Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([O:14][CH3:15])=[C:12](Cl)[N:11]=[CH:10][N:9]=1>O>[CH3:15][O:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[N:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: COc1c(Cl)ncnc1Cl
Solvent: O
Product: COc1cncnc1N1CCNCC1

Procedure:
Piperazine (20 g) was dissolved in water (100 mL) in a Parr bottle and then solid 4,6-dichloro-5-methoxypyrimidine (5.00 g, 27.9 mmol) was added. The mixture was vigorously stirred for 2 h at room temperature during which the 4,6-dichloro-5-methoxypyrimidine dissolved. The stirring bar was removed, catalyst (10% Pd/C, 1.0 g) was added to the turbid solution, and the mixture was then hydrogenated (60 psi, 3 h) at room temperature. The catalyst was filtered off and the filtrate extracted 3 times with CH2Cl2. The CH2Cl2 extracts were dried over Na2SO4 and concentrated in vacuo to give a clear oil which solidified upon standing (3.34 g, 61.7%). This crude product was Kugelrohr distilled (yield 3.24 g), dissolved in acetonitrile, and concentrated HCl added to precipitate the product as a white powder which was dried in vacuo (4.32 g, 94.0% from crude product, m.p. 219°-221.5° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C@H:12]([NH:23]C(OCC2C=CC=CC=2)=O)[C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[N:8][CH:9]=1)([O-])=O.C.[H][H]>CO.O.[Pd]>[NH2:23][C@@H:12]([CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][N:8]=1)[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: O=C(N[C@@H](CCc1ccc([N+](=O)[O-])cn1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Nc1ccc(CC[C@H](N)C(=O)O)nc1
Yield: 91.3 %

Procedure:
A mixture of 5.16 g (11.5 mmol) of phenylmethyl (S)-5-nitro-α-[[(phenylmethoxy)carbonyl]amino]-2-pyridinebutanoate, 2 g of active charcoal and 0.77 g of active palladium-on-charcoal in 100 ml of methanol and 100 ml of water is stirred for 4 days at 50 psi of hydrogen at room temperature. The reaction medium is filtered through a cake of Celite and the cake is rinsed with 3×50 ml of boiling water. The aqueous phases are combined and concentrated under reduced pressure. 2.05 g of (S)-α,5-diamino-2-pyridinebutanoic acid are thus obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)=[C:6]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:36]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:7]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]3[C:5]([C:6]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:16]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc2c(=O)n(C)c(C3CCCNC3)c(-c3ccccc3)c2c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C)c(C3CCCN(C(=O)c4ccccc4)C3)c(-c3ccccc3)c2c1

Procedure:
To a dichloromethane (0.100 mL) solution of (±)-6-methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one (30 mg, 0.086 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.095 mmol) was added benzoyl chloride (0.011 mL, 0.095 mmol). After 24 hours saturated sodium bicarbonate and additional dichloromethane were added. The layers were separated and the organic phase dried with anhydrous magnesium sulfate. Evaporation of the solvent in vacuo followed by trituration with ether-EtOAc gave a white solid which was isolated by vacuum filtration to give the titled product. ESI+MS: 453.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=2[O:16][CH3:17])=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[CH:22]=[CH:21]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][C:22]3[C:23]4[C:28](=[N:27][CH:26]=[CH:25][CH:24]=4)[NH:20][CH:21]=3)=[CH:10][C:9]=2[O:16][CH3:17])=[CH:4][CH:3]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: COc1cc(C=O)ccc1OCc1ccc(Cl)cc1
Product: COc1cc(Cc2c[nH]c3ncccc23)ccc1OCc1ccc(Cl)cc1

Procedure:
Additional compounds were prepared using the protocol of Scheme 33, Steps 2 and 3, replacing 4-(4-chlorobenzyloxy)-3-methoxybenzaldehyde 106 with a suitable aldehyde (prepared as described in Example 34), and optionally replacing 1H-Pyrrolo[2,3-b]pyridine 94 with an appropriate substituted 7-azaindole (see Example 9 or Example 16) in Step 2. The following compounds were made following this procedure:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.O>C(Cl)(Cl)Cl>[Br:1][C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[NH:10][CH:11]=1
Reactant: BrBr
Reactant: Clc1cnc2[nH]ccc2c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1cnc2[nH]cc(Br)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of bromine (3.5 ml) in chloroform (40 ml) was added dropwise to an ice-cold solution of the 5-chloro-1H-pyrrolo[2,3-b]pyridine (3) (10 g, 65 mM) in chloroform (260 ml). The reaction mixture was stirred for 60 minutes at 0° C. The reaction mixture was then hydrolysed with water and the pH of the solution was adjusted to 10. The resulting solid was removed by filtration, and the aqueous was extracted with dichloromethane. The organic was washed with water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (10.5 g, 69%). 1H NMR (DMSO-d6) 7.8 (1H, s), 7.9 (1H, s), 8.3 (1H, s)
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[C:14]12([N:24]=[C:25]=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:25]([NH:24][C:14]23[CH2:23][CH:18]4[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]4)[CH2:21]2)[CH2:15]3)=[O:26])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)NC23CC4CC(CC(C4)C2)C3)c1O
Yield: 56.5 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (120 mg, 0.54 mmol) and 1-adamantyl isocyanate (115 mg, 0.64 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), gave the desired product (122 mg, 56%). LC-MS (m/z) 400.0 (M+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:32])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:20]=[CH:21][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][CH:24]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][N:6]=2)=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1ccc(CO)cn1)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.7 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared in Example 30B-b, 59 mg, 0.13 mmol) in diethyl ether (5 mL) was cooled to 0° C. and then treated with lithium aluminum hydride (8 mg, 0.20 mmol). The reaction was slowly warmed to 25° C. where it was stirred for 16 h. At this time, the reaction mixture was slowly diluted with water (5 mL) and then extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-phenoxy-phenyl)-propionamide (28 mg, 51%) as a yellow foam: FAB-HRMS m/e calcd for C26H28N2O3 (M+H)+ 417.2178. found 417.2163.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][C:11](OC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:17][NH2:18]>CCO>[NH:17]([C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH3:15])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[NH2:18]
Reactant: COC(=O)CCN(C)C(=O)OC(C)(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN(CCC(=O)NN)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of methyl 3-(tert-butoxycarbonyl(methyl)amino)propanoate (6.9 g, 0.0317 mol) in EtOH (15 mL) was added hydrazine monohydrate (7.7 mL, 0.158 mol) at rt. The reaction mixture was heated to 80° C. and stirred at 80° C. overnight. The reaction mixture was concentrated, and then DCM (300 mL) was added. The organic layer was washed with water and saturated sodium chloride, dried over Na2SO4, and concentrated to afford tert-butyl 3-hydrazinyl-3-oxopropyl(methyl)carbamate (6.8 g, 98%) as sticky oil, which was used directly in the next step. ESI-MS (EI+, m/z): 118 [M−100+H]+.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:25])([F:24])[C:14]([NH:16][CH:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15]>>[CH2:7]([N:6]1[C:2]([N:20]2[CH2:21][CH2:22][CH2:23][CH:17]([NH:16][C:14](=[O:15])[C:13]([F:24])([F:12])[F:25])[CH2:18][CH2:19]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=[N:5]1)[CH3:8]
Reactant: CCn1ncc([N+](=O)[O-])c1Cl
Reactant: O=C(NC1CCCNCC1)C(F)(F)F
Product: CCn1ncc([N+](=O)[O-])c1N1CCCC(NC(=O)C(F)(F)F)CC1
Yield: 55 %

Procedure:
Following the procedure for Example 503 starting with 5-chloro-1-ethyl-4-nitro-1H-pyrazole and 2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.136 g, 55%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 6.39-6.37 (m, 1H), 4.22-4.19 (m, 1H), 4.12 (q, J=7 Hz, 2H), 3.42-3.35 (m, 1H), 3.27-3.18 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 4H), 1.47 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])[N:19]=[C:18]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH2:17]3)[CH:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:36][OH:37].O>C(O)C>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH:16]([C:12]2[CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1](=[N:36][OH:37])[CH3:2])=[CH:5][CH:6]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:17][C:18]([C:28]([F:34])([F:33])[C:29]([F:30])([F:31])[F:32])=[N:19]1
Reactant: NO
Reactant: CC(=O)c1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
5-(4′-acetyl-biphenyl-3-yl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (18.0 mg, 0.04 mmol) prepared in Example 107 and hydroxylamine hydrochloride (5.0 mg, 0.07 mmol) were added to a mixed solvent of distilled water (30.0 uL) and ethanol (1.5 mL). The reaction mixture was stirred at 50° C. for 3 hours, concentrated under reduced pressure and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 17.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[NH:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11])[CH3:7])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43]>CN(C=O)C>[CH2:1]([O:5][CH:6]([O:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:19][CH:20]3[CH:22]([CH:21]3[N:24]([CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:23]2)=[N:16][CH:17]=1)=[O:11])[CH3:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CCN(CC)CCBr
Reactant: CC(C)COC(C)ONC(=O)c1cnc(N2CC3C(C2)C3NCc2ccc3ccccc3c2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN(Cc1ccc2ccccc2c1)C1C2CN(c3ncc(C(=O)NOC(C)OCC(C)C)cn3)CC21
Reaction time: 0.25 h
Yield: 28.5 %

Procedure:
N-(1-Isobutoxyethoxy) 2-{6-[(naphthalen-2-ylmethyl)-amino]-3-azabicyclo[3.1.0]hex-3-yl}-pyrimidine-5-carboxamide (52 mg, 0.11 mmol) was dissolved in anhydrous DMF (2 ml) and cooled over ice. To the solution was added sodium hydride (13 mg, 0.55 mmol-60% dispersion in mineral oil) and the mixture was stirred for 15 min. To the stirring mixture was then added (2-bromoethyl)-N,N-diethylamine (22 mg, 0.12 mmol). After stirring for 30 min, the reaction was quenched by the careful addition of water and stirred for 10 min. The aqueous mixture was extracted with EtOAc (3×20 ml) and the combined organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness to give the title compound as a white solid (18 mg, 29%). LCMS purity 100%, m/z 575 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:20][CH3:21])[CH2:18][OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OCC)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:30]([O:19][CH2:18][C:17]([NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])([CH2:20][CH3:21])[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)(=[O:32])[CH3:31]
Reactant: CCOC(C)=O
Reactant: CCC(CO)(CCc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(CCc1ccc(OCc2ccccc2)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 4-(4-benzyloxyphenyl)-2-tert-butoxycarbonylamino-2-ethylbutanol (24 g) in pyridine (200 ml) and acetic anhydride (32 ml) was allowed to stand at room temperature overnight. Ethyl acetate was added to the reaction mixture and the mixture was washed with water, a dilute hydrochloric acid, an aqueous sodium hydrogencarbonate solution and a saturated brine in order, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1) to give the subject compound (13 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]I.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[S:8][CH2:7]1
Reactant: O=C1CSCN1CCCCBr
Reactant: ICCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CC2(CCCC2)SCN1CCCCBr
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of 3-(4-bromobutyl)-4-thiazolidinone (25 g) in THF (350 ml) cooled to -60° C. was added 1,5-diiodopentane (100 g), and the resultant slurry was cooled to -65° C. A solution of lithium bis(trimethylsily)amide (0.220 mole) in hexanes (220 ml) was added dropwise, during which the internal temperature was maintained at or below -55° C. The addition was complete within 30 minutes. The mixture was stirred for additional 15 minutes at the same temperature and thereafter warmed to 0° C. with the aid of an ice bath. The mixture was stirred for additional 20 minutes and thereafter quenched with 500 ml of 0.5N HCl solution. The resultant mixture was placed under vacuum to remove some of the THF and thereafter extracted with ether (350 ml, 2×250 ml). The combined extracts were washed successively with water (400 ml) and brine (400 ml), dried with Na2SO4 and concentrated to a liquid. The liquid was chromatographed (2 silica gel columns) using 20-60% ethyl acetate/hexane as an eluent to obtain about 20.5 g of solid product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH:17]([O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:20][CH:19]=1)[N:5]([CH3:16])SC1C=CC=CC=1[N+]([O-])=O.C1(S)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH:17]([O:28][C:29](=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:20][CH:19]=1)[NH:5][CH3:16]
Reactant: COCOc1ccc(C(OC(=O)c2ccccc2)[C@@H](C(=O)OC)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: Sc1ccccc1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](C(=O)OC)C(OC(=O)c1ccccc1)c1ccc(OCOC)cc1
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
To a solution of O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-benzoyloxytyrosine methyl ester (threo isomer) (4.94 g) in dichloromethane (50 ml) were added thiophenol (4.8 ml) and trifluoroacetic acid (2.5 ml) at 0° C. After stirring for 30 minutes, sodium bicarbonate aqueous solution was added to the mixture. The organic layer was washed with sodium bicarbonate aqueous solution and brine. After evaporating, the residue was put on a column of silica gel (MERCK 7734, 100 g) and eluted with 5% methanol in chloroform to give O-methoxymethyl-N-methyl-β-benzoyloxytyrosine methyl ester (threo isomer) (0.32 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:40](=[O:41])[CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)Cc3ccccc3)cc1)N2
Yield: 81 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (80 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.52 mmol) in dichloromethane (5 mL) was added 2-phenylacetyl chloride (0.05 mL, 0.34 mmol). The resultant mixture was stirred at room temperature for 16 hrs under nitrogen. The solvent was removed and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 3,3-dimethyl-2-(4-(2-phenylacetamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 90 mg, yield: 81%.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-:20].[K+].[K+].OO>CS(C)=O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]([NH2:13])=[O:20])=[CH:17][CH:18]=1)=[O:2]
Reactant: N#Cc1cccc(COc2ccc(C=O)cc2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cccc(COc2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-Formyl-phenoxymethyl)benzonitrile (1 equiv), in DMSO was added potassium carbonate (0.5 equiv), and hydrogen peroxide (4 equiv). The reaction mixture stirred at room temperature for 2 hours. The reaction was monitored by TLC. It was poured on water and extracted with ethyl acetate (×3). The organic phase was dried over magnesium sulphate, filtered and concentrated under vacuum to yield a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(Nc1ccc(O)c(C(=O)O)c1)c1ccc([N+](=O)[O-])cc1
Yield: 55.8 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-nitrobenzoyl chloride (700 mg, 3.77 mmole), 550 mg (56% yield) of 5-(4-nitrobenzoyl)aminosalicylic acid was obtained as a pale yellow solid.:mp 270-271° C.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@H:12]([OH:13])[C@H:11]([CH3:14])[O:10][C@H:7]([O:8][CH3:9])[CH2:6]1)(=[O:3])[CH3:2].[CH2:15](I)[CH3:16]>CN(C)C=O.[Ag]=O>[C:1]([NH:4][C@@H:5]1[C@H:12]([O:13][CH2:15][CH3:16])[C@H:11]([CH3:14])[O:10][C@H:7]([O:8][CH3:9])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CO[C@@H]1C[C@H](NC(C)=O)[C@H](O)[C@H](C)O1
Reactant: CCI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCO[C@H]1[C@@H](NC(C)=O)C[C@@H](OC)O[C@H]1C
Reaction time: 17 h

Procedure:
5.0 g of methyl 3-acetamido-2,3,6-trideoxy-β-L-lyxohexopyranoside were heated at 45° C. in the dark in a mixture of 25 ml of ethyl iodide and 20 ml of dimethylformamide containing 10 g of silver oxide. After 17 hours, the mixture was filtered through Celite and the filtrate was evaporated. The gum obtained was purified by column chromatography to give 3.4 g of methyl 3-acetamido-2,3,6-trideoxy-4-O-ethyl-β-L-lyxohexopyranoside in the form of colourless crystals of melting point 199°-200° C.; [α]D20 =-75.0° (c=0.5% in methanol).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7](S(C)(=O)=O)=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1.[NH3:16]>O1CCOCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:16])=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: N
Reactant: Cn1nc(Br)c2cnc(S(C)(=O)=O)nc21
Solvent: C1COCCO1
Product: Cn1nc(Br)c2cnc(N)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromo-6-methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (WO 2003029209, page 46) (0.215 g, 0.0074 mol) is dissolved in 0.5M ammonia in 1,4-dioxane (11 ml) and stirred overnight at room temperature. The reaction mixture is concentrated in vacuo to afford the title compound.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:11])[CH2:6][CH:7]1[CH2:10][NH2+:9][CH2:8]1)[CH3:3].[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:32][CH:31]=2)=[C:21]([CH:25]=1)[C:22](O)=[O:23])=[O:16])[CH3:13]>>[CH2:2]([O:4][C:5](=[O:11])[CH2:6][CH:7]1[CH2:10][N:9]([C:22]([C:21]2[CH:25]=[C:17]([CH:18]=[CH:19][C:20]=2[O:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:32][CH:31]=2)[C:15]([O:14][CH2:12][CH3:13])=[O:16])=[O:23])[CH2:8]1)[CH3:3]
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)O)c1
Reactant: CCOC(=O)CC1C[NH2+]C1
Agent: [Cl-]
Product: CCOC(=O)CC1CN(C(=O)c2cc(C(=O)OCC)ccc2OCCCc2ccc(OCCCCOc3ccccc3)cc2)C1

Procedure:
Preparation takes place in analogy to Example IX, method 3, from 3-(2-ethoxy-2-oxoethyl)azetidinium chloride and 5-(ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)-phenyl]propoxy}benzoic acid.