Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:38]C1C=C(S(CC2C(C(OC)=O)=C(O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=1.C(OC(NCCBr)=O)(C)(C)C>>[C:29]([O:28][C:26]([NH:25][CH2:24][CH2:23][O:22][C:15]1[C:14]([C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)=[CH:13][CH:12]=[C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[C:3]([Cl:38])[CH:2]=2)(=[O:9])=[O:8])[C:16]=1[C:17]([O:19][CH3:20])=[O:18])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(-c2ccoc2)c1O
Agent: CC(C)(C)OC(=O)NCCBr
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from methyl 6-(3-chlorobenzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 37) and 2-[N-(t-butoxycarbonyl)amino]ethyl bromide.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[H-].[Na+].[Na].[CH3:10][CH:11](Br)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH:21]([CH3:24])[CH2:22][CH3:23])=[CH:16][CH:15]=1>>[CH3:10][CH:11]([S:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1)[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([S:20][CH:21]([CH3:24])[CH2:22][CH3:23])=[CH:18][CH:19]=1
Reactant: CCC(C)Sc1ccc(OCC(C)Br)cc1
Reactant: SC1=NCCS1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: CCC(C)Sc1ccc(OCC(C)SC2=NCCS2)cc1

Procedure:
Generally following the procedure of Example 7, 2-mercapto-2-thiazoline (0.67 g, 5.6 mmol) is treated with sodium hydride (0.35 g, 7.3 mmol), with cooling, and the resulting sodium salt is reacted with 1-methyl-2-[4-(1methylpropylthio)phenoxy]ethyl bromide (1.70 g, 5.6 mmol) at RT to give 2-{1-methyl-2-[4-(1-methylpropylthio)phenoxy]ethylthio}-2-thiazoline.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[F:23][C:24]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:25]=1[CH:26]=O.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:26]\[C:25]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:24]=1[F:23])/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C(=C/c1cc(F)ccc1F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A stirred solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (6.1 g) and 2,5-difluorobenzaldehyde (2.0 g) in dry dichloromethane (60 mL), was treated dropwise with a solution of DBU (2.5 mL) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 h, then was concentrated to approximately 20 mL and partitioned between ethyl acetate (150 mL) and 1N hydrochloric acid (50 mL). The organic extract was collected, consecutively washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and brine, dried (sodium sulfate), filtered and evaporated. The crude product (6.5 g) was purified by flash chromatography (20% ethyl acetate/hexanes) to yield the title compound (4.0 g, 82%). 1H NMR (300 MHz, CDCl3) δ 3.85 (s, 3H), 5.10, (s, 2H), 6.60 (bs, 1H), 6.9-7.1 (m, 2H), 7.21 (m, 1H), 7.2-7.3 (m, 6H). MS APCI, m/z=348 (M+1). LC/MS: 2.53 min.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:25]([CH2:27][C:28]([O:30]CC)=[O:29])[CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O>O1CCOCC1.O>[C:15]([O:14][C:12](=[O:13])[CH2:11][C@H:10]([C:19]1[O:23][N:22]=[C:21]([CH2:24][N:25]([CH2:27][C:28]([OH:30])=[O:29])[CH3:26])[N:20]=1)[CH2:9][CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)CN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CN(CC(=O)O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 120.7 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-([(2-ethoxy-2-oxoethyl)(methyl)amino]methyl}-1,2,4-oxadiazol-5-yl)hexanoate (preparation 132) (1.00 g, 2.21 mmol) in dioxan (20 ml) and H2O (20 ml) was treated with LiOH.H2O (193 mg, 2.21 mmol) and the reaction mixture stirred at room temperature for 19 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with brine. The aqueous was extracted with EtOAc (×3). The combined organic extracts were dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to afford the title compound as a white foam (1.13 g).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:36]O)[CH3:23].C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:36][C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[O:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: CCc1oc(-c2ccc(F)cc2)nc1CO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1oc(-c2ccc(F)cc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 80.7 %

Procedure:
Intermediate 63 was prepared as described above for the preparation of intermediate 52. From 962 mg of N-(Boc)-L-Tyrosine methyl ester and 720 mg of Intermediate 10D was prepared 1.32 g of BOC-protected intermediate methyl ester (81% yield; 1H NMR (CDCl3, 300 MHz) δ8.07-8.03 (m, 2H), 7.19-7.13 (m, 2H), 7.08 (d, 2H, J=8.4), 6.97 (d, 2H, J=8.4), 4.99-4.97 (m, 3H), 4.58-4.57 (m, 1H), 3.74 (s, 3H), 3.09-3.03 (m, 2H), 2.82 (q, 2H. J=7.5), 1.59 (s, 9H), 1.30 (t, 3H, J=7.5); From 1.31 g of BOC-protected ester intermediate was prepared the crude TFA salt of intermediate 63. The TFA salt was suspended into water and the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered and dried to yield 1.01 g of the title compound; 1H NMR (DMSO-d6, 300 MHz) δ8.01-7.97 (m, 2H), 7.36 (t, 2H, J=9.0), 7.18 (d, 2H, J=8.4), 6.96 (d, 2H, J=8.4), 4.97 (s, 2H), 3.53-3.51 (m, 2H), 3.09-3.04 (m, 2H), 2.84 (q, 2H, J=7.5), 1.22 (t, 3H, J=7.5); low resolution MS (ES+)m/e 384.87 (MH+); TLC Rf=0.44 (4/1, DCM/MeOH).
Reaction SMILES: [OH-].[OH:2][P:3]([O:14][CH2:15][CH:16]1[CH2:20][CH:19]([S:21][C:22]2[CH:28]([CH3:29])[CH:27]3[N:24]([C:25](=[O:33])[CH:26]3[CH:30]([OH:32])[CH3:31])[C:23]=2[C:34]([O:36]CC2C=CC([N+]([O-])=O)=CC=2)=[O:35])[CH2:18][O:17]1)([O:5][CH2:6][CH2:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(=O)(O)[O-].[Na+].O>[Pd].O1CCOCC1>[OH-:2].[C:34]([C:23]1[N:24]2[CH:27]([CH:28]([CH3:29])[C:22]=1[S:21][CH:19]1[CH2:18][O:17][CH:16]([CH2:15][O:14][P:3]([OH:4])([O:5][CH2:6][CH2:7][N+:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:2])[CH2:20]1)[CH:26]([CH:30]([OH:32])[CH3:31])[C:25]2=[O:33])([OH:36])=[O:35]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COP(=O)(O)OCC[n+]4ccccc4)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(COP(=O)(O)OCC[n+]4ccccc4)C3)C(C)C12
Yield: 130.7 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.150 g of product from Example 95, 0.025 g of sodium bicarbonate, 3 ml of water, 9 ml of dioxane and 0.030 g of 10% palladium/carbon to give 0.0786 g of the desired product.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:2].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH:22]=O>C(O)C.Cl.C(O)(C)C.O>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH2:9][CH2:22][C:21]2[CH:24]=[C:25]([CH3:28])[C:26]([OH:27])=[C:19]([CH3:18])[CH:20]=2)=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCc1sc(C(C)=O)cc1-c1ccc(C)cc1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CCO
Product: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccc(C)cc1
Reaction time: 18 h
Yield: 105.7 %

Procedure:
A solution of 1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-ethanone (28 mg, 0.115 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (26 mg, 0.172 mmol) in ethanol (1.5 mL) and 5 N HCl in isopropanol (0.3 mL) is stirred at rt for 18 h. The solution is diluted with water and extracted with EA. The organic extract is evaporated, dissolved in methanol (3 mL) and THF (3 mL) and treated with Pd/C (30 mg, 10% Pd). The slurry is stirred under 1.5 bar of H2 for 18 h. The mixture is filtered, the solvent of the filtrate is removed in vacuo and the crude product is purified by prep. HPLC to give 1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (46 mg) as a colourless oil; LC-MS: tR=1.13 min, [M+1]+=379.22.
Reaction SMILES: [OH-].[Na+].[CH:3]([O:6][C:7]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]=1[CH2:22][CH3:23])=[CH:18][C:17]([NH:24][C:25](=[S:27])[CH3:26])=[CH:16][CH:15]=3)=[O:8])([CH3:5])[CH3:4]>O.N1C=CC=CC=1.C(OCC)(=O)C>[CH:3]([O:6][C:7]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]=1[CH2:22][CH3:23])=[C:18]1[S:27][C:25]([CH3:26])=[N:24][C:17]1=[CH:16][CH:15]=3)=[O:8])([CH3:5])[CH3:4]
Reactant: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(NC(C)=S)cc3c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc4nc(C)sc4c3c12
Temperature: 4 °C
Reaction time: 2 h
Yield: 15.1 %

Procedure:
450 mg of K3Fe(CN)6 is dissolved in 1.8 ml of water, mixed with 1.4 ml of 1N NaOH and cooled to 4° C. 200 mg of 4-ethyl-6-thioacetylamino-β-carboline-3-carboxylic acid isopropyl ester in 4 ml of pyridine is added in drops to this solution and stirred for another 2 hours at this temperature. The reaction mixture is taken up in ethyl acetate, washed with water, dried and concentrated by evaporation. The residue is chromatographed on silica gel with toluene+ethanol=95+5. The desired fractions are concentrated by evaporation and stirred up with ether. 30 mg of the title compound with a melting point of 239-240° C. is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:4]([N+:15]([O-])=O)[CH:3]=1.[C:18](O)(=[O:20])[CH3:19]>C(OC(=O)C)(=O)C.[Pd]>[C:18]([NH:15][C:4]1[CH:3]=[C:2]([F:1])[C:7]([F:8])=[CH:6][C:5]=1[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:20])[CH3:19]
Reactant: CC(=O)O
Reactant: O=C(O)CCCc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(F)c(F)cc1CCCC(=O)O

Procedure:
The compound obtained in (3) above (380 mg) was dissolved in a mixed solvent of 5 ml of acetic acid and 10 ml of acetic anhydride. Upon the addition of 60 mg of 10% palladium-on-carbon, the mixture was catalytically hydrogenated. The catalyst was removed by filtration, the solvent was evaporated, and the residue was subjected to silica gel column chromatography using a chloroform-methanol (10:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 90 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([SH:8])[O:5][CH2:6][CH3:7])[CH3:2].CC[O-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>C1C=CC=CC=1.C(O)C>[CH2:1]([O:3][P:4]([CH2:15][CH:14]=[CH2:13])(=[S:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: C=CCBr
Reactant: CCOP(S)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: C=CCP(=S)(OCC)OCC
Temperature: 40 °C
Reaction time: 3 h

Procedure:
1 mole of thiophosphorous acid O,O-diethyl ester was dissolved in 600 ml of absolute benzene, and 1 mole of sodium ethylate, dissolved in absolute ethanol, was added at 0°-5° C., while cooling. 1.15 moles of allyl bromide were added dropwise to this mixture at 0°-5° C. and the mixture was stirred at 10° to 20° C. for a further 2 hours and at 40° C. for 3 hours. The NaBr which had separated out was filtered off and the filtrate was distilled.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[OH:10])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[C:5]1([CH2:8][N:1]([CH2:9][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[OH:10])=[CH:6][CH:7]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: [H][H]
Reactant: Cc1ccccc1C(O)Cc1ccc(N)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(O)Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Reaction time: 4 h
Yield: 106.2 %

Procedure:
To a solution of Compound XII (900 mg, 2.2 mmol) in 50 ml of ethyl acetate was added 10 percent palladium on activated carbon (100 mg). The reaction vessel was pressurized to 50 psi with hydrogen on a PARR hydrogenation apparatus. The reaction was complete after four hours, and was then filtered through celite and concentrated in vacuo yielding 476 mg of Compound XIII, 95 percent of the theoretical amount. This material was used without further purification in the next example. TLC Rf =0.05, 4:1 methylene chloride:hexanes.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([OH:1])[CH:11]=[C:10]([O:12][CH2:21][CH:20]=[CH2:19])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
Methyl 3,5-dihydroxybenzoate (20.9 g, 124 mmol) was dissolved in DMF (30 mL). Potassium carbonate (34.4 g, 249 mmol) was added, followed by allyl bromide (10.5 mL, 124 mmol). The resulting suspension was stirred at room temperature overnight under argon atmosphere. The reaction mixture was quenched with H2O, extracted with EtOAc (2×150 mL). The organic layers were washed with H2O (2×200 mL), dried with MgSO4 and concentrated in vacuo to yield a pale yellow oil which was purified by flash column chromatography eluting with 20% EtOAc in hexane to give a pale yellow solid (10.25 g, 40% yield). 1H NMR (400 MHz, CDCl3) δ 7.08-7.22 (m, 2 H) 6.65 (t, J=2.40 Hz, 1 H) 5.94-6.21 (m, 1 H) 5.73 (s, 1 H) 5.42 (dd, J=17.18, 1.52 Hz, 1 H) 5.31 (dd, J=10.48, 1.39 Hz, 1 H) 4.55 (d, J=5.05 Hz, 2 H) 3.91 (s, 3 H); LCMS for C14H12O4 m/z 209.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[C@@H:13]([OH:20])[C@H:12]([Br:21])[CH2:11][N:10]3[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:30][C@H:31]([C:44](O)=[O:45])[C:32]1[CH:33]=[CH:34][C:35]2[CH:36]=[C:37]([O:42][CH3:43])[CH:38]=[CH:39][C:40]=2[CH:41]=1.[Cl-].C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH3:43][O:42][C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[CH:41]=[C:32]([C@@H:31]([CH3:30])[C:44]([O:20][C@H:13]1[C:14]3[C:19]4=[C:18]([N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:9](=[O:22])[N:10]4[CH2:11][C@@H:12]1[Br:21])[CH:17]=[CH:16][CH:15]=3)=[O:45])[CH:33]=[CH:34]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: O=c1n(Cc2ccccc2)c2cccc3c2n1C[C@@H](Br)[C@@H]3O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc2cc([C@@H](C)C(=O)O[C@H]3c4cccc5c4n(c(=O)n5Cc4ccccc4)C[C@@H]3Br)ccc2c1

Procedure:
(5R,6R)-1-Benzyl-5-bromo-6-hydroxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (III, EXAMPLE 2, 143 g), methylene chloride (3.136 g), N-methyl morpholine (100.2 g) and 4-dimethylaminopyridine (497 mg) are added to the reactor and the mixture is cooled to 0 to 5°. (R)-Naproxen chloride (PREPARATION 1, 118.5 g) dissolved in methylene chloride (694 ml) is added to the reactor over about 1 hr and the mixture is stirred at 0 to 50 to complete the reaction. If necessary, additional naproxen chloride is added to complete the reaction. Potassium carbonate solution diluted with water is added to the mixture. The aqueous phase is extracted with methylene chloride and the combined methylene phase is washed with water. The washed mixture is concentrated by vacuum distillation and solvent exchange with ethyl acetate is performed. The concentrate is cooled to −10° and stirred. The crystal slurry is filtered and the crystal cake is washed with precooled methyl t-butyl ether and dried at 50° to give the title compound in solid form, (5S,6S)-1-benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl (2R)-2-(6-methoxy-2-naphthyl)propanoate (IVA), CMR (CDCl3) δ173.2, 157.8, 153.4, 136.1, 134.6, 133.7, 129.2, 128.8, 127.8, 127.8, 127.6, 127.2, 125.9, 125.9, 125.6, 121.5, 121.4, 119.1, 113.2, 109.0, 105., 105.6, 69.2, 55.3, 45.4, 45.2, 42.5, 41.7 and 18.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:21][CH2:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24]>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH:21][CH2:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[O:24])[C:5]([CH:9]=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: NCC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)c(C=O)c(NCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a 25 mL round bottomed flask cooled to 0° C. was added 2-amino-4,6-di-chloro-5-formyl-pyrimidine (192 mg, 1.0 mmol, 1.0 eq.), THF (10 mL), DIEA (0.34 mL, 2.0 mmol, 2.0 eq.), and 2-amino-N-(3-trifluoromethyl-phenyl)-acetamide (245 mg, 1.0 mmol, 1.0 eq.). The reaction mixture was warmed to RT and allowed to stir overnight before quenching with H2O (10 mL) and EtOAc (50 mL). The EtOAc layer washed with brine, dried with Na2SO4, and concentrated to give crude product as a solid. The solid was then rinsed with 5:95 EtOAc:Hexanes to give pure 2-(2-Amino-6-chloro-5-formyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as a yellow solid (159 mg, 43%). LC/MSD (HP Series 1100 MSD): Expected MW: 373, Observed M+H, 374.0, Retention time: 1.45 min. ANALYTICAL HPLC: >95%, Retention time: 4.15 min (8 minute run). 1H-NMR (d6-DMSO): 10.5 (s, 1H), 9.9 (s, 1H), 9.42 (t, 1H), 8.08 (s, 1H), 7.80 (d, 1H), 7.59 (t, 1H), 7.42 (d, 1H), 4.40 (d, 2H) ppm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.[C:20]1([CH:26]([NH2:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.Cl>C(#N)C.O1CCCC1.C(OCC)C.[Fe].C(O)(=O)C.O>[C:20]1([CH:26]([NH:33][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[NH2:17])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: NC(c1ccccc1)c1ccccc1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 20.2 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (0.50 g, 1.9 mmol) in acetonitrile (10 mL) was added diphenylmethylamine (0.39 g, 2.1 mmol) and triethylamine (0.29 g, 2.4 mmol), and this was heated to reflux for 10 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To the residue obtained was added iron powder (0.33 g, 5.8 mmol), and aqueous acetic acid (50 mL), and this was heated to reflux for 2 hours. After cooling the reaction solution, filtration through Celite and concentration, the residue obtained was purified by silica gel column chromatography. The oil obtained was dissolved in tetrahydrofuran (3 mL), and to this was added a 1M solution of hydrogen chloride in diethyl ether (1 mL). The precipitated crystals were filtered, and after washing with tetrahydrofuran, they were dried to yield the title compound (0.15 g, 20% yield) as a light brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[NH:16][N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:18]=2)=[CH:20][N:21]=1
Reactant: COc1ccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)n[nH]2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(C3CCNCC3)n[nH]2)cn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 4-[5-(6-methoxy-pyridin-3-yl)-1H-[1,2,4]triazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.23 g, prepared in analogy to intermediate example 44) in THF (15 mL) was treated with 4M HCl in dioxane (1.19 mL) and the reaction stirred at 50° C. for 1 hour. On cooling, the reaction was stirred overnight at rt. The volatiles were removed in vacuo and the residue was dissolved in water, made basic with 2M aqueous NaOH solution and extracted with EtOAc. The aqueous phase was extracted with CH2Cl2/MeOH, the organic phase was washed with brine and concentrated in vacuo to give the crude title compound which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[CH2:25][CH2:26][CH2:27][CH2:28][C:29]=4[CH:30]=[CH:31][C:16]2=3)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>O1CCCC1.CO.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[CH2:25][CH2:26][CH2:27][CH2:28][C:29]=4[CH:30]=[CH:31][C:16]2=3)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CC(=O)N(c2cccc(OCc3ccccc3)c2)c2ccc3c(c2N1)CCCC3
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CC(=O)N(c2cccc(O)c2)c2ccc3c(c2N1)CCCC3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-(3-Benzyloxyphenyl)-8,9,10,11-tetrahydronaphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione (58 mg, 0.14 mmol) was dissolved in tetrahydrofuran (3 mL)-methanol (3 mL). To the solution was added 10% palladium-carbon (6 mg). The mixture was stirred under hydrogen atmosphere at room temperature for 6 hours. Insoluble was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to give the titled compound as slightly yellow crystal (30 mg, yield 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[C:13]([CH3:22])[C:14]([O:20][CH3:21])=[C:15]([CH3:19])[C:16]=3[CH3:18])[C:11](=[O:23])[C:10]3([CH2:26][CH2:25][CH2:24]3)[CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O.CCOC(C)=O>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[C:13]([CH3:22])[C:14]([O:20][CH3:21])=[C:15]([CH3:19])[C:16]=3[CH3:18])[CH:11]([OH:23])[C:10]3([CH2:24][CH2:25][CH2:26]3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COc1c(C)c(C)c2c(c1C)C(=O)C1(CCC1)CN2c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c2c(c1C)C(O)C1(CCC1)CN2c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
To a solution of 1′-(4-chlorophenyl)-6′-methoxy-5′,7′,8′-trimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one (80 mg) in THF (6 mL) and methanol (1.5 mL) cooled in ice bath, was added NaBH4 (81.7 mg). After 1.5 h, 5 mL acetone was added to the solution and the mixture was evaporated to yield a thick oil, which was taken up by EtOAc. The organic phase was then washed with brine, dried and evaporated to give 1′-(4-chlorophenyl)-6′-methoxy-5′,7′,8′-trimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-4′-ol (64.3 mg) 1H-NMR (300 MHz, CDCl3) δ=7.21-6.977 (d, 2H); 6.67 (br s, 2H); 4.745 (s, 1H); 3.949-3.753 (d, 1H); 3.687 (s, 3H); 3.629-3.54 (d, 1H); 2.426 (s, 3H); 2.312-2.174 (m, 1H); 2.147 (s, 3H); 1.967-1.737 (m, 3H); 1.705 (s, 3H); 1.672-1.489 (m, 2H) ppm.