Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:38])[C@H:12]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[NH:13][C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22]C(OC(C)(C)C)=O)=[CH:17][CH:16]=1)[CH3:9]>C(Cl)Cl>[NH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][C@H:12]([C:11]([O:10][CH2:8][CH3:9])=[O:38])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:30])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CN)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
About 1.8 ml trifluoroacetic acid was added dropwise to a stirred solution containing about 1.0 g of Compound 34 in about 20 ml CH2Cl2. The mixture was stirred at room temperature for 15 minutes, evaporated to dryness under reduced pressure, and co-evaporated twice with about 30 ml absolute ethanol. The residue was then subjected to column chromatography on silica gel (1.5×15 cm), eluting with a gradient of 5-10% methanol in CHCl3 to yield about 0.68 g of Compound 35.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C[N:6]([CH3:13])[C:7]1[CH:12]=[CH:11]C=CC=1.[CH3:14][S:15][C:16]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:17]=1[NH2:18]>C1(C)C=CC=CC=1>[N:6]1([C:1]([NH:18][C:17]2[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:16]=2[S:15][CH3:14])=[O:2])[CH2:7][CH2:12][CH2:11][CH2:13]1
Reactant: COc1cc(N)c(SC)cc1OC
Reactant: CN(C)c1ccccc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)N2CCCC2)c(SC)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 24 g. of phosgene in toluene was added rapidly to a solution of 58.1 g. of N,N-dimethylaniline in 500 ml. of toluene, which solution has been previously cooled to about 0° C. with an ice-water bath. After stirring the resulting solution for about five minutes, a solution of 39.8 g. of 2-methylthio-4,5-dimethoxyaniline in 350 ml. of toluene was added on dropwise fashion over a 30 minute period to the cooled, stirred reaction mixture. The reaction mixture was allowed to warm to ambient temperature, at which temperature it was stirred for an additional four hours. The reaction mixture was then filtered, and the filtrate concentrated under reduced pressure to a thick oil. The oil was dissolved in 1 l. of acetonitrile and 50 ml. of pyrrolidine were added thereto. This new reaction mixture was stirred for about 20 hours, after which time it was concentrated under reduced pressure to a thick oil. The residual oil was dissolved in 1 l. of methylene chloride. The methylene chloride solution was washed twice with 5 percent aqueous hydrochloric acid and once with water. The methylene chloride solution was then dried and the solvent removed therefrom in vacuo, leaving a solid residue comprising N-pyrrolidinylcarbonyl-2-methylthio-4,5-dimethoxyaniline. Recrystallization of the solid from a benzene-hexane solvent mixture yield crystalline material melting at 141°-3° C. (91 percent yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[C:13]([Cl:19])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.Cl[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28]>C1COCC1.C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[C:13]([Cl:19])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(CO)c(Cl)c2)n1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2N)cc1Cl)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
To a solution of 3-(tert-butyl)-1-(3-chloro-4-(hydroxymethyl)phenyl)-1H-pyrazol-5-amine (1.15 g, 70% purity, 2.9 mmol) in dry THF (10 mL) under N2 was added imidazole (320 mg, 4.7 mmol) and chlorotriisopropylsilane (970 μL, 870 mg 4.5 mmol) and the reaction mixture maintained at RT for 18 hr. The resulting mixture was diluted with DCM (5.0 mL) and was treated with an additional aliquot of chlorotriisopropylsilane (970 μL, 870 mg, 4.5 mmol) and after a further 5 hr with imidazole (320 mg, 4.7 mmol). After 20 hr the reaction mixture was treated for a third time with chlorotriisopropylsilane (200 μL, 180 mg, 0.90 mmol) and imidazole (100 mg, 1.6 mmol) and after 3 days was evaporated in vacuo. The residue was taken up into EtOAc (20 mL) and was washed with water (20 mL) and brine (10 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-100%, gradient elution) and then by SCX capture and release to afford a blue oily liquid which comprised of a mixture of starting material and the desired product. This mixture was taken up into THF (1.0 mL) and was treated with imidazole (50 mg, 0.74 mmol) chlorotriisopropylsilane (140 μL, 130 mg, 0.65 mmol) and maintained at RT for 24 hr and then evaporated in vacuo. The residue was taken up EtOAc (10 mL) and was washed with water (10 mL) and brine (10 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 0-100%, gradient elution) to afford the title compound, Intermediate A22 as a white solid (300 mg, 24%); Rt 3.42 min (Method 2); m/z 436 (M+H)+, (ES+).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C1COCC1>CCOCC.[Zn]>[F:15][C:9]([F:16])([C:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=C1CCCCC1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)C1(O)CCCCC1
Yield: 69.3 %

Procedure:
A stirred suspension of zinc (0.981 g, 15.01 mmol) in a solution of cyclohexanone (0.491 g, 5.0 mmol) and ethyl 2-bromo-2,2-difluoroacetate (2.031 g, 10.01 mmol) in an. THF (5 mL) was sonicated for 4-5 h and then heated to reflux for 1-2 h. The reaction mixture was cooled and diluted with ether and washed with 1 N HCl, satd. NaHCO3, water, brine and dried (MgSO4). Evaporation of solvents afforded an oil which was purified by silica gel FCC (5-10% EtOAc in DCM) to afford ethyl 2,2-difluoro-2-(1-hydroxycyclohexyl)acetate as a clear oil (770 mg, ˜70%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 4.37 (q, J=7.2 Hz, 2H), 2.10-2.01 (m, J=3.4 Hz, 1H), 1.82-1.69 (m, 3H), 1.68-1.54 (m, 6H), 1.38 (t, J=7.2 Hz, 3H), 1.20 (br. s, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:16]([NH:26][CH2:27][C:28](O)=[O:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)C(C)C)(C)C>[CH2:19]([O:18][C:16]([NH:26][CH2:27][C:28]([N:5]([CH2:4][CH:3]([O:14][CH3:15])[O:2][CH3:1])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:29])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(CNCc1ccc(F)cc1)OC
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(CN(Cc1ccc(F)cc1)C(=O)CNC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2,2-dimethoxyethyl)-N-(4-fluorobenzyl)amine (50.6 g, 237.3 mmol), N—CBZ-glycine (54.6 g, 260.8 mmol), EDC (50.0 g, 260.8 mmol), and HOBt (4.2 g, 27 mmol) in anhydrous DMF (500 mL), N,N-diisopropylethylamine (˜10 mL) was added until the solution is about pH 7. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between dichloromethane (1 L) and water (250 mL). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])[O:5][C@@H:4]([N:18]2[CH:25]=[C:24](I)[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:3]1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>C(N(CC)CC)C.CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])[O:5][C@@H:4]([N:18]2[CH:25]=[C:24]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:3]1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cc(I)c(=O)[nH]c3=O)C[C@@H]2F)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cc(C#C[Si](C)(C)C)c(=O)[nH]c3=O)C[C@@H]2F)cc1
Reaction time: 8 h

Procedure:
A solution of the product of Stage b), (0.8 g, 1.69 mmoles), bis(triphenylphosphine) palladium (II) chloride (25 mg) and copper (I) iodide (25 mg) in dry triethylamine (40ml) and N,N-dimethylformamide (3 ml) was degassed thoroughly with nitrogen. (Trimethylsilyl) acetylene (0.47 ml, 3.37 mmoles) was added and the mixture stirred under N2 at 50° for 8 hours. The solvent was removed under reduced pressure, the residue dissolved in methylene chloride (40 ml) and the solution washed with 2% aqueous disodium EDTA solution (4 ml), water (50 ml) and dried (sodium sulphate). Evaporation of the solvent and purification of the residue by silica column chromatography eluting with 2% MeOH/CH2Cl2 afforded the title compound. Trituration with ether/hexane afforded analytically pure title compound as an off-white powder.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([CH2:17][CH2:18][CH2:19][C@H:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:21]([OH:23])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[N:14]([CH2:17][CH2:18][CH2:19][C@H:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:21]([O:23][CH2:2][C:1]#[N:4])=[O:22])=[N+:15]=[N-:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN=[N+]=[N-])C(=O)O
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCN=[N+]=[N-])C(=O)OCC#N
Reaction time: 4 h
Yield: 107.1 %

Procedure:
N,N-Diisopropylethylamine (111 μL, 0.639 mmol) and subsequently bromoacetonitrile (203 μL, 2.90 mmol) were added to a solution of (S)-5-azido-2-((tert-butoxycarbonyl)amino)pentanoic acid (Compound tk69) (150 mg, 0.581 mmol) in acetonitrile (0.8 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 4 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 5-azido-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk70) (185 mg, quant.).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[SH:10].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.O>CO.CCCCCC>[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[S:10][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: ClCc1ccccn1
Reactant: Cc1occc1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CO
Product: Cc1occc1SCc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 25 ml 3 neck round bottom flask equipped with magnetic stirrer, pot thermometer, Y tube, nitrogen inlet tube, reflux condenser and heating mantle is placed a solution of 0.54 g (0.01 moles) of sodium methoxide dissolved in 3 ml absolute methanol. The reaction mass is maintained at 25° -30° C and a solution of 0.57 g (0.005 moles) of 2-methyl-3-furan thiol in 3 ml absolute methanol is added to the reaction mass. While maintaining the reaction mass at 25° C, picolyl chloride hydrochloride (0.82 g; 0.005 moles) dissolved in 2 ml absolute methanol is added to the reaction mass. The reaction being exothermic, the reaction mass warms up to 42° C and a white solid precipitate forms. The reaction mass is then allowed to cool to 25° C (with stirring) over a period of 30 minutes. The reaction is then heated to reflux (60° - 65° C) under nitrogen and reflux is continued for a period of 1 hour. The reaction mass is cooled to 25° C. After remaining at room temperature for a period of 12 hours, 10 ml of water is added to the reaction mass with stirring, causing the reaction mass to now exist in two phases; an aqueous phase and an organic phase. The pH of the reaction mixture is 5. 7 ml of n-hexane is then added to the reaction mass with stirring and transferred to a separatory funnel. The aqueous layer is separated from the organic phase and extracted with 8 ml n-hexane after first diluting the aqueous phase with another 10 ml of water. The hexane extracts are combined, washed with 7 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, gravity filtered, then concentrated on a rotary evaporator using water-aspirator vacuum.
Reaction SMILES: CO.C[O-].[Na+].[CH3:6][C:7]1[C:8]([C:31]([O:33]CC)=O)=[C:9]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[F:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:38]=1[CH2:39]Br>C(#N)C.O>[F:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:38]=1[CH2:39][N:21]1[C:9]2[S:10][C:11]([C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)=[C:7]([CH3:6])[C:8]=2[C:31](=[O:33])[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]1=[O:23]
Reactant: Fc1cccc(F)c1CBr
Reactant: CCOC(=O)c1c(NC(=O)Nc2ccccc2)sc(-c2ccc([N+](=O)[O-])cc2)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: Cc1c(-c2ccc([N+](=O)[O-])cc2)sc2c1c(=O)n(-c1ccccc1)c(=O)n2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Acetonitrile (240 ml), methanol (150 ml) and 28% sodium methoxide (15.24 g, 78.97 mmol) were added to ethyl 4-methyl-5-(4-nitrophenyl)-2-(3-phenylureido)thiophene-3-carboxylate (30.00 g, 70.51 mmol), and the mixture was stirred for 1 hour while refluxing under heating. 2,6-difluorobenzyl bromide (17.52 g, 84.61 mmol) was dissolved in acetonitrile (60 ml), and the solution was added to the previous reaction mixture under refluxing. After refluxing under heating for 5 hours, 28% sodium methoxide (1.36 g, 7.05 mmol) was added thereto under reflux, and the mixture was stirred for 1 hour. The reaction mixture was cooled to room temperature, water (150 ml) was added dropwise, which was stirred at room temperature for 1 hour. The crystals were filtered and washed with water (240 ml) and diisopropyl ether/ethanol=9/1 (240 ml). The resulting crystals were suspended in ethyl acetate (600 ml), and the suspension was stirred for 1 hour under reflux. The mixture was cooled to room temperature and, after stirred for 1 hour, the crystals were filtered, washed with ethyl acetate (60 ml) and dried under vacuum at 60° C. to give 1-(2,6-difluorobenzyl)-5-methyl-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione (31.4 g, 62.12 mmol, 88.1%).
Reaction SMILES: [OH-].[K+].O.[CH2:4]([C:6]1([CH2:22][CH3:23])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[C:17][Si](C)(C)C)[CH:14]=2)[S:9][CH2:8][CH2:7]1)[CH3:5]>C(O)C>[CH2:22]([C:6]1([CH2:4][CH3:5])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[CH:17])[CH:14]=2)[S:9][CH2:8][CH2:7]1)[CH3:23]
Reactant: CCC1(CC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#Cc1ccc2c(c1)C(CC)(CC)CCS2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2.21 g (39 mmol) of potassium hydroxide in 2.0 mL-of water and 20.0 mL of ethanol was added to 1.49 g (4.93 mmol) of (4,4-diethylthiochroman-6-yl)(trimethylsilyl)acetylene (Compound 26) and the resulting mixture stirred at room temperature for 5 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aqueous H2SO4. The product was extracted with 2×50 mL of ether.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=O.N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)[O:33]C2)C1=O.Cl[CH2:46][C:47]1[CH:48]=[C:49]([S:53]([N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)(=[O:55])=[O:54])[CH:50]=[CH:51][CH:52]=1.BrCCCCC>>[N:56]1([S:53]([C:49]2[CH:48]=[C:47]([CH:52]=[CH:51][CH:50]=2)[CH2:46][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][C:17](=[O:33])[O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[CH2:2]2)(=[O:55])=[O:54])[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1
Reactant: O=S(=O)(c1cccc(CCl)c1)N1CCOCC1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: O=C1COc2cc3c(cc2O1)C1(CO3)CN(Cc2cccc(S(=O)(=O)N3CCOCC3)c2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 4-(3-(chloromethyl)phenylsulfonyl)morpholine to replace 1-bromopentane, 1′-[3-(morpholin-4-ylsulfonyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2(1′H)-one was obtained (40%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 7.73-7.64 (m, 4H), 7.29-7.18 (m, 2H), 7.05 (dd, J=7.3, 5.6 Hz, 2H), 6.52 (s, 1H), 6.11 (s, 1H), 5.09 (ABq, 2H), 4.74 (dd, J=9.3 Hz, 2H), 4.04-4.21 (m, 4H), 3.56 (t, J=4.5 Hz, 4H), 2.84-2.65 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.9, 154.8, 144.2, 141.9, 138.0, 137.9, 134.7, 132.2, 131.6, 130.1, 128.8, 126.7, 125.9, 123.9, 123.3, 121.0, 110.9, 109.5, 98.9, 79.5, 65.2, 64.2, 63.6, 57.3, 45.8, 42.5; MS (ES+) m/z 534.9 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[C:14]([F:23])=[C:15]([OH:22])[C:16]([OH:21])=[C:17]([O:19][CH3:20])[CH:18]=1.Cl>CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]2[O:21][CH2:2][CH2:3][CH2:4][O:22][C:15]=2[C:14]=1[F:23]
Reactant: COc1cc(Br)c(F)c(O)c1O
Reactant: BrCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c(F)c2c1OCCCO2
Temperature: 80 °C
Reaction time: 6 h
Yield: 53.3 %

Procedure:
After adding 830 mg of 1,3-dibromopropane and 1.4 g of potassium carbonate to a solution of 880 mg of 4-bromo-3-fluoro-6-methoxybenzene-1,2-diol (Example (41a)) in 10 ml of DMF, the mixture was stirred at 80° C. for 6 hours. After adding 1N hydrochloric acid to the reaction mixture, the organic layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-heptane) to give the title compound (548 mg) as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][CH2:25][C:26]2[O:30][N:29]=[C:28]([C@@H:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3C(OC(C)(C)C)=O)[N:27]=2)[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[NH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[C:28]1[N:27]=[C:26]([CH2:25][O:24][CH:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:23][CH2:22]2)[O:30][N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1c1noc(COC2CCN(C(=O)OCc3ccccc3)CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCC(OCc2nc([C@@H]3CCCCN3)no2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
Trifluoroacetic acid (25 ml) was added to a solution of tert-butyl (2S)-2-{5-[(1-[(benzyloxy)carbonyl]-4-piperidyloxy)methyl]-1,2,4-oxadiazol-3-yl}-1-piperidinecarboxylate (1.73 g) [see Preparation 94] in dichloromethane (25 ml) at 0° C. The reaction mixture was stirred for 2 hrs at room temperature, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was separated and washed with 2N aqueous hydrochloric acid and brine, the combined aqueous layers were then neutralised with saturated sodium hydrogen carbonate and the product re-extracted with ethyl acetate. The organic layer was then separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford benzyl 4-(3-[(2S)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)-1-piperidinecarboxylate (1.33 g) as a brown oil.
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:17]([OH:19])=O)[CH3:16])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[O:7][CH:8]=1.[NH2:20][C@@H:21]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:22][C@H:23]([OH:42])[C@@H:24]([NH:32][C:33]([O:35][CH2:36][C:37]1[O:41][N:40]=[CH:39][CH:38]=1)=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)Cl>CO>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:17]([NH:20][C@@H:21]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:22][C@H:23]([OH:42])[C@@H:24]([NH:32][C:33]([O:35][CH2:36][C:37]1[O:41][N:40]=[CH:39][CH:38]=1)=[O:34])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:19])[CH3:16])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[O:7][CH:8]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@@H](C)C(=O)O)co1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc(CN(C)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccno2)co1
Yield: 64 %

Procedure:
Using the procedure of Example 1U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-alanine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxy-carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane provided, after silica gel chromatography using 92:8 CH2Cl2 :CH3OH, the desired compound (Rf 0.48, 92:8 CH2Cl2 :CH3OH) in 64% yield. 1H NMR (DMSO-d6) δ 1.08 (d, 3H), 1.24 (d, 6H), 1.50 (m, 2H), 2.82 (s, 3H), 3.0 (m, 1H), 4.25 (s, 2H), 4.60 (d, 1H), 5.05 (s, 2H), 6.20 (br d, 1H), 6.32 (d, 1H), 7.20 (m, 11H), 7.50 (br d, 1H), 7.78 (s, 1H), 8.51 (d, 1H). Mass spectrum: (M+H)+ =661.
Reaction SMILES: [F:1][C:2]1[C:8](F)=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[C:3]=1[NH2:4].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[NH2:4][C:3]1[C:2]([F:1])=[C:8]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[C:7]([F:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1F
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(F)c(Oc2ccc(C=O)cc2)c1F

Procedure:
2,3,4-Trifluoro-6-nitroaniline (5 g, 26 mmol), 4-hydroxybenzaldehyde (3.5 g, 28.6 mmol) and Cs2CO3 (10.5 g, 32.6 mmol) were stirred in 150 mL of dimethylformamide at 65 degrees Centigrade for approximately 18 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, washed five times with brine, dried over Mg2SO4 and concentrated onto basic alumina. The residue was purified by silica gel column chromatography (hexane to ethyl acetate gradient) to give 4-[(3-amino-2,6-difluoro-4-nitrophenyl)oxy]benzaldehyde. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.29 (d, J=8.8 Hz, 2 H) 7.46 (s., 2 H) 7.93 (d, J=8.8 Hz, 2 H) 7.98 (dd, J=11.0, 1.7 Hz, 1 H) 9.93 (s., 1 H)