Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].[CH3:20]C([N-]C(C)C)C.CI>C1COCC1>[CH3:20][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of O1-tert-butyl O4-ethyl piperidine-1,4-dicarboxylate (1.5 g, 5.84 mmol) in THF (25 mL) was cooled to −78° C. followed by dropwise addition of LDA (1.80 M in THF, 6.5 mL, 11.68 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 45 min followed by addition of methyl iodide (1.2 mL, 17.52 mmol). The temperature was slowly raised up to RT and left at RT for 6 h. The reaction was cooled to 0° C. and quenched by the dropwise addition of saturated NH4Cl solution (50 mL). The reaction was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by chromatography on silica eluting with 2% EtOAc in hexane gave i (1.0 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of [9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (143.5 mg, 0.379 mmol) in dimethylsulfoxide (2.0 mL) was added Dess-Martin reagent (177.0 mg, 0.417 mmol). The reaction mixture was stirred at room temperature for 2 hrs. The mixture was, quenched with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium thiosulfate. The generated precipitate was collected by filtration and washed with water to give the title compound as a colorless solid (129.6 mg, 0.344 mmol, 91%).
Reaction SMILES: [CH2:1]1[C@@H:9]([O:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:12])[C@H:8]([CH2:25]O)[C@H:3]2[CH2:4][C:5]([O:7][C@@H:2]12)=[O:6].[Na+].[Br-].C([O-])(O)=O.[Na+].CC(O)C.[O-]Cl.[Na+].[C:41]1([CH2:47][CH2:48][C:49]([CH2:51]P(OC)(OC)=O)=[O:50])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O.CC1(C)N([O])C(C)(C)CCC1>[O:50]=[C:49]([CH2:48][CH2:47][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)/[CH:51]=[CH:25]/[C@@H:8]1[C@@H:3]2[C@@H:2]([O:7][C:5](=[O:6])[CH2:4]2)[CH2:1][C@H:9]1[O:10][C:11](=[O:12])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1)CCc1ccccc1
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A solution of (−)-Corey lactone 5-(4-phenylbenzoate) (17.6 g, 50.0 mmol) and TEMPO (0.16 g, 1.0 mmol) in CH2Cl2 (100 mL) was added to a solution of NaBr (0.5 g, 5.0 mmol), NaHCO3 (12.6 g, 150.0 mmol) and IPA (6.0 g, 100.0 mmol) in water (100 mL). 5% aq. NaOCl (about 150 mL) was added dropwise to the stirred mixture at −5 to 0° C. until disappearance of Corey lactone (TLC monitoring). The obtained mixture was stirred for 0.5 h at the same temperature. The aqueous layer was separated and extracted with CH2Cl2 (50 mL). The combined organic layers was added dropwise over 1 h to a stirred mixture of a solution of PhCH2CH2COCH2PO(OMe)2 (15.4 g, 60.0 mmol) in CH2Cl2 (20 mL) and 30% NaOH (8.0 g, 60.0 mmol) at 0–5° C. The mixture was stirred 0.5 h at the same temperature and treated with 10% aq. citric acid (100 mL). The aqueous layer was separated and extracted with CH2Cl2 (50 mL). The combined organic layers were dried over Na2SO4, filtered through short silica gel column and concentrated in vacuo. The oily residue (24.2 g) was dissolved in refluxed EtOH (150 mL) and cooled in ice bath. The precipitate was filtered off, washed with cold EtOH and dried in vacuo to give 20.1 g (84%) of (3aR,4R,5R,6aS)-4-(3-oxo-5-phenyl-1E-pentenyl)-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one with 99.4% purity by HPLC: mp 129–130° C., [α]20D −142° (c 1.0, CHCl3); 1H NMR spectrum confirms the structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.CO[C:15](=[O:29])[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:20]1>C(Cl)Cl>[CH2:25]([CH:22]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:29])[CH2:24][CH2:23]1)[CH2:26][CH2:27][CH3:28]
Reactant: Brc1ccccn1
Reactant: CCCCC1CCN(CCCC(=O)OC)CC1
Agent: [Li]CCCC
Solvent: ClCCl
Product: CCCCC1CCN(CCCC(=O)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12 %

Procedure:
To a dry 25 mL reaction flask was added 2-bromopyridine (200 mg, 1.3 mmol) dissolved in CH2Cl2 (3 mL) and the temperature was adjusted to −78° C. After being stirred for 20 min, addition of n-BuLi (0.84 mL, 1.4 mmol) was conducted under inert atmosphere. After additional 30 min, a solution of 23 dissolved in CH2Cl2 (2 mL) was added. The reaction mixture was left to warm to rt over-night before being quenched with H2SO4 (5 mL, 1 M). The reaction mixture was extracted with ethyl acetate (6×25 mL) and the combined organic phases were dried (MgSO4) and evaporated to dryness, to produce 0.31 g of crude 24. The crude product was subjected to CC [eluent: CH2Cl2: MEOH (10:1)] to give pure 24 (75 mg, 12%). LC-MS [M+H]+ 288 (cald. 288.2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc(Br)cc2C=O)cc1
Yield: 100.9 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (2.1 g, 10 mmol) (Alfa) was reacted with 4-methoxyphenol (1.24 g, 10 mmol) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(4-methoxy-phenoxy)-benzaldehyde as a white solid (Yield 3.1 g, 92%).
Reaction SMILES: [CH:1]1([C:4](=O)[C:5]#[C:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH2:3][CH2:2]1.Br.[CH2:16]([S:22][C:23](=[NH:25])[NH2:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[N:25]=[C:23]([S:22][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:24]=2)[CH2:3][CH2:2]1
Reactant: CCOC(C#CC(=O)C1CC1)OCC
Reactant: CCCCCCSC(=N)N
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCSc1nc(C2CC2)cc(C(OCC)OCC)n1
Temperature: 20 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
Cyclopropyl-4,4-diethoxy-but-2-yn-1-one (2 g, 10 mmol) and 2-hexyl-isothiourea hydrobromide (2.7 g, 11.2 mmol) were dissolved under nitrogen in THF (20 mL). Then triethylamine (3.1 mL, 22.4 mmol) was added slowly. The reaction was slightly exothermic (28° C.). The suspension was stirred for 5 h at 20° C. The product was extracted with AcOEt, sat. NH4Cl solution, dried and concentrated. The residue was purified by silica gel chromatography in heptane/ethyl acetate 95:5. One obtained 2.86 g (83%) of a colorless oil. MS: m/z=339 (M+H).
Reaction SMILES: [CH2:1]([C:3]1([O:35][C:36](=[O:45])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)[CH3:2].[S:46]1[CH:50]=[CH:49][CH:48]=[C:47]1[C:51](Cl)=[O:52]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:38]([O:37][C:36]([O:35][C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH2:26][CH2:27][CH2:28][O:29][C:51]([C:47]2[S:46][CH:50]=[CH:49][CH:48]=2)=[O:52])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1cccs1
Temperature: 21 °C
Reaction time: 5 h

Procedure:
A mixture of Compound 53 (162 mg, 0.26 mmol), 4-dimethylaminopyridine (63 mg, 0.52 mmol), and 2-thiophenecarbonyl chloride (50 μL, 0.47 mmol) in 6.0 mL of dichloromethane was stirred at 21° C. for 5 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford a crude product, which was chromatographed to give the desired product.
Reaction SMILES: [OH:1][CH:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18].C1COCC1.[OH-].[Li+].Cl>O.CO>[OH:1][CH:2]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)CCCCCCN1C(=O)SC[C@@H]1/C=C/C(O)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCN1C(=O)SC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 3-8 (45 mg, 0.11 mmol) in 5.5 mL 2:2:1 THF:MeOH:water, at 0° C., was added lithium hydroxide (170 μL of a 2M solution in water) and the resulting solution was allowed to warm up to room temperature and stirred overnight. To the solution was added a 1M aqueous solution of HCl (1 mL) and the solution was extracted with ethyl acetate. The organic phases were then combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 50–100% ethyl acetate/hexanes to yield 37 mg of 3-9 as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.30–7.18 (m, 5H), 5.81 (dd, 1H), 5.53 (dd, 1H), 4.39 (q, 1H), 4.33 (q, 1H), 3.45 (dd, 1H), 3.33 (m, 1H), 2.97 (m, 2H), 2.77 (dd, 1H), 2.67 (m, 1H), 2.30 (t, 2H), 1.65–1.21 (m, 8H); MS (+ESI): m/z 378.2 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:15])[C:7](=[O:14])[CH2:8][CH2:9][N:10]2[CH3:13])=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:22])=[CH:19][C:18]=1[O:33][CH3:34].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH3:13][N:10]1[CH2:9][CH2:8][C:7](=[O:14])[N:6]([CH3:15])[C:5]2[C:11]1=[N:12][C:2]([NH:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[O:22])=[CH:19][C:18]=1[O:33][CH3:34])=[N:3][CH:4]=2
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CN1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C)CCC(=O)N2C
Temperature: 25 °C
Yield: 48.4 %

Procedure:
10-Chloro-2,6-dimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 9; 185 mg, 0.82 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (215 mg, 0.82 mmol) and p-toluenesulphonic acid (389 mg, 2.05 mmol) in (R/S)-4-methyl-2-pentanol (6 mL) were heated at 115° C. for 5 h. The reaction mixture was cooled to ambient temperature then passed through a SCX-2 cartridge and washed with MeOH (40 mL). The crude product was eluted off the SCX-2 cartridge with NH3 (40 mL, 7M in MeOH). Purification by preparative HPLC (Gemini RP C18 30×100 mm, gradient mobile phase: 10-80% MeCN/water+0.5% NH3) afforded the title compound (180 mg, 48%) as a foam.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([CH2:9][C:10]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=[CH:6][CH:5]=1.[CH:19]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH2:20].[NH4+].[Cl-]>O1CCCC1>[CH3:3][C:4]1[N:8]([CH2:9][C:10]2([O:18][CH2:20][CH2:19][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[N:7]=[CH:6][CH:5]=1
Reactant: C=CS(C)(=O)=O
Reactant: Cc1ccnn1CC1(O)CCCCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccnn1CC1(OCCS(C)(=O)=O)CCCCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 200 mg) was added to a stirred solution of EXAMPLE 65A (667 mg) in tetrahydrofuran (10 mL) and the mixture was stirred at room temperature for 30 minutes before the addition of methyl vinyl sulfone (1.27 g). The mixture was stirred at room temperature for 3 hours. Aqueous NH4Cl was added to quench the reaction and the mixture was extracted with ethyl acetate (three times) and the combined organic layers were washed with water and brine, dried over Na2SO4, and filtered. The filtrate was concentrated to provide the crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:9]2[CH2:12][CH:11]([C:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[C:30]([Mg]Cl)([CH3:33])([CH3:32])[CH3:31].CCOCC.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:9]2[CH2:12][CH:11]([C:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)([OH:14])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: CC(C)(C)[Mg]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 120 mg (0.278 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)methanone (Example 19, Step 4) in 3 mL of THF, 0.35 mL (0.69 mmol) of tert-butyl magnesium chloride (2M in THF) was added and stirred for 1 h at −78° C. Then to the reaction mixture was added 30 μL of ether and 5 mL of 7 mL of qNaHCO3. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford of the title compound as a white solid; 1H-NMR (CDCl3) δ 0.88 (s, 9H), 2.46 (t, J=7.2 Hz, 1H), 2.97 (s, 1H), 3.05 (t, J=7.6 Hz, 1H), 3.31-3.39 (m, 2H), 3.42 (m, 1H), 4.25 (s, 1H), 6.56 (m, 2H), 6.68 (m, 1H), 7.24-7.36 (m, 8H); Mass Spectrum m/e=490 (M+1 35Cl, 35Cl) and 492 (M+1 35Cl, 37Cl).
Reaction SMILES: [Br: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.[Cs+].[Cs+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[C:6]([CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:20][CH2:21][O:22][CH3:23])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(Br)c1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1c(Br)cc(C=O)cc1OC
Temperature: 75 °C

Procedure:
To a 500 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 5-bromovanillin (10 g, 43.28 mmol), DMF (125 mL), powdered Cs2CO3 (28.2 g, 86.56 mmol) and 2-bromoethylmethyl ether (5.08 mL, 54.10 mmol). This well stirred mixture was heated at 75° C. for 24 h. The cooled mixture was filtered through a frit to remove the cesium salts and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. 1H NMR (CDCl3): δ3.44 (s, 3H); 3.77 (t, j=4 Hz, 2H); 3.92 (s, 3H); 4.27 (t, j=4 Hz, 2H); 7.38 (d, j=2 Hz, 1H); 7.65 (d, j=2Hz, 1H); 9.84 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:13])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[C:8]([I:13])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(-n2ccnc2)cc1I
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(-n4ccnc4)cc3I)c2cc1OC
Temperature: 140 °C
Reaction time: 7.5 h
Yield: 45.2 %

Procedure:
4-(Imidazol-1-yl)-2-iodophenol (123 mg), 4-chloro-6,7-dimethoxyquinoline (288 mg), and 4-dimethylaminopyridine (158 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 140° C. for 7.5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (92 mg, yield 45%).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:11]2)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.CC(O)C>[ClH:39].[Br:1][C:2]1[C:3]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][NH:24][CH3:25])=[CH:11]2)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cscc2Br)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cscc2Br)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a solution of tert-butyl {[1-[(4-bromo-3-thienyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (195 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 114 mg, 66%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.O.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[Br:24][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(OS(C)(=O)=O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccc(OS(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the product from Step B, (2.05 g, 6.08 mmol) in acetic acid (50 mL) was added N-bromosuccinimide (1.14 g, 6.38 mmol) in one portion. The reaction mixture was stirred at ambient temperature for 2 hrs, then H2O (100 mL) and CH2Cl2 (100 mL) were added and the resulting mixture was cooled to 0° C. The aqueous layer was adjusted to pH of about 7 by addition of 10 N aqueous NaOH and the organic layer was extracted. The aqueous phase was extracted with a further portion of CH2Cl2 (100 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with 1:1 hexane-EtOAc to provide the titled product as a grey solid.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:32][NH2:33]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:32][N:33]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: CN
Reactant: O=C1CCC(c2ccccc2)c2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CN=C1CCC(c2ccccc2)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In a dry 5-liter three-necked, round-bottomed flask equipped with dropping funnel, mechanical stirrer and thermometer, there were placed 133 g. (0.6 mole) of 4-phenyltetralone [prepared from benzophenone according to procedures described in the Journal of the American Chemical Society, Vol. 69, p. 77 (1947); ibid., Vol. 70, p. 1071 (1948); ibid., Vol. 72, p. 501 (1950); ibid., Vol. 76, p. 1642 (1954)] dissolved in two liters of benzene. Stirring commenced and the solution was then cooled to 50° C., at which point 111.6 g. (3.6 mole) of liquid methylamine were slowly added thereto, followed by the dropwise addition of 33 ml. (0.3 mole) of titanium tetrachloride in 500 ml. of benzene at 0° -5° C. The latter step was carried out during the course of a 30-minute period at such a rate that the temperature never exceeded 5° C. The resulting mixture was then allowed to warm slowly to room temperature (~25° C.), stirred continuously thereafter at said temperature for a period of four hours and finally, allowed to stand overnight (a period of approximately 16 hours) at ambient temperatures without any further stirring being necessary. At this point, the spent reaction mixture was filtered while under a dry nitrogen atmosphere and the solids that had been collected on the filter funnel in this manner were thereafter washed with a fresh portion of benzene. The combined benzene filtrate and washings were then evaporated to near dryness while under reduced pressure to give 135.1 g. (95%) of oily ketimine, i.e., an almost quantitative yield of N-methyl-4-phenyl-3,4-dihydro-1(2H)-naphthalenone imine (m.p. 69° -70° C. after crystallization from n-hexane). The oily product was used as such in the next reaction step.