 48.33, 118.95, 125.61, 127.18), 127.26, 128.38, 128.96, 130.02, 130.98, 138.09, 142.47, 143.22, 143.72, 167.55, 170.64. νmax (solid)/(cm−1) 3316, 3277), 1668, 1595, 1531, 1408, 1317, 1254, 1152. MS (API-ES): m/z 451[M−H]− (100%), HRMS (API-ES) m/z found 451.1334 [M−H]−.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([N:6]1[CH:10]=[C:9]([C:11](=[O:21])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[N:8]=[CH:7]1)(=[O:5])=[O:4].[NH4+].[Cl-]>O.C(O)C.[Fe]>[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([C:9]1[N:8]=[CH:7][N:6]([S:3]([N:2]([CH3:22])[CH3:1])(=[O:4])=[O:5])[CH:10]=1)=[O:21]
Reactant: CN(C)S(=O)(=O)n1cnc(C(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C)S(=O)(=O)n1cnc(C(=O)c2cccc(N)c2)c1
Yield: 101.9 %

Procedure:
To a mixture of Example 55B (3.24 g, 10 mmol) and NH4Cl (540 mg, 10 mmol) in water (15 mL) and ethanol (35 mL) was added iron powder (3.92 g, 70 mmol) and the mixture was refluxed for 1 hour. The mixture was filtered, the solid was washed with THF, and the combined filtrate and washings were removed under vacuum to provide 3 g (˜100%) of the title compound.
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([Br:38])[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]>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.C1(C)C=CC=CC=1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([Br:38])[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35].[CH3:37][O:36][C:32]1[CH:31]=[C:30]([P:1](=[O:18])([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:29]=[C:28]([O:27][CH3:26])[C:33]=1[O:34][CH3:35]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1cc(Br)cc(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(P(=O)(OCc2ccccc2)OCc2ccccc2)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxybromobenzene is prepared following the procedure of Tetrahedron Lett. 26 (1985):5939-5942. Dibenzyl phosphite is heated in the presence of tetrakis(triphenylphosphine)palladium (0), triethylamine and toluene with 3,4,5-trimethoxybromobenzene to give Dibenzyl 3,4,5-trimethoxyphenylphosphonate 2 following the procedure of J. Med. Chem. 32 (1989):1580-1590.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:10].[C:25](Cl)(=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C(Cl)Cl>O1CCCC1>[C:25]([NH:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:10])(=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: NCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (50% in water, 29 ml) was added in three portions to a stirred solution of 2-amino-4′-benzyloxyacetophenone HCl (4.6 g, 17 mmol) and tetrahydrofuran (200 ml). Palmitoyl chloride (19 mmol) in tetrahydrofuran (25 ml) was added dropwise over 20 min yielding a dark brown solution. The mixture was stirred overnight at room temperature. The aqueous fraction was removed by use of a separatory funnel and chloroform/methanol (2/1, 150 ml) was added to the organic layer which was then washed with water (50 ml). The yellow aqueous layer was extracted once with chloroform (50 ml). The organic solutions were then pooled and rotoevaporated until near dryness. The residue was redissolved in chloroform (100 ml) and crystallized by the addition of hexane (400 ml). The flask was cooled to 4° C. for 2 h. The crystals were filtered and washed with cold hexane and dried in a fume hood overnight. The product yield was 3.79 g (8 mmol). An Rf of 0.21 was observed when resolved by thin layer chromatography using methylene chloride. [M+H]+: 479 for C31H45NO3. 1H nmr (δ, ppm, CDCl3), 7.96 (2H, δ, 8.8 Hz, O—Ar—C(O)), 7.40 (5H, m, Ar′CH2O—), 7.03 (2H, δ, 8.8 Hz, O—Ar—C(O)), 6.57 (1H, bs, NH2), 5.14 (2H, s, Ar′CH2O—), 4.71 (2H, s, C(O)CH2NHC(O)), 2.29 (2H, t, 7.4 Hz, C(O)CH2(CH2)13CH3), 1.67 (2H, m, C(O)CH2(CH2)13CH3), 0.87 (3H, t, 6.7 Hz, C(O)CH2(CH2)13CH3).
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1)=O.[Cl:16][C:17]1[N:22]=[N:21][C:20]([NH2:23])=[C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:18]=1>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:20]2[N:21]([CH:2]=[C:3]([CH:5]3[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]3)[N:23]=2)[N:22]=1
Reactant: Nc1nnc(Cl)cc1N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)CBr)C1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(c2cn3nc(Cl)cc(N4CCOCC4)c3n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 3-(2-bromoacetyl)azetidine-1-carboxylate (207 mg, 0.744 mmol) in DMF (1 mL) was added to a solution of compound 19a (99.8 mg, 0.465 mmol) and Na2HPO4 (165 mg, 2.50 mmol) in DMF (20 mL). The resulting mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue obtained was purified by normal phase column chromatography on silica gel (0-100% EtOAc/heptane) to obtain compound 19b. Mass Spectrum (LCMS, ESI pos.): Calcd. for C19H25ClN4O3: 393.2 (M+H). found: 393.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:14](C(OCC(Cl)(Cl)Cl)=O)[C@H:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=1.OP([O-])(O)=O.[K+]>C1COCC1.[Zn]>[Br:1][C:2]1[C:3]([NH:14][C@H:15]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:4][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH:6]=1
Reactant: COc1ccc(COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c2nn(C(=O)OC(C)(C)C)cc2Br)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@H](CC(C)C)Nc2nn(C(=O)OC(C)(C)C)cc2Br)cc1
Reaction time: 1 h

Procedure:
To 4-methoxybenzyl N-[4-bromo-1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl]-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate (2.38 g, 3.54 mmol) in THF (40 mL) was added activated zinc powder (2.3 g, 35.4 mmol) and an aqueous solution of KH2PO4 (1.0 M, 14.2 mL, 14.2 mmol) dropwise. After 1 hour additional aliquots of activated zinc powder (2.3 g, 35.4 mmol) and aqueous KH2PO4 solution were added (1.0 M, 14.2 mL, 14.2 mmol) and the reaction mixture was stirred for 1 hour. The zinc powder was filtered off, rinsed with Et2O and water and the product extracted with ether (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 3/7) to afford 4-methoxybenzyl N-[4-bromo-1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl]leucinate.