Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([C:30]([O:32][CH3:33])=[O:31])=[CH:23][C:22]=2[O:34][CH3:35])=[C:7]([O:36][CH3:37])[CH:6]=1)=[O:4].C([O-])(O)=O.[Na+].[O:43](C(OC(C)(C)C)=O)[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=O>C1COCC1>[C:47]([O:46][C:44]([N:17]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([C:30]([O:32][CH3:33])=[O:31])=[CH:23][C:22]=1[O:34][CH3:35])[CH2:16][CH2:15][O:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[O:36][CH3:37])=[O:43])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(OC)c(OCCNCCOc2cc([N+](=O)[O-])c(C(=O)OC)cc2OC)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(OCCN(CCOc2cc([N+](=O)[O-])c(C(=O)OC)cc2OC)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
N,N-di[2-(4-methoxycarbonyl-2-methoxy-5-nitrophenyl-oxy)ethyl]amine, compound 9, (crude, 4.16 mmol) and NaHCO3 (210 mg, 2.50 mmol) was suspended in THF, and treated with (BOC)2O (999 mg, 4.58 mmol) at 0° C. and stirring was continued at rt for 3 h. After removal of THF, the residue was partitioned between H2O and EtOAc (100/100 mL). Aqueous layer was further extracted with EtOAc (2×50 mL). The combined EtOAc layers were washed with brine (80 mL), dried (MgSO4), and concentrated. Purification of the residue by flash chromatography (silica gel, 6:4 hexanes/EtOAc) yielded N-tert-butoxycarbonyl-N,N-d i[2-(4-methoxycarbonyl-2-methoxy-5-nitro-phenyloxy)ethyl]amine, compound 10, as light yellow solid: 1HNMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 3.77 (m, 4H), 3.83, 3.86 and 3.87 (3×s, 12H), 4.20 and 4.26 (2×t, J=3.9 Hz, 4H), 6.97 and 6.99 (2×s, 2H), 7.36 and 7.40 (2×s, 2H); EIMS m/z 646 ([M]++Na).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[Br:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19](F)[CH:18]=1.CCN(C(C)C)C(C)C>CC(O)C>[Br:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:1][CH2:2][CH:3]([OH:15])[CH2:4][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)[CH:18]=1
Reactant: Fc1cc(Br)ccn1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: OC(CNc1cc(Br)ccn1)CN1CCc2ccccc2C1
Temperature: 100 °C
Reaction time: 26 h
Yield: 58.3 %

Procedure:
A mixture of 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (14.0 g, 67.9 mmol), 4-bromo-2-fluoropyridine (10.0 g, 56.8 mmol) and DIPEA (11.0 g, 85.3 mmol) in i-PrOH (35 mL) were combined in a sealed tube and stirred at 100° C. for 26 h. The reaction mixture was then concentrated and the residue purified by column chromatography to give the desired product (12.0 g, 58.5%). LCMS (m/z): 362.0/364.0 [M+H]+/[M+2+H]+
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(NC(=O)C(C)(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)cc(NC(=O)C(C)(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-6-(2,2-dimethylpropionylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)[N:6]=1)=[O:4].[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:16]([N:12]1[C:13]2[C:8](=[C:7]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=3)[N:6]=[C:5]([C:3]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2cncc(F)c2)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A mixture of 1-benzyl-5-(5-fluoro-pyridin-3-yl)-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (23 mg, 0.056 mmol), glycine (417 mg, 5.6 mmol) and NaOMe solution (9 mL, 4.4 mmol) was refluxed for 16 h. After cooling to r.t., solvent was evaporated. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH about 3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH). The product isolated was then dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 10 mg of the title compound. MS: (+) m/z 449.34 (M+1).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>ClCCl>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reaction time: 2.5 h

Procedure:
To a solution of 428 g (959 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 151, Step A) in dichloromethane (4.55 L) was added 25.9 mL (1.44 mol) of water. A solution of 610 g (1.44 mol) of Dess-Martin periodinane in dichloromethane (4.55 L) was added slowly over a 25 min period so as to maintain an internal reaction temperature not exceeding 25° C. The white slurry was stirred for 2.5 h and then was quenched by cautious, slow addition of saturated aqueous sodium thiosulfate (5.2 L) so as to maintain an internal reaction temperature below 30° C. Water was added and the mixture was extracted with dichloromethane (3×). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (4×) and then saturated aqueous sodium chloride (1×), dried over Na2SO4, filtered and the filtrate was concentrated to afford a yellow oily solid. A mixture of ethyl ether and DCM were added, and precipitated solids were filtered off. The precipitation/filtration process was repeated. The filtrate was concentrated to provide the title compound as a white solid. The crude product was used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14](=[N:20][N:21]([CH2:23][CH3:24])[CH:22]=3)[C:15](Cl)=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:25]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14](=[N:20][N:21]([CH2:23][CH3:24])[CH:22]=3)[C:15]([NH2:25])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1cc2c(n1)c(Cl)nc1cc(OCc3ccccc3)ccc12
Reactant: N
Solvent: CO
Product: CCn1cc2c(n1)c(N)nc1cc(OCc3ccccc3)ccc12
Temperature: 150 °C

Procedure:
A mixture of 7-benzyloxy-4-chloro-2-ethyl-2H-pyrazolo[3,4-c]quinoline (1.20 g, 3.55 mmol) and 7 N ammonia in methanol (25 mL) was heated in a pressure vessel at 150° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, purified via column chromatography on silica gel (eluting with 0-35% CMA/chloroform), concentrated under reduced pressure, and crystallized from acetonitrile to yield 0.93 g of 7-(benzyloxy)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a tan solid, mp 229-230° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[CH2:30][C@@:28]2([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]2[OH:31])[C@@:23]2([CH:32]=[CH2:33])[C@H:14]1[C:15]1[CH:16]=[CH:17][C:18]([OH:34])=[CH:19][C:20]=1[CH2:21][CH2:22]2>>[N:1]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]3[OH:31])[C@@:23]3([CH:32]=[CH2:33])[C@H:14]2[C:15]2[CH:16]=[CH:17][C:18]([OH:34])=[CH:19][C:20]=2[CH2:21][CH2:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCBr)C[C@@]1(C)[C@H]2CC[C@@H]1O
Reactant: C1CCNCC1
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCN1CCCCC1)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with piperidine (10 equivalents) analogously to instructions 17.2, 50 mg of bromide 30a yields 41 mg of amine 34a as a colorless foam (GC-MS: m/z theor.: 451, pract.: 451).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:36][C@@H:35]([OH:37])[C:32]4([CH2:34][CH2:33]4)[CH2:31]3)[N:26]=[C:25]([CH3:38])[N:24]=2)=[O:20])[CH2:8][N:9]([O:12]C2CCCCO2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CC(O)=O.O>[CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:36][CH:35]([OH:37])[C:32]4([CH2:34][CH2:33]4)[CH2:31]3)[N:26]=[C:25]([CH3:38])[N:24]=2)=[O:20])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2C[C@@H](O)C3(CC3)C2)n1
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CC(O)C3(CC3)C2)n1
Temperature: 25 °C
Yield: 27.5 %

Procedure:
[(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(7S)-7-hydroxy-5-azaspiro[2.4]hept-5-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (91 mg, 0.202 mmol) was dissolved in a mixture of AcOH/H2O (10 mL, 4:1) and stirred at RT until LCMS indicated completion of the deprotection (overnight). The reaction mixture was concentrated to dryness under vacuum and was purified by RP-HPLC to provide ((2R)-2-(cyclopentylmethyl)-3-{2-[5-fluoro-6-(7-hydroxy-5-azaspiro[2.4]hept-5-yl)-2-methyl-4-pyrimidinyl]hydrazino}-3-oxopropyl)hydroxyformamide (25 mg, 27%). LCMS: (M+H)+: 451.2.
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:2]2[O:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Reactant: OB(O)c1ccccc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2ccccc2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 12 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and phenylboronic acid. The title compound (49 mg) was obtained as a pale-yellow solid, m/z 325 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:4]1.C(OC([NH:23][CH2:24][C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][CH2:24][C:25]([NH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:4]1)=[O:26]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC[C@H]1CCCN(CC2CCCCC2)C1
Product: NCC(=O)NC[C@H]1CCCN(CC2CCCCC2)C1

Procedure:
The title compound was prepared by conducting procedures similar to Steps 1-2 of Example 17, using (3R)-3-aminomethyl-1-(cyclohexylmethyl)piperidine and (tert-butoxycarbonyl)-glycine.
Reaction SMILES: [Br:1][C:2]([F:26])([F:25])[C:3]([F:24])([F:23])[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[Br:14])=[CH:7][C:6]=1[S:19](O)(=[O:21])=[O:20].[K].S1(CCCC1)(=O)=O.P(Cl)(Cl)([Cl:37])=O>C(Cl)Cl.C(#N)C>[Br:1][C:2]([F:26])([F:25])[C:3]([F:24])([F:23])[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[Br:14])=[CH:7][C:6]=1[S:19]([Cl:37])(=[O:21])=[O:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cc(OC(F)(F)C(F)(F)Br)ccc1OC(F)(F)C(F)(F)Br
Agent: [K]
Solvent: CC#N
Solvent: O=S1(=O)CCCC1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cc(OC(F)(F)C(F)(F)Br)ccc1OC(F)(F)C(F)(F)Br
Temperature: 75 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A mixture of 5.86 g (0.01mol) of the 2,5-di(2-bromotetrafluoroethoxy) benzenesulfonic acid, potassium salt, 10 mL acetonitrile, 10 mL sulfolane and 6 mL phosphoryl chloride was placed into a 100 mL round-bottom flask, and stirred at 68-82° C. for 1 hour. The mixture was then cooled down to below 5° C. (with the reaction vessel resting in an ice-bath ) and 15 mL ice-cold water was added dropwise. Stirring was continued at a temperature below 10° C. for 20 minutes and the precipitated oily product was isolated by suction and then diluted with 100 mL of methylene chloride. The combined organic layer was washed with saturated aq. sodium chloride in a 500 mL separatory funnel until neutral and dried over sodium sulfate overnight. After the removal of the salt by filtration and the evaporation of the solvents, the crude product was purified by distillation at reduced pressure (10 to 10−2 torr) to collect 102-106° C. fraction at vacuum. A total of 5.00 g (0.0088 mol) of 2,5-di(2-bromotetrafluoroethoxy) benzenesulfonyl chloride was obtained in 88.2% yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[CH:12]=[C:13]([CH3:16])[C:14]=1[NH2:15])=[O:4].[OH-].[Na+]>O1CCOCC1.CO>[NH2:15][C:14]1[C:13]([CH3:16])=[CH:12][C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(N)c(C)cc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2ncccc2c(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
To a solution of 550 mg (2.54 mmol) of 6-amino-7-methyl-quinoline-5-carboxylic acid methyl ester in 11 mL of dioxane and 0.5 mL of methanol, is added 6.4 mL (6.4 mmol) of an aqueous solution of NaOH 1N. The mixture is stirred at ambient temperature for 16 hours. The solvents are evaporated and water is added to the residue. The product is precipitated at pH 6 by addition of concentrated HCl, filtrated, washed with a minimum of water and dried on high vacuum pump. The yellow crude solid (282 mg) obtained is used directly in the next step; LC/MS: 203/204 (M+H)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([N:12]1[CH2:16][CH2:15][C:14](=O)[NH:13]1)=[O:11]>>[Cl:3][C:14]1[CH2:15][CH2:16][N:12]([C:10](=[O:11])[C:9]2[CH:18]=[CH:19][CH:20]=[C:7]([F:6])[CH:8]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCN(C(=O)c2cccc(F)c2)N1
Product: O=C(c1cccc(F)c1)N1CCC(Cl)=N1
Temperature: 85 °C
Yield: 88.9 %

Procedure:
Phosphorus oxychloride (54 ml for 5.4 gm of SM, 10 volume) was added drop wise directly to 1-(3-fluorobenzoyl)pyrazolidin-3-one (5.4 gm, 0.0238 mmol, 1 equiv.) at 0° C. and then refluxed at 85° C. for an hour. The reaction mixture was cooled to RT, concentrated and basified with solid NaCO3 (pH: 8-9), extracted with dichloromethane (100 ml×2) and concentrated. The crude product was purified by silica gel column using (60-120) mesh to get the pure product as off green solid (4.8, 88.9% yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:38]=4)[CH:18]=[CH:19][CH:20]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N(c2ccccc2)C(c2cccc(Br)c2)CN1S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2cccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)c2)c1

Procedure:
In analogy to example 1, step 3, 1-benzenesulfonyl-4-(3-bromo-phenyl)-3-phenyl-imidazolidin-2-one (example 5, step 2) was reacted with (3-methylsulfonylphenyl)boronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(3′-methanesulfonyl-biphenyl-3-yl)-3-phenyl-imidazolidin-2-one as an off-white solid. MS: 533.1 ([M+H]+)
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:32](O)(=[O:37])[CH:33]([CH2:35][OH:36])[OH:34].ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:35](=[O:36])[CH:33]([CH2:32][OH:37])[OH:34])=[CH:30][CH:31]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCOc1ccc(CN)cc1
Reactant: O=C(O)C(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(CNC(=O)C(O)CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
Dicyclohexylcarbodiimide (160 mg) was added to a solution of 200 mg of p-heptyloxybenzylamine, 150 mg of glyceric acid (65% aqueous solution) and 110 mg of 1-hydroxybenzotriazole in 2 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate, washed in sequence with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography to give 80 mg of N-(p-heptyloxybenzyl)glyceramide.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:15]([C:18]1[CH:19]=[C:20]([C@H:36]2[CH2:40][CH2:39][C@H:38]([C:41]3[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH3:50])=[C:43]([O:51][CH3:52])[CH:42]=3)[O:37]2)[CH:21]=[C:22]([O:34][CH3:35])[C:23]=1[O:24][CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:17])=[O:16])[CH2:13][CH3:14]>ClCCl>[CH2:12]([S:15]([C:18]1[CH:19]=[C:20]([C@H:36]2[CH2:40][CH2:39][C@H:38]([C:41]3[CH:42]=[C:43]([O:51][CH3:52])[C:44]([O:49][CH3:50])=[C:45]([O:47][CH3:48])[CH:46]=3)[O:37]2)[CH:21]=[C:22]([O:34][CH3:35])[C:23]=1[O:24][CH2:25][CH2:26][S:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:9])(=[O:16])=[O:17])[CH2:13][CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1OCCSc1ccccc1
Solvent: ClCCl
Product: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1OCCS(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
m-Chloroperbenzoic acid (50 mg, 1.1 eq) was added to a solution of trans-2-[3-propylsulfonyl-4-{2-(phenylthio)ethoxy}-5-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (300 mg) in dichloromethane (3 mL), and the mixture was stirred at room temperature for 1 h. The solid was filtered off and the filtrate was washed with 1N NaOH, dried, and concentrated to a residue. Purification by flash column chromatography (hexane-ethyl acetate 1:2) afforded the title compound.
Reaction SMILES: [CH2:1]([CH:7]([O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=1)[CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(OCC)(=O)C.[Ni]>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([O:30][C:31](=[O:41])[C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:19])=[CH:26][CH:25]=1
Reactant: CCCCCCC(CC=CCCCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1)OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCCCCCC(CC=CCCCCCCCC(=O)Oc1ccc(N)cc1)OC(=O)c1ccc(N)cc1
Temperature: 62.5 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-benzoic acid 1-hexyl-11-(4-nitro-phenoxy carbonyl)-undec-3-enyl ester (300 g) in ethyl acetate (1.5 L) in a pressure vessel was added Raney Nickel (120 g) added, and the mixture stirred under an atmosphere of Hydrogen (8-10 Kg) for 8 hours at a temperature of 60-65° C. The catalyst was removed by filtration. The solvent was distilled off completely under reduced pressure at 65-70° C. and removed traces for 1 hour at 85-90° C. to get pure 4-aminobenzoic acid 11-(4-amino-phenoxycarbonyl)-1-hexyl-undec-3-enyl ester product as deep yellow thick syrup (190 g). The resulting compound was characterized by 1H NMR (CDCl3) δ 0.88 (t, 3H, CH3), 1.2-1.65 (m, 24H, 12×CH2), 2.12 (t, 2H, COCH2), 3.5 (m, 1H, CH) 5.12 (m, 1H, CH), 5.45 (m, 1H, CH), 6.55 (m, 4H, Ar), 6.85 (m, 2H, Ar), 7.75 (m, 2H, Ar).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:23]([NH:25][NH:26][CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]1([CH2:41][C:42](O)=[O:43])[CH:40]=[CH:39][N:38]=[N:37]1>>[CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:23]([NH:25][N:26]([CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])[C:42](=[O:43])[CH2:41][N:36]1[CH:40]=[CH:39][N:38]=[N:37]1)=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1ccnn1
Reactant: CC[C@H](C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Product: CC[C@H](C)CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1)C(=O)Cn1ccnn1

Procedure:
In a manner analogous to that described in Example 8 from (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-4-methyl-2′-(2(S)-methylbutyl)valerohydrazide and using 1,2,3-triazole-1-acetic acid in place of N-tert-butoxycarbonyl-β-alanine there was obtained (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-4-methyl-2′-(2(S)-methylbutyl)-2′-[2-(1H-1,2,3-triazol-1-yl)acetyl]valerohydrazide in the form of a gum.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:35])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)OCC)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A179) and ethyl chloroformate the title compound was obtained as colorless solid.