Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.[CH:15]([O:18][C:19]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:20]=1[C:21](O)=[O:22])([CH3:17])[CH3:16]>>[CH:15]([O:18][C:19]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:20]=1[C:21]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)=[O:22])([CH3:17])[CH3:16]
Reactant: FC(F)(F)c1cccc2c1CNCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cccc(C(F)(F)F)c2C1

Procedure:
Prepared in analogy to example 1.1 from 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [CH:1]1([CH:4]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH3:5])[CH2:3][CH2:2]1.[CH2:12]([O:19][C:20](ON1C(=O)CCC1=O)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl>[CH:1]1([CH:4]([CH:6]2[CH2:7][CH2:8][N:9]([C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:21])[CH2:10][CH2:11]2)[CH3:5])[CH2:2][CH2:3]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C1CCNCC1)C1CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C1CC1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 91.4 %

Procedure:
Dissolve racemic 4-(1-cyclopropylethyl)-piperidine (1.75 g, 11.42 mmol) and N,N-dimethyl-4-pyridinamine (139.5 mg, 1.14 mmol) in pyridine (15 mL) and dichloromethane (30 mL). Add N-(benzyloxycarbonyloxy)succinimide (3.70 g, 14.84 mmol) and stir the solution for 4 hours. Pour the reaction mixture into 5N HCl and extract twice with EtOAc. Wash the organic extracts with sodium bicarbonate, followed by brine; dry over sodium sulfate; filter; collect the filtrate; and concentrate under reduced pressure. Purify the crude material on a silica gel flash column chromatography using a gradient of 0-20% EtOAc in hexane to give the title compound (3.0 g, 91%) as a clear oil. MS (m/z): 288 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C@@H:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])=[C:4]([NH:23][C:24]2[CH:25]=[N:26][C:27](F)=[CH:28][CH:29]=2)[CH:3]=1.CC(O)=[O:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([CH:10]([NH:12][C:13]3[N:21]=[CH:20][N:19]=[C:18]4[C:14]=3[N:15]=[CH:16][NH:17]4)[CH3:11])[N:23]([C:24]3[CH:29]=[CH:28][C:27](=[O:33])[NH:26][CH:25]=3)[C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccc(=O)[nH]c1
Temperature: 100 °C
Yield: 16 %

Procedure:
A mixture of (S)—N-[4-fluoro-2-(6-fluoropyridin-3-ylamino)phenyl]-2-(9H-purin-6-ylamino)propionamide (255 mg, 0.62 mmol) in AcOH (10 mL) was heated at 100° C. for 24 h. After cooling to RT, the volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% 2M NH3/MeOH in DCM) to afford 382 as a pink solid (38 mg, 16%). LCMS (Method K): RT 2.40 min [M+H]+ 391.0. 1H NMR (DMSO-d6+TFA-D, 400 MHz, 80° C.): δ 8.58-8.49 (2H, m), 7.82 (1H, d, J=2.96 Hz), 7.75 (1H, dd, J=8.81, 4.70 Hz), 7.51 (1H, dd, J=9.59, 2.99 Hz), 7.21-7.07 (2H, m), 6.40 (1H, d, J=9.60 Hz), 5.86 (1H, br d), 1.79 (3H, d, J=6.82 Hz)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH:9][C:10](=[O:14])[C:11]([OH:13])=O)[CH:3]=1.[CH:15]([N:18]([CH:21]([CH3:23])C)CC)([CH3:17])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH:9][C:10](=[O:14])[C:11](=[O:13])[N:18]2[CH2:15][CH2:17][CH2:23][CH2:21]2)[CH:3]=1
Reactant: O=C(O)C(=O)NNc1cc(I)ccn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(NNc1cc(I)ccn1)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.4 %

Procedure:
To a solution of [2-(4-iodopyridin-2-yl)hydrazino](oxo)acetic acid (0.64 g, 2.10 mmol) in di-methylformamide (21 mL) was added diisopropylethylamine (1.65 mL, 9.47 mmol), pyrrolidine (0.74 mL, 8.84 mmol) and finally HATU (2.40 g, 6.31 mmol). The resulting mixture was stirred at room temperature under argon atmosphere for 18 hours. The solvent was removed under reduced pressure, water was added and it was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The crude was purified by reverse phase chromatography on a silica C18 cartridge eluting with water/acetonitrile:methanol (1:1), using a gradient from 100% water to 100% acetonitrile:methanol (1:1), to yield the title compound (0.26 g, 30%) as a white solid.
Reaction SMILES: C(OC(=O)[N:7]([C:9]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH:17][C:18](=O)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:23][CH:22]=1)[CH3:8])(C)(C)C.[ClH:37]>O1CCOCC1>[ClH:37].[CH3:16][S:15][C:13]1[CH:12]=[CH:11][C:10]2[N:17]=[C:18]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:34])=[CH:23][CH:22]=3)[N:7]([CH3:8])[C:9]=2[CH:14]=1
Reactant: CSc1ccc(NC(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c(N(C)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CSc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-methylthiophenyl]-N-methylcarbamic acid t-butyl ester (2.54 g) (obtained in Example 4-1) was dissolved in dioxane (25 ml). To the solution was added 4N hydrochloric acid in dioxane (25 ml) and the resulting mixture was stirred for 30 minutes at room temperature and allowed to stand for two nights. The reaction mixture was filtered and the crystals were washed with ethyl acetate and dried in vacuo to afford the title compound (2.98 g). softening point: 247-249° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[O:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30](Cl)=O>COCCOC>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:30]2[CH:26]2[CH2:27][CH2:28][CH2:29][O:25]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Reactant: O=C(Cl)C1CCCO1
Solvent: COCCOC
Product: Cc1c(Cl)cccc1Cn1c(C2CCCO2)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in 1,2-Dimethoxyethane (DME) (1000 μl) was added tetrahydro-2-furancarbonyl chloride (73.4 mg, 0.545 mmol) in 1,2-Dimethoxyethane (DME) (400 μl). The mixture was stirred at room temperature overnight, then additional tetrahydro-2-furancarbonyl chloride (1 equiv.) was added and the mixture was irradiated (uwave) for 15 min at 90° C. The mixture was quenched with methanol, concentrated, and purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-(tetrahydro-2-furanyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (18 mg, 15%); LC/MS: MS (ES+) m/e 447 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.91 (m, 1H), 1.94-2.05 (m, 2H), 2.35-2.42 (m, 1H), 2.43 (s, 3H), 3.55-3.60 (m, 4H), 3.67 (m, 4H), 3.76 m, 1H), 3.84 (qm, 1H), 4.79 (m, 1H), 5.64 (s, 2H), 6.52 (d, J=7.6 Hz, 1H), 7.14 (m, 1H), 7.37 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:22][CH2:23][O:24][CH3:25])[C:12]=1[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:8]=[O:9].[OH-:26].[Na+]>CO.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:25][O:24][CH2:23][O:22][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:12]=1[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:8]([OH:26])=[O:9]
Reactant: [OH-]
Reactant: COCOc1cc(C=O)cc(OCOC)c1C/C=C/c1ccccc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCOc1cc(C(=O)O)cc(OCOC)c1C/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzaldehyde (220f) (42 g, 0.12 mol) in MeOH/H2O (500 mL) was added AgNO3 (21 g, 0.12 mol), followed by NaOH (15 g, 0.36 mol) in one portion at room temperature. The mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated under vacuum to remove MeOH. The residue was extracted with Et2O (2×100 mL) to remove impurities. The aqueous layer was acidified with conc. HCl to pH 4. The resulting white solid was filtered and dried under vacuum to give the title compound (31 g, 62% yield) as white solid.
Reaction SMILES: [CH2:1]([O:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:17](OC)(=[O:22])[CH2:18][C:19]([CH3:21])=O>>[CH2:1]([O:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:22])[CH2:18][C:19]([CH3:21])=[N:16][CH2:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCCCOCCCNCCN
Product: CCCCCCCCOCCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 230.1 g (1 mole) of N-octoxypropylethylenediamine and 116.1 g (1 mole) of methyl acetoacetate. At 140° to 145° C., 18 g of water and 32 g of ethanol were distilled off to obtain 4-octoxypropyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [OH-].[Li+].CO[C:5]([C@@H:7]1[CH2:27][CH2:26][CH2:25][NH:24][C:23](=[O:28])[C:22]2=[CH:29][C:18](=[C:19]([CH3:31])[CH:20]=[C:21]2[CH3:30])[C:17]2[CH:32]=[C:13]([N:14]=[C:15]([NH2:33])[N:16]=2)[S:12][CH2:11][CH2:10][C:9](=[O:34])[NH:8]1)=[O:6].Cl.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CC1C=C(C)C=C(C)N=1.[NH2:69][CH2:70][CH2:71][OH:72]>CN(C)C=O.CO.O1CCCC1>[OH:72][CH2:71][CH2:70][NH:69][C:5]([C@@H:7]1[CH2:27][CH2:26][CH2:25][NH:24][C:23](=[O:28])[C:22]2=[CH:29][C:18](=[C:19]([CH3:31])[CH:20]=[C:21]2[CH3:30])[C:17]2[CH:32]=[C:13]([N:14]=[C:15]([NH2:33])[N:16]=2)[S:12][CH2:11][CH2:10][C:9](=[O:34])[NH:8]1)=[O:6]
Reactant: COC(=O)[C@@H]1CCCNC(=O)c2cc(c(C)cc2C)-c2cc(nc(N)n2)SCCC(=O)N1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: Cc1cc(C)c2cc1C(=O)NCCC[C@@H](C(=O)NCCO)NC(=O)CCSc1cc-2nc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
An aqueous solution of 1N lithium hydroxide (0.263 ml) was added at 0° C. to a methanol/tetrahydrofuran solution (1:10 v/v, 2.5 ml) mixed with (S)-4-amino-19,21-dimethyl-10,17-dioxo-7-thia-3,5,11,16-tetraazatricyclo[16.3.1.12,6]tricosa-1(21),2,4,6(23),18(22),19-hexaene-12-carboxylic acid methyl ester (30 mg) obtained in Step 3 of Example 2-9. After stirring for 10 minutes, the mixture was warmed to room temperature and stirred for 1.5 hours. The pH of the reaction solution was adjusted to about 4 using 1N hydrochloric acid. The solution was extracted four times with ethyl acetate (20 ml). The organic layers were combined together, and dried over anhydrous sodium sulfate. After the inorganic salt was removed by filtration, the filtrate was concentrated under reduced pressure to give crude product (39 mg). An aliquot (20 mg) of the crude product was dissolved in N,N-dimethylformamide (1.0 ml), and then 2-3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (7 mg, 0.053 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (20 mg, 0.052 mmol),2,4,6-trimethylpyridine (14 μl), and 2-aminoethanol (3 μl, 0.053 mol) were added thereto at 0° C. After stirring at 0° C. for 30 minutes, the mixture was warmed to room temperature and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure. The resulting crude product was purified by high performance liquid chromatography (developing solvent: A, acetonitrile containing 0.05% trifluoroacetic acid; B, 0.05% aqueous trifluoroacetic acid solution; gradient condition: B, 1% (0 min)→1% (1 min)→30% (7 min)→95% (8 min)→95% (9 min)→1% (10 min); flow rate, 35 ml/min; column, Waters, SunFire PrepC18, 5 μm, 30×50 mm). A fraction containing the material of interest was neutralized with solid-supported tetraalkyl ammonium carbonate (Polymer Laboratories, PL-HCO3 MP-Resin) to yield (S)-4-amino-19,21-dimethyl-10,17-dioxo-7-thia-3,5,11,16-tetraazatricyclo[16.3.1.12,6]tricosa-1(21),2,4,6(23),18(22),19-hexaene-12-carboxylic acid (2-hydroxyethyl) amide (Compound 46) (7 mg) was obtained as a white solid material.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:24][CH2:25][OH:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:28].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.[Cl-].[Na+].O>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:9]([CH2:24][C:25]([OH:28])=[O:26])[CH2:10]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1CCO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
(S)-2-(2-Hydroxy-ethyl)-piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (cf. WO 96/31501; S. Fustero et al., Org. Lett. 9 (2007), 5283; 2.862 g, 7.85 mmol) was dissolved in 78.5 ml of DCM and pyridinium dichromate (14.772 g, 39.27 mmol) was added. The mixture was stirred at room temperature overnight, then diluted into brine (330 ml) and extracted three times with EA (70 ml). The combined organic phases were washed with water (300 ml), filtered over diatomaceous earth, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The product was dissolved in EA and extracted three times with a 1 N solution of sodium hydroxide. The combined aqueous phases were acidified to pH 1 with 6 N hydrochloric acid, extracted with EA and the combined extracts were washed with water and brine, dried over sodium sulfate, filtered and evaporated to dryness. 2.226 g of the title compound were obtained as a thick colorless oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:19]1([CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CCCCC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCCCC1CCCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.3 %

Procedure:
A solution of n-butyllithium (100 ml, 250 mmol, 2.5M in hexanes) was added via a cannula to a solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (44.30 g, 250 mmol) in anhydrous tetrahydrofuran (400 ml) at −78° C. The yellow solution was then stirred for 45 minutes. A solution of 5-cyclohexylpentanoyl chloride (55.5 g, 275 mmol) in tetrahydrofuran (100 ml) was then added over 1 hour. The mixture was stirred at −78° C. for 30 minutes then warmed to room temperature over 1 hour. The mixture was quenched with an aqueous solution of ammonium chloride (20% w/v, 400 ml) and extracted with ethyl acetate. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The solid was recrystallised from hexane (500 ml) to afford the title compound as a white solid (81.0 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12]([CH:14]1[CH2:26][CH2:25][N:17]2[C:18]3[C:23]([CH:24]=[C:16]2[CH2:15]1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH3:10].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25][N:17]2[C:18]3[C:23]([CH:24]=[C:16]2[CH2:15]1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH3:10]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1CCn2c(cc3ccccc32)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(cc3ccccc32)C1
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a -78° C. THF (12 mL) solution of lithium diisopropylamide (generated in situ from diisopropylamine (3.8 mL) and 15% n-butyl lithium in hexane (17 mL) at 0° C.) was added dropwise a THF solution of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylic acid ethyl ester. After 30 minutes, the temperature was brought to 0° C. After 1 hour, ethyl chloroformate (2.6 mL) was added over one hour. The reaction was allowed to come to room temperature overnight. The reaction was quenched with saturated NH4Cl and extracted t-butyl methyl ether (3×). The extract was washed with water, dried, filtered, and concentrated to give a residue. The residue was purified by flash chromatography eluting with 15% ethyl acetate/hexane to give the title compound 1.29 g (33% yield) as off white crystals (M.Pt. 69° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].C[Si]([C:13]#[N:14])(C)C.CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methyl-pyridine 1-oxide (10.9 g, 100 mmol) was dissolved into methylene chloride (100 mL) and dried over MgSO4. The solution was filtered and the filtrate was added to trimethylsilyl cyanide (16.7 mL, 125 mmol) at ambient temperature. To which was added dropwise a solution of dimethylcarbamyl chloride (11.5 mL, 125 mmol) in methylene chloride (25 mL). The resulting mixture was stirred at ambient temperature for 24 h. A solution of 10% K2CO3 was added slowly to the reaction mixture and stirring was continued for 10 minutes after the addition was complete. The layers were separated and the aqueous layer was extracted with methylene chloride (2×50 mL). The combined organic extracts were dried (Na2SO4), and concentrated to dryness under high vacuum to yield the title compound I-4h (6.64 g).
Reaction SMILES: C([O:8][C:9](=[O:20])[C:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH2:11])C1C=CC=CC=1.N[C@H](C(O)=O)C[OH:24].[OH-].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>O1CCOCC1.O>[C:13]([NH:12][CH:10]([C:9]([OH:8])=[O:20])[CH2:11][OH:24])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: N[C@@H](CO)C(=O)O
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(CO)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
2-tert-butoxycarbonylamino-acrylic acid benzyl ester: Rac-serine (50 g, 0.475 mol) in dioxane (500 mL) was combined with sodium hydroxide (38 g, 0.98 mol) in water (200 mL) and cooled to 0° C. Boc anhydride (105 g, 0.48 mol) was added dropwise and the reaction was stirred at rt overnight. The reaction mixture was concentrated to remove dioxane and the aqueous layer was washed with petroleum ether. The aqueous layer was acidified to pH 4 with citric acid solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine and concentrated to give N-boc-dl-serine (79 g, 81%). To this intermediate (14 g, 0.068 mol) in DMF (140 mL) was added cesium carbonate (13.2 g, 0.041 mol) and the reaction mixture was stirred at rt for 30 min under a nitrogen atmosphere. Benzyl bromide (11.7 g, 0.07 mol) was added dropwise at 0° C. and the reaction was stirred at rt overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated. The crude product obtained was purified by flash chromatography on silica gel using chloroform as eluent to give the benzyl ester intermediate (17 g, 85%). To the benzyl ester (10 g, 0.0339 mol) in DCM (150 mL) at 0° C. under a nitrogen atmosphere was added mesyl chloride (5 g, 0.0435 mol). Triethyl amine (10 g, 0.0990 mol) was then added dropwise and the reaction was stirred at rt for 1 h. The reaction mixture was washed with 1% sodium bisulphate solution, dried over anhydrous Na2SO4, and concentrated to give 84A (10 g).
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].[CH3:21][NH:22][C:23](=[O:26])[NH:24][NH2:25].C(O)C>C(O)(=O)C.O>[CH3:21][NH:22][C:23](=[O:26])[NH:24]/[N:25]=[C:10]1/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:18]([CH3:20])[CH3:19])[CH:1]([CH3:3])[CH3:2])[C:17]2[C:12]/1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: CNC(=O)NN
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CNC(=O)N/N=C1/C(=O)N(CCN(C(C)C)C(C)C)c2ccccc21
Temperature: 60 °C
Yield: 49.9 %

Procedure:
To a solution of 1.37 g of 1-(2-diisopropylaminoethyl)isatin and 0.49 g of 4-methylsemicarbazide in ml of a mixture of ethanol and water (2:1) was added 3 drops of acetic acid, and then the mixture was heated at 60° C. for 6 hours. The yellow precipitates were collected by filtration and recrystallized from aqueous ethanol to obtain 0.86 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-(4-methylsemicarbazone) having a melting point of 175°-177° C.
Reaction SMILES: BrC1C=C[C:5]([O:8]C(F)(F)F)=[CH:4]C=1.[Mg].II.[N:16]1[N:17]([CH:21]([CH3:34])[C:22](C2C=CC(C(F)(F)F)=CC=2)=[O:23])[N:18]=[N:19][CH:20]=1.Cl>O1CCCC1.O>[CH2:5]([O:8][C:22](=[O:23])[CH:21]([N:17]1[N:18]=[N:19][CH:20]=[N:16]1)[CH3:34])[CH3:4]
Reactant: CC(C(=O)c1ccc(C(F)(F)F)cc1)n1ncnn1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)n1ncnn1
Reaction time: 1 h

Procedure:
The Grignard reagent from 4-bromotrifluoromethoxybenzene (2.41 g) was prepared in a similar manner to that described in Example 3 from magnesium turnings (0.24) in dry tetrahydrofuran (14 ml) with iodine (1 crystal) as an activator. To the Grignard solution was added dropwise over 10 minutes 2-(2H-tetrazol-2-yl)p-trifluoromethylpropiophenone from Example 16 (2.7 g in dry tetrahydrofuran (10 ml), then the reaction stirred for 1 hour. The reaction was worked up as for previous examples, by pouring into water, acidifying with aqueous hydrochloric acid and extracting the product into diethyl ether, which was dried over anhydrous sodium sulphate and evaporated. The residual oil (4.3 g) was purified by h.p.l.c. on silica gel eluting with 5:1 hexane/ethyl acetate to give a colourless oil 2.3 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([CH2:16][C:17]([OH:19])=O)[CH:7]=[CH:6]2.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([CH2:16][C:17]([Cl:22])=[O:19])[CH:7]=[CH:6]2
Reactant: O=S(Cl)Cl
Reactant: COc1cc2ccc(CC(=O)O)cc2c(C)c1OC
Solvent: c1ccccc1
Product: COc1cc2ccc(CC(=O)Cl)cc2c(C)c1OC

Procedure:
A mixture of 24.0 g. of 6,7-dimethoxy-8-methyl-2-naphthaleneacetic acid and 30 ml. of thionyl chloride in 250 ml. of benzene was kept at 40° C. one hour and then overnight at room temperature. The reaction mixture was then evaporated to dryness in vacuo at 50° C. Additional benzene was added and evaporation repeated to give 6,7-dimethoxy-8-methyl-2-naphthaleneacetyl chloride. An infrared spectrum indicated no remaining carboxylic acid and this material was used directly in the preparation of 6,7-dimethoxy-8-methyl-2-naphthaleneacetamide as described hereinabove in Example 98.