Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH2:18]([O:20][C:21]([CH2:23][NH:24][C:25](=[O:28])[CH2:26]Cl)=[O:22])[CH3:19].Cl>CN(C)C=O>[CH2:18]([O:20][C:21]([CH2:23][NH:24][C:25](=[O:28])[CH2:26][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)CNC(=O)CCl
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)COc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (6.1 g), potassium carbonate (13.8 g), sodium iodide (0.75 g) and N,N-dimethylformamide (110 ml) was added N-(ethoxycarbonylmethyl)-2-chloroacetamide (8.9 g), and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was poured into 3% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was chromatographed on silica gel column (eluent; ethyl acetate), the desired fractions were collected and recrystallized from ethyl acetate/hexane to give N-(ethoxycarbonylmethyl)-2-(4-formylphenoxy)acetamide (4.09 g).
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C([Cl:9])=O.O[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:23][C:24](=[O:26])[CH3:25])[CH:21]=2)[N:16]=[CH:15][N:14]=1>ClCCCl>[Cl:9][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:23][C:24](=[O:26])[CH3:25])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2ncnc(O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
To a stirred solution of anhydrous DMF (4.5 mL) in DCE (20 mL), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (7.9 ml, 90 mmol) in DCE (40 mL). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 min. Acetic acid 4-hydroxy-7-methoxy-quinazolin-6-yl ester (6.5 g, 27.8 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 3 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice:water mixture (100 mL) and extracted with DCM (500 mL). The aqueous layer is further extracted with DCM (2×50 mL). The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 5.63 g (22.34 mmol, 80%) of desired product as a tan solid.
Reaction SMILES: P(O[CH2:10][C:11]#[N:12])(OCC)(OCC)=O.CC(C)([O-])C.[K+].[C:19]([O:23][C:24]([N:26]1[CH2:29][C:28](=O)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1.O.[Cl-].[Na+]>[C:11]([CH:10]=[C:28]1[CH2:29][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27]1)#[N:12]
Reactant: CCOP(=O)(OCC)OCC#N
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Temperature: -14 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Diethyl cyanomethyl phosphate (745 g, 4.20 mol, 1.20 equiv) and anhydrous tetrahydrofuran (THF, 9 L) were added to a four-neck flask equipped with a thermowell, an addition funnel and the nitrogen protection tube at room temperature. The solution was cooled with an ice-methanol bath to −14° C. and a 1.0 M solution of potassium tert-butoxide (t-BuOK) in anhydrous tetrahydrofuran (THF, 3.85 L, 3.85 mol, 1.1 equiv) was added over 20 min keeping the reaction temperature below −5° C. The resulting reaction mixture was stirred for 3 h at −10° C. and a solution of 1-tert-butoxycarbonyl-3-azetidinone (600 g, 3.50 mol) in anhydrous tetrahydrofuran (THF, 2 L) was added over 2 h keeping the internal temperature below −5° C. The reaction mixture was stirred at −5 to −10° C. over 1 h and then slowly warmed up to room temperature and stirred at room temperature for overnight. The reaction mixture was then diluted with water (4.5 L) and saturated aqueous sodium chloride solution (NaCl, 4.5 L) and extracted with ethyl acetate (EtOAc, 2×9 L). The combined organic layers were washed with brine (6 L) and dried over anhydrous sodium sulfate (Na2SO4). The solvent was removed under reduced pressure and the residue was diluted with dichloromethane (CH2Cl2, 4 L) before being absorbed onto silica gel (SiO2, 1.5 Kg). The crude product, which was absorbed on silica gel, was purified by flash column chromatography (SiO2, 3.5 Kg, 0-25% EtOAc/hexanes gradient elution) to afford tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 414.7 g, 679.8 g theoretical, 61% yield) as a white solid. For 2: 1H NMR (300 MHz, CDCl3) δ 5.40 (m, 1H), 4.70 (m, 2H), 4.61 (m, 2H), 1.46 (s, 9H) ppm; C10H14N2O2 (MW, 194.23), LCMS (EI) m/e 217 (M++Na).
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=O)=[CH:12][CH:13]=2)[CH2:8][O:7]1>C1(C)C=CC=CC=1>[CH3:21][C:18]1([CH3:22])[CH2:19][O:20][C:15]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[C:6](=[O:5])[O:7][CH2:8]3)=[N:17]1
Reactant: CC(C)(CO)NC(=O)c1ccc2c(c1)COC2=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc3c(c2)COC3=O)=N1
Temperature: 29 °C

Procedure:
To stirred thionyl chloride (800 ml), at 0° C., 2-[[(1-oxo-1,3-dihydroisobenzofuran-5-yl)carbonyl]amino]-2-methyl-1-propanol (560 g, 2.25 mol) is added portionwise while maintaining the temperature below 10° C. The temperature is allowed to rise, and then the mixture is heated between 28-30° C. for 5 hours. The thionyl chloride is destined off under reduce pressure at 60° C. The residue is taken up in toluene (2×700 ml) and concentrated under reduce pressure at 60° C. The solid is filtered off, washed with toluene (2×100 ml) and dried at in vacuo. The product is suspended in deionized water (3000 ml). The suspension is cooled and pH is adjusted to basic pH by addition of 28% aqueous ammonia (1000 ml). The product is filtered off, washed with deionized water, and dried at 50° C. in vacuo. Yield: 407 g (78%) having m.p.=109-111° C. and purity (HPLC, peak area)≧95%.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][OH:27])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH:26]=[O:27])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)COc1ccccc1-3
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C=O)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 14-cyclohexyl-7-(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (from step 2) in dry DCM (0.1 M) was treated with DMP (1.2 eq.) and the resulting solution was stirred for 2 h at RT. The reaction mixture was diluted with EtOAc and washed with a 1:1 (v/v) mixture of sodium thiosulfate and NaHCO3 (both aqueous saturated solutions), then with brine. Drying over Na2SO4, filtration and concentration i. vac. gave the crude methyl 14-cyclohexyl-7-formyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate, which without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cc1O
Temperature: 25 °C

Procedure:
A solution of 4-chloro salicylic acid (10.0 g, 58.0 mmol) in THF (150 mL) was treated with LAH (1.5 equivalent) at reflux for 2 h. After cooling to ambient temperature, the reaction solution was quenched by 1 N NaHSO4 solution (200 mL), and then extracted with ether (300 mL). After separation, the organic layer was dried over anhydrous MgSO4, filtered and concentrated. The dried crude product 25 (7.5 g, 81%) was obtained as a gray solid, and was pure enough for use without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:5][CH:4]([C:6]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=O)[CH2:3]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([NH2:30])[CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH2:5][CH:4]([CH:6]([NH:30][C:22]2[CH:21]=[N:20][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:3]1
Reactant: Nc1cnc2ccccc2c1
Reactant: CCOC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1ccc(C(Nc2cnc3ccccc3c2)C2CC(C)(C)C2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 3.1 %

Procedure:
A flask containing ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate (397 mg, 1.53 mmol) was charged with toluene (13.9 mL), quinolin-3-amine (200 mg, 1.39 mmol), and para-toluene sulfonic acid (26.8 mg, 0.139 mmol). The reaction was refluxed with a Dean-Stark for 24 h. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 508 mg of crude material. To this crude material was added anhydrous methanol (6.47 mL) and the solution was cooled to 0° C. Sodium borohydride (147 mg, 3.88 mmol) was then added. After 5 h, the reaction was partly concentrated and quenched with saturated aqueous ammonium chloride. The reaction mixture was extracted three times with ethyl acetate. The combined organic layers were then dried over sodium sulfate, filtered, and concentrated to give 560 mg of crude material. Purification by column chromatography (0-50% ethyl acetate in heptane) provided ethyl 4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzoate (17.0 mg, 3.4% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ: 8.47 (d, J=2.9 Hz, 1H), 8.03-7.97 (m, 2H), 7.90-7.86 (m, 1H), 7.46-7.42 (m, 2H), 7.42-7.30 (m, 3H), 6.69 (d, J=2.7 Hz, 1H), 4.40-4.31 (m, 2H), 4.27 (dd, J=9.2, 4.3 Hz, 1H), 2.58-2.47 (m, 1H), 2.03 (ddd, J=11.2, 7.6, 4.2 Hz, 1H), 1.79-1.67 (m, 2H), 1.67-1.55 (m, 1H), 1.36 (t, J=7.1 Hz, 3H), 1.14 (s, 3H), 1.09 (s, 3H). MS (M+1): 389.3.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([C@@H:9]([NH:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH3:10])=[C:4]([F:18])[CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].[F:53][C:54]([F:65])([F:64])[C:55]1[CH:60]=[C:59](B(O)O)[CH:58]=[CH:57][N:56]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:4]1[CH:3]=[C:2]([C:59]2[CH:58]=[CH:57][N:56]=[C:55]([C:54]([F:65])([F:64])[F:53])[CH:60]=2)[C:7]([F:8])=[CH:6][C:5]=1[C@@H:9]([NH:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH3:10]
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1cc(F)c(Br)cc1F
Agent: [Pd]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](N[S@](=O)C(C)(C)C)c1cc(F)c(-c2ccnc(C(F)(F)F)c2)cc1F
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of (R)—N—((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (230 mg, 0.676 mmol) in dioxane/H2O (5 mL/1 mL) was added sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxy-[1,1′-biphenyl]-3-sulfonate (34.7 mg, 0.068 mmol), (2-(trifluoromethyl)pyridin-4-yl)boronic acid (194 mg, 1.014 mmol), K2CO3 (234 mg, 1.690 mmol) followed by Pd2dba3 (31.0 mg, 0.034 mmol). The reaction mixture was sealed and heated to 110° C. and stirred for 2 hours. LCMS show complete conversion. The reaction mixture was then cooled to room temperature and diluted with EtOAc (20 mL) and water (10 mL). The aqueous layer was then extracted with EtOAc (2×20 mL). The combined organic was then concentrated. The residue was purified by silica gel chromatography (50% heptane in EtOAc to 10% MeOH in EtOAc) to give product. (0.25 g). LCMS (B) m/z 407.6 (M+H)+
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][O:17][C:18]=2[N:19]=1.[ClH:27].C(OCC)(=O)C>>[ClH:27].[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][NH:14][CH2:15][CH2:16][O:17][C:18]=2[N:19]=1
Reactant: CC1CCCCC1Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1CCCCC1Oc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A mixture of the compound obtained in step 1 (0.55 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.38 g, 85%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([CH:7]=[O:8])=[N:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl([O-])=[O:14].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>>[CH3:1][C:2]1[NH:6][C:5]([C:7]([OH:14])=[O:8])=[N:4][C:3]=1[C:9]([F:12])([F:10])[F:11]
Reactant: Cc1[nH]c(C=O)nc1C(F)(F)F
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: Cc1[nH]c(C(=O)O)nc1C(F)(F)F
Yield: 118.2 %

Procedure:
The same operation as in Example (33c) was performed using 5-methyl-4-(trifluoromethyl)-1H-imidazole-2-carbaldehyde obtained in Example (36c) (90 mg, 0.51 mmol), sodium chlorite (95 mg, 1.05 mmol), sodium dihydrogenphosphate (154 mg, 0.99 mmol) and 2-methyl-2-butene (0.3 mL, 2.84 mmol), to obtain 117 mg of the title compound as a white solid (100%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]1>>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:19]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Yield: 46.7 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (160 mg, 0.537 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (537 mg, 2.68 mmol) were processed as described in Example 1, Step J. The crude material was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-80% CH3CN/water gradient; 25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (120 mg, 47% yield) as solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.57 (d, 1H), 9.61 (s, 1H), 8.14 (s, 1H), 7.52 (br s, 1H), 6.85 (br s, 1H), 3.61-3.48 (m, 1H), 3.25-3.13 (m, 3H), 3.09-3.01 (m, 1H), 1.87-1.80 (m, 1H), 1.77-1.65 (m, 3H), 1.45-1.32 (m, 1H), 1.29 (s, 9H), 0.77 (d, 4H); LCMS (APCI+) m/z 478, 480 (M+H)+, Retention time=3.59 minutes (Method 2).
Reaction SMILES: Br[C:2](=[CH2:26])[CH2:3][CH:4]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:11]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:27]1([Mg]Br)[CH2:29][CH2:28]1.Cl>CCOCC.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH:27]1([C:2](=[CH2:26])[CH2:3][CH:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:29][CH2:28]1
Reactant: Br[Mg]C1CC1
Reactant: C=C(Br)CC(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C=C(CC(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
Dichloro [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (137 mg, 0.187 mmol) was added to a solution of benzyl 4-[3-bromo-1-(ethoxycarbonyl)but-3-en-1-yl]piperidine-1-carboxylate (795 mg, 1.87 mmol) in ether (6 mL). The reaction mixture was cooled to 0° C. and cyclopropylmagnesium bromide (0.544 g, 3.75 mmol) was added. After 1 h, the mixture was warmed to ambient temperature. After 1 h, the mixture was cooled back to 0° C. and two additional portions of dichloro [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (137 mg, 0.187 mmol) and cyclopropylmagnesium bromide (544 mg, 3.75 mmol) were added. The mixture was warmed to ambient temperature. After 18 h, hydrochloric acid (10% in water) was added and the mixture was extracted with ether (2×). The combined organic extracts were washed with saturated aqueous sodium bicarbonate, water, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (173 mg). MS 386.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:15](=[O:34])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:43]>C(OCC)(=O)C>[ClH:43].[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15](=[O:34])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc(N(C(=O)c2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(N(C(=O)c2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzoyl]amino]piperidine (416 mg) in ethyl acetate (5 mL) was added 4 M hydrogen chloride in ethyl acetate (5 mL). The mixture was stirred at room temperature for 4 hr, resulting precipitates were collected and washed with ethyl acetate on a funnel to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:11]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCBr
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 61.5 %

Procedure:
A mixture of 2,4,5-triphenylimidazole (11.5 g), 1,7-dibromo-heptane (50 g) and potassium carbonate (27 g) in dry butanone (250 ml) was heated at reflux for 20 hours. The mixture was filtered and the flitrate evaporated to an oil. Chromatography on silica gel (hexane/ethyl acetate) and recrystallisation from hexane gave 1-(7-bromoheptyl)-2,4,5-triphenylimidazole (11.3 g, 61.4%) as a colourless solid, m.p. 69°-71°.
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].Cl[CH2:15][C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:17].[H-].[Na+]>CS(C)=O>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:15]=1[C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:17]
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Reactant: COCCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reaction time: 2 h

Procedure:
To a solution of 3.0 g. (0.015 mole) of N-methylsaccharin and 2.3 g. (0.015 mole) of 2-methoxyethyl chloroacetate in 15 ml. of dimethylsulfoxide at 40° C. was added 810 mg. (0.033 mole) of sodium hydride over a 2 hour period. The resulting reaction mixture was stirred for 2 hours at 40°-50° C. and was then quenched in 5% hydrochloric acid solution. The resulting suspension was extracted with methylene chloride (2×100 ml.) and the organic layers separated, combined and washed with water (50 ml.) and a brine solution (50 ml). The organic layer was dried over magnesium sulfate and concentrated to an oil, 4.1 g. The product was purified by dissolution of the residue in 5 ml. of acetone and addition of the acetone slowly to 125 ml. of 0.25 N hydrochloric acid. The suspension was allowed to stir for several hours, and was then filtered and dried 2.6 g. (55%). The product is indistinguishable from that reported in U.S. Patent Application Ser. No. 191,716, filed Sept. 29, 1980.
Reaction SMILES: [I:1]Cl.[F:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[I:1][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:11])[C:4]=1[F:3]
Reactant: ClI
Reactant: Cc1c(N)cccc1F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(N)ccc(I)c1F
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Iodine monochloride (0.5 ml) was added to a solution of 3-fluoro-2-methylaniline (1.25 g) in glacial acetic acid (15 ml). The mixture was stirred for two hours at 70° C. The mixture was allowed to cool to ambient temperature and saturated sodium sulphite solution (50 ml) was added. The solution was extracted with EtOAc (2×100 ml), and the extracts were combined, washed with saturated sodium bicarbonate solution (100 ml) and dried. The volatile material was removed by evaporation and the residue was purified by chromatography on silica gel, eluted with 0-10% EtOAc in hexane to give the title compound (1.53 g) as a solid. NMR: 1.98 (s, 3H), 5.32 (s, 2H), 6.30 (d, 1H), 7.20 (t, 1H); m/z: 250.