Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:35]#[CH:36])([CH3:34])([CH3:33])[CH3:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:36]#[C:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: C#CC(C)(C)C
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(C#CC(C)(C)C)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3,3-dimethylbut-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid (72) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using t-butylacetylene. 1H-NMR: 400 MHz, (CD3OD) δ: 7.70 (d, J=8 Hz, 1H), 7.65 (s, 1H), 7.57 (m, 3H), 7.33 (m, 2H), 7.19 (s, 1H), 5.16 (s, 1H), 2.59 (s, 3H), 1.27 (s, 9H), 0.97 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=3.78.
Reaction SMILES: [OH:1][CH:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:26]([O:28][CH3:29])=[O:27]>C(Cl)Cl>[CH3:29][O:28][C:26]([O:1][CH:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:27]
Reactant: COC(=O)Cl
Reactant: O=C1CCCCCCCCCCC(O)CCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)OC1CCCCCCCCCCC(=O)OCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
480 g (1.89 mol) of 12-hydroxy-15-pentadecanolide (VII) are dissolved in 900 ml of methylene chloride with 205.5 g of pyridine. 213 g (2.2 mol) of methyl chloroformate in 900 ml of methylene chloride are added dropwise to this mixture at 0° to 5° C. in the course of 1 hour. The reaction mixture is stirred at room temperature for a further 5 hours. The organic phase is washed neutral and dried over Na sulphate. The organic phase is freed from methylene chloride and subjected to fractional distillation. 540 g of 12-methoxycarbonyloxy-15-pentadecanolide are obtained; yield: 91% of theory.
Reaction SMILES: [S:1](=[O:35])(=[O:34])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9]C(C)(C)[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:24][C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[O:6]1)[NH2:2]>FC(F)(F)C(O)=O.O>[S:1](=[O:35])(=[O:34])([O:3][CH2:4][C@@H:5]1[C@@H:12]([OH:11])[C@@H:8]([OH:9])[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:24][C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[O:6]1)[NH2:2]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 0.17 h
Yield: 67 %

Procedure:
((3aR,4R,6R,6aR)-6-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate (400 mg, 0.80 mmol) was dissolved in a preformed mixture of trifluoroacetic acid (1.8 mL) and water (0.2 mL). The solution was allowed to stand at room temperature for 10 minutes and evaporated to dryness. This was twice evaporated from methanol and the residue was purified by reverse phase HPLC to yield 248 mg (67%) of final compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1.ClC1C=C(Cl)C=CC=1CC(Cl)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1)=[O:12]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Agent: O=C(Cl)Cc1ccc(Cl)cc1Cl
Product: O=C(Cc1ccc(Cl)cc1Cl)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 33.9 %

Procedure:
2,4-Dichlorophenylacetic acid (65 mg, 0.317 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.158 mmol) obtained in Example 1, (3), and 2,4-dichlorophenylacetic acid chloride mentioned above, the title compound (27 mg, yield 34%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:2]1.C([Li])CCC.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>C1COCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[OH:24])=[CH:21][CH:20]=1
Reactant: c1cc(CCN2CCCC2)cs1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1sccc1CCN1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
A solution of 1-(2-(thiophen-3-yl)ethyl)pyrrolidine (1.0 g, 5.5 mmol) in THF (11.0 mL) was cooled to −78° C. in a dry-ice acetone bath before dropwise addition of n-butyllithium solution (2.5 M in hexanes, 2.4 mL, 6.0 mmol). The reaction mixture was stirred at −78° C. for 1 h and then neat p-fluorobenzaldehyde (0.65 mL, 6.1 mmol) was added dropwise via syringe. The mixture was allowed to warm to room temperature over 16 h and subsequently diluted with saturated aqueous NaHCO3 and EtOAc. The organic layer was separated, washed with brine, and dried over Na2SO4. The residue remaining after solvent removal in vacuo was purified by flash chromatography to afford the desired alkylation product as a white solid (353 mg, 1.16 mmol, 21% yield). MS (M+H)+ 306.
Reaction SMILES: [CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]2[O:19][C:20]([CH:23]=[O:24])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]O)[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.[I:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1.CN(C1C=CC=CN=1)C>O1CCCC1>[CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]2[O:19][C:20]([CH:23]=[O:24])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:45](=[O:46])[C:44]1[CH:48]=[CH:49][C:41]([I:40])=[CH:42][CH:43]=1)[CH3:2]
Reactant: CCN(CCCCCO)c1ccc(C=Cc2ccc(C=O)o2)cc1
Reactant: O=C(O)c1ccc(I)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCN(CCCCCC(=O)c1ccc(I)cc1)c1ccc(C=Cc2ccc(C=O)o2)cc1
Reaction time: 8 h

Procedure:
In a 200 mL flask, 5 (7.63 g, 23.3 mmol), DCC (4.81 g, 23.3 mmol), 4-iodobenzoic acid (5.79 g, 23.3 mmol), and dimethylamino pyridine (0.85 g, 7.0 mmol) were dissolved in tetrahydrofuran (20 vol., 150 mL, freshly distilled from sodium and benzophenone) at room temperature and stirred overnight under Ar. The reaction mixture was filtered and the filtrate was added to a separatory funnel containing ether and water. The ether layer was rinsed several times with water, followed by dilute K2CO3, and then with dilute aqueous brine. The organic layer was evaporated onto silica gel and subsequently purified on silica gel with 3:1 hexane:ethyl acetate. Product 6A was a red viscous liquid (100% trans).
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C@@H:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7]1=[O:18])=[O:4].[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH2:21]([O:28][C:29]([NH:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C@@H:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7]1=[O:18])=[O:4])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(N)C(=O)N[C@@H]1CCc2cc(F)ccc2NC1=O
Solvent: ClCCl
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc(F)ccc2NC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
To a solution of 33 mg (0.12 mmol) of 2-amino-2-methyl- N-[7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]propanamide (Step D) in 1 mL of methylene chloride was 32 mg (0.13 mmol) of N-(benzyloxycarbonyloxy)succinimide. The solution was stirred at room temperature for 24 hours then quenched with 5 drops of 33% aqueous ammonium hydroxide. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel eluting with ethyl acetateexanes (75:25) to afford 25 mg (46%) of the product as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 1.48 (s, 3H), 1.50 (s, 3H), 1.82 (m, 1H), 2.56 (m, 1H), 2.71 (m, 1H), 2.86 (m, 1H), 4.42 (m, 1H), 5.05 (s, 2H), 5.43 (s, 1H), 6.90 (m, 2H), 7.09 (d, 8 Hz, 1H), 7.30 (m, 5H), 8.09 (s, 1H). FAB-MS: calculated for C22H24 FN3O4 413; found 414 (M+H, 100%).
Reaction SMILES: [CH2:1]([N:8]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:9]1[C:10]([F:33])=[C:11]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:25]=3)[NH:20][CH:19]=2)=[O:17])[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:43]([Si:46](Cl)([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])([CH3:45])[CH3:44].O>O1CCCC1>[CH2:34]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([F:33])=[C:11]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:25]=3)[N:20]([Si:46]([CH:50]([CH3:52])[CH3:51])([CH:47]([CH3:49])[CH3:48])[CH:43]([CH3:45])[CH3:44])[CH:19]=2)=[O:17])[C:12]([F:15])=[CH:13][CH:14]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=C(c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(=O)c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)c2cc(-c3cccnc3)cnc21
Reaction time: 0.08 h

Procedure:
To (3-dibenzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (55, 0.84 g, 1.6 mmol) in tetrahydrofuran (150 mL) was added sodium hydride (210.0 mg, 60% in mineral oil, 5.3 mmol) under an atmosphere of nitrogen. The reaction was stirred for 5 minutes. Triisopropylsilyl chloride (0.80 mL, 3.8 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to provide the compound (56, 420 mg, 39%). MS (ESI) [M+H+]+=687.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:20])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:21]Br>C(Cl)Cl.O>[Br:21][C:10]1[C:11](=[O:20])[C:12]2[C:17]([C:9]=1[C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2
Reactant: BrBr
Reactant: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=CC2=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=C(Br)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-5-methoxy-1H-inden-1-one (810 mg, 2.98 mmol) obtained in Step 2 in CH2Cl2 (10 mL) at 0° C. was added dropwise a solution of Br2 (571 mg, 3.57 mmol) in CH2Cl2 (3 mL). The mixture was stirred for 3 h at room temperature. The reaction was diluted with H2O (10 mL) and extracted with CH2Cl2. The extracts were washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2/hexanes) to afford the desired product (1.0 g, 95%).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:8]([CH2:10][CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].CS(C)=[O:25].OO.[OH-].[Na+]>O.CO>[CH2:10]([C:8]1[N:7]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)[C:6]2[CH:21]=[CH:22][C:3]([C:1]([NH2:2])=[O:25])=[CH:4][C:5]=2[N:9]=1)[CH3:11]
Reactant: CS(C)=O
Reactant: CCc1nc2cc(C#N)ccc2n1-c1ccc(CCO)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc2cc(C(N)=O)ccc2n1-c1ccc(CCO)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-[4-(5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 of Example 82, 200 mg, 0.68 mmol), DMSO (0.06 mL, 0.82 mmol) and methanol (10 mL) was added 30% aqueous solution of hydrogen peroxide (0.12 mL, 1.0 mmol) and 0.2 M aqueous NaOH (0.06 mL). The mixture was stirred at 50° C. for 4 h, then cooled. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with 2N aqueous NaOH (50 mL) and brine (50 mL), then dried (Na2SO4), and concentrated to afford the title compound as pale yellow solids: 1H-NMR (CDCl3) δ 8.23 (1H, d, J=1.1 Hz), 7.96 (1H, br.s), 7.76 (1H, dd, J=1.1 Hz, 8.4 Hz), 7.42–7.51 (4H, m), 7.25 (1H, br.s), 7.09 (1H, d, J=8.4 Hz), 3.70 (2H, t, J=6.6 Hz), 2.85 (2H, t, J=6.9 Hz), 2.76 (2H, q, J=7.4 Hz), 1.24 (3H, t, J=7.4 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1C[CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C([Li])CCC.CCCCCC.[C:35]1([CH2:41][CH:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH:42]([OH:43])[CH2:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:3]=3)[N:7]([CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:6]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)cc1
Reactant: O=CCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C1CCCO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
To a solution of 5-bromo-3-(4-fluorophenyl)-1-(tetrahydropyran-2-yl)-1H-indazole (0.50 g, 1.0 mmol) in dried tetrahydrofuran (15 mL) under nitrogen at −78° C. was added dropwise a 1.6 M solution of butyl lithium in hexane (1.1 mL, 1.7 mmol). After stirring for 20 minutes, to the reaction mixture was added phenylacetaldehyde (0.228 g, 1.9 mmol). The reaction mixture was stirred additional 1 hour at −78° C. and the temperature was gradually raised to room temperature. It was quenched with water and extracted with dichloromethane. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide the title compound (0.246 g, 44% yield): 1H NMR (CDCl3) δ 7.86 (m, 2H), 7.80 (d, 1H), 7.09-7.47 (m, 9H), 6.98 (dd, 1H), 5.70 (dd, 1H), 5.07 (t, 1H), 4.08 (m, 1H), 3.65 (m, 1H), 3.06 (d, 1H), 2.67 (m, 2H), 2.11 (m, 2H), 1.75 (m, 3H); ES-MS (m/z) 417 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=O.[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[O:21]=[C:16]1[NH:17][C:18](=[O:20])[C:19](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])[S:15]1
Reactant: COC(=O)c1cc(C=O)ccc1OC
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1cc(C=C2SC(=O)NC2=O)ccc1OC
Yield: 85.7 %

Procedure:
A mixture of methyl 5-formyl-2-methoxybenzoate (490 mg), thiazolidine-2,4-dione (358 mg), ammonium acetate (401 mg), acetic acid (0.8 ml) and benzene (10 ml) was submitted to Dean-Stalk dewatering apparatus to reflux for 4 hours under heat. After cooling, the crystals deposited were collected by filtration, washed with benzene and with 20% aqueous solution of acetone, and then dried to obtain 634 mg (86%) of aimed compound as crystals.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH2:20][CH3:21].O>CN(C=O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([I:1])[C:3]=1[O:12][CH2:19][CH2:20][CH3:21])[CH:7]=[O:8]
Reactant: CCCI
Reactant: COc1cc(C=O)cc(I)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(I)cc(C=O)cc1OC
Temperature: 25 °C
Yield: 933.7 %

Procedure:
5-Iodovanillin (25 g, 0.009 mol) in DMF (100 mL) was treated with potassium carbonate (32 g, 0.23 mol) and n-propyl iodide (52 g, 0.3 mol, 31 mL) and heated for 16 hours. The solution was allowed to cool to room temperature and then poured into water (500 mL) and extracted with ether (3×250 mL). The organic layers were combined and washed with water and saturated sodium chloride solution, and then dried over magnesium sulfate. The organic layer was evaporated by distillation under diminished pressure to an oil, and then purified by column chromatography (silica, 7:3 petroleum ether-ethyl acetate), to provide an amber colored solid (26.9 g, 93%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[O:26][CH3:27].[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39]>O1CCCC1>[OH:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:17]([C:18]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:42])[NH:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:20])=[CH:16][C:15]=1[O:26][CH3:27]
Reactant: CC(C)(C)NC(=O)OCCCCCCN
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCCCCCCOC(=O)NC(C)(C)C)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
8.9 g of 1,1'-carbonyldiimidazole are added to a solution of 10.7 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 500 ml of dry tetrahydrofuran and the reaction mixture is subsequently heated to 65°-70° for 5 hours. It is then cooled to room temperature and a solution of 21.6 g of 6-aminohexyl-t-butylcarbamate in 50 ml of dry tetrahydrofuran is added dropwise thereto within 15 minutes. The reaction mixture is then heated to 65°-70° for 18 hours, evaporated, the residue is suspended in ethyl acetate, suction filtered and the suction filtered material is chromatographed on silica gel with acetone/methylene chloride (3:1). There is obtained [6-(4-hydroxy-5-nitro-m-anisamido)hexyl]-t-butylcarbamate of m.p. 145°-147° (from isopropanol).
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:25][CH2:24][C:19]3(OCC[O:20]3)[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:26][CH3:27])[N:7]=1>Cl.C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:26][CH3:27])[N:7]=1
Reactant: COc1cc(NS(=O)(=O)N2CCC3(CC2)OCCO3)nc(SCc2cccc(F)c2F)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(NS(=O)(=O)N2CCC(=O)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-{2-[(2,3-Difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonamide (the product of step ii) (0.85 g) was heated to 50° C. in a mixture of 2 M aqueous hydrochloric acid (17 mL) and THF (17 mL). After 24 h, the reaction was allowed to cool to room temperature then diluted with ethyl acetate, the layers separated and the organic material washed with saturated aqueous sodium bicarbonate, water, saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated to afford the subtitle compound as a yellow oil. Yield: 0.83 g
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:11][C:12]\2=[O:13])[CH:3]=[N:2]1.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].N12CCCN=C1CCCCC2.[Cl-].[Na+]>C(#N)C>[CH2:38]([O:37][C:35]([CH2:34][N:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:11][C:12]\2=[O:13])[CH:3]=[N:2]1)=[O:36])[CH3:39]
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cn[nH]c1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of (E)-3-[(1H-pyrazol-4-yl)methylidene]-1-(triphenylmethyl)piperidin-4-one (6.0 g) in acetonitrile (100 ml) were added ethyl bromoacetate (7.2 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (6.4 ml). The resulting mixture was stirred at room temperature for one hour, and the reaction was stopped by addition of a saturated aqueous sodium chloride solution. The products were extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (2:1:1) as the eluent to afford the title compound as a yellow amorphous solid (6.08 g, yield: 84%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[CH:32][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH:22]4[CH2:27][CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23]4)=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH:22]4[CH2:27][CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23]4)=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCN(S(C)(=O)=O)C2)ccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCCC(Oc2ccc3c(c2)OCCn2c-3c(C3CCCCC3)c3ccc(C(=O)O)cc32)C1
Temperature: 55 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a solution of methyl 12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a -azadibenzo[a,e]azulene-9-carboxylate (47 mg, 0.085 mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) was added 4N aqueous sodium hydroxide solution (0.5 ml), and the mixture was stirred at 55° C. for 2 hr. The mixture was adjusted to pH 6.5 by adding 1N hydrochloric acid (2 ml), and extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure. Hexane and ethyl acetate were added to the obtained residue, and the precipitate was collected by filtration, washed with hexane and dried in vacuo to give 12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (25 mg, yield 56%).