Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][NH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([O:45][CH3:46])[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[N+:1]([C:4]1[C:5]([N:10]2[C:21](=[O:20])[NH:22][C:23]([CH:24]([C:38]3[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([O:45][CH3:46])[CH:39]=3)[NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[N:36]=[C:35]([CH3:37])[O:34][N:33]=4)=[CH:28][CH:27]=3)=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(C)nc(OC)c1
Reactant: NNc1ncccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)cc(C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.4 %

Procedure:
After adding 32 mg of (3-nitropyridin-2-yl)hydrazine [CAS No. 15367-16-5] and 29 μl of triethylamine to a solution of 90 mg of {2-(2-methoxy-6-methylpyridin-4-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 3 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 2 ml of a methanol:THF=1:1 mixed solvent. After adding 42 μl of acetic acid and 64 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 4 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 2-(3-nitropyridin-2-yl)-5-{(2-methoxy-6-methylpyridin-4-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro-[1,2,4]triazol-3-one (30 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[F:19].[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[F:19]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(N)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)c(F)c1
Temperature: 90 °C

Procedure:
Diethyl (4-amino-3-fluorophenyl)propanedioate (11.85 g, 44.1 mmol) was dissolved in ethanol (80 ml) and treated with NaOH (2.6 g, 1.5 eq) dissolved in 18 ml of water to give a pink solution. This was heated to 90° C. for 1 hour until complete. Heating continued for 1 further hour, and then cooled to room temperature. Solvent evaporated and acidified with 2N HCl. Extracted with ethyl acetate (3×100 ml). Organics washed with brine and dried over MgSO4. Evaporated to give the title compound as a yellow oil which crystallised slowly on standing (6.6 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5].Br[CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:25]=[C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23](=[O:24])[N:15]1[CH2:14][CH2:13][CH2:12][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: N#Cc1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCCCN1C(=O)c2ccccc2C1=O
Yield: 94.8 %

Procedure:
2-fluoro-6-hydroxybenzonitrile (411 mg, 3 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (885 mg, 3.3 mmol), and potassium carbonate (1.24 g, 9 mmol) were heated overnight at 70° C. in N,N-dimethylformamide (6 mL). The mixture was cooled, diluted with water, and the precipitate filtered and dried to give 922 mg of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.79-7.87 (m, 4H), 7.69 (td, J=8.6, 6.9 Hz, 1H), 7.01-7.07 (m, 2H), 4.22 (t, J=5.8 Hz, 2H), 3.79 (t, J=6.6 Hz, 2H), 2.11 (quin, J=6.1 Hz, 2H).
Reaction SMILES: [CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C@H:2]1N.C(C1C(=O)C(=[O:28])C=C(C(C)(C)C)C=1)(C)(C)C.C(O)(=O)C(O)=O.[OH-].[NH4+]>CO.O>[CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C:2]1=[O:28]
Reactant: N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Agent: O=C(O)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
To a stirred solution of valiolamine (80 mg, 0.414 mmol), in 96% aq. methanol (5.2 mL) was added 3,5-di-t-butyl-1,2-benzoquinone (92 mg, 0.418 mmol) dissolved in methanol (2 mL) at room temperature. After stirring for 90 min, water (1 mL) was added, the pH lowered to 5.0 (pH paper control) with an aqueous solution of oxalic acid, and the mixture shaken vigorously for 45 min. Subsequently, the pH was adjusted to 8 with ammonium hydroxide. The mixture was diluted with water (80 mL) and extracted with chloroform (4×40 mL). The water phase was concentrated to approximately 5 mL in a vacuum and loaded onto an IRA-68 anion exchange column (40 mL, OH- -form). Elution with water gave a fraction containing the product. This solution was concentrated to 1 mL and further purified by chromatography on a weak cation exchanger (Wk-100, 40 mL, NH4+ -form, mobile phase: water) to give pure valiolone (42 mg, 0.219 mmol, 53% yield). 1H NMR (300 MHz, D2O), δ(ppm): 2.39 (d, 1H, J=14.6 Hz, HCH--C=O); 2.79 (d, 1H, J=14.6 Hz, HCH--C=O); 3.3 (d, 1H, J=11.5 Hz, HCH--C--OH); 3.62 (d, 1H, J=11.3 Hz, HCH--C--OH); 3.63 (t, 1H, J=9.5 Hz, HC-3); 3.84 (d, 1H, J=9.4 Hz, HC-4) and 4.19 (d, 1H, J=9.7 Hz, Hc-2). 13C NMR (75 MHz, D2O), δ (ppm): 45.45, 64.37, 72.91, 75.79, 76.01, 78.62 and 209.43.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][CH2:24][CH2:25]Cl>CS(C)=O.O>[CH2:7]([NH:11][CH2:25][CH2:24][CH2:23][O:22][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCNCCCOc1ccc2ccccc2c1
Temperature: 135 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-butylamine (0.34 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 135° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-butyl)-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 112° C., (yield 0.55 gm, 94.5%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@@H:11]([N:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1)[CH3:12].C(N(C(C)C)CC)(C)C.[Cl:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[O:36][C:35](=[O:40])[CH:34]=[C:33]2OS(C(F)(F)F)(=O)=O>C1COCC1>[Cl:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[O:36][C:35](=[O:40])[CH:34]=[C:33]2[NH:19][CH:16]1[CH2:17][CH2:18][N:13]([C@H:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH3:12])[CH2:14][CH2:15]1
Reactant: C[C@@H](c1ccc2ccccc2c1)N1CCC(N)CC1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2o1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc2ccccc2c1)N1CCC(Nc2cc(=O)oc3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
To a mixture of (S)-1-(1-naphthalen-2-yl-ethyl)-piperidin-4-ylamine (0.24 g, 0.94 mmol) and diisopropylethylamine (0.34 mL, 2 mmol) in 5 mL THF was added trifluoromethanesulfonic acid 6-chloro-2-oxo-2H-chromen-4-yl ester (0.30 g, 0.93 mmol). The reaction was stirred at room temperature for about 3 hours. The reaction mixture was then washed with water, dried with MgSO4 and evaporated. The residue was purified by chromatography on silica gel with methanol/dichloromethane (2:98) to give the title compound (0.1 g, 25%). The final product was converted to the mono-HCl salt by addition of 1.0N HCl in ether to a suspension of the compound in dichloromethane. The solvent was removed by evaporation. 1H NMR of the mono-HCl salt (300 MHz, DMSO-d6) δ 1.20-1.28 (2H, m), 1.81 (3H, d, J=6.97 Hz), 1.74-2.18 (4H, m), 2.83-3.05 (2H, m), 3.30-3.80 (2H, m), 4.65-4.78 (1H, br), 5.37 (1H, s), 7.30-7.79 (5H, m), 7.92-8.16 (4H, m), 8.32 (1H, d, J=2.64 Hz), 10.09 (1H, br, s).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:8][Br:11]
Reactant: COc1cccc(C)c1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(CBr)c1Br
Temperature: 5 °C
Yield: 58 %

Procedure:
2-Bromo-3-methylanisole (2.02 g, 1.00 mmol) and N-bromosuccinimide in carbon tetrachloride (25 ml) were heated to reflux over a 150 W light bulb for 2 h. The solution was cooled to 5° C., filtered and evaporated to drynes under reduced pressure. Purification by flash chromatography using hexane/dichloromethane (8:1) as eluent gave the title compound (162 g, 58%) as a white low melting point solid; δH (CDCl3) 3.90 (3H, s, OCH3), 4.64 (2H, s, CH2Br), 6.85 (1H, dd, J 8.2 and 1.3 Hz, 6-H), 7.08 (1H, dd, J 7.5 and 1.3 Hz, 4-H9, 7.23-7.30 (1H, m, 5-H): δC (CDCl3) 33.7 (CH2Br), 56.4 (OCH3), 111.8, 114.1 (C-2), 123.1, 128.3, 138.6 (C-1), 156.4 (C-3): m/z 282 (M+, 12%), 280 (M+, 13%). 199 (100%): (Found: M+, 277.8947. C8H8OBr2 requires M, 277.8942).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:14]1[C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:21][CH:22]=3)[O:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=c1[nH]cnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12

Procedure:
Compound 26 (60 mg, 0.149 mmol) was refluxed in phosphorous oxychloride (2 mL) for 1 h. The reaction mixture was concentrated and diluted with ice-cold water, brought to pH ˜8 with slow addition of saturated NaHCO3 and extracted with dichloromethane. The organic layer was dried over Na2SO4 and concentrated to afford 27, which was used in Step 3 without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][Cl:11]>>[Cl:11][CH2:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: ClCCCBr
Product: ClCCCN1CCOCC1

Procedure:
Morpholine and 1-bromo-3-chloropropane are reacted using the procedure for Example OO to afford 4-(3-chloropropyl)morpholine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22][CH2:23][CH2:24]Br>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:24][CH2:23][CH2:22][O:21][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCOc1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 28.8 g of 4-benzyloxy-3-hydroxy-benzaldehyde in 100 ml of dimethylformamide is added dropwise to a suspension of 5.54 g of NaH (60% dispersion in mineral oil) in 150 ml of absolute dimethylformamide. The reaction mixture is stirred at room temperature. After 30 minutes, a solution of 29 g of 3-methoxybromopropane in 120 ml of dimethylformamide is added thereto, and the mixture is stirred at room temperature for a further 4 hours and is then concentrated by evaporation under reduced pressure. The residue is partitioned between diethyl ether and water. The combined organic phases are dried over sodium sulfate and concentrated by evaporation, and the residue is purified by FC (100 g of silica gel, dichloromethane), yielding the title compound, which crystallises spontaneously: Rf (dichloromethane/diethyl ether)=0.44.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[OH:24].C1(O)C=CC=CC=1>[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([O:24][C:18]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=1[Cl:16])=[CH:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)C#COc1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Oc1ccccc1
Product: CC(C)(C)C=C(Oc1ccc(Cl)cc1Cl)Oc1ccc(Cl)cc1Cl
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
24.3 g (0.1 mole) of 1-(2,4-dichlorophenoxy)-3,3-dimethylbut-1-yne were initially taken together with 16.3 g (0.1 mole) of 2,4-dichlorophenol and 1.4 g (0.01 mole) of zinc chloride, and the stirred mixture was heated at 160° C. After 30 minutes, the phenol had reacted quantitatively with the phenoxyalkyne to give 1,1-bis-(2,4-dichlorophenoxy)-3,3-dimethylbut-1-ene.
Reaction SMILES: [N:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[C:2]=[S:3].CO[CH:11](OC)[CH2:12][NH2:13]>C1(C)C=CC=CC=1>[S:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[N:1]1[CH:11]=[CH:12][NH:13][C:2]1=[S:3]
Reactant: COC(CN)OC
Reactant: S=C=Nc1cccs1
Solvent: Cc1ccccc1
Product: S=c1[nH]ccn1-c1cccs1

Procedure:
A mixture of 2-isothiocyanatothiophene (16.9 g, 0.12 mol), and aminoacetaldehyde dimethyl acetal (12.6 g, 0.12 mol) in 200 ml toluene is refluxed for 2 hours. After removal of the toluene, the residue is dissolved in 200 ml ethanol and 45 ml conc. HCl added. After the reaction is refluxed for 5 hours, it is poured onto ice. The product is collected and purified by recrystallization.
Reaction SMILES: F.[O:2]([CH:10]([C:31]([F:36])([F:35])[CH2:32][CH2:33][CH3:34])[CH2:11][CH2:12][CH2:13][C@H:14]1[C@H:18]([CH3:19])[CH2:17][C:16](=[O:20])[C@@H:15]1[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[Si](C(C)(C)C)(C)C>C(#N)C>[OH:2][CH:10]([C:31]([F:35])([F:36])[CH2:32][CH2:33][CH3:34])[CH2:11][CH2:12][CH2:13][C@H:14]1[C@H:18]([CH3:19])[CH2:17][C:16](=[O:20])[C@@H:15]1[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: CCCC(F)(F)C(CCC[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CC#N
Product: CCCC(F)(F)C(O)CCC[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC

Procedure:
Hydrofluoric acid (1 ml) was added to a solution of the compound (30) (0.201 g) in acetonitrile (20 ml). The resultant mixture was stirred at room temperature for 1 hour. The crude product obtained after the usual work-up was subjected to silicagel column chromatography to give the alcohol (31).
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.[CH2:18]1[C:26]2[C:21](=[CH:22][C:23]([N:27]=[C:28]=[O:29])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1>>[CH2:18]1[C:26]2[C:21](=[CH:22][C:23]([NH:27][C:28](=[O:29])[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:24][CH:25]=2)[CH2:20][CH2:19]1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=Nc1ccc2c(c1)CCC2
Product: O=C(Nc1ccc2c(c1)CCC2)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 2 (2), but with 5-indanylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a solid (14.3 mg, 75%) having the following characteristics.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[C:10](OC(=O)C)(=[O:12])[CH3:11].Cl>[OH-].[Na+]>[C:10]([NH:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C(C)(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC(C)(C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-amino-2,3-dimethylbutyric acid (13.1 g) in 55 ml 2N NaOH maintained at 5° C is added simultaneously dropwise but separately 17 ml acetic anhydride and 95 ml 2N NaOH so that the pH of the solution is maintained at about 8.5. After stirring at room temperature for a further 1/2 hour, the mixture is acidified with concentrated HCl and the product, (±)-2-acetylamino-2,3-dimethylbutyric acid, removed by filtration, washed with cold water and air-dried. A sample recrystallized from acetonitrile had melting point 189°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:13]C(OCC1C=CC=CC=1)=O)=[CH:5][CH:6]1[CH:10]2[CH2:11][CH2:12][CH:7]1[CH2:8][CH2:9]2.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH2:13])[CH2:5][CH:6]1[CH:10]2[CH2:9][CH2:8][CH:7]1[CH2:12][CH2:11]2
Reactant: COC(=O)C(=CC1C2CCC1CC2)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)CC1C2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.7 %

Procedure:
In a flask was placed 2-benzyloxycarbonylamino-3-bicyclo[2.2.1]hept-7-yl-acrylic acid methyl ester (130 mg, 0.40 mmol) and methanol (5 mL). To the mixture was added 10% palladium on activated carbon (15 mg) and the flask was fitted with a balloon filled with hydrogen. The mixture was allowed to stir at 25° C. for 1 h. After such time, the mixture was filtered through celite and concentrated in vacuo to afford crude 2-amino-3-bicyclo[2.2.1]hept-7-yl-propionic acid methyl ester (100 mg) which was used without purification.
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH2:6]1)C=C.I([O-])(=O)(=O)=O.[Na+].[C:32]([O:36]C)(C)(C)[CH3:33]>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:15]2[O:16][C:17]([CH3:18])=[C:13]([CH2:12][O:11][CH:7]3[CH2:8][CH2:9][CH2:10][CH:5]([CH2:33][CH:32]=[O:36])[CH2:6]3)[N:14]=2)=[CH:24][CH:23]=1
Reactant: C=CCOC1CCCC(OCc2nc(-c3ccc(F)cc3)oc2C)C1
Reactant: COC(C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: O
Product: Cc1oc(-c2ccc(F)cc2)nc1COC1CCCC(CC=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of 4-(3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyloxazole are dissolved in 50 ml of diethyl ether, and 3.8 g of sodium periodate, dissolved in 50 ml of water, are added. At 0° C., 1 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) is added, and the mixture is stirred vigorously at room temperature. After 8 h, 100 ml of methyl tert-butyl ether are added and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified on silica gel (n-heptane:ethyl acetate=1:1→1:5). This gives 1.4 g of [3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]-acetaldehyde as a yellow-brown oil. C20H25NO4 (343.42), MS(ESI): 344 (M+H+), Rf(n-heptane:ethyl acetate=1:1)=0.25.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])[CH3:3].[C:16]1([CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14]([NH:24][CH2:23][CH:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:15])[CH3:1]
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC(c1ccccc1)c1ccccc1

Procedure:
The title compound, mp 175°-176° C., was prepared from 2,6-bis(1-methylethyl)phenyl isocyanate and 2,2-diphenylethylamine according to the method of Example 1.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[H][H]>CN(C=O)C.[OH-].[OH-].[Pd+2]>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8](=[O:13])[C:7]=2[C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1c([N+](=O)[O-])ccc2[nH]c(=O)oc(=O)c12
Agent: [Pd+2]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1c(N)ccc2[nH]c(=O)oc(=O)c12
Yield: 87.3 %

Procedure:
A mixture of the product of step B (13.5 g, 60.8 mmol), di-tert-butyldicarbonate (6.53 g, 30 mmol) and 20% Pd(OH)2/C (2.5 g) in 200 mL of DMF was stirred under 5 psi of hydrogen for 20 hours. The catalyst was filtered and the filtrate was evaporated under reduced pressure. The resulting yellow solid was triturated with Et2O, filtered, washed with Et2O and dried affording 10.2 g (87%) of 6-amino-5-methyl-4H-3,1-benzoxazin 2,4-dione. This material (9.0 g, 46.8 mmol) was redissolved in 100 mL of DMF and 15.35 g (70 mmol) of di-tert-butyldicarbonate was added followed by a catalytic amount of DMAP was added. The reaction mixture was stirred at room temperature under nitrogen overnight (ca. 30 hours). The reaction mixture was diluted with 200 mL of 1/2 saturated NaCl, filtered, washed with water then with hexane and dried affording 11.1 g (81%) of 1,1-dimethylethyl(1,4-dihydro-5-methyl-2,4-dioxo-2H-3,1-benzoxazin-6-yl)carbamate: Anal. Calc'd. for C14H16N2O5: C, 57.53; H. 5.52; N, 9.58. Found: C, 57.47; H, 5.80; N, 9.59.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>C(OCC)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:19][CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (200 mg, 1.06 mmol) was added sodium hydride (55% dispersion in mineral oil, 996 mg, 22.8 mmol). After stirring for 0.5 h at ambient temperature methyl 6-chloronicotinate (1.06 mmol) was added and the reaction mixture was stirred for 5 h at ambient temperature. It was diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL). After drying over sodium sulfate and concentration purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 70:30) afforded 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (191 mg, 42%) as a white solid. To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (3.89 g, 120 mmol) in ethanol (40 mL) was added aqueous sodium hydroxide (1 M, 36.0 mL, 36.0 mmol). After heating at reflux for 2 h it was cooled to ambient temperature and concentrated. Addition of aqueous sodium hydroxide (1 M, 50 mL) was followed by washing with tert-butylmethylether (100 mL). The aqueous phase was acidified with aqueous hydrogen chloride (conc.) to pH=1 and extracted with tert-butylmethylether (100 mL). The organic layer was washed with water (50 mL) and aqueous sodium chloride (saturated, 50 mL). Drying over sodium sulfate and concentration afforded the title compound (1.68 g, 45%) as an off white solid. MS: m/e=309.3 [M−H]−.