Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11](C(O)=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC[N:19]([CH2:22]C)CC.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:31])C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([N:19]=[C:22]=[O:31])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(C(=O)O)cc1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCc1ccc(N=C=O)cc1
Reaction time: 2 h

Procedure:
To a degassed solution of 4-heptylbenzoic acid (3.0 g, 13.6 mmol) in anhydrous toluene (30 mL) and Et3N (3 mL, 21.5 mmol), was added diphenyl phosphoryl azide (2 mL, 9.3 mmol) dropwise. After completion of the addition, the reaction mixture was heated to reflux and stirred for 2 hours. The mixture was concentrated to dryness under reduced pressure to give the product, 1-heptyl-4-isocyanatobenzene (79), as an oil, which was used directly in the next reaction without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:11])=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C>>[NH2:20][C:19]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=2[CH3:11])[N:10]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1c(Cl)cccc1NN
Agent: Cl
Product: Cc1c(Cl)cccc1-n1ncc(C#N)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
(3-Chloro-2-methylphenyl)hydrazine hydrochloride (CAS no. 65208-12-0) (9 g, 46.61 mmol) was partitioned between EtOAc (100 mL) and NaOH (2M, aq) (60 mL). The organic layer separated and washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated. The resultant oil was suspended in MeOH (100 mL) under nitrogen at −5° C. 2-(Ethoxymethylene)malononitrile (5.69 g, 46.61 mmol) was added portionwise over 5 mins and the mixture stirred at ˜0° C. for 30 mins. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford the product(6.33 g, 58.4%). 1H NMR (400 MHz, DMSO) δ 2.02 (3H, s), 6.57 (2H, s), 7.25-7.32 (1H, m), 7.37 (1H, t), 7.58-7.64 (1H, m), 7.77 (1H); m/z (ES+) (M+H)+=233.28; HPLC tR=1.89 min.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:37](=[O:38])[CH2:36][O:35][CH3:34])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: COCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.07 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, methoxyacetyl chloride (0.22 g, 2.03 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 100:2.5) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-methoxyacetamide (0.44 g, 66%) as a white solid: mp 196-198° C.; 1H NMR (DMSO-d6) δ d 11.14 (s, 1H), 8.49 (t, J=6.1 Hz, 1H), 7.86-7.79 (m, 2H), 7.68-7.65 (m, 1H), 5.19-5.12 (dd, J=5.3 and 12.5 Hz, 1H), 4.77 (d, J=6.1 Hz, 2H), 3.92 (s, 2H), 3.36 (s, 3H), 2.96-2.83 (m, 1H), 2.64-2.49 (m, 2H), 2.09-2.04 (m, 1H); 13C NMR (DMSO-d6) δ d 172.71, 169.78, 169.58, 167.52, 166.94, 139.09, 134.70, 133.00, 131.51, 127.08, 121.82, 71.46, 58.70, 48.86, 37.47, 30.91, 21.95; Anal. Calcd. For C17H17N3O6: C, 56.82; H, 4.77; N, 11.69. Found: C, 57.02; H, 4.87; N. 11.36.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH2:13][OH:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.C(Cl)Cl>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[CH2:13][O:14][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1-c1ccccc1
Reactant: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(COCc2ccccc2-c2ccccc2)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 1.53 g (6.26 mmol) (3,5-bis-trifluoromethyl-phenyl)-methanol in 15 ml N,N-dimethylformamide 0.30 g (7.52 mmol) sodiumhydride (60% dispersion in mineral oil) was added and the reaction mixture was stirred for 1 hr. After the addition of 1.27 g (6.26 mmol) 2-chloromethyl-biphenyl in 5 ml N, N-dimethylformamide at 0°, the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 50 ml H2O, 50 ml brine and 50 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, hexane/ethyl acetate 40:1) to give 1.25 g (47%) 2-(3,5-bis-trifluoromethyl-benzyloxymethyl)-biphenyl as a colorless oil, MS (EI):410 (M+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl[C:17]1[N:22]=[C:21]([N:23]([CH3:43])[CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C@H:33]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:32][CH2:31]3)[C:20]([CH3:44])=[CH:19][N:18]=1>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:17]1[N:22]=[C:21]([N:23]([CH3:43])[CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C@H:33]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:32][CH2:31]3)[C:20]([CH3:44])=[CH:19][N:18]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3C)ccc21
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Oc4cccc(OC)c4)ncc3C)ccc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To a suspension of K2CO3 (132 mg, 0.96 mmol) in DMF (5 mL) was added 3-methoxyphenol (36 mg, 0.290 mmol), followed by the portionwise addition of ethyl ((1S)-5-{3-[(2-chloro-5-methyl-4-pyrimidinyl)(methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate prepared in Example 342. The reaction mixture was stirred at 80° C. for 48 h, and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to yield the title compound (56.5 mg, 47%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.29 (t, 3H), 1.71-1.83 (m, 1H), 2.02 (m, 2H), 2.28 (s, 3H), 2.35-2.47 (m, 2H), 2.75 (dd, 1H), 2.79-2.96 (m, 2H), 3.15 (s, 3H), 3.49-3.57 (m, 1H), 3.56-3.61 (m, 2H), 3.78 (s, 3H), 3.81 (t, 2H), 4.19 (q, 2H), 6.64 (dd, 1H), 6.69-6.78 (m, 3H), 7.05 (d, 1H), 7.21-7.27 (m, 2H), 7.80 (s, 1H); LC-MS: RT=2.85 min, (M+H)+ 506.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([OH:12])[C:10]#[N:11].[CH3:13][OH:14].Cl>C(OCC)C.O1CCOCC1>[ClH:8].[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH:9]([OH:12])[C:10](=[NH:11])[O:14][CH3:13])[CH:4]=1
Reactant: N#CC(O)c1cc(Cl)ccc1F
Reactant: CO
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=N)C(O)c1cc(Cl)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 121A (640 mg, 3.48 mmol) in anhydrous diethyl ether (115 mL) at 0° C. was added MeOH (1.4 mL) and 4.0 N HCl in dioxane (3.5 mL). The mixture was stirred at 0° C. for 30 min and then at rt for 4 h. The solvent was removed to give methyl 2-(5-chloro-2-fluorophenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (10 mL) was added H2O (10 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 121B (610 mg, 80% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.55 (d, J=4.83 Hz, 1H) 3.80 (s, 3H) 5.38 (d, J=4.83 Hz, 1H) 7.03 (t, J=9.23 Hz, 1H) 7.27-7.31 (m, 1H) 7.39 (dd, J=6.15, 2.64 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[Br:11][C:12]1[CH:13]=[C:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]([NH:18][C:19]([NH2:21])=[S:20])=[N:16][CH:17]=1.C(N(CC)CC)C>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]([NH:18][C:19]2[S:20][CH:2]=[C:3]([CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[N:21]=2)=[N:16][CH:17]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Reactant: COC(=O)CCC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A mixture of methyl 5-bromo-4-oxopentanoate (2.51 g, 12.0 mmol), 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (3.00 g, 9.25 mmol), triethylamine (2.19 mL, 15.7 mmol), and ethanol (60 mL) was refluxed for 3 hours and then stirred at ambient temperature overnight. The solvent was removed to about one third original volume and partitioned between CH2Cl2 and water. The organics were concentrated and purified on silica gel eluting with 40% EtOAc/Hexanes to give the title compound (3.22 g, 80.1% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[C:16](Cl)(=[O:18])[CH3:17]>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:16](=[O:18])[CH3:17]
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Reactant: CC(=O)Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and acetyl chloride.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:14])[CH2:10][C@H:11]([OH:13])[CH3:12])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.[I-].CCCCC>>[CH2:1]([O:8][C@H:9]([CH3:14])[CH2:10][C@H:11]([OH:13])[CH3:12])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C[C@H](C[C@@H](C)O)OCc1ccccc1
Agent: [I-]
Solvent: CCCCC
Product: CCCCCO[C@H](C)C[C@@H](C)O
Yield: 42.3 %

Procedure:
2.90 g of the (2R, 4R)-4-benzyloxy-2-pentanol produced in Example 99 i) and 2.90 g of pentane iodide were subjected to the same procedure as in Example 99 i) to obtain 1.10 g of (2R, 4R)-4-pentyloxy-2-pentanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:43]=1[C:49]1[C:53]([CH2:54]O)=[C:52]([C@H:56]([CH3:59])[CH2:57][CH3:58])[O:51][N:50]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([Cl:41])[C:43]=1[C:49]1[C:53]([CH2:54][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:52]([C@H:56]([CH3:59])[CH2:57][CH3:58])[O:51][N:50]=1
Reactant: CC[C@@H](C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC[C@@H](C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)OC)ccc3c2)cc1
Temperature: 90 °C
Yield: 51.2 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (154 mg, 0.550 mmol), triphenylphosphine (144 mg, 0.550 mmol) and {3-(2,6-dichlorophenyl)-5-[(1R)-1-methylpropyl]-4-isoxazolyl}methanol (150 mg, 0.500 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.099 mL, 0.550 mmol) dropwise. The solution was heated in a microwave reactor at 90° C. for 10 minutes. The solution was adsorbed onto silica gel and purified by chromatography (silica gel, 0-60% ethyl acetate in hexanes gradient elution). A second purification was done by chromatography (silica gel, 1% methanol in dichloromethane) to afford methyl 6-{4-[({3-(2,6-dichlorophenyl)-5-[(1R)-1-methylpropyl]-4-isoxazolyl}methyl)oxy]phenyl}-2-quinolinecarboxylate (144 mg 0.256 mmol, 51%). 1H-NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.18-8.10 (m, 3H), 7.73 (d, J=8 Hz, 2H), 7.63-7.51 (m, 3H), 6.92 (d, J=8 Hz, 2H), 4.88 (app q, J=12 Hz, 2H), 3.94 (s, 3H), 3.27-3.22 (m, 1H), 1.73-1.66 (m, 2H), 1.32 (d, J=7 Hz, 3H), 0.83 (t, J=7 Hz, 3H).
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.[CH:25]1([N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35](F)[C:36]=3[CH3:38])[C:31](=[O:40])[C:30]([C:41]([OH:43])=[O:42])=[CH:29]2)[CH2:27][CH2:26]1>CS(C)=O>[CH:25]1([N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([N:15]4[CH2:16][CH2:17][C@@H:13]([C:10]5([NH:8][CH3:9])[CH2:11][CH2:12]5)[CH2:14]4)[C:36]=3[CH3:38])[C:31](=[O:40])[C:30]([C:41]([OH:43])=[O:42])=[CH:29]2)[CH2:26][CH2:27]1
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn(C5CC5)c4c3C)C2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (880 mg, 3.25 mmol) and triethylamine (1.0 ml) to dried dimethyl sulfoxide (5 ml), 1-cyclopropyl-7-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (425 mg, 1.63 mmol) was added thereto and heated under reflux in an oil bath of 70° C. for 38 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in ethyl acetate (200 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (6 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (12 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by recrystallization from a mixed solvent of methanol/2-propanol, and then dried under a reduced pressure. 331 mg (53%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.CCCCC.[CH:19]([C:21]1[CH2:25][CH2:24][CH2:23][CH:22]=1)=[O:20]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:21]1([CH:19]([OH:20])[CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: CSc1ccccc1
Reactant: O=CC1=CCCC1
Agent: [Li]C(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: OC(CSc1ccccc1)C1=CCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of thioanisol (3.73 g, 30 mmol) in a mixture of dry THF (50mL) and HMPA (14 mL) is added dropwise a solution of tert-butyllithium in pentane (30 mmol) at -78° C. over a period of 10 minutes. The resulting yellow-orange mixture is stirred at ambient temperature for an additional 45 minutes. A solution of 1-formyl-cyclopent-1-ene (2.88 g, 30 mmol) in dry THF (10 mL) is then added slowly. After stirring for 5 minutes, the reaction mixture is quenched with saturated ammonium chloride (20 mL), and allowed to warm to room temperature. The mixture is diluted with H2O (100 mL) and extracted with ethyl acetate (50 mL×3). The combined extracts are washed with H2O, dried (Na2SO4) and evaporated in vacuo to dryness. The residue is chromatographed over a silica gel column (5×30 cm) using toluene/EtOAc (9:1) as the eluent. The desired product is obtained as a pale yellow syrup, 5.0 g (76%). 1H NMR (CDCl3): δ1.66-1.99 (2H, m, CH2 -4'), 2.16-2.38 (4H, m, CH2 -3' and CH2 -5'), 2.61 (1H, brs, OH), 2.98 (1H, dd, J=8.21 Hz, J=13.45 Hz, Ha-2), 3.23 (1H, dd, J=4.39 Hz, J=13.45 Hz, Hb-2), 4.33 (1H, dd, J=4.39, J=8.21 Hz, H-1), 5.67 (1H, brs, H-1'), 7.14-7.45 (5H, m, Ph). Anal. Calc'd for C13H16OS: C, 70.87; H, 7.32; S, 14.34. Found: C, 70.88; H, 7.83; S, 14.37.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[CH3:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:8]3[CH2:9][CH2:10][C:5]4[CH:4]=[CH:3][O:2][C:6]=4[CH2:7]3)=[O:24])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(C(=O)N3CCc4ccoc4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.308 g (1.2 mmol) of 4-(4-methoxybenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times, The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate/dichloromethane=3/1/1). The resulting purified product was washed with diethyl ether to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:27])([CH3:26])[CH2:15][N:16]3[CH2:20][CH:19]4[O:21]C(C)(C)[O:23][CH:18]4[CH2:17]3)[CH:11]=[CH:10][C:9]=2[NH:28][C:29]([C:31]2[NH:32][CH:33]=[C:34]([C:36]#[N:37])[N:35]=2)=[O:30])=[CH:4][CH2:3]1.[ClH:39].C1COCC1>CCOC(C)=O>[ClH:39].[OH:21][CH:19]1[CH:18]([OH:23])[CH2:17][N:16]([CH2:15][C:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:28][C:29]([C:31]3[NH:32][CH:33]=[C:34]([C:36]#[N:37])[N:35]=3)=[O:30])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:38])([CH3:1])[CH2:3][CH:4]=3)[CH:13]=2)([CH3:27])[CH3:26])[CH2:20]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)CN3CC4OC(C)(C)OC4C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(C(C)(C)CN3CC(O)C(O)C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 4-cyano-1H-imidazole-2-carboxylic acid {2-(4,4-dimethyl-cyclohex-1-enyl)-4-[2-(2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-yl)-1,1-dimethyl-ethyl]-phenyl}-amide (as prepared in Example 140, 42.0 mg, 0.0811 mmol) in 2 mL of 1:1 1N HCl/THF was stirred at 80° C. for 0.5 h. After cooling to RT, the mixture was treated with 40 mL of EtOAc and concentrated in vacuo to give the title compound (38.8 mg, 91%) as a colorless oil. 1H-NMR (1:1 CD3OD; 400 MHz): 8.29 (d, 1H, J=8.6 Hz), 8.00 (s, 1H), 7.43 (dd, 1H, J=8.6, 2.3 Hz), 7.32 (d, 1H, J=2.3 Hz), 5.77 (m, 1H), 4.17 (m, 2H), 3.64 (s, 2H), 3.31-3.37 (m, 2H), 2.98-3.07 (m, 2H), 2.34 (m, 2H), 2.09 (m, 2H), 1.61 (t, 2H, J=6.3 Hz), 1.51 (s, 6H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H35N5O3, 478.3 (M+H). found 478.3.
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([OH:13])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.C(=O)([O-])O.[Na+].O.[Br:20][CH:21]([CH2:25][CH2:26][CH2:27][Br:28])[C:22](Cl)=[O:23]>C(OCC)(=O)C>[Br:20][CH:21]([CH2:25][CH2:26][CH2:27][Br:28])[C:22]([NH:2][C:3]1[C:4]([OH:13])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)=[O:23]
Reactant: O=C(Cl)C(Br)CCCBr
Reactant: Nc1cc2c(cc1O)CCCC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2c(cc1O)CCCC2)C(Br)CCCBr
Reaction time: 0.5 h

Procedure:
To a mixture of 3-amino-5,6,7,8-tetrahydro-2-naphthol hydrobromide (1.70 g), sodium hydrogencarbonate (1.46 g), ethyl acetate (15 ml) and water (10 ml) was added under ice-cooling while stirring a solution of 2,5-dibromovaleryl chloride (1.94 g) in ethyl acetate (6 ml). The whole mixture was stirred for further 30 minutes. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layer was washed with an aqueous saline. solution, then dried (MgSO4), followed by distilling off the solvent to obtain 3-(2,5-dibromovaleryl)amino-5,6,7,8-tetrahydro-2-naphthol. This compound was dissolved in dimethylformamide (20 ml). To the solution was added powdery potassium carbonate (1.2 g), and the mixture was stirred at room temperature for 1.5 hour. To the resultant was added water, and precipitated crystals were collected by filtration, washed with water and dried, followed by recrystallization from ethyl acetate to obtain 1.53 g (67.8%) of 2-(3-bromopropyl)-6,7,8,9-tetrahydro-2H-naphtho [2,3 -b][1,4]oxazin-3(4H)-one as crystals, m.p. 139°-140° C. This compound was found to be identical with the product obtained in Reference Example 7.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]N1C(=O)CCC1=O)=O.[CH3:16][O:17][C:18]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:19]=1[CH2:20][NH:21][CH2:22][C:23]#[CH:24].C([O-])(O)=O.[Na+]>CC#N.O>[CH3:16][O:17][C:18]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:19]=1[CH2:20][N:21]([CH2:22][C:23]#[CH:24])[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: C#CCNCc1ccc(OC)cc1OC
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C#CCN(Cc1ccc(OC)cc1OC)C(=O)c1ccc[nH]1

Procedure:
A solution of 1-[(1H-pyrrol-2-ylcarbonyl)oxy]pyrrolidine-2,5-dione (1 eq), N-(2,4-dimethoxybenzyl)prop-2-yn-1-amine (1.05 eq) and NaHCO3 (1 eq) in a mixture of CH3CN and H2O (20:1) was heated at reflux for 12 hrs and then the MeCN was removed under reduced pressure. The resulting residue was partitioned between DCM and sat. aq. NaHCO3 solution. The organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and the resulting brown oil was purified by Biotage system eluting with EtOAc/petrol ether to obtain the desired amide. MS (ES) C17H18N2O3 requires: 298, found: 299 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ: 11.56 (1H, br. S), 7.40 (1H, d, J=8.3 Hz), 6.91 (1H, s), 6.60 (1H, d, J=2.1 Hz), 6.52 (1H, dd, J=8.3, 2.1 Hz), 6.48-6.35 (1H, m), 6.09 (1H, s), 4.68 (2H, s), 4.22 (2H, s), 3.80 (3H, s), 3.76 (3H, s), 3.24 (1H, s).