Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH:10]([C:13]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]2[C:14]=1[C:15](=[O:28])[NH:16][S:17]2(=[O:19])=[O:18])([CH3:12])[CH3:11].[C:29]1([S:35][CH2:36]Cl)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O.C(OCC)(=O)C>[C:29]1([S:35][CH2:36][N:16]2[C:15](=[O:28])[C:14]3[C:20](=[C:21]([O:26][CH3:27])[C:22]([O:24][CH3:25])=[CH:23][C:13]=3[CH:10]([CH3:12])[CH3:11])[S:17]2(=[O:18])=[O:19])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1cc(C(C)C)c2c(c1OC)S(=O)(=O)NC2=O
Reactant: ClCSc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(C)C)c2c(c1OC)S(=O)(=O)N(CSc1ccccc1)C2=O
Temperature: 80 °C
Yield: 49 %

Procedure:
Diisopropylethylamine (0.5 mL) was added to a solution of 4-isopropyl-6,7-dimethoxysaccharin (0.5 g) in dimethylformamide (3 mL). After 15 minutes chloromethyl phenyl sulfide (0.35 g) was added. The mixture was heated at 80° C. for 16 hours, diluted with ethyl acetate, washed with aqueous sodium carbonate solution, hydrochloric acid (3N) and saturated aqueous sodium chloride solution, dried over sodium sulfate, and stripped of solvents. Purification of the residue by flash chromatography on silica gel using dichloromethane as eluant gave 2-phenylthiomethyl-4-isopropyl-6,7-dimethoxysaccharin (0.35 g), chlorination of which with sulfuryl chloride (0.1 mL) in dichloromethane (3 mL) and purification of the product by trituration with hexane gave 2-chloremethyl-4-isopropyl-6,7-dimethoxysaccharin, 0.3 g.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:8])([CH3:7])[C:5]([CH3:10])([CH3:9])[NH:4][C:3]1=[O:11].C([Li])CCC.CCCCCC.[Br:23][CH:24]([CH3:28])[C:25](Br)=[O:26].P([O-])([O-])([O-])=O>O1CCCC1>[Br:23][CH:24]([CH3:28])[C:25]([N:4]1[C:5]([CH3:9])([CH3:10])[C:6]([CH3:8])([CH3:7])[N:2]([CH3:1])[C:3]1=[O:11])=[O:26]
Reactant: CC(Br)C(=O)Br
Reactant: CN1C(=O)NC(C)(C)C1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(Br)C(=O)N1C(=O)N(C)C(C)(C)C1(C)C
Reaction time: 0.08 h

Procedure:
To a solution of 1,4,4,5,5-pentamethylimidazolidin-2-one (14 mg; 0.091 mmol) in dry tetrahydrofuran (0.2 ml), a 1.57 N solution of n-butyl lithium in hexane (0.06 ml; 0.1 mmol) was added at 0° C. After 5 minutes, a solution of 2-bromopropionyl bromide (24 mg; 0.11 mmol) in dry tetrahydrofuran (0.1 ml) was added thereto at the same temperature and followed by stirring for 10 minutes. A phosphate buffer (pH 7.0) was added to decompose the excess reaction agent. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were successively washed with a 5% aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was purified by preparative thin layer chromatography (benzene:ethyl acetate=5:1) to give 3-(2'-bromopropionyl)-1,4,4,5,5-pentamethylimidazolidin-2-one.
Reaction SMILES: NC1C=CC=CC=1.N[C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1OC)[C:12]([NH:14]C1C=CC(F)=C(F)C=1)=[O:13]>>[C:12]([NH2:14])(=[O:13])[C:11]1[CH:23]=[CH:24][CH:25]=[CH:9][CH:10]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Solvent: Nc1ccccc1
Product: NC(=O)c1ccccc1
Yield: 32.6 %

Procedure:
The title compound was synthesized in the same manner as Example 1 using aniline (0.59 g, 6.4 mmol), CSI (0.67 mL, 7.7 mmol), and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.19 g, 4.3 mmol) to give 0.17 g of pure benzamide, N-(3,4-difluorophenyl)-4-methoxy-3-[[[[(phenylamino)carbonyl]amino]sulfonyl]amino]-. Microanalysis: C21H18F2N4O5S; calculated: C=52.94; H=3.81; N=11.76. found: C=52.70; H=4.04; N=11.51. MS: M++1=477 Da.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[CH:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH:1](=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[NH2:12])[CH2:2][CH2:3][CH3:4]
Reactant: NC1CCCCC1
Reactant: CCCC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCCC=C1CCCCC1N
Reaction time: 1 h
Yield: 86 %

Procedure:
At 0° C., 16.3 g (20 mL, 0.23 mol) of butyraldehyde (Formula IV) was added dropwise to 21.7 g (25 mL, 0.22 mol) of cyclohexylamine (Formula III). After 1 h, 6 g of anhydrous sodium sulfate was added and the mixture stirred for 5 h. The product was decanted from the salt water slurry, dried by addition of further 10 g of anhydrous sodium sulfate, filtered and distilled. Characteristics of the product: bp 88° C. (20 mm); yield 86%; NMR (CDCl3, δ): 1.0 (3H, t) 1.1-2.1 (12H), 2.3 (2H, g), 3.0 (1H, m), 7.8 (1H, t).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:80]1([CH:86]2[CH2:90][CH2:89][CH2:88][NH:87]2)[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:80]1([CH:86]2[CH2:90][CH2:89][CH2:88][N:87]2[C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]2[S:20][N:19]=[CH:18][N:17]=2)(=[O:14])=[O:13])=[CH:7]3)[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: O=S(=O)(Nc1ncns1)c1ccc2c(N3CCCC3c3ccccc3)cccc2c1
Temperature: 100 °C
Yield: 44.7 %

Procedure:
A vial was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (205 mg, 0.394 mmol), Xantphos (45.6 mg, 0.079 mmol), Pd2(dba)3 (36.1 mg, 0.039 mmol), and cesium carbonate (257 mg, 0.788 mmol). The vial was flushed with Ar (g), then toluene (3939 μl) and 2-phenylpyrrolidine (81 μl, 0.551 mmol) were added in sequence. The vial was sealed and heated at 100° C. for 16 h. The reaction mixture was partitioned between EtOAc and water. The layers were separated, and the organic extract was washed with brine. The combined aq. layers were extracted with EtOAc, and the organic layers were combined. The combined solution was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel with 0 to 50% EtOAc/Heptane to give a clear oil. This material was dissolved in DCM (2 mL) and TFA (1 mL), and the resulting mixture was stirred for 2 h. The mixture was diluted with MeOH, then concentrated. The crude product was purified by chromatography on silica gel with 0 to 5% MeOH/DCM to give 5-(2-phenylpyrrolidin-1-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (76.7 mg, 0.176 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.55-8.46 (m, 2H), 8.34 (d, J=2.1 Hz, 1H), 7.78 (dd, J=2.1, 9.0 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.43-7.33 (m, 3H), 7.22-7.16 (m, 2H), 7.12-7.06 (m, 2H), 4.82 (dd, J=6.3, 9.1 Hz, 1H), 4.19-4.12 (m, 1H), 3.03 (dt, J=4.5, 8.9 Hz, 1H), 2.47-2.40 (m, 1H), 2.14-2.10 (m, 1H), 2.00-1.79 (m, 2H). m/z (ESI) 437.2 (M+H)+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17]Br>CC(C)=O>[C:1]1(=[O:11])[N:5]([CH2:17]/[CH:16]=[CH:15]/[CH2:14][Br:13])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: BrC/C=C/CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1C/C=C/CBr
Temperature: 85 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
Potassium phthalimide (18.5 g, 0.1 mol) was added in portions over 5 h to a stirred solution of (E)-1,4-dibromobut-2-ene (21.4 g, 0.1 mol) in acetone (200 ml) at 85° C. The suspension was stirred for 24 h at 85° C., then cooled and filtered. The filtrate was concentrated in vacuo to afford a white solid, which was recrystallised three times from acetone to yield (E)-1-phthalimido-4-bromobut-2-ene (15.76 g, 56.2%). δH (90 MHz, CDCl3) 3.88 (2H, d), 4.28 (2H, d), 5.92 (2H, m) and 7.80 (4H, m).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:41])[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:25]3)=[O:23])[C:17]1=[O:42])(=[O:14])=[O:13])[CH:6]=[CH:5]2>[Pd].C(O)C>[CH:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:41])[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:25]2)=[O:23])[C:17]1=[O:42])(=[O:13])=[O:14]
Reactant: C[C@@H](C(=O)N1CCC[C@@H](NC(=O)OCc2ccccc2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](C(=O)N1CCC[C@@H](NC(=O)OCc2ccccc2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C1=O
Reaction time: 17 h
Yield: 3 %

Procedure:
A mixture of benzyl (3R)-1 -[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate (0.350 g), 10% palladium on carbon (0.035 g) and ethanol (1000 ml) was stirred under an atmosphere of hydrogen for 17 h. The reaction mixture was filtered through Harbolite™ and the filtrate was concentrated under reduced pressure to give an oil. The oil was partially purified using SPE (silica, eluting with methanol and then 10% aqueous ammonia in methanol) and then fully purified using mass directed preparative h.p.l.c. to give the title compounds (Example 403, 0.01 g; Example 404, 0.028 g), both as oils.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][C:12]([C:21]#[N:22])([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[OH-].[Na+].C([OH:27])C.OO>O.C(OCC)(=O)C.CO>[N:18]1[CH:19]=[CH:20][C:15]([C:12]2([C:21]([NH2:22])=[O:27])[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[CH:16][CH:17]=1
Reactant: CCO
Reactant: N#CC1(c2ccncc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: NC(=O)C1(c2ccncc2)CCNCC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Alternately, combine 1-benzyl-4-cyano-4-(pyridin-4-yl)-piperidine hydrochloride (20.3 g, 58 mmol), a concentrated aqueous sodium hydroxide solution (20 mL, 50%) and ethanol (400 mL). Heat to about 50° C. Add an aqueous solution of hydrogen peroxide (40 mL, 30%) over about 10 minutes. After 18 hours, add an aqueous solution of hydrogen peroxide (10 mL). After 3 hour, cool to ambient temperature and dilute with water (200 mL), concentrate in vacuo to remove most to the ethanol (about 400 mL). Add water (200 mL) and extract twice with ethyl acetate. Extract the combined organic layers with water and then brine, dry over MgSO4, filter, and evaporate in vacuo to give a solid. Dissolve the residue in hot ethyl acetate (500 mL) by the addition of methanol. Filter and concentrate the filtrate in vacuo to give a solid. Triturate the solid with dichloromethane and collect by filtration, and dry to give 1-benzyl-(4-(pyridin-4-yl)-piperidine-4-carboxylic acid amide: Rf =0.62 (silica gel, 7/3 dichloromethane/methanol).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7](=O)[CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[NH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH2:17]>CO>[Br:1][C:2]1[O:6][C:5]([C:7]2[N:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=[C:9]([C:10]([F:13])([F:12])[F:11])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNN
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)o1
Solvent: CO
Product: CCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(Br)o1
Temperature: 0 °C
Yield: 23.3 %

Procedure:
A mixture of compound 44 (4 g, 14.0 mmol), ethyl 2-hydrazinylacetate (2.37 g, 15.0 mmol) and methanol (60 mL) was heated for 1.5 h. The reaction mixture was cooled to 0° C. and solvent was removed under reduced pressure. Water (100 mL) was added and the reaction mixture extracted with ethyl acetate (50 mL×3). Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by column chromatography using 10% ethyl acetate in n-hexane as an eluent to afford the separated isomer 45 (1.2 g, 24%).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[N:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1.Cl.O.[OH-].[Na+]>O1CCOCC1>[CH:2]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[N:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: Cc1cncc(C(=O)Nc2cccc(C3OCCO3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cncc(C(=O)Nc2cccc(C=O)c2)c1
Temperature: 60 °C

Procedure:
A solution of N-(3-[1,3]dioxolan-2-yl-phenyl)-5-methyl-nicotinamide (3.0 g, 10.55 mmol) in dioxane (50 mL) is treated with a 4M HCl in 1,4-dioxane (30 mL). The mixture is heated at 60° C. for 3 h. Water (100 mL) is added to the mixture followed by NaOH 2M (70 mL) solution to get pH 10. The mixture is extracted twice with EtOAc (100 mL). The combined organic phases are dried over MgSO4, filtered and evaporated. The crude title compound is obtained as a brownish solid (1.744 g. 69%) LC-MS A: tR=0.58 min; [M+H]+=241.24.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[O:13][C:12](=[O:14])[C:11]([C:15](O)=[O:16])=[CH:10][C:9]=2[CH:18]=1)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O.C1C=CC=CC=1>CN(C)C=O.CCCCCC>[C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[O:13][C:12](=[O:14])[C:11]([C:15]([Cl:25])=[O:16])=[CH:10][C:9]=2[CH:18]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc2cc(C(=O)O)c(=O)oc2cc1OC(C)=O
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2cc(C(=O)Cl)c(=O)oc2cc1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture of 6,7-diacetoxy-2-oxo-2H-1-benzopyran-3-carboxylic acid (306 mg), thionyl chloride (80 μL), dimethyl formamide (one drop), and benzene (15 mL) was refluxed for 1 hour. After cooling to room temperature, hexane (10 mL) was added. Solids were filtered off to give 6,7-diacetoxy-2-oxo-2H-1-benzopyran-3-carbonyl chloride (286 mg).
Reaction SMILES: C(C1N(C[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])C(/C(/C)=C(\CC2C=CSC=2)/C(O)=O)=CN=1)CCC.[CH2:30]([C:34]1[N:35]([CH2:56]OCC[Si](C)(C)C)[C:36](/[C:39](/[CH2:52][CH2:53][CH2:54][CH3:55])=[C:40](\[CH2:46][C:47]2[S:48][CH:49]=[CH:50][CH:51]=2)/[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:37][N:38]=1)[CH2:31][CH2:32][CH3:33]>>[CH2:30]([C:34]1[N:35]([CH2:56][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:36](/[C:39](/[CH2:52][CH2:53][CH2:54][CH3:55])=[C:40](\[CH2:46][C:47]2[S:48][CH:49]=[CH:50][CH:51]=2)/[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:37][N:38]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC/C(=C(/Cc1cccs1)C(=O)OCC)c1cnc(CCCC)n1COCC[Si](C)(C)C
Reactant: CCCCc1ncc(/C(C)=C(\Cc2ccsc2)C(=O)O)n1Cc1ccccc1Cl
Product: CCCC/C(=C(/Cc1cccs1)C(=O)OCC)c1cnc(CCCC)n1Cc1ccccc1Cl

Procedure:
The procedure of Example 6, Method B (iv, v) is followed using ethyl (E)-3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2heptenoate in in place of ethyl (E)-3-[2-n-butyl-1-{(trimethylsilyl) ethoxymethyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-heptanoate to give the title compound.
Reaction SMILES: [CH2:1]([O:8]C1C=C2C(C=CN2)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27](OC(F)(F)F)[CH:28]=2)[N:23]([CH2:35][C:36]([OH:38])=[O:37])[CH:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:27][CH:28]=2)[N:23]([CH2:35][C:36]([OH:38])=[O:37])[CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Product: CC(=O)c1cn(CC(=O)O)c2cc(OCc3ccccc3)ccc12

Procedure:
was prepared from 6-benzyloxy-1H-indole in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)acetic acid. MS: 324 [M+H]+, 647 [2M+1]+; tR (HPLC conditions k): 3.38 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:35]([O:39][C:40](=[O:70])[CH2:41][N:42]([CH2:56][C:57]1[N:58]([CH2:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH:59]=[CH:60][N:61]=1)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](O)=[O:54])([CH3:38])([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:66]([O:65][C:63](=[O:64])[CH2:62][N:58]1[CH:59]=[CH:60][N:61]=[C:57]1[CH2:56][N:42]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](=[O:54])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:41][C:40]([O:39][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:70])([CH3:69])([CH3:67])[CH3:68]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN(CCCCCCCCCCC(=O)O)Cc1nccn1CC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCCCCCN(CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 64.8 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (85 mg, 0.175 mmol), 11-((2-tert-butoxy-2-oxoethyl)((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)undecanoic acid (89 mg, 0.175 mmol), EDCI (38 mg, 0.20 mmol), HOBt (26 mg, 0.20) and DIPEA (0.30 mL) in DCM (5.0 mL) was stirred at rt for 3 days. The reaction mixture was purified by biotage eluting with 1% to 10% MeOH in DCM to afford (19S,23S)-tetra-tert-butyl 2-((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylate (111 mg, 65%) as a yellow oil. MS (ESI), 490.5 (M/2+H)+.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[CH3:12]C(C)=O.C([O-])([O-])=O.[K+].[K+].CI>O>[CH:1]1([C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]1
Reactant: O=C(O)C1CCC=CCCC1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)C1CCC=CCCC1
Reaction time: 8 h

Procedure:
A 50 mL, 3-neck round bottom flask was charged with cyclooct-4-ene carboxylic acid (0.517 g, 3.35 mmol, prepared as described below in Example 35) and 30 mL reagent-grade acetone and vigorously stirred for several minutes. K2CO3 (1.15 g, 8.32 mmol) was then added, followed by an excess of methyl iodide (4 mL). A reflux condenser (water temperature 5° C.) was then fitted to the flask and the reaction was gently refluxed overnight. The mixture was filtered, the filtrate was concentrated using a rotary evaporator, and the residue was purified by flash chromatography on silica (1:9 ethyl acetate:hexanes mobile phase) to give methyl cyclooct-4-ene carboxylate as a single isomer (0.560 g, 99%). A copolymer of methyl cyclooct-4-ene carboxylate and cyclooctene, prepared similarly to polymer 15 at room temperature, would have the following features: The end groups R2 and R3 would be H or CH3. For this polymer, e and f would be derived from methyl cyclooct-4-ene carboxylate and would equal 3 and 4, respectively; d would derive from cyclooctene and would equal 8. The run lengths would therefore be: rHH=(3+3)+8z; rHT=(3+4)+8z; and rTT=(4+4)+8z; therefore rtotal=(6+8z), (7+8z), (8+8z).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([O:37][CH2:38][CH3:39])[CH2:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:38]([O:37][CH:27]([C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)=[CH:16][CH:17]=1)[CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH3:39]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(CCCc4ccccc4)OCC)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(CCCc1ccccc1)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1
Temperature: 70 °C

Procedure:
1-{4′-[4-(1-Ethoxy-4-phenyl-butyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.070 g, 0.133 mmol) was dissolved in THF (3 mL) and MeOH (0.3 mL) then NaOH (3 N aq., 0.150 mL) was added. The reaction was heated to 70° C. overnight then an additional portion of NaOH (3 N aq., 0.150 mL) was added and the reaction was heated overnight again. After cooling the reaction was submitted to standard aqueous workup then purified by preparatory HPLC to afford a separable mixture of products, of which the major product was the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[F:17])[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:18])[C:6]([C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])=[C:5]2[OH:30]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[F:17])[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:18])[C:6]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[C:5]2[OH:30]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)c(F)cc2C2(CCOCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2cc(F)c(F)cc2C2(CCOCC2)C1=O
Yield: 87.2 %

Procedure:
1,1-Dimethylethyl N-((6,7-difluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (152 mg, 359 μmol) was dissolved in TFA at ambient temperature for 30 minutes and then concentrated, precipitated with hexanes, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound (115 mg) as a white solid. MS (m/z)=368 (M+H)+. Calculated for C17H15F2NO6 367.09.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[H-].[Na+].[N+:10]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH2:24]Br)=[CH:18][C:17]=2[CH:26]=1)([O-:12])=[O:11].O>CN(C)C=O.C(OCC)(=O)C>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH2:24][NH:5][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])=[CH:18][C:17]=2[CH:26]=1)([O-:12])=[O:11]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C=C1CBr
Reactant: NC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C=C1CNC(=O)C(F)(F)F
Temperature: 70 °C
Yield: 32.9 %

Procedure:
2,2,2-trifluoroacetamide (0.53 g, 4.7 mmol) in dimethylformamide (2 ml) was added dropwise to a suspension of sodium hydride (80%, 1.4 g, 4.7 mmol) in dimethylformamide (2 ml). After one hour at room temperature 6-nitro-2,2-dimethyl-3-bromomethyl-2H-1-benzopyran (1.4 g, 4.7 mmol) was added and the mixture heated at 70° C. for eighteen hours. Water and ethyl acetate were added to the cooled solution and the organic phase separated and evaporated to give 0.51 g of 6-nitro-2,2-dimethyl-3-(trifluoroacetamido)methyl-2H-1-benzopyran, 1NMR (CDCl3): δ 1.5 (s, 6H) , 4.15 (d, 2H) , 6.25 (s, 1H) , 6.85 (d, 1H), 6.9 (br.s), 1H), 7.85 (s, 1H), 8.05 (d, 1H).