Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[NH:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:18]([C:23](O)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21].C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>CCOC(C)=O>[NH:17]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C@H:18]([C:23]([NH:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)CN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dipeptide H-Leu-Gly-OCH3 : DIEA (21 mL) was added to a stirred solution of HCl.H-Gly-OCH3 (13 g) in EtOAc (500 mL). After 15 min, Boc-Leu-OH.H20 (20 g) and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (25.5 g) were added in succession. The reaction mixture was stirred at room temperature for 18 h, and then filtered. The filtrate was washed serially with H20, 1N HCl, H20, 5% aqueous NaHCO3 and water. The dried (Na2SO4 +MgSO4) organic phase was concentrated to near dryness. Et20 was added to the concentrate and the mixture was stored at 4° C. for 18 h. The resultant precipitate was collected and dried to give Boc-Leu-Gly-OCH3 (15.6 g). The latter compound (15.5 g) was dissolved in CH2Cl2 (150 mL) and the solution cooled to 0° C. TFA (60 mL) was added dropwise to the cooled solution. The mixture was stirred at 0° C. for 1.5 h and then evaporated to dryness. TFA was removed from the residue by adding Dowex 1×2-400 ion exchange resin (40 g), prewashed with methanol (4×100 mL), 1N HCl (3×200 mL) and methanol (4×100 mL), to a solution of the crude residue in methanol (300 mL). (Note: Dowex is a trademark). The mixture was stirred at room temperature for 1h and then filtered. The filtrate was concentrated under reduced pressure to give TFA.H-Leu-Gly-OCH3 (17.9 g).
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]1=[O:18].Br[CH2:20][C:21]([C:23]1[C:24]([CH3:33])=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[O:27][CH2:26]2)=[O:22].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:33][C:24]1[C:23]([C:21](=[O:22])[CH2:20][N:15]2[CH2:16][CH2:17][C:10]3([C:9](=[O:18])[N:8]([C:3]4[CH2:4][O:5][C:6](=[O:7])[C:2]=4[CH3:1])[CH2:12][CH2:11]3)[CH2:13][CH2:14]2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][O:27][C:28]2=[O:32]
Reactant: Cc1c(C(=O)CBr)ccc2c1COC2=O
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(N2CCC3(CCN(CC(=O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O

Procedure:
2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-17) (2 g, 7.99 mmol), 5-(2-Bromo-acetyl)-4-methyl-3H-isobenzofuran-1-one (I-4B, method 2, step F) (2.150 g, 7.99 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.48 mL, 19.98 mmol) in DCM (50 mL) were stirred overnight at rt. The mixture was washed with saturated ammonium chloride aqueous and brine, dried over MgSO4, and concentrated under reduced pressure. The crude material was used in the next step without further purification. 1H-NMR (500 MHz, CDCl3): δ ppm 7.83 (1H, d, J=7.8 Hz), 7.79 (1 H. , d, J=7.8 Hz), 5.34 (2 H, s), 5.32 (2 H, s), 5.26 (2 H, s), 4.03 (2 H, t, J=7.0 Hz), 3.71 (1 H, m), 3.15 (1 H, m), 2.94 (2 H, m), 2.47 (2 H, t, J=7.0 Hz), 2.42 (3 H, s), 2.17 (2 H, m), 2.07 (3 H, s), 2.02 (2 H, m), 1.58 (2 H, m). LCMS 438.9 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([S:20][CH3:21])=[CH:15][N:14]=1>C(Cl)Cl>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([S:20]([CH3:21])=[O:9])=[CH:15][N:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cnc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cnc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
8.9 g (0.052 mol) of m-chloroperbenzoic acid were added, a little at a time, to a suspension of 10 g (0.052 mol) of 2,3-dichloro-5-methylthiopyridine in 60 ml of methylene chloride. After the mixture had been stirred for 2 hours at approximately 20° C., a further 0.9 g (5 mmol) of m-chloroperbenzoic acid was added. The mixture was subsequently refluxed for a further 2 hours. After cooling, the solids were separated off, whereupon the organic phase was washed once with sodium hydrogen sulfite, once with sodium hydrogen carbonate and once with water. After the mixture had been dried over sodium sulfate, it was concentrated. The crude product which was obtained as a red oil was purified by means of flash chromatography over silica gel (eluent: cyclohexane/ethyl acetate=1:1). Yield: 6.3 g (58%) as a brown oil; 1H-NMR (in d6 dimethyl sulfoxide): δ [ppm]=2.9 (s, CH3); 8.4 and 8.7 (2×d, pyr H).
Reaction SMILES: Cl.[C:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]2)[CH:6]=1)#[N:3].[CH3:27][OH:28]>>[NH:3]=[C:2]([O:28][CH3:27])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16]2)[CH:6]=1
Reactant: N#CCc1ccnc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Reactant: CO
Agent: Cl
Product: COC(=N)Cc1ccnc(N2CCN(C(=O)OCc3ccccc3)CC2)c1

Procedure:
Hydrochloric acid gas was bubbled into a stirred solution of benzyl 4-(4-(cyanomethyl)pyridin-2-yl)piperazine-1-carboxylate (500 mg, 1.5 mmol) in dry MeOH (10 mL) for 5 h at 0° C., and then concentrated at 10° C. to give the crude product, which was used directly for the next step. MS (ES+) C20H24N4O3 requires: 368, found: 369 [M+H]+.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH2:5][N:4]1[CH2:9][C:10]([OH:12])=O.[NH2:13][C@@H:14]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:33]([O:32][CH2:31][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:4]1[CH2:5][C:6](=[O:8])[NH:7][C:3]1=[O:2])[C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:23]=1)=[O:16])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)CN1CC(=O)NC1=O
Agent: Cl
Product: O=C1CN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccccc3)cc2)C(=O)N1
Yield: 45 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,4-dioxoimidazolidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-phenoxyphenyl)propanamide, gave Compound 201, (S)-3-(benzyloxy)-2-(2-(2,4-dioxoimidazolidin-1-yl)acetamido)-N-(4-phenoxyphenyl)propanamide (54.1 mg, 45%). 1H-NMR (400 MHz, DMSO-D6): σ 10.62 (d, 1H), 10.15 (d, 1H), 8.47-8.41 (m, 1H), 7.83 (d, 1H), 7.65-7.61 (m, 2H), 7.39-7.26 (m, 6H), 7.10 (t, 1H), 7.02-6.96 (m, 4H), 4.73-4.66 (m, 1H), 4.53 (s, 2H), 4.25-4.20 (m, 1H), 3.71-3.63 (m, 2H), 2.73-2.63 (m, 1H). MS (EI) for C27H26N4O6. found 503.1 (MH+).
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:17])[CH:9]=1)[CH3:7])(=O)=O.[F:18][C:19]([F:26])([F:25])[C:20]1[CH:24]=[CH:23][NH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[CH3:17][C:10]1[CH:9]=[C:8]([CH:6]([N:22]2[CH:23]=[CH:24][C:20]([C:19]([F:26])([F:25])[F:18])=[N:21]2)[CH3:7])[CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cc(C(C)OS(C)(=O)=O)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1cc[nH]n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(C)n2ccc(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 66.7 %

Procedure:
1-(3-Methyl-4-nitrophenyl)-ethyl methanesulfonate (2.59 g), 3-trifluoromethyl-1H-pyrazole (1.09 g), potassium carbonate (1.66 g) and 18-crown-6 (0.26 g) were refluxed in acetonitrile (100 ml) for 6 hours. After finishing the reaction, water (100 ml) was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and then dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography to obtain 1-[1-(3-methyl-4-nitrophenyl)-ethyl]-3-trifluoromethyl-1H-pyrazole (1.60 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[C:5](Br)=[CH:4][N:3]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1B(O)O>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[C:5]([C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[CH:4][N:3]=1
Reactant: CC[C@H](CO)Nc1nc(Cl)ncc1Br
Reactant: OB(O)c1cccs1
Product: CC[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Yield: 71 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-bromopyrimidine-4-ylamino)butan-1-ol (18.17 g, 64.8 mmol) with thiophen-2-boronic acid (e. g.: Aldrich, Acros, Apin) (9.12 g, 128.0 mmol) according to procedure 3, the desired product is obtained in 71% yield (13.1 g) after chromatographic purification (silica gel, ethyl acetate/hexane (20%-50% ethyl acetate)).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[CH3:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][CH:21]([C:23]2[S:27][C:26]([N:28]=[C:29]=[O:30])=[N:25][N:24]=2)[CH3:22])=[CH:18][CH:17]=1>C1C=CC=CC=1.CCCCCC>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH:21]([C:23]2[S:27][C:26]([NH:28][C:29](=[O:30])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:25][N:24]=2)[CH3:22])=[CH:31][CH:32]=1
Reactant: Cc1ccc(OC(C)c2nnc(N=C=O)s2)cc1
Reactant: CNCC(OC)OC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccc(C)cc2)s1)OC
Reaction time: 8 h

Procedure:
Methylaminoacetaldehyde dimethylacetal (1.8 grams, 0.015 mole) was added to a benzene solution containing 4.0 grams (0.015 mole) of the 5-[1-(4-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was refluxed for 20 minutes, topped on a roto-vac at 70° C. to form a viscous red-orange oil, which was redissolved in benzene-hexane mixture and left to stand overnight. Crystals formed which were removed by suction filtration, and dried in a vacuum oven at 70° C. to 3.2 grams of tan crystals of [5-[1-(4-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl-1-methyl-1-(2,2-dimethoxyethyl)urea, (melting point 94°-100° C.).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[N+:13]([C:12]1[CH:11]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 20.0 grams (0.12 mole) of ethyl 4-hydroxybenzoate in 200 mL of acetic acid was added a solution of 7.5 mL (excess) of 70% nitric acid in 30 mL of acetic acid. After the reaction mixture stirred for about one hour, it gradually turned orange and warmed to about 40° C. The reaction mixture was stirred for an additional eighteen hours and then was poured into 800 mL of ice-water. The mixture was stirred until the ice melted, and filtered to collect a solid, which was dissolved in ethyl acetate and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 22.0 grams of ethyl 3-nitro-4-hydroxybenzoate, mp 70°-71° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][CH:26]=1)(=[O:30])=[O:29])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CCCCOc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 124 mg of 4-butoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.98 (t, 3H, J=7.6 Hz), 1.45 (m, 2H), 1.72 (m, 2H), 3.79 (t, 2H, J=6.6 Hz), 6.66 (d, 2H, J=8.8 Hz), 7.31 (d, 1H, J=2.8 Hz), 7.35-7.42 (m, 4H), 7.47 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.53-7.60 (m, 3H), 7.75 (d, 1H, J=8.8 Hz), 9.62 (s, 1H). MS: m/z 444.9 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38][Si](C(C)(C)C)(C)C)=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCOCC1.Cl.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([OH:38])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O[Si](C)(C)C(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
To solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-tert-butyldimethylsilyl 9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (3.12 g, 4.54 mmol) in dioxane (25 mL) was added TBAF (75% wt in water) (2.375 g, 6.81 mmol). The mixture was stirred at rt for 4 h then was diluted with 1N HCl (25 mL) and water (5 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried with Na2SO4, filtered, and partially concentrated under reduced pressure to about 10 mL in volume. To the partially concentrated mixture was added 1N HCl (50 mL). The solids that formed were collected by filtration and were washed with water. The expected product, (1R,3aS,5aR,5bR,7aR,11aS,11bR,13 aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (2.58 g, 99% yield), was isolated as a white solid. LCMS: m/e 571.47 (M−H)−, 3.60 min (method 1). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.80 (br. s., 1H), 7.92 (d, J=8.24 Hz, 2H), 7.18 (d, J=8.24 Hz, 2H), 5.32-5.26 (m, 1H), 4.75 (s, 1H), 4.62 (br. s., 1H), 3.90 (s, 3H), 3.07-2.99 (m, 1H), 2.33-2.21 (m, 2H), 2.10 (dd, J=17.09, 6.10 Hz, 1H), 2.06-1.94 (m, 2H), 1.70 (s, 3H), 1.01 (br. s., 3H), 1.00 (br. s., 3H), 0.98 (s, 3H), 0.91 (s, 6H), 1.79-0.89 (m, 17H).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)(=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])(=[O:12])[CH3:11]
Reactant: O=Cc1ccccc1O
Reactant: CC(=O)OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCCCCOc1ccccc1C=O
Yield: 43.5 %

Procedure:
A mixture of 12.2 g (0.1 mol) of salicylaldehyde, 23 g (0.11 mol) of 5-bromopentyl acetate, 44.2 g (0.3 mol) of anhydrous, granular potassium carbonate, and 700 mL of acetonitrile was stirred and refluxed for 20 hr. After being cooled, the resulting mixture was filtered with suction and the solids were washed well with ether. The filtrate and washes were combined and concentrated in vacuo giving a yellow oil which was purified by flash chromatography on silica gel, eluting with 4:1 hexane-ether. There was obtained 10.9 g (43.6%) of 2-[[5-(acetyloxy)pentyl]oxy]benzaldehyde as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:20]([O:22][CH3:23])=[O:21]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CC1CCCCC1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-cyclohexylpropionate (Novabiochem), the title compound was prepared as a solid (mp=116-119° C.). The reaction was monitored by tlc (Rf=0.4 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/hexanes.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:28]
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: COc1ccccc1/C=C/C(=O)O
Product: COc1ccccc1/C=C/C(=O)Nc1ccn(CCCCC(C)=O)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2-methoxy-phenyl)-acrylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[CH3:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:4][CH:3]=2)[CH:32]=[CH:31][N:30]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCC(N)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide and 2-methylpyridine-4-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=0.917 min, m/z=444.4; 1H NMR (CDCl3) 1.51 (d, 3H), 1.92 (m, 1H), 2.13-2.32 (m, 5H), 2.44 (m, 1H), 2.82 (s, 3H), 2.93 (m, 1H), 5.50-5.68 (m, 3H), 7.06 (d, 2H), 7.19-7.35 (m, 5H), 7.39 (d, 2H), 7.58 (s, 1H), 7.65 (d, 1H), 8.74 (d, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C:6]2[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.[N:26]1([C:32]2[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:8]2[C:6]3[CH2:7][C@H:2]([NH:1][S:38]([C:35]4[CH:34]=[CH:33][C:32]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:37][CH:36]=4)(=[O:39])=[O:40])[CH2:3][O:4][C:5]=3[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=S(=O)(Cl)c1ccc(N2CCOCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NS(=O)(=O)c2ccc(N4CCOCC4)cc2)CO3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (120 mg, 0.485 mmol) in anhydrous methylene chloride (10 mL) were added triethylamine (81 μL, 0.582 mmol) and 4-(4-morpholinyl)benzenesulfonyl chloride (140 mg, 0.534 mmol; described in: Galliani, G. Eur. Pat. Appl. EP 335, 758, 1989, Chem. Abstr. 1990, 112, 98374d [125393-22-8]). The reaction mixture was stirred at room temperature for 4 h, washed with a 2 M NH3 solution, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica (eluent: chloroform/ethanol, 90:10+0.5% conc. NH3) affording 141 mg (61% yield) of the title compound as a white solid: mp sinters >100° C.; [α]22D +10° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 472 (56, M+).
Reaction SMILES: [I-:1].[CH3:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=2[NH+:7]=1.[C:17]1(C)C=CC(S(OCC)(=O)=O)=C[CH:18]=1.[I-]>CO.C(O)C>[I-:1].[CH2:17]([N+:7]1[C:6]2[CH:8]=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:11][C:5]=2[O:4][C:3]=1[CH3:2])[CH3:18]
Reactant: Cc1[nH+]c2cc(NS(C)(=O)=O)ccc2o1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: [I-]
Solvent: CCO
Solvent: CO
Product: CC[n+]1c(C)oc2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 121.4 %

Procedure:
Intermediate D (4.52 g) and ethyl p-toluenesulfonate (4.4 g) were combined in a large test tube and heated over a hot air gun with manual stirring for 5 minutes. A brownish melt formed, which solidified to a glass on cooling to room temperature. The glas was dissolved in 50 ml hot methanol, diluted with an 100 ml hot ethanol, and 9.0 g tetrabutylamonnium iodide dissolved in 20 ml ethanol was added. The brown, clear solution was cooled to room temperature and then ice cooled for 4 hours. Filtration of the resulting crystalline product gave 5.92 g of 3-ethyl-2-methyl-5-methylsulfonamidobenzoxazolium iodide (Intermediate E).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([Li])CCC.[CH3:13][C:14]([CH3:24])([C:16](=[O:23])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH3:15]>O1CCCC1.CCCCCC>[CH3:15][C:14]([CH3:24])([C:16]([OH:23])([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH3:13]
Reactant: C#CCCCCC
Reactant: CC(C)(C)C(=O)Cn1cncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC#CC(O)(Cn1cncn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
To a solution of hept-1-yne (3.9 g, 0.041 mol) in dry tetrahydrofuran (30 mls) at -70° C. under nitrogen was added n-butyl lithium (30 mls of a 1.55M solution in hexane) and the resulting mixture stirred for 1 hour. To this mixture was added a solution of 2,2-dimethyl-4-(1,2,-4-triazol-1-yl)-butane-3-one (6.8 g, 0.041 mol) in dry tetrahydrofuran (50 mls), and the resulting mixture was allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous HCl (1.0M). The aqueous was further extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water, saturated sodium bicarbonate solution and brine, dried (anhydrous MgSO4) and then concentrated in-vacuo to give a yellow oil. Chromatography on silica using gradient elution (diethyl ether 20-80% in petrol) gave the title compound (2.87 g) as a yellow crystalline solid melting point 76°-78° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[CH3:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:7].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][CH2:3][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH3:5])=[CH:9][CH:10]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(C(C)=O)cc1
Temperature: 25 °C

Procedure:
Chloromethyl methyl ether (19.2 mL, 252 mmol) was added dropwise to a 0° C. solution of 4-hydroxyacetophenone (6.855 g, 50.35 mmol) and triethylamine (8.4 mL, 60.42 mmol) in dichloromethane (100 mL). The solution was then allowed to warm to rt overnight, quenched with MeOH (40 mL), filtered and the filtrate concentrated and purified by flash chromatography to give the title compound which was used as is in the next step.