Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH:10]1[NH:19][C:20](=[O:29])[CH2:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:16]2>O1CCOCC1>[CH:9]12[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:17]3)[CH:10]1[NH:19][C:20](=[O:29])/[C:21](/[C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])=[CH:3]\[N:4]([CH3:5])[CH3:6])[CH2:18]2
Reactant: COC(OC)N(C)C
Reactant: O=C(CC(=O)C1CCCC1)NC1C2CC3CC(C2)CC1C3
Solvent: C1COCCO1
Product: CN(C)/C=C(\C(=O)NC1C2CC3CC(C2)CC1C3)C(=O)C1CCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (0.587 mL, 4.42 mmol) was added to N-(2-adamantyl)-3-cyclopentyl-3-oxo-propanamide (Intermediate #72), (1.023 g, 3.53 mmol) in 1,4-dioxane (25 mL). The resulting solution was stirred at 100° C. for 2 hours. The resulting mixture was evaporated to dryness to afford (Z)—N-(2-adamantyl)-2-(cyclopentanecarbonyl)-3-dimethylamino-prop-2-enamide (1.210 g, 99%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]=O>>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1nc2ccccc2o1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4nc5ccccc5o4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1,3-benzoxazole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1,3-benzoxazol-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH3:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>CO>[CH3:4][C:3]1([CH3:5])[S:6][CH:16]([C:15]2[CH:18]=[CH:19][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)[NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: CSc1ccc(C=O)cc1
Solvent: CO
Product: CSc1ccc(C2N[C@@H](C(=O)O)C(C)(C)S2)cc1
Reaction time: 6 h
Yield: 97.2 %

Procedure:
A solution containing 4.48 g (30 mmoles) of D-penicillamine and 3.99 ml (30 mmoles) of 4-methylmercaptobenzaldehyde in 90 ml of 30% aqueous methanol is stirred for 6 hours. The white solid precipitate is filtered out to give 8.26 g (97.1%) of the title product which can be recrystallized from methanol by adding water, m.p.: 150°-152° C., [α]D20 =+74.4° (c=0.516, dimethylsulphoxide).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[C:27]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CO)cc1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(C)=O)cc1C(=O)OCc1ccccc1
Yield: 99 %

Procedure:
Next, benzyl 5-hydroxymethyl-2-methoxybenzoate and 100 ml of methylene chloride were mixed and, after pyridine (660 ml, 8.16 mmol), acetic anhydride (460 ml, 4.88 mmol) and N,N-dimethylaminopyridine (25 mg, 0.205 mmol) were added under stirring and cooling with ice, the mixture was stirred overnight. The reaction mixture was washed with 1 mol/l hydrochloric acid, aqueous solution of sodium hydrogencarbonate and brine, then dried over anhydrous sodium sulfate and concentrated to obtain 1.27 g (99%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34]O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCCCCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(O)c2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(OCCCCOCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate (0.400 g), 4-benzyloxy-1-butanol (0.313 g) and triphenylphosphine (0.456 g) in tetrahydrofuran (6.7 mL) was added dropwise diisopropyl azodicarboxylate (40% toluene solution, 0.878 g), and the resulting mixture was stirred at room temperature for 75 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/ethyl acetate=6/1) to give the title compound (0.551 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13](=O)[CH2:14][CH3:15])=[C:6](OS(C)(=O)=O)[CH:7]=1.[CH:17]1([NH:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])(=O)C.[NH4+]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:13]([CH2:14][CH3:15])=[N:24][N:23]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Reactant: NNC1CCCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCc1nn(C2CCCCC2)c2cc(Br)ccc12
Temperature: 135 °C
Yield: 76.6 %

Procedure:
Methanesulfonic acid 5bromo-2-propionyl-phenyl ester (36.6 g, 119 mmol) was combined with cyclohexylhydrazine (27.2 g, 238 mmol) and ammonium acetate (23.0 g, 299 mmol) in xylenes (220 mL). The reaction mixture was heated to 135° C. in a Dean-Stark apparatus for 48 hours. The reaction was cooled to room temperature and concentrated to a low volume under reduced pressure. The crude product was filtered through a pad of silica gel (weight ratio product/silica gel 1/5) eluting first with hexanes then with a 10/90 mixture of ethyl acetate and hexanes. The fractions containing principally 6-bromo-1-cyclohexyl-3-ethyl-1H-indazole were collected. A second crop was obtained by repeating the above silica treatment with the mixed fractions. The two crops were combined and dried under vacuum to yield 28.0 g of 6-bromo-1-cyclohexyl-3-ethyl-1H-indazole (76% yield). 1H NMR (400 MHz, CDCl3) δ 1.35 (t, 3, J=7.7), 1.39-2.06 (m, 10), 2.95 (q, 2, J=7.7), 4.21-4.28(m, 1), 7.15 (d, 1, J=8.5), 7.51 (d, 1, J=8.5), 7.56 (s, 1). 13C NMR (100 MHz, CDCl3) δ 13.95, 20.50, 25.35, 25.84, 32.44, 58.15, 112.01, 120.10, 121.37, 121.65, 122.82, 140.37, 146.60. IR 2934, 2855, 1606, 1502, 1451, 1048, 951, 834 cm-1. Analysis calculated for C15H19BrN2 : C, 58.64; H, 6.23; N, 9.12. Found: C, 58.82; H, 6.20; N, 9.01.
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]3[NH:16][C:17]([CH2:20][O:21][CH3:22])=[CH:18][N:19]=3)=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH3:23])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:5]2[C:14]([C:15]3[NH:16][C:17]([CH2:20][O:21][CH3:22])=[CH:18][N:19]=3)=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:23])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COCc1cnc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1cnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C

Procedure:
A solution of methyl 4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate (compound 246.3, 150 mg, 0.430 mmol, 1.00 equiv, 90%) and aqueous sodium hydroxide (76.0 mg, 1.90 mmol, 4.00 equiv in 2 mL water) in methanol (4 mL) was stirred for 2 h at 60° C. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The pH value of the remaining aqueous phase was adjusted to −4 with hydrogen chloride (aq., 4 M). The resulting mixture was extracted with 2×50 mL of ethyl acetate, and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. This resulted in 120 mg (84%) of 4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acid as a white solid.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C@H:8]([OH:11])[CH2:9][CH3:10].F[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1>C(OCC)(=O)C>[CH3:7][C@H:8]([O:11][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1)[CH2:9][CH3:10]
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Reactant: CC[C@H](C)O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Yield: 78.8 %

Procedure:
Sodium tert-butoxide (3.24 g, 33.7 mmol) was added portionwise with stirring to (2S)-2-butanol (10 g, 135 mmol). 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2 g, 8.43 mmol) was added to the resulting suspension and the mixture heated to 50° C. for 6 hours when LCMS showed complete reaction. After cooling the mixture was diluted with ethyl acetate (100 ml), and washed with water (50 ml) and the aqueous layer extracted again with ethyl acetate (50 ml). The combined organic extracts were washed with brine, dried using a hydrophobic frit and evaporated in vacuo (at 62° C. to remove the excess alcohol). The residue (2.52 g) was dissolved in dichloromethane and purified on an aminopropyl cartridge (110 g) using a Flashmasterll apparatus and eluting with a 0-100% ethyl acetate in cyclohexane gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (1.935 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:7]([F:17])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:2][CH2:3][CH2:4][C:5]2[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:7]([F:17])[CH:6]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)COc1ccc(CCN)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1F
Reaction time: 2 h
Yield: 93.6 %

Procedure:
1 g of methyl 4-(2-aminoethyl)-2-fluorophenoxyacetate hydrochloride is added to a mixture of 30 ml of ethyl acetate, 1.58 g of potassium carbonate and 15 ml of water, and a solution of 0.78 g of 4-chlorophenylsulfonyl chloride in 15 ml of ethyl acetate is added dropwise thereto at room temperature. After the mixture is stirred for 2 hours, the ethyl acetate layer is separated therefrom, washed, dried and evaporated to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate, isopropylether and n-hexane. 1.39 g of methyl 4-[2-(4-chlorophenyl)sulfonylaminoethyl]-2-fluorophenoxyacetate are obtained as colorless prisms.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]2[N:19]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:20]([CH3:27])=[C:21]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:22]=2)[CH:17]=1)[C:8]([O:10]C(C)(C)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]2[N:19]([CH2:28][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[C:20]([CH3:27])=[C:21]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:22]=2)[CH:17]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)OC(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)O)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
Compound 13a (180 mg, 0.37 mmol) was treated with a mixture of TFA (0.5 mL) and DCM (5 mL) and stirred at rt overnight. After the reaction was complete (monitored by LC-MS), the mixture was concentrated to give compound 13b (145 mg, 91%). 1H-NMR (400 MHz, CDCl3) δ: 8.12 (s, 1H), 7.88 (s, 1H), 7.58 (s, 1H), 6.51 (s, 1H), 4.77-4.75 (m, 2H), 3.76 (m, 2H), 2.56 (s, 3H), 1.53 (s, 3H), 1.37-1.35 (m, 12H), 1.00-0.99 (m, 3H), 0.64-0.63 (m, 2H). MS Found: 433 (M+1).
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.Br[C:30]1[CH:50]=[CH:49][C:33]([CH2:34][CH2:35][N:36]([CH3:48])[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]#[N:47])[CH:41]=2)=[O:38])=[C:32]([CH2:51][CH3:52])[CH:31]=1>>[C:46]([C:42]1[CH:41]=[C:40]([NH:39][C:37](=[O:38])[N:36]([CH2:35][CH2:34][C:33]2[CH:49]=[CH:50][C:30]([B:25]([OH:27])[OH:26])=[CH:31][C:32]=2[CH2:51][CH3:52])[CH3:48])[CH:45]=[CH:44][CH:43]=1)#[N:47]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CCc1cc(Br)ccc1CCN(C)C(=O)Nc1cccc(C#N)c1
Product: CCc1cc(B(O)O)ccc1CCN(C)C(=O)Nc1cccc(C#N)c1
Yield: 40 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 36D (500 mg, 1.3 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 36E (183 mg, 40%) as a tan foam. MS (ESI) m/z 352.6 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7](OC)[CH:6]=[CH:5]2.[CH3:17][NH2:18]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([NH:18][CH3:17])[CH:6]=[CH:5]2
Reactant: CN
Reactant: COc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CNc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6-bromo-2 methoxy-1-nitronaphthalene (5.64 g, 20 mmol) in 100 ml of dry N,N-dimethylformamide saturated with methylamine was stirred in a stoppered flask at 80° C. for 4 h. During the reaction period the mixture was saturated twice with a further quantity of methylamine. The cooled mixture was poured into 1 l of ice/water. After stirring for 1 h, the orange solid was collected by filtration and washed with water, and dried in vacuo over phosphorus pentoxide affording 5.43 g (96%) of the title compound. M.p. 169°-170° C.; 1H-NMR (CDCl3): 3.11 (d, J=5 Hz, 3H, CH3), 7.00 (d, J=9 Hz, 1H, ArH), 7.45- 7.78 (m, 3H, ArH), 8.60 (d, J =9 Hz, 1H, ArH), 8.7 (broad, 1H, NH).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]([CH2:20][CH2:21][CH3:22])[CH:7]1[CH2:19][C:10]2=[CH:11][C:12]3[C:13](=[O:18])[NH:14][CH2:15][C:16]=3[CH:17]=[C:9]2[CH2:8]1)[CH2:4][CH3:5].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1.Cl>CN(C=O)C>[CH2:20]([N:6]([CH2:3][CH2:4][CH3:5])[CH:7]1[CH2:19][C:10]2=[CH:11][C:12]3[C:13](=[O:18])[N:14]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=4)[CH2:15][C:16]=3[CH:17]=[C:9]2[CH2:8]1)[CH2:21][CH3:22]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(C#N)cc1)C3
Temperature: 84 °C
Reaction time: 24 h

Procedure:
To a slurry of washed NaH (0.05 g, 1.32 mmol) in DMF (5 mL) was added a slurry of 6-(Dipropylamino)-3,5,6,7-tetrahydrocyclopent[f]isoindol-1(2H)-one (94, 0.30 g, 1.10 mmol) in DMF (10 mL). The slurry was heated to 84° C. and after 40 min, was treated with a solution of alpha-bromo-p-tolunitrile (0.43 g, 2.20 mmol) in DMF (10 mL). After 24 h, the reaction was quenched with H2O and extracted with CH2Cl2. The organic layers were washed with brine, dried (MgSO4), and concentrated on hi-vac. The reside was purified on silica gel, eluting with CH2Cl2 /MeOH to give an oil that was converted to an HCl salt and recrystallized to afford 133 as a white solid (m.p. 141-145° C.).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([O:28][CH2:29][C@@H:30]([CH3:33])[CH2:31]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([O:28][CH2:29][C@@H:30]([CH3:33])[CH2:31][N:2]([CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1)[CH3:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: C[C@@H](CBr)COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)C[C@H](C)COCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 10.93 g (0.056 mol) of N-methylhomoveratrylamine in 50 ml of abs. dimethylformamide was treated at 5° with 15.7 g of potassium carbonate and 13.6 g (0.056 mol) of (R)-(-)-3-benzyloxy-2-methylpropyl bromide [Helv. Chim. Acta 60, 940, (1977)]. The mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was taken up in a mixture of water and ethyl acetate. The organic extracts were dried over magnesium sulphate and evaporated under reduced pressure. The residue was distilled at 218°/260 Pa. The N-[(S)-3-(benzyloxy)-2-methylpropyl]-3,4-dimethoxy-N-methylphenethylamine, which was obtained as a colourless oil, was used directly in the next step. [α]D ;20 =+7.3° (c=1, ethanol).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([CH3:30])[C:9]3[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=3[CH:11]=[C:12]([CH2:13][C:14]([O:16]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:6]=2[CH:5]=1)[CH3:2].[CH3:33][NH:34][CH3:35].O>C(Cl)(Cl)Cl>[CH2:1]([S:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([CH3:30])[C:9]3[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=3[CH:11]=[C:12]([CH2:13][C:14](=[O:16])[N:34]([CH3:35])[CH3:33])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCSc1ccc2c(c1)C(CC(=O)Oc1ccc([N+](=O)[O-])cc1)=Cc1ccccc1N2C
Reactant: CNC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCSc1ccc2c(c1)C(CC(=O)N(C)C)=Cc1ccccc1N2C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 11.35 g of 2-ethylthio-5-methyl-11-(p-nitrophenoxycarbonyl)methyl [5H] dibenzo (b,f) azepine in 45 ml of chloroform was stirred until dissolution occured and a solution of 12 ml of dimethylamine in 45 ml of chloroform was added dropwise thereto in 10 minutes. The mixture was stirred for 1 hour at room temperature and then was poured into 250 ml of ice and water. The organic phase was recovered by decanting and was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure to obtain 9 g of 2-ethylthio-5-methyl-11-dimethylcarbamoylmethyl [5H] dibenzo (b,f) azepine which was used as is for the next step. The product occured as a yellow oil soluble in chloroform, ethanol and ethyl acetate and insoluble in water.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(OC(C)(C)C)=O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].[O:32]=[C:33]1[NH:37][C:36](=[O:38])[CH:35]([CH2:39][C:40]2[CH:50]=[CH:49][C:43]([O:44][CH2:45][C:46](O)=[O:47])=[CH:42][CH:41]=2)[S:34]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:46](=[O:47])[CH2:45][O:44][C:43]3[CH:42]=[CH:41][C:40]([CH2:39][CH:35]4[S:34][C:33](=[O:32])[NH:37][C:36]4=[O:38])=[CH:50][CH:49]=3)=[C:3]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(N)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 57.3 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-t-butoxycarbonylaminophenoxy)phenyl]-N-methylcarbamate (500 mg), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (366 mg), diethyl cyanophosphonate (212 mg), triethylamine (132 mg) and anhydrous tetrahydrofuran (10 ml) and the reaction mixture was purified to give the desired compound (395 mg).
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[C:13]([O-:16])(O)=O.[Na+]>C1CCCCC1>[CH3:12][C@@H:2]1[CH:7]=[CH:6][CH2:5][C:4]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[C@H:3]1[C:13](=[O:16])/[CH:3]=[CH:2]/[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: C/C=C/C(=O)[C@H]1[C@H](C)C=CCC12CCCC2
Temperature: 0 °C
Yield: 79 %

Procedure:
At −70° C., a solution of diisopropylamine (0.5 g, 4.93 mmol) in tetrahydrofuran (4 ml) was treated with n-butyl lithium (3.3 ml, 1.6M in hexane, 5.14 mmol). The resulting solution was stirred at −70° C. for 20 min. and treated with a solution of 1-(rel-(6S,7R)-7-methylspiro[4.5]dec-8-en-6-yl)ethanone (0.79 g, 4.11 mmol) in tetrahydrofuran (4 ml). The resulting solution was stirred 20 min. at −70° C. warmed to 0° C., cooled to −70° C., and treated with a solution of acetaldehyde (0.9 g, 20.5 mmol) in tetrahydrofuran (4 ml). After 20 min. stirring, the reaction mixture was warmed to −5° C., treated with a 1:1 mixture of a 2N aqueous HCl solution and saturated aqueous NaCl solution (25 ml) and extracted three times with MTBE (60 ml). The combined organic phases were washed with a saturated solution of NaHCO3, with a saturated solution of NH4Cl, and with water, dried (MgSO4), and concentrated. Fluid chromatography (FC, SiO2, hexane/MTBE 35:1) of the crude product (1.3 g) gave the desired intermediate β-hydroxyketone (0.47 g, 1.98 mmol, 48%) which was dissolved in cyclohexane (1 ml). The resulting solution was treated with para-toluene sulfonic acid monohydrate (13 mg, 6.7 mmol) and refluxed 1.5 h. The reaction mixture was cooled to 0° C., treated with a saturated aqueous solution of NaHCO3 and the aqueous phase was extracted twice with MTBE. The combined organic phases were washed with water, dried (MgSO4) and concentrated. FC (SiO2, hexane/MTBE 50:1) of the crude product (0.42 g) gave (E)-1-(rel-(6S,7R)-7-Methylspiro[4.5]dec-8-en-6-yl)but-2-en-1-one (0.34 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][C:13](=[O:23])[C:14]=1[O:15]CC1C=CC=CC=1)=[O:8].[Br:27]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[C:12]([Br:27])[C:13](=[O:23])[C:14]=1[OH:15])=[O:8]
Reactant: O=C(NCc1cccc(Cl)c1)c1occc(=O)c1OCc1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(NCc1cccc(Cl)c1)c1occ(Br)c(=O)c1O

Procedure:
To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (5.13 g) obtained in Example 10, Step 1 in chloroform (100 ml) was added a solution of bromine (1.5 ml) in chloroform (50 ml) and the mixture was stirred with heating under reflux for 2 hr. A solution of bromine in chloroform (1.0 ml) was added, and after stirring with heating for 16 hr, the solvent was evaporated. Toluene was added to the residue and the mixture was concentrated, which operations were performed twice to give a crude product of 5-bromo-3-hydroxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide. The obtained crude product was dissolved in dimethylformamide (50 ml), and potassium carbonate (3.87 g) and benzyl bromide (2.75 ml) were added thereto. The reaction mixture was stirred at room temperature for 1 hr. Water (100 ml) and 1N aqueous hydrochloric acid (50 ml) were added to the reaction mixture and the mixture was extracted twice with ethyl acetate (200 ml each). The ethyl acetate layer was washed, dried, concentrated and purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (3.31 g).