Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][CH:6]([F:34])[O:7][CH:8]=[C:9]([C:24]1[CH:33]=[CH:32][C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=1)=[O:11].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C.O>[F:5][CH:6]([F:34])[O:7][CH:8]=[C:9]([C:24]1[CH:33]=[CH:32][C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:1](=[O:3])[CH3:2])=[C:17]([O:22][CH3:23])[CH:16]=1)=[O:11]
Reactant: CC(=O)Cl
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Eighty milligrams (80 mg) of acetyl chloride (1.00 mmol) were added to a mixture of 420 mg (1.00 mmol), of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl) acrylamide, 120 mg (1.20 mmol) of triethylamine and 5 ml of tetrahydrofuran at 0° C. and stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=3:1) to give 260 mg of 3-difluoromethoxy-N-[2-(3-methoxy-4-acetyloxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1282).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[Cl:18][C:19]1[N:24]=[C:23]([C:25](Cl)=[O:26])[CH:22]=[C:21]([Cl:28])[N:20]=1>C(Cl)Cl>[Cl:18][C:19]1[N:24]=[C:23]([C:25]([NH:2][C@@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[O:26])[CH:22]=[C:21]([Cl:28])[N:20]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)n1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)NC(=O)c1cc(Cl)nc(Cl)n1
Yield: 33.2 %

Procedure:
To a mixture of (S)-methyl 2-aminopropanoate hydrochloride (1.397 g, 10.01 mmol) in DCM (80 mL) was added iPr2NEt (4.35 mL, 24.97 mmol). The mixture was stirred for a few minutes and a solution of the 2,6-dichloropyrimidine-4-carbonyl chloride (2.107 g, 9.97 mmol) in DCM (20 mL) was added over a period of 1 minute. After stirring overnight, the reaction was concentrated in vacuo to a residue. The residue was chromatographed over silica gel using 10-40% EtOAc in hexanes. The product fractions were evaporated in vacuo to give (S)-methyl 2-(2,6-dichloropyrimidine-4-carboxamido)propanoate as a yellow oil (0.921 g, 3.31 mmol, 33% yield). LC/MS: m/z=278.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:13])[CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c15) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C@@H:3]1[C:9]([O-:11])=[O:10].[K+].[F:14][C:15]1[C:20]([CH2:21]Cl)=[C:19]([F:23])[C:18]([F:24])=[C:17]([F:25])[C:16]=1[F:26]>C(#N)C>[F:14][C:15]1[C:20]([CH2:21][O:10][C:9]([C@H:3]2[C@H:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:2]2([CH3:12])[CH3:1])=[O:11])=[C:19]([F:23])[C:18]([F:24])=[C:17]([F:25])[C:16]=1[F:26]
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)[O-]
Reactant: Fc1c(F)c(F)c(CCl)c(F)c1F
Agent: [K+]
Solvent: CC#N
Product: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1c(F)c(F)c(F)c(F)c1F

Procedure:
0.1 mole of potassium (±) trans-2,2-dimethyl-3-dichlorovinyl-cyclopropanecarboxylate and 0.1 mole of pentafluorobenzyl chloride were heated in acetonitrile until the reaction was complete. After concentrating, taking up in water/petroleum ether and concentrating the organic phase, a colorless oil was obtained, in the NMR spectrum of which the doublet mentioned in Example 2 for the vinyl proton of the cis-ester was lacking.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[C:10]2[CH2:18][CH:19]([C:21]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])([C:23](OC)=[O:24])[CH3:22])[CH2:20][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[C:10]2[CH2:18][CH:19]([C:21]([S:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)(=[O:28])=[O:29])([CH3:22])[CH2:23][OH:24])[CH2:20][C:9]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)(C1Cc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c2c(c3cc(Cl)ccc31)CC(C(C)(CO)S(=O)(=O)c1ccccc1)C2
Reaction time: 0.67 h
Yield: 35.2 %

Procedure:
152 mg (0.29 mmol) (RS,SR)-2-(1-benzenesulfonyl-1-methoxycarbonyl-ethyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]indole-4-carboxylic acid tert-butyl ester were dissolved in 3 mL dry THF at RT. 0.32 mL (0.32 mmol, 1.1 eq) of LiAlH4 (1M in THF) were added dropwise. The reaction mixture was stirred for 1 hour and 40 minutes. The reaction was quenched with a saturated NaHCO3 solution. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (EtOAc/heptane 1:2) yielded 50 mg (35%) (RS,SR)-2-(1-benzenesulfonyl-2-hydroxy-1-methyl-ethyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]indole-4-carboxylic acid tert-butyl ester as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][C@H:10]([CH3:15])[C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CO.O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH3:15])[C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1OCC(=O)N(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: B
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1OCCN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
To a solution of (2R,3S)-benzyl 4-benzyl-2-methyl-5-oxomorpholine-3-carboxylate (15.7 g, 46.1 mmol) in THF (60 mL) was added a solution of borane in THF (1 mol/L, 69.2 mL) dropwise over a period of 1 hour at −10° C. under N2. After the end of addition, the mixture was warmed to 25° C. and stirred for 16 hours, then cooled to −10° C. And to the mixture was added methanol slowly until gas evolution was ceased, then added water (10 mL). The mixture was concentrated in vacuo and the residue was dissolved in EtOAc (150 mL). The organic layer was washed with aqueous NaOH solution (2 mol/L, 50 mL×2) and brine (50 mL×2). The organic phase was concentrated in vacuo to give the title compound as colorless oil (13 g, 86.7%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[Li]CCCC.[I:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([OH:23])=[O:22].ICC>C1COCC1>[I:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:1][CH3:2])[C:21]([OH:23])=[O:22]
Reactant: O=C(O)Cc1ccccc1I
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(C(=O)O)c1ccccc1I
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of diisopropylamine (5.6 mL, 40 mmol) in dry THF (60 mL) at -10° C. was added 1.6M BuLi (25 mL, 40 mmol). After 30 min, a solution of 2-iodophenylacetic acid (5.24 g, 20 mmol) in THF (20 mL) was slowly added. The solution was stirred for 1 h, at which point iodoethane (1.6 mL, 117 mmol) was added. After 2 h at r.t. the reaction was quenched with 0.5M NH4OAc solution and 6M HCl (10mL) and the product was extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated to give an oily residue which was purified by flash chromatography (15:85 EtOAc:hexane containing 5% AcOH) to give 4.37 g of the title compound as an off-white solid.
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[C@@H:12](O)[CH2:11][C@H]1O.C(OC(Cl)=O)C(C)C>C(N(CC)CC)C>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:20]=1[OH:22]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: Oc1ccc2ccccc2c1

Procedure:
Following the procedure of Example 1 but using 0.535 g. of PGF2 α , 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.327 g. of β-naphthol, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate followed by acetonitrile. The residue obtained by concentration of selected fractions, 0.410 g., is crystallized from ethyl acetate diluted with 1.5 volumes of hexane as the title compound, white free-flowing crystals, m.p. 98.8°-100° C. having Rf 0.25 (TLC on silica gel in ethyl acetate).
Reaction SMILES: [C:1]([CH:6]1[CH:11]([OH:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH:18]([S:20][CH2:21][CH:22]=[CH2:23])[CH3:19])[CH2:8][CH:7]1[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:26](O[NH3+])[CH:27]=[CH2:28]>C(O)C.C([O-])(=O)C.[Na+]>[CH2:28]([O:5][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH:18]([S:20][CH2:21][CH:22]=[CH2:23])[CH3:19])[CH2:8][C:7]1=[O:24])[CH2:2][CH2:3][CH3:4])[CH:27]=[CH2:26]
Reactant: C=CCO[NH3+]
Reactant: C=CCSC(C)CC1CC(O)C(C(=O)CCC)C(O)C1C(=O)OC
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: C=CCOC(CCC)=C1C(=O)CC(CC(C)SCC=C)C(C(=O)OC)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
10.6 parts by weight of 2-butyryl-4-methoxycarbonyl-5-(2-allylthiopropyl)-cyclohexane-1,3-diol are dissolved in 150 parts by volume of ethanol, 3.3 parts by weight of allyloxiammonium chloride and 2.9 parts by weight of sodium acetate are added and the mixture is stirred for 20 hours at room temperature. Thereafter, the mixture is poured into ice water, the resulting mixture is extracted with methylene chloride and the latter is stripped off to give 11.3 g of 2-(1-allyloxibutylidene)-4-methoxycarbonyl-5-(2-allylthiopropyl)-cyclohexane-1,3-dione as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([OH:16])=O)=[CH:8]2)=[O:4].Cl.[CH:18]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)([CH3:20])[CH3:19].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14](=[O:16])[NH:27][CH:24]1[CH2:25][CH2:26][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23]1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CC(C)N1CCC(N)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 500 mg 1H-Indole-2,5-dicarboxylic acid 5-methyl ester and 491 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride in 20 ml absolute DMF, 746 mg TOTU and 1.1 ml DIPEA were added and the mixture was stirred at RT for 2 h. The solvent was removed in vacuo and the residue was directly purified by chromatography on silica gel eluting with a gradient of DCM/MeOH 100%->60%. The fractions containing the product were combined and the solvent evaporated under reduced ressure. Yield: 0.73 g.
Reaction SMILES: [NH2:1]C(OCC)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:13][O:14][CH2:15][CH:16]1[CH2:20][O:19][C:18](=O)[O:17]1>CN(C)C=O>[CH3:13][O:14][CH2:15][CH:16]1[O:17][C:18](=[O:19])[NH:1][CH2:20]1
Reactant: COCC1COC(=O)O1
Reactant: CCOC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC1CNC(=O)O1
Temperature: 140 °C
Reaction time: 100 h
Yield: 23.2 %

Procedure:
Urethane (10.0 g, 113 mmol) was dissolved in N,N-dimethylformamide (40 ml), and thereto were added potassium carbonate (20.8 g, 151 mmol) and 4-methoxymethyl-1,3-dioxolan-2-one (10.0 g, 75.7 mmol), in order. The mixture was stirred for 100 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by silica gel chromatography give the subject 5-methoxymethyloxazolidin-2-one (2.3g, yield 23.1%).
Reaction SMILES: [Na].[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:31])[CH:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18](=[O:31])[CH:19]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=2)=[CH:13][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:16]
Reactant: Oc1ccc(C2=CCCCC2)cc1
Reactant: CCCCCCCCCCC(Br)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)OCC
Temperature: 50 °C

Procedure:
To a solutuion of 1.6 g of sodium in 100 ml of absolute ethanol are added initially 10 g of p-(1-cyclohexenyl)-phenol in a small amount of absolute ethanol at room temperature under anhydrous conditions and with stirring. 26 Grams of α-bromo-dodecanoic acid ethyl ester are then added dropwise and the mixture is maintained at 50° C for 24 hours. The ethanol is subsequently stripped off in vacuo and the residue is partitioned between water and ice-cold N sodium hydroxide solutuion. The organic phase is washed until neutral, dried over sodium sulphate and concentrated in vacuo. The residue yields the crude α-[p-(1-cyclohexenyl)-phenoxy]-dodecanoic acid ethyl ester of the formula ##STR17## in the form of an oil.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[CH2:14]([CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:19](O)=[O:20])[CH2:15][CH2:16][CH3:17].S(Cl)([Cl:30])=O>ClCCl.C(OCC)C>[CH2:14]([CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:19]([Cl:30])=[O:20])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC(CCCC)C(=O)O
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCC(CCCC)C(=O)Cl
Temperature: 25 °C

Procedure:
500 μl (2.5 mmol) of dicyclohexylamine are added to 500 mg (2.5 mmol) of 2-butyloctanoic acid placed in 5 ml of dichloromethane, and the solution is stirred at room temperature for minutes. 200 μl (2.5 mmol) of thionyl chloride are then added and this mixture is stirred at room temperature for 2 hours. The reaction is diluted with ethyl ether. The precipitate is filtered off and rinsed with ethyl ether. Concentration of the filtrate gives the 2-butyloctanoyl chloride.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:8]=[C:9]([C:13]2[C:17]([C:18]3[N:19]=[CH:20][N:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26](O)=[O:27])[CH:22]=3)=[C:16]([CH3:32])[O:15][N:14]=2)[CH:10]=[CH:11][CH:12]=1>>[CH:1]1([NH:5][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([N:21]3[CH:22]=[C:18]([C:17]4[C:13]([C:9]5[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=5)=[N:14][O:15][C:16]=4[CH3:32])[N:19]=[CH:20]3)[CH:24]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Reactant: NC1CCC1
Product: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)NC3CCC3)c2)cn1
Yield: 38 %

Procedure:
As described for Example 71c, cyclobutylamine was converted, using 3-{4-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid (100 mg, 0.28 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (44 mg, 38%) which was obtained as an off-white solid. MS: m/e=417.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34](Cl)(=[O:40])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:34](=[O:40])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC(=O)Cl
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(OCC(=O)OC)cc1

Procedure:
The titled compound was prepared following the procedure B using methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate and hexanoyl chloride as a colorless oil (79%). 1H NMR (CDCl3, 300 MHz) δ 7.41-7.50 (m, 4H), 7.03-7.16 (m, 6H), 6.85 (m, 2H), 4.62 (s, 1H), 4.60 (s, 1H), 4.55 (s, 1H), 4.51 (s, 1H), 4.41 (s, 1H), 4.36 (s, 1H), 3.80 (s, 1.5H), 3.79 (s, 1.51, 2.60 (t, J=7.6 Hz, 2H), 2.38 (m, 2H), 1.56-1.67 (m, 4H), 1.30-1.37 (m, 6H), 0.91 (m, 6H). M+ (ESI): 540.4. HPLC, Rt: 5.85 min (Purity: 99.3%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C=Nc1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Nc4ccccc4)nc23)CC1
Yield: 60.3 %

Procedure:
Beginning with 0.15 gm (0.65 mmol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.092 mL (0.85 mMol) phenyl isocyanate, 0.137 gm (60%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from methanol.
Reaction SMILES: C(OC([C:6]1[C:10](=[O:11])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][CH:7]=1)=O)C.Cl>[OH-].[Na+]>[C:12]1([N:9]2[C:10](=[O:11])[CH:6]=[CH:7][NH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1c[nH]n(-c2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc[nH]n1-c1ccccc1
Yield: 72.7 %

Procedure:
4-Ethoxycarbonyl-1-phenyl-3-pyrazolin-5-one (2.139 g, 9.2 mmol) in 1N sodium hydroxide (50 ml) was stirred under nitrogen at vigorous reflux for three hours. The reaction mixture was allowed to cool and acidified (HCl) to pH 3.5, whereupon ethyl acetate extraction, followed by drying (MgSO4) and evaporation produced the desired product (1.072 g, 72%) δ max(CHCl3) 1705, 1595, 1495 cm-1 δ(D6 -DMSO) 5.60 (1H,d,J2 Hz, C4 proton), 7.60 (6H, m, phenyl protons and C3 proton) Found; M+ ; 160.0641. C9H8N2O6 requires M; 160.0637.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[O:9][C:8]([CH3:13])([CH3:12])[O:7][C:6]=2[CH:14]=1.C(P(CCCC)CCCC)CCC.[CH2:28]([C:32]1[CH:37]=[CH:36][C:35]([C:38]#[C:39][C:40]2[CH:45]=[CH:44][C:43]([CH:46](O)[CH2:47][CH2:48][CH2:49][CH3:50])=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)[CH2:29][CH2:30][CH3:31]>C1(C)C=CC=CC=1>[CH2:28]([C:32]1[CH:37]=[CH:36][C:35]([C:38]#[C:39][C:40]2[CH:45]=[CH:44][C:43]([CH:46]([O:1][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[O:11])[O:9][C:8]([CH3:12])([CH3:13])[O:7][C:6]=4[CH:14]=3)[CH2:47][CH2:48][CH2:49][CH3:50])=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCc1ccc(C#Cc2ccc(C(O)CCCC)cc2)cc1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCCc1ccc(C#Cc2ccc(C(CCCC)Oc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.8 %

Procedure:
A solution of 7-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one (363 mg, 1.87 mmol, described in J. Chem. Soc., Perkin Trans. 1, 2000, 4265-4278) and tri-n-butylphosphine (378 mg, 1.87 mmol) in anhydrous toluene (10 mL) was chilled at 0° C. To this solution was added N,N,N′,N′-tetramiethylazodicarboxamide (322 mg, 1.87 mmol) at once and the resulting reaction mixture was stirred 10 min at 0° C. Then 1-{4-[(4-butylphenyl)ethynyl]phenyl}-1-pentanol (461.5 mg; 1.44 mmol; 1.0 eq.) was added and the resulting mixture was stirred overnight at rt. The solvent was removed under reduced pressure and the crude mixture was purified by chromatography on silicagel (EtOAc/c-Hex (1/9)) to give 456 mg (64%) of the title compound. HPLC, Rt: 6.2 min (purity: 97.0%). 1H NMR (CDCl3) δ 7.78 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), 6.61 (dd, J=2.4 Hz, J=9.0 Hz, 1H), 6.29 (d, J=2.3 Hz, 1H), 5.16-5.07 (m, 1H), 2.61 (t, J=7.8 Hz, 2H), 2.08-1.93 (m, 1H), 1.91-1.75 (m, 1H), 1.73-1.24 (m, 14H), 0.98-0.84 (m, 6H).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[OH:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: CCOC(=O)[C@H](Cc1cccc([N+](=O)[O-])c1)NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N[C@H](CO)Cc1cccc([N+](=O)[O-])c1
Yield: 95.4 %

Procedure:
The process is performed as in Example 2, starting with 7.15 g of ethyl (2S)-2-(acetylamino)-3-(3-nitrophenyl)propanoate and 1.46 g of sodium borohydride in 70 cm3 of ethanol. After an identical work-up, 5.8 g of N-[(1S)-2-hydroxy-1-(3-nitrobenzyl)-ethyl]acetamide are obtained in the form of a white solid melting at 131° C.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH3:25])[CH:22]=2)[O:19][C:18]([CH3:30])([CH3:29])[CH2:17][C:16]3([CH3:32])[CH3:31])=[CH:7][C:6]=1[F:33].[OH-].[Na+]>CO.O1CCCC1>[CH:26]1([N:24]([CH2:23][C:21]2[CH:22]=[C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:34])=[O:2])=[C:6]([F:33])[CH:7]=3)[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([CH3:29])([CH3:30])[CH2:17][C:16]3([CH3:32])[CH3:31])[CH3:25])[CH2:28][CH2:27]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cc(C#Cc2ccc(CC(=O)O)c(F)c2)cc2c1OC(C)(C)CC2(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A solution of (4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-2-fluoro-phenyl)-acetic acid methyl ester (Intermediate 13, 0.060 g, 0.13 mmol) in methanol (1 mL) and tetrahydrofuran (3 mL) was treated with a 1M solution of sodium hydroxide (0.4 mL, 0.4 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo to a residue that was washed with hexane, neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow oil (0.056 g, 95%).