Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([OH:12])[CH2:6][C:5]1([CH3:14])[CH3:13].[CH2:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CO>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].CS(O)(=O)=O>[CH:15]1([O:3][N:4]2[C:9]([CH3:10])([CH3:11])[CH2:8][CH:7]([OH:12])[CH2:6][C:5]2([CH3:14])[CH3:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCCCC1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: [Fe+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: O
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Yield: 59 %

Procedure:
A solution of 80.2 g (1.18 mol) of 50% aqueous hydrogen peroxide is added at 70° C. over 12 hours to a mixture of 17.2 g (100 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 0.556 g (2.00 mmol) of iron(II) sulfate heptahydrate, 0.679 g (2.0 mmol) of tetrabutylammonium hydrogen sulfate, 0.15 ml (2.0 mmol) of methanesulfonic acid, 44 ml of cyclohexane, and 200 ml of methanol. Five hours after the peroxide addition is started, a solution of 0.556 g (2.0 mmol) of iron(II) sulfate heptahydrate and 0.15 ml (2.0 mmol) of methanesulfonic acid in 4 ml of water is added to the reaction mixture. Shortly after the peroxide addition is completed, the reaction mixture tests negative for hydrogen peroxide. Methanol is distilled from the reaction mixture at reduced pressure, and water and saturated sodium bicarbonate solution are added to the reaction mixture. A total of 60 ml of 12% by weight sodium borohydride in 14 N sodium hydroxide solution is added to the reaction mixture to convert any 4-oxo derivative of the title compound to the desired product. The reaction mixture is extracted with dichloromethane, and the organic layer is neutralized by the addition of hydrochloric acid followed by sodium bicarbonate. After drying, the organic layer is concentrated, and the crude product is purified by flash chromatography on silica gel to afford 15.0 g (59% yield) of the title compound, an off white solid having a melting point of 72-75° C. Structure is confirmed by mass spectrometry and NMR analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:24])=[C:6]([CH:22]=[O:23])[C:7]([C:10]2[C:11]([CH:20]=[O:21])=[C:12]([F:19])[C:13]([CH2:16][CH2:17][CH3:18])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)[CH3:2]>[Zn].[Cl-].[Zn+2].[Cl-].CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:11](=[C:12]([F:19])[C:13]([CH2:16][CH2:17][CH3:18])=[CH:14][CH:15]=3)[CH:20]([OH:21])[CH:22]([OH:23])[C:6]=2[C:5]=1[F:24])[CH3:2]
Reactant: CCCc1ccc(-c2ccc(OCC)c(F)c2C=O)c(C=O)c1F
Agent: [Cl-]
Agent: [Zn+2]
Agent: [Zn]
Solvent: CN(C)C=O
Product: CCCc1ccc2c(c1F)C(O)C(O)c1c-2ccc(OCC)c1F
Yield: 59.7 %

Procedure:
Under a nitrogen atmosphere, zinc powder (0.295 g, 4.513 mmol) and zinc chloride (0.1 g, 0.752 mmol) were added to a DMF (5 mL) solution of compound (56) (0.5 g, 1.504 mmol), and the resultant mixture was agitated at 80° C. for 8 hours. The reaction mixture was quenched with 20 mL of 1N hydrochloric acid aqueous solution, and extracted with 10 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 2-ethoxy-1,8-difluoro-7-propyl-9,10-dihydrophenanthrene-9,10-diol (57) (0.3 g, yield 59.7%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:20][CH3:21])[CH:15]=[CH:16][C:17]=3[F:19])[C:12]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:12]2[C:13]3[C:18](=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:39](=[O:41])[CH3:40])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(C)=O)c1
Reaction time: 0.08 h
Yield: 34 %

Procedure:
N-[1-{[3-(aminomethyl)phenyl]methyl}-7-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 46) (70 mg, 0.15 mmol) was dissolved in DCM (0.75 mL) and triethylamine (0.203 mL, 1.45 mmol) was added to the solution. The solution was stirred for 5 min and acetic anhydride (0.013 mL, 0.13 mmol) was added. The reaction was stirred for 1 h, and then concentrated under a stream of nitrogen. The residue was dissolved in MeOH-DMSO (1:1) (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was evaporated in vacuo to give the title compound (26 mg, 34%): LCMS (System A) RT=1.04 min, ES+ve m/z 523/524 (M+H)+.
Reaction SMILES: C1(=O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.[CH2:13]([O:25][C:26](=[O:30])[CH:27]([CH3:29])[NH2:28])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C(O)(C)C>[NH2:28][C@H:27]([C:26]([O:25][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:30])[CH3:29]
Reactant: CCCCCCCCCCCCOC(=O)C(C)N
Agent: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCCCCCCCCCCOC(=O)[C@H](C)N
Temperature: 60 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
A 100 ml round bottom flask equipped with a condenser, addition funnel, thermometer and mechanical stirrer was charged with D-glucono-1,5-lactone (7.0 g, 0.04 mole) and isopropanol (30 g). The suspension was heated to 60° C. over 15 minutes. A mixture of DL-alanine dodecyl ester ptoluenesulfonate salt (16.9 g, 0.04 mole), triethylamine (4.0 g 0.04 mole) and isopropanol (20 g) were added dropwise over 15 minutes from an addition funnel. The reaction mixture was stirred rapidly for about 6 hrs and then cooled to room temperature. The white product was filtered, washed with chloroform (3×150 ml) and dried under high vacuum at 35° C. giving 12.5 g (73% yield) of N-D-gluconyl dodecyl alaninate with a melting point of 97°-98° C. and 98.8% purity.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2=[N:11][S:12][N:13]=[C:9]2[C:8]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[Cl:29][C:27]1[CH:28]=[C:23]([C:17]2([C:19]([F:22])([F:20])[F:21])[O:16][N:15]=[C:14]([C:8]3[C:9]4[C:10](=[N:11][S:12][N:13]=4)[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)[CH2:18]2)[CH:24]=[C:25]([Cl:30])[CH:26]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2nsnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2nsnc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.1 %

Procedure:
To a solution of 7-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzo[1,2,5]thiadiazole-4-carboxylic acid methyl ester (Example 5.7) (4.01 g) in tetrahydrofuran (30 ml) was added aqueous sodium hydroxide (1M) (25.3 ml). The reaction mixture was stirred at ambient temperature for 1.5 hours. Aqueous hydrochloric acid (1M) (100 ml) was added and the mixture diluted with ethyl acetate (150 ml). After separation of the layers, the aqueous layer was extracted with ethyl acetate (2×75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (dichloromethane/methanol) to give 7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzo[1,2,5]thiadiazole-4-carboxylic acid (1.29 g) as yellow solid. 1H-NMR (DMSO-d6, 400 MHz): 13.67 (bs, 1H), 8.37-7.26 (m, 5H), 4.76 (d, 1H), 4.53 (d, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]([CH3:14])[CH3:13])[C:6]2=[O:11].C1C(=O)N([Cl:22])C(=O)C1.O>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:22])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]([CH3:14])[CH3:13])[C:6]2=[O:11]
Reactant: CC(C)N1Cc2c(N)cccc2C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1Cc2c(N)ccc(Cl)c2C1=O
Yield: 29.7 %

Procedure:
A solution of 2.8 grams (0.015 mole) of 4-amino-2-(1-methylethyl)isoindolin-1-one and 2.0 grams (0.015 mole) of NCS in 80 mL of DMF was stirred at 25° C. for about 18 hours. The reaction mixture was then poured into water, and the mixture was extracted repeatedly with diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of EtOAc and methylene chloride as eluants. The fractions containing product were combined and concentrated under reduced pressure, yielding about 1.0 gram of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:24]2[S:28][C:27]([CH:29]3[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]3)=[N:26][CH:25]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:12]=1)=[O:5])[CH3:2].C[N:39](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C.C([O-])(O)=O.[Na+].CC1OCCC1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:24]2[S:28][C:27]([CH:29]3[CH2:34][CH2:33][CH:32]([C:35]([NH2:39])=[O:36])[CH2:31][CH2:30]3)=[N:26][CH:25]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=2)[CH:12]=1)=[O:5])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCNC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCC(C(=O)O)CC3)s2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC1CCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCC(C(N)=O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Step 1 (396 mg, 0.741 mmol) was dissolved in DMF (3.50 mL). To this solution was added HATU (563 mg, 1.482 mmol) and DIPEA (0.776 mL, 4.44 mmol), followed by ammonium chloride (119 mg, 2.222 mmol). Reaction was complete after stirring 1 hour at room temperature. The reaction mixture was diluted with saturated NaHCO3(aq) and 2-MeTHF. The phases were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. The mixture of syn and anti iomers was diluted in DMSO was purified by reversed phase HPLC(C18 column; MeCN/water with 0.1% TFA added) to yield:
Reaction SMILES: COC(=O)CO[C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]2[C@H:30]([CH3:31])[C@H:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:28][C:27]2=[O:38])[CH:7]=1.Br.[C:41]([OH:44])(=[O:43])[CH3:42]>>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:42][C:41]([OH:44])=[O:43])=[CH:7][C:8]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=1[CH2:25][N:26]1[C@H:30]([CH3:31])[C@H:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:28][C:27]1=[O:38]
Reactant: COC(=O)COc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1
Reactant: CC(=O)O
Agent: Br
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)O)ccc1O
Temperature: 100 °C

Procedure:
{4-Methoxy-3-[2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenoxy}-acetic acid methyl ester (2.0 g, 3.78 mmol) was treated with a 1:1 mixture of 48% hydrogen bromide and acetic acid, and the reaction was heated to 100° C. overnight. The mixture was concentrated to dryness, and then worked-up with EtOAc and saturated aqueous NaHCO3. The crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])[CH2:5]1)([OH:3])=O.S(Cl)(Cl)=O.[CH2:18]([NH:21][CH2:22][CH:23]=[CH2:24])[CH:19]=[CH2:20].[OH-].[Na+]>ClCCl.O>[CH2:18]([N:21]([CH2:22][CH:23]=[CH2:24])[C:1]([CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])[CH2:5]1)=[O:3])[CH:19]=[CH2:20]
Reactant: CC1(C)CC(C(=O)O)CC(C)(C)N1
Reactant: C=CCNCC=C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: C=CCN(CC=C)C(=O)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Yield: 42 %

Procedure:
4-Carboxy-2,2,6,6-tetramethylpiperidine (100 grams; 0.5405 mole) is added to thionyl chloride (300 mls) in portions and the reaction mixture is heated at reflux for 3 hours. The thionyl chloride is then removed by distillation, the last traces being removed by azeotropic distillation with toluene. The residual acid chloride is slurried in dichloromethane (300 mls), and a solution of diallylamine (105 grams; 1.081 mole) in dichloromethane (100 mls) is slowly added thereto while stirring and allowing the temperature to rise. Upon completion of the addition, the reaction mixture is heated at reflux for 18 hours, cooled to room temperature, and treated successively with 100 mls of water, and 5 N sodium hydroxide, while stirring, to adjust the pH to about 11. The organic phase is separated, and washed with dilute aqueous sodium hydroxide having a pH of 11. The aqueous phase is separated and the organic phase is washed twice with 100-ml portions of very dilute aqueous hydrogen peroxide (5 mls of 30% hydrogen peroxide diluted to 100 mls with water). After the second washing, the organic phase is washed twice with water, treated with activated carbon, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum to remove dichloromethane and unreacted diallylamine. The residue is then distilled under vacuum to obtain 60 grams of the desired product, bp 118°-128° C. at 0.05 mm of mercury, mp 64°-67° C.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].[CH2:9]([O:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][N:17]([CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(NOCc1ccccc1)Nc1ccccc1
Reactant: CCCC(Br)CCC
Product: CCCC(CCC)N(OCc1ccccc1)C(=O)Nc1ccccc1
Yield: 38.9 %

Procedure:
Using the general method of Compound 42 Part B, 4-bromoheptane (5.84 g, 32.6 mmole) was reacted with 1-benzyloxy-3-phenylurea (7.3 g, 30.2 mmole) to provide about 4 g of 1-benzyloxy-1-(1-propylbutyl)-3-phenylurea.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([OH:18])=[O:17])[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O.O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([O:18][CH3:20])=[O:17])[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution of (3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-carboxymethyl-2-oxoazetidine (302.6 mg) in dimethylformamide (10 ml was added potassium carbonate (160 mg) at 0° C. After 10 minutes, to the mixture was added dropwise methyl iodide (68.8 μl ). After stirring at 0° C. for 1.5 hours, the reaction mixture was poured into a mixture of ethyl acetate (100 ml) and water (30 ml). The organic layer was separated, washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave (3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-methoxycarbonylmethyl-2-oxoazetidine (285.5 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C:24]2[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:32])[O:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]4)=[CH:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(Nc1ccc(-c2ccccc2)cc1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 1 (2), but with 4-phenylphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (0.9 mg, 3%) having the following characteristics.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7](=[O:17])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])C.Cl>[OH-].[Na+]>[O:17]=[C:7]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])[CH2:6][CH2:5][C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)CCC(=O)c1cc(C)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C)cc1C(=O)CCC(=O)O
Yield: 80.6 %

Procedure:
A solution of ethyl-4-keto-γ-(2-methoxy-5-methylphenyl)-butyrate (180 g, 0.81 mole) and 1200 mL 20% NaOH was stirred at reflux for 3 hours. After cooling to 0°, the solution was acidified with concentrated HCl. The solid was filtered, washed with water, dried (in-vacuo) to yield 145 g orange solid. Recrystallization from CCl4 yielded 123 g light yellow powder, (68%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:22]([OH:24])=[O:23])[NH:4][C:5]([O:7][CH2:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:6].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](O)=[O:31].C1C=NC2N(O)N=NC=2C=1.C(N=C=NC(C)C)(C)C>CN1CCCC1=O>[CH:11]1[C:10]2[CH:9]([CH2:8][O:7][C:5]([NH:4][C@H:3]([C:22]([OH:24])=[O:23])[CH2:2][NH:1][C:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)=[O:31])=[O:6])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cccs1
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Product: O=C(N[C@@H](CNC(=O)c1cccs1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 3 h

Procedure:
A mixture of 3-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-alanine on Wang resin (2 g), thiophene-2-carboxylic acid (1.41 g, 11.0 mmol), HOAT (1.50 g, 11.0 mmol) and diisopropylcarbodiimide (1.68 mL, 10.7 mmol) in N-methylpyrrolidinone (20 mL) was shaken for 3 h and then washed with dichloromethane and methanol to give N-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-(thiophene-2-carbonyl)amino-L-alanine on Wang resin. The Fmoc group was cleaved by treatment with 25% piperidine in N-methylpyrrolidinone, followed by shaking for 1 h. The resin was washed with dichloromethane and methanol to give 3-(thiophene-2-carbonyl)amino-L-alanine on Wang resin.
Reaction SMILES: O.[NH2:2][NH2:3].O=[C:5]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=O)[CH2:6][CH2:7][C:8]([OH:10])=[O:9]>C(O)C>[N:2]1[NH:3][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[C:11]2[C:12]=1[CH2:13][CH2:14][CH2:15][CH2:16]2
Reactant: O=C(O)CCC(=O)C1CCCCC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1[nH]nc2c1CCCC2
Yield: 97.1 %

Procedure:
Hydrazine hydrate (1.1 g) was added to a solution (40 ml) of 4-oxo-4-(2-oxocyclohexyl)-n-butyric acid (4.1 g) in ethanol and the mixture was refluxed for 1 hour. After the completion of the reaction, the reaction mixture was cooled and the precitated crystals were collected by filtration to give 3.9 g of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid, m.p. 135-136° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]1=[O:15].CC1(C)CC(=O)NC(=O)C1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:26]1([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]2=[O:15])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: CC1(C)CC(=O)N(CCCCBr)C(=O)C1
Reactant: C1CNCCN1
Agent: CC1(C)CC(=O)NC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CC(=O)N(CCCCN2CCNCC2)C(=O)C1
Yield: 85 %

Procedure:
A mixture of N-(4-bromobutyl)-3,3-dimethylglutarimide (20.0 g; 0.07 mole [prepared from 3,3-dimethylglutarimide using the method of Example 2]); piperazine (31.0 g; 0.36 mole); K2CO3 (29.8 g; 0.22 mole); and KI (0.1 g) was refluxed in 250 mL acetonitrile for 18 hr. The mixture was filtered, concentrated and the unreacted piperazine removed by vacuum sublimation. The residual material was distilled to yield 17.2 g (85%) product, b.p. 170°-178° C. at 0.01 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: BrCC1CCCCC1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCC4CCCCC4)nc3N21

Procedure:
This compound was prepared in analogy to Example 15 intermediate c), from (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and (bromomethyl)cyclohexane.
Reaction SMILES: C[O:2][C:3](=[O:50])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][C:23]=2[CH2:45][CH3:46])[C:12]=1[CH2:47][CH2:48][CH3:49].Br[C:52]1[S:53][CH:54]=[CH:55][N:56]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:45]([C:23]1[CH:24]=[C:25]([C:52]2[S:53][CH:54]=[CH:55][N:56]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:47][CH2:48][CH3:49])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:50])=[O:2])[CH3:46]
Reactant: Brc1nccs1
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(B3OC(C)(C)C(C)(C)O3)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCCc1c(OCCCOc2cc(O)c(-c3nccs3)cc2CC)cccc1Oc1ccccc1C(=O)O
Temperature: 60 °C
Reaction time: 7 h
Yield: 37.5 %

Procedure:
A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (960 mg, 1.41 mmol), 2-bromothiazole (0.25 mL, 2.8 mmol), cesium carbonate (1.15 g, 3.52 mmol), and PdC12(dppf) (35 mg, 0.040 mmol) in de-oxygenated toluene (35 mL) was heated at 60° C. for 16 h then at 100° C. for 7 h. Additional portions of 2-bromothiazole (0.13 mL) and PdCl2(dppf) (˜30 mg) were added and heating continued at 100° C. for 72 h. The mixture was cooled to room temperature, concentrated in vacuo, diluted with methylene chloride, and filtered down a short plug of silica gel. The filtrate was concentrated in vacuo. Chromatography (silica gel, hexane to 35% ethyl acetate/65% hexane) of the residue provided 282 mg (31%) of the title compound. 1H NMR (CDCl3) δ 8.20 (s, 1H), 7.86 (dd, J=8, 1 Hz, 1H), 7.82 (d, J=3 Hz, 1H), 7.49 (d, J=7 Hz, 2H), 7.35 (m, 4H), 7.23 (d, J=3 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz, 1H), 6.7B (d, J=9 Hz, 1H), 6.65 (d, J=9 Hz, 1H), 6.57 (s, 1H), 6.42 (d, J=8 Hz, 1H), 5.24 (s, 2H), 4.17 (m, 4H), 3.81 (s, 3H), 2.63 (m, 4H), 2.33 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=8 Hz, 2H), 1.19 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H).