Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([NH2:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1)=[O:3].[CH:15]([S:17]([F:20])(=[O:19])=[O:18])=[CH2:16]>C(O)(=O)C.CCOCC>[C:2]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([O:11][CH3:12])=[CH:8][C:9]=1[NH:10][CH:16]=[CH:15][S:17]([F:20])(=[O:19])=[O:18])(=[O:3])[CH3:1]
Reactant: C=CS(=O)(=O)F
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc(NC=CS(=O)(=O)F)c(C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a mixture of 2-amino-4,5-dimethoxyacetophenone (18 g, 92 mmol) in 125 mL of glacial acetic acid was added in one portion ethenesulfonyl fluoride (11.4 g, 0.1 mol) under nitrogen. After stirring for 1 hour at room temperature the resulting yellow mixture was refluxed for 1 hour. The yellow crystalline solid was diluted with an equal volume of ether, filtered, washed with ether, and air dried. There was obtained the title compound (23.7 g, 85% yield) as a yellow solid, mp 142.5°-146.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22]CS([O-])(=O)=O)([C:13]2[CH:18]=[CH:17][C:16](Cl)=[C:15](Cl)[CH:14]=2)[CH2:9]1)=[O:7].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(OCC)(=O)C>CO.C(OCC)(=O)C>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[C:13]1([C:10]2([CH2:21][CH2:22][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=3)[CH2:9]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: NC(=O)N1CCOCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using 2-[1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid morpholine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with ethyl acetate and then 10% methanol/ethyl acetate, the title compound. HRMS calculated for C38H47N3O6 : 642.354312. Found: 642.356150.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.[Br:12][C:13]1[CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][C:18]=1F.C1OCCOCCOCCOCCOCCOC1.[F-].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([O:10][C:18]2[CH:17]=[CH:16][C:15]([C:20](=[O:22])[CH3:21])=[CH:14][C:13]=2[Br:12])[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(O)c1
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cncc(Oc2ccc(C(C)=O)cc2Br)c1
Yield: 27.8 %

Procedure:
Methyl-5-hydroxynicotinate (1.0 g, 6.53 mmol), 3′-bromo-4′-fluoroacetophenone (1.42 g, 6.53 mmol), 18-crown-6 (155.3 mg, 0.59 mmol) and potassium fluoride (40 wt. % on alumina, 996 mg, 6.86 mmol) were dissolved in ACN (10 mL). The reaction was refluxed for three days. After cooling the mixture was quenched with 2N aqueous potassium carbonate solution, extracted with ether, dried with sodium sulphate, filtered, evaporated and purified by silica gel chromatography (ethyl acetate:n-heptane 1:4). 635 mg (yield: 28%) of the pure compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[CH2:22][O:21][CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: COC[C@@H]1CCCN1
Product: COC[C@@H]1CCCN1C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (2S)-2-methoxymethyl-pyrrolidine (0.087 g, 0.76 mmol) gives the title compound.
Reaction SMILES: CN(C)/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[CH3:22][O:23][CH2:24][CH:25]([NH2:29])[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[I:17][C:15]1[CH:16]=[C:11]2[C:12](=[CH:13][CH:14]=1)[N:29]([CH:25]([CH:26]([CH3:28])[CH3:27])[CH2:24][O:23][CH3:22])[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]2=[O:19]
Reactant: COCC(N)C(C)C
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C(COC)C(C)C)c2ccc(I)cc2c1=O
Temperature: 60 °C
Reaction time: 48 h
Yield: 59.1 %

Procedure:
To a solution of ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (Intermediate 24, 1 g, 2.56 mmol) dissolved in THF (10 mL) was added 1-methoxy-3-methylbutan-2-amine hydrochloride (366 mg, 2.38 mmol) followed by potassium carbonate. The reaction mixture was stirred at 60° C. for 2 d. The reaction mixture was concentrated under reduced pressure and the residue was resuspended in DMF (10 mL). Potassium carbonate was added (978 mg, 7.08 mmol), and the reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was cooled down to room temperature and quenched with 1 N HCl. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate, and the organics were dried and concentrated to provide ethyl 6-iodo-1-(1-methoxy-3-methylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (623 mg, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@@H:28]3[CH2:32][C@H:31]([OH:33])[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34]I.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:26]=[C:25]([O:27][C@@H:28]3[CH2:32][C@H:31]([O:33][CH3:34])[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C=C[C@@H](O)C3)c3ccccc3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO[C@@H]1C=C[C@H](Oc2nc(N3CCN(C(=O)OCc4ccccc4)CC3)nc3ccccc23)C1
Yield: 91 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,4S)-(4-hydroxycyclopent-2-en-1-yl)oxy]quinazoline [cf. Example 35(3)] (6.31 g) and methyl iodide (4.00 g) in dimethylformamide (52 ml) is added 60% sodium hydride (in oil) (678 mg) with stirring under ice-cooling, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate, and washed with water 5 times. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=500:1, v/v) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,4S)-(4-methoxycyclopent-2-en-1-yl)oxy]quinazoline (5.92 g) as oil.
Reaction SMILES: [Br:1]Br.[CH:3]1[C:20]2[C:7](=[C:8]3[C:17](=[CH:18][CH:19]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[S:10](=[O:22])(=[O:21])[NH:9]3)[N:6]=[CH:5][CH:4]=1.C(Cl)(Cl)Cl>O1CCOCC1.C(Cl)(Cl)Cl>[Br:1][C:19]1[CH:18]=[C:17]2[C:8](=[C:7]3[C:20]=1[CH:3]=[CH:4][CH:5]=[N:6]3)[NH:9][S:10](=[O:21])(=[O:22])[C:11]1[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S1(=O)Nc2c(ccc3cccnc23)-c2ccccc21
Reactant: BrBr
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=S1(=O)Nc2c(cc(Br)c3cccnc23)-c2ccccc21
Reaction time: 2 h
Yield: 64.6 %

Procedure:
Bromine (170 μl, 3.30 mmol) was added dropwise to a solution of 5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 184 (467 mg, 1.65 mmol) in 1,4-dioxane/chloroform (1:1, 124 ml) at 0° C. After 2 h, chloroform (30 ml) was added and the resulting precipitate was collected by filtration. The solid was triturated from MeOH to give the title compound (385 mg, 64%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][CH2:12][CH:13]([OH:18])[CH2:14][N:15]=[N+]=[N-].O>O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][CH2:12][CH:13]([OH:18])[CH2:14][NH2:15]
Reactant: [N-]=[N+]=NCC(O)COc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC(O)COc1cccc(Cl)c1
Reaction time: 1.5 h
Yield: 43.4 %

Procedure:
0.19 g of lithium aluminum hydride was gradually added, whilst ice-cooling and under a stream of nitrogen gas, to a solution of 0.39 g of 3-(3-chlorophenoxy)-2-hydroxypropylazide (prepared as described in Preparation 12) in 5 ml of anhydrous tetrahydrofuran. The mixture was then stirred for a further 1.5 hours under the same conditions, after which excess lithium aluminum hydride was decomposed by adding water. Insolubles were then removed by filtration from the reaction mixture, using a Celite (trade name) filter aid, and the filtrate was dried over anhydrous sodium sulfate. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, to give 0.15 g of the title compound as white crystals, melting at 55° C. to 58° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7]Br)=[CH:3][CH:2]=1.[H-].[Na+].CN([CH:14]=[O:15])C>>[CH3:5][C:4](=[CH2:3])[CH2:7][CH2:14][O:15][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C=C(C)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BnBr was added to the mixture of alcohol and NaH in DMF cooled in an ice bath. The mixture was stirred at room temperature overnight and the solid was filtered. The solvent was removed and the residue was purified by column chromatography to give compound 1.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>CC(C)=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:3])=[O:24]
Reactant: OCCCCCCCCCBr
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
2 N Jones' reagent (20 ml) was gradually and dropwise added to an acetone (20 ml) solution of 9-bromononanol (2.2 g,10 mmols) with cooling with ice, and then stirred at room temperature for 10 minutes. The reaction mixture was extracted three times with hexane (40 ml). The organic layer was washed with water, and then extracted three times with an aqueous saturated solution of potassium carbonate (40 ml). The aqueous layers were combined, then made acidic (pH=1) with 10% sulfuric acid added thereto, and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. 1.8 g (yield: 77%) of 9-bromononanoic acid was obtained as colorless needle-like crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C1C=CC=CC=1>[C:31]([O:1][CH2:2][CH2:3][CH2:4][Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:34])[CH:32]=[CH2:33]
Reactant: OCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
32.9 g (91.4 mmol) of compound (C) was added to a 1 N solution of sodium carbonate in ethanol and the mixture was heated at 70° to 80° C. for 3 h to conduct the hydrolysis. 27.7 g (87.1 mmol) of 3-hydroxypropyltriphenylsilane (D) was thus obtained (yield: 95.4%). 250 ml of dry benzene was placed in a flask after replacing air in the flask with a dry inert gas (argon). 5.0 g (15.7 mmol) of compound (D) and 1.9 g of triethylamine were dissolved therein. 50 ml of a solution of 1.6 g (17.7 mmol) of acryloyl chloride in benzene was added slowly thereto. After the completion of the addition, the mixture was stirred at room temperature for 6 h. The reaction solution was washed with a 0.5 N hydrochloric acid, water, a 1 N sodium carbonate solution and water successively and then dried over magnesium sulfate. Benzene was distilled off and the residue was purified according to column chromatography (silica gel/benzene) to obtain 5.1 g (13.7 mmol) of 3-acryloyloxypropyltriphenylsilane in the form of white crystals (yield: 87.3%).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[NH:23][C:22]2=[O:36])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:40])[CH:38]=[O:39].O>C1C=CC=CC=1>[OH:39][CH:38]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:22]1=[O:36])[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]
Reactant: O=C1NC(SCC#Cc2ccc(F)cc2)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1

Procedure:
3-(Triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one (1.02g) and t-butyl glyoxalate (2.76g) were refluxed in dry benzene (50ml) with provision for the removal of water. After 1 hour the benzene solution was washed 5 times with water, dried and evaporated. The residue was chromatographed on silica to give 1-(1-Hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one as an amorphous solid (.969g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:8]([NH2:28])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:30][CH3:31]>>[NH2:28][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:26])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:30][CH3:31])[CH2:22][CH2:21]1
Reactant: CCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[5-(4-piperidinyl)pentyl]-9H-purin-6-amine and iodoethane.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15]>>[OH:15][CH2:14][CH:13]([NH:12][C:9](=[O:11])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:16][OH:17]
Reactant: NC(CO)CO
Reactant: O=C(O)CCc1ccccc1
Product: O=C(CCc1ccccc1)NC(CO)CO

Procedure:
The procedure of example 79c was followed, using 3-phenylpropionic acid and serinol. At the end of the reaction, the DMF was evaporated and CH2Cl2 was added to the residue. The white crystalline material was collected and gave pure N-(2-hydroxy-1-hydroxymethyl-ethyl)-3-phenyl-propionamide as a white solid (56%, MS: m/e=224.2 (M+H+)).
Reaction SMILES: COC1C=CC(C[C@@:8]2([C:26]([O-:28])=[O:27])[C@@H:11]([CH2:12][CH:13]=[N:14][NH:15][C:16]([NH2:18])=[NH:17])[C:10](=[O:19])[N:9]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=CC=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:15]([N:14]=[CH:13][CH2:12][C@H:11]1[C:10](=[O:19])[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C@@H:8]1[C:26]([OH:28])=[O:27])[C:16]([NH2:18])=[NH:17]
Reactant: COc1ccc(C[C@@]2(C(=O)[O-])[C@@H](CC=NNC(=N)N)C(=O)N2c2ccccn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)NN=CC[C@H]1C(=O)N(c2ccccn2)[C@@H]1C(=O)O

Procedure:
The crude ester 82 was treated with TFA/DCM (0.75 mL/1 mL). After one and half hours, LC-MS analysis indicated completion of the reaction. The solvent was removed and the residue was purified by preparative HPLC (Vydac reverse phase C-18 column, 22×250 mm ID). Mobil phase: A=0.1% TFA in water, B=0.1% TFA in acetonitrile. The flow rate was 12 mL/min. The gradient time was 5% B to 50% B over 45 min. The desired product, 83, was obtained as a white solid (5.5 mg). Anal. C19H24N6O4, Mol. Wt.: 290.28. Found: ESI-MS: 291.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:17]([NH:25][C:14]([C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCN
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCNC(=O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 25 h

Procedure:
(R)-(+)-1-(tert-Butoxycarbonyl)-2-piperidinecarboxylic acid (Aldrich Chemical Company, Milwaukee, Wis.) (1.00 g; 4.36 mmol) is dissolved in methylene chloride (20 mL) at ambient temperature. n-Octylamine (0.620 g; 4.80 mmol), N,N-diisopropylethylamine (1.24 g; 9.60 mmol) and PyBOP (2.50 g; 4.80 mmol) are added sequentially. The reaction is stirred for 25 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography using a gradient elution (20%→40% ethyl acetate in hexanes) affording the desired product (22) as an oil. ISMS: MH+341.2
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[C:19]([Cl:22])[CH:20]=2)[N:15]=[CH:14][C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[C:2]1([CH2:1][O:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:23])=[C:19]([Cl:22])[CH:20]=3)[NH:15][C:14](=[O:25])[C:13]2=[O:24])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1c(=O)cnc2cc(Cl)c(Cl)cc21)OCc1ccccc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: O=C(Cn1c(=O)c(=O)[nH]c2cc(Cl)c(Cl)cc21)OCc1ccccc1

Procedure:
The above ester (12.0 g, 33 mmol) was reacted with 30% H2O2 (50 ml) in glacial acetic acid (350 ml) at 55° C. for 24 h. The mixture was cooled and 600 ml of icecold water was added. The precipitate was filtered off and recrystallized from DMF-water to afford 7.16 g of the title compound. M.p. 286°-289° C. 1H-NMR(DMSO-d6):δ5.08(s, 2H), 5.22(s, 2H), 7.28-7.45(m, 6H), 7.75(s, 1H), 12.35(s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=1)=[O:18])C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:25]3[CH:26]=[CH:27][C:22]([CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[CH:23][C:24]=3[F:29])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(F)c1
Reactant: ClCc1cccnc1SC1CCC1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SC2CCC2)c(F)c1
Yield: 102.6 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.040 g, 0.18 mmol) obtained in Step C of Preparation Example 23 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.046 g, 0.18 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.069 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:35]([O:37][C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)=[O:36])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCCCO)OC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A solution of the alcohol (50 g, 0.13 moles) produced in Example 22 and pyridine (10.7 ml, 0.13 moles) in 500 ml of methylene chloride was added dropwise under nitrogen to a solution of 4-nitrophenyl chloroformate (26.64 g, 0.13 mol) in 500 ml of methylene chloride at room temperature. After the addition, the reaction was stirred overnight at room temperature. A solid had formed which was removed by filtration. The filtrate was extracted two times with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure. Recrystallization of the crude reaction product from hexane gave 27.9 g (39%) of the title compound as a light yellow crystalline solid, mp 78-80° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:11](Cl)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:11]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(Cl)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Reactant: C1CNCCN1
Solvent: ClCCl
Product: N#Cc1c(N2CCNCC2)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A solution of Compound 45 (1.0 g, 3.2 mmol) in dichloromethane was added slowly to a stirred solution of piperazin (826 mg g, 9.59 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water sonicated briefly and filtered. The solid was dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 1.1 g (96%) yellow solids. M.P. 162° C. 1H NMR (DMSO-d6): δ 2.70 (s, 1H), 2.94 (m, 4H), 3.53 (m, 4H), 5.47 (s, 2H), 7.19–7.25 (m, 3H), 7.42 (m, 2H), 7.51 (dd, J=4.3, 9.3 Hz, 1H), 7.54 (td, J=2.4, 8.0 Hz, 1H), 7.58 (dd, J=2.9, 8.9 Hz, 1H). EIMS m/z 363 (M+1).