Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]1.C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cc(Cl)ncc2[N+](=O)[O-])C1
Yield: 107.1 %

Procedure:
A solution of 2,4-dichloro-5-nitropyridine (from AstaTech, 0.500 g, 2.59 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (0.52 g, 2.6 mmol) and triethylamine (1.1 mL, 7.9 mmol) in isopropyl alcohol (10 mL) was heated at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was re-dissolved in EtOAc (40 mL) and washed with saturated aq. NaHCO3 and water (3×3 mL). The combined aqueous phases were extracted with EtOAc (3 mL). The combined organic layers were washed with brine (3 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to afford the sub-title compound (0.99 g), which was used in the subsequent reaction without further purification. LCMS (ESI) calc. for C15H22ClN4O4[M+H]+: m/z=357.1. found 357.0.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][O:26]CC4C=CC(OC)=CC=4)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(#N)C.[N+]([O-])([O-])=O.[NH4+]>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:20][CH2:21][C@H:22]([CH2:25][OH:26])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[N:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](COCc4ccc(OC)cc4)CC3)cc2)nc1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](CO)CC3)cc2)nc1

Procedure:
A mixture of 0.485 g of 5-hexyl-2-[p-(trans-4-(p-anisyloxymethyl)cyclohexyl)phenyl]pyridine, 9.6 ml of acetonitrile and 2.4 ml of water is treated at 0° C. with 1.25 g of cer-(IV) ammonium nitrate. After 10 minutes the reaction mixture is diluted with water and extracted with diethyl ether. The organic phase is washed several times with water, then dried over magnesium sulphate and evaporated. Purification of the residue by chromatography on silica gel gives 5-hexyl-2-[p-(trans-4-(hydroxymethyl)-cyclohexyl)phenyl]pyridine.
Reaction SMILES: C[O:2][P:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:6])[O:4]C>Cl>[C:9]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][P:3](=[O:2])([OH:6])[OH:4]
Reactant: COP(=O)(Cc1ccccc1-c1ccccc1)OC
Agent: Cl
Product: O=P(O)(O)Cc1ccccc1-c1ccccc1
Yield: 64.8 %

Procedure:
A solution of ([1,1'-Biphenyl]-2-ylmethyl)phosphonic acid dimethyl ester (Compound 6, 515 mg, 1.87 mM) in concentrated hydrochloric acid (5 mL) is heated at reflux temperature for six hours. The reaction is then allowed to stand at room temperature until a white precipitate is formed. The aqueous HC1 is removed under reduced pressure. The white solid is recrystallized from water to yield 300 mg of title compound as white crystals, mp 168.5°-169° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][C:36]([CH3:38])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][N:21]([CH:36]([CH3:38])[CH3:35])[CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CC(C)=O
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(C(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-2-methylphenyl)octahydropyrano[3,4-c]pyrrole (29.6 mg, 0.06 mmol), acetone (0.044 mL, 0.60 mmol) and NaB(OAc)3H (69 mg, 0.33 mmol) in DCM was added 1 drop of HOAc and was stirred at rt for 16 hr. The mixture was diluted with DCM and was washed with NaHCO3. The organic phase was dried with Na2SO4, filtered and concentrated. The crude was purified by reverse phase HPLC to afford the title compound. MS: (MH)+534.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O.Cl.[NH2:15][OH:16].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[N:15][OH:16]
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(c1)C(=NO)CCC2
Temperature: 80 °C
Yield: 93.9 %

Procedure:
A solution of 5,7-Dimethyl-1-tetralone (5.0 g) in ethanol (100 mL) was treated with hydroxylamine hydrochloride (2.2 g) and sodium carbonate monohydrate (3.6 g). The reaction mixture was heated overnight at 80° C. with a condenser and behind a blast shield. Cooled to room temperature after seventeen hours, transferred to a 300 mL flask and concentrated. The residue was triturated in water and filtered to yield the title product as a beige solid (5.1 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH:19][C:20]1[O:21][C:22]([CH3:38])([CH3:37])[CH:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=2)[S:24](=[O:27])(=[O:26])[N:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])(C(C)(C)C)(C)C.[CH3:39][Mg]Br.[Cl-].[NH4+].O>C1COCC1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C@@H:11]([NH:19][C:20]1[O:21][C:22]([CH3:37])([CH3:38])[CH:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:36])([CH3:39])[CH3:35])=[CH:30][CH:29]=2)[S:24](=[O:27])(=[O:26])[N:25]=1)[CH2:10][CH2:9][OH:8]
Reactant: CC(=O)c1ccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3F)=NS2(=O)=O)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C2C(C)(C)OC(N[C@@H](CCO)c3ccccc3F)=NS2(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-{2-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl}phenyl)ethanone (174 mg) in THF (2.5 ml) was added dropwise, at −78° C., a solution of methylmagnesium bromide (1.4 M, 0.44 ml). After 30 min at −78° C., ammonium chloride solution was added to the mixture. After the addition of water, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (2 ml), and 0.2 ml of conc. HCl was added. The resulting mixture was purified in a purification laboratory by means of preparative HPLC. This gave the product (28 mg) with a molecular weight of 464.6 g/mol (C23H29FN2O5S); MS (ESI): m/e=465 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[N:16][C:17]#[N:18])OC2C=CC=CC=2)[CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]([NH2:29])[CH2:27][CH3:28])[CH:23]=[CH:24][CH:25]=1.CN1CCOCC1>C(O)(C)C>[C:17]([N:16]=[C:8]([NH:29][CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=1)[CH2:27][CH3:28])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)#[N:18]
Reactant: N#CN=C(Nc1cccnc1)Oc1ccccc1
Reactant: CCC(N)c1cccc(Cl)c1
Solvent: CN1CCOCC1
Solvent: CC(C)O
Product: CCC(NC(=NC#N)Nc1cccnc1)c1cccc(Cl)c1

Procedure:
According to Procedure B, a stirred mixture of N-(3-pyridyl)-N'-cyano-O-phenylisourea (Step 2) (3.00 g, 0.0126 mol), 1-(3-chlorophenyl)propylamine (2.35 g, 0.0139 mol), N-methylmorpholine (30 mL) and isopropanol (20 mL) was refluxed, under nitrogen, for 2.5 hours. The product was purified by silica gel chromatography with 1% to 3% MeOH-CHCl3 and crystallized from MeOH-EtOAc-hexane to give the product: mp 153°-155 ° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12][CH2:11]1.[OH-].[K+]>CO>[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[CH:15][CH2:14]2)[O:12][CH2:11]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Yield: 93.2 %

Procedure:
Indole (45.3 g, 0.38 mol), 1,4-cyclohexanedione monoethylene ketal (45.5 g, 0.29 mol) and potassium hydroxide (9.12 g, 0.16 mol) are heated to reflux in 100 mL of methanol for 18 hours. The reaction is cooled and the product is isolated by filtration and washed with water to give a white solid (69.0 g).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[CH2:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N+:55]1([O-:61])[CH2:56][CH2:57][CH2:58][CH2:59][CH:60]=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:61][N:55]4[CH2:56][CH2:57][CH2:58][CH2:59][C@H:60]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [O-][N+]1=CCCCC1
Reactant: C=Cc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(=O)c2c1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc([C@@H]3C[C@@H]4CCCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 10 %

Procedure:
To a solution of 0.500 g of 2-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 100 ml of toluene is added 0.291 g of 2,3,4,5-tetrahydropyridine 1-oxide and the reaction mixture heated at reflux for 18 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel by elution with 1:1 ethyl acetate-hexanes to give 0.160 g of the first desired product as a foam, FAB MASS SPEC 826 (M+Na), and 0.057 g of the second desired product as a foam. FAB MASS SPEC 826 (M+Na).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[OH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21](O)[CH:22]=2)[CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][C:22]1[C:23]3[C:18](=[CH:17][C:16]([OH:15])=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=1)=[O:13])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Oc1cccc2cc(O)ccc12)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixture of 9.41 g (0.05 mol) of 6-hydroxy-2-naphthoic acid, 24.03 g (0.15 mol) of 2,6-dihydroxynaphthalene, 0.8 g of p-toluenesulfonic acid monohydrate and 3 drops of concentrated sulfuric acid in 100 ml of toluene was heated under reflux with occasional addition of concentrated sulfuric acid (3 drops every 3 h) for 12 h. The resulting suspension was cooled to room temperature and filtered. The filtercake was suspended in methanol, the suspension was stirred for 3 h and the solid was finally filtered off. 10.9 g of 6-hydroxynaphthyl 6-hydroxy-2-naphthoate (“NpNp”) were obtained as a brownish solid which was processed in the subsequent step without further purification.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39].O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:39][CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([O:34][CH3:33])[CH:36]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(CN)c1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: CCO
Solvent: O
Product: COc1cccc(CNc2ncnc3c2ncn3C2O[C@H](COC(=O)c3ccccc3)C(C)(OC(C)=O)[C@@]2(C)F)c1
Yield: 20.6 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.4 g, 0.86 mmol) in ethanol (about 5 ml) was added 3-methoxybenzylamine (about 1.34 ml, 10.38 mmol) and refluxed for about 20 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.10 g) as a colorless gummy mass. Yield: 21%; 1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.03-7.98 (m, 3H), 7.60-7.42 (m, 3H), 6.99-6.94 (m, 2H), 6.84-6.81 (m, 2H), 6.55 (d, 1H, J=23.1 Hz), 6.31 (bs, 1H), 4.84-4.78 (m, 3H), 4.49-4.45 (m, 1H), 3.79 (s, 3H), 2.18 (s, 3H), 1.89 (d, 3H, J=2.4 Hz), 1.47 (d, 3H, J=23.1 Hz); Mass: [M+1]+ 564 (100%), [M+Na]+ 586 (40%); IR cm−: 3430, 2928, 2381, 2170, 1734, 1624, 1461, 1053, 950, 713; HPLC: 90.1%.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5](F)[C:4]=1[CH3:12].[CH3:13][OH:14]>>[Br:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:14][CH3:13])[C:4]=1[CH3:12]
Reactant: CO
Reactant: Cc1c(Br)ccc(C#N)c1F
Agent: [Na]
Product: COc1c(C#N)ccc(Br)c1C
Temperature: 0 °C

Procedure:
Sodium (3.00 g, 130 mmol) was added in portions into 80 mL of methanol and the mixture was stirred for 20 min until the sodium was completely dissolved. Then 4-bromo-2-fluoro-3-methylbenzonitrile (8.00 g, 37.3 mmol) was added and the solution was refluxed for 4 hours before cooling down. The reaction mixture was poured into ice/water (300 mL) and the resulting precipitate was collected by filtration. The solid afforded was dried under reduced pressure at 40° C. to give 4-bromo-3-methyl-2-(methyloxy)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.39 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 4.00 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5]1)#[C-:2].C[O-].[Na+].[F:33][C:34]([F:47])([F:46])[C:35]([C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][CH:39]=1)([OH:37])[CH3:36]>CO.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[F:33][C:34]([F:46])([F:47])[C:35]([C:38]1[CH:45]=[CH:44][C:41]([C:42]2[O:43][CH:2]=[N:1][C:3]=2[CH:4]2[CH2:5][CH2:6][N:7]([S:10]([C:13]3[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[CH2:8][CH2:9]2)=[CH:40][CH:39]=1)([OH:37])[CH3:36]
Reactant: [C-]#[N+]C(C1CCN(S(=O)(=O)c2ccc(C)cc2)CC1)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(O)(c1ccc(C=O)cc1)C(F)(F)F
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC(c3ncoc3-c3ccc(C(C)(O)C(F)(F)F)cc3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4-(Isocyano(tosyl)methyl)-1-tosylpiperidine (260 mg, 0.73 mmol) was dissolved in MeOH (6 mL) and treated with sodium methoxide (1.0 M solution in MeOH, 0.7 mL), and 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzaldehyde (159 mg, 0.73 mmol) was then added. After being stirred at 80° C. for 2 h, the mixture was then cooled to r.t. and diluted with ethyl acetate (80 mL) and saturated aqueous NaHCO3 (30 mL). The separated organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (15% EtOAc/hexane) to provide 1,1,1-trifluoro-2-(4-(4-(1-tosylpiperidin-4-yl)oxazol-5-yl)phenyl)propan-2-ol as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.69-7.65 (m, 2H), 7.51-7.49 (m, 2H), 7.36-7.33 (m, 4H), 3.90 (d, J=11.7 Hz, 2H), 3.30-3.28 (s, 1H), 2.79 (tt, J=3.9 Hz, 11.7 Hz, 1H), 2.45 (s, 3H), 2.37 (td, J=2.3 Hz, 12.1 Hz, 2H), 2.17-2.07 (m, 2H), 1.85 (d, J=12.1 Hz, 2H), 1.80 (s, 3H); MS (ESI) 495.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[N+]([O-])([O-])=O.[Na+].[ClH:26]>CN(C)C=O.O>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:26])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: Cl
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(Oc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The product (10 g) from paragraph (a) was dissolved in dimethyl formamide (150 ml), cooled to 5°-10° C. and concentrated hydrochloric acid (40 ml) added dropwise, the temperature being kept at 10°-15° C. The mixture was then kept at 5° C. while sodium nitrate (5.2 g) in water (20 ml) was added dropwise with stirring over a period of 30 minutes. The solution so prepared was added dropwise to a solution of cuprous chloride (19 g) in concentrated hydrochloric acid (150 ml) kept at 10° C., giving a thick green suspension. When addition was complete, the mixture was left to stand overnight and then heated to 60° C. for 30 minutes. The white solid was filtered off, dried, and recrystallised from petroleum (100°-120° C.) to give 3(2,4-dichlorophenoxy)benzoic acid (5.1 g) with a melting point of 143°-144° C. This compound was used as starting material for compound no 19 of Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH:4]([O:12][CH:13]1[CH2:16][NH:15][CH2:14]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH:4]([O:12][CH:13]1[CH2:14][N:15]([C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:16]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1
Reactant: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2Cl)cc1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a stirred solution of 3-(2,4,4′-trichlorobenzhydryloxy)azetidine (4) (3 mmol) in dichloromethane (10 mL) was added tert-butyl isocyanate (3 mmol) and triethylamine (catalytic amount) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was eluted through a pre-wetted (CH2Cl2) SCX-2 (2 g) cartridge with dichloromethane to yield the desired product as a white foam (424 mg, 33%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.I[CH3:14]>C1COCC1>[CH3:14][O:3][C:4]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)C1(O)CCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(OC)CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
A 0° C. suspension of NaH (60% in mineral oil, 0.644 g, 16.09 mmol) (pre-washed with hexanes, 2×) in THF (10 mL) was treated slowly with a solution of methyl 1-hydroxycyclopentanecarboxylate (1.45 g, 10.06 mmol) in THF (10 mL), stirred at 0° C. for 15 min, treated with iodomethane (1.258 mL, 20.12 mmol), warmed to RT and stirred overnight. The mixture was poured into satd. NH4Cl, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford methyl 1-methoxycyclopentanecarboxylate (1.0 g, 63%). 1H NMR (400 MHz, CDCl3): δ 3.76 (s, 3H), 3.24 (s, 3H), 1.98-1.96 (m, 4H), 1.76-1.74 (m, 4H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[N:19]=3)[N:14]=[CH:13][C:12]=2[C:22](=[O:24])[CH3:23])[CH2:6][CH2:5]1.[C:25]([O:29][C:30]([NH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:31])[NH:32][CH:33]([CH:37]([CH3:38])[CH3:39])[C:34]([NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[N:19]=3)[N:14]=[CH:13][C:12]=2[C:22](=[O:24])[CH3:23])[CH2:6][CH2:5]1)=[O:35])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(N)CC1
Agent: Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](NC(=O)C(NC(=O)OC(C)(C)C)C(C)C)CC1

Procedure:
Following general procedure VI, 1-{4-[(4-aminocyclohexyl)amino]-6-chloro-1,5-naphthyridin-3-yl}ethanone dihydrochloride (300 mg, 0.94 mmol) was reacted with 2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (310 mg, 1.4 mmol) to afford the desired product (320 mg, 65%) as a white solid. ESI MS m/z 518 [M+H]+
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4].[CH3:9][C@H:10]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12]>CN(C)C=O>[NH:23]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C@H:10]([C:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4])=[O:12])[CH3:9]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Reaction time: 18 h
Yield: 86.2 %

Procedure:
2.28 g of H-Pro-NH2 and 7.57 g of Z-Ala-ONP are dissolved in 20 ml of dimethylformamide and the yellow solution is left standing at room temperature for 18 hours. It is then evaporated to dryness in a high vacuum, the residue is mixed with ether and the resulting powder is thoroughly triturated. After filtering off and drying, 5.5 g of Z-Ala-Pro-NH2 of melting point 167.5°-168.5°C are obtained. [α]D20 = -74° (c =1 in methanol).