Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.Cl[Sn]Cl>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:6])=[CH:7][C:8]=1[F:9]
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(F)c(Br)cc1N
Temperature: 25 °C
Yield: 43.4 %

Procedure:
To a suspension of 96 (1.57 g, 6.74 mmol) in EtOH (16 mL) was added SnCl2 (3.82 g, 20.2 mmol). The reaction mixture was heated at reflux for 14 h, cooled to RT and concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and sat'd. aq. NaHCO3 (200 mL). The resulting slurry was filtered through a pad of Celite® and the wet cake was washed with EtOAc (3×50 mL). The organic layer was washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered and concentrated in vacuo to afford 600 mg (43%) of 4-bromo-5-fluorobenzene-1,2-diamine (98) as yellow solid: MS (ESI) m/z=205 [M+1]+.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:8]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:7]2[C:6]=1[OH:23])=[O:4].[NH2:24][CH2:25][C:26]([O-:28])=[O:27].[Na+]>>[Cl:22][C:20]1[CH:21]=[C:7]2[C:6]([OH:23])=[C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:8]2[CH:19]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2cccnc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cn2n(Cc2cccnc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6-chloro-4-hydroxy-2-oxo-1-pyridin-3-ylmethyl-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (5 eq.). ESI (m/z): 377 (M+H)+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C1S(=O)(=O)CCC1.[C:22]([C:25]1[CH:42]=[CH:41][CH:40]=[CH:39][C:26]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=1)([OH:24])=O.[OH-].[Na+]>C(O)C>[O:24]=[C:22]1[C:25]2[CH:42]=[CH:41][CH:40]=[CH:39][C:26]=2[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][C:30]1=2
Reactant: O=C(O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 1 h

Procedure:
To 49 ml. of absolute ethanol is added with vigorous stirring, 81 g. of phosphorus pentoxide. After addition, the mixture is allowed to stir at 95°-100° C. for 1 hour, 400 ml. of tetramethylene sulfone are added, and the temperature is adjusted to 86°-90° C. Then, 38.5 g. of 4-(2-carboxybenzyloxy)phenylacetic acid are added, the mixture is stirred for 4 hours and poured onto ice water. The aqueous mixture is made basic with sodium hydroxide and extracted with toluene. Cooling of the aqueous layer followed by acidification with concentrated hydrochloric acid gives light brown crystals. Recrystallization from acetic acid-water or from dimethoxyethane provides colorless crystals, m.p. 126°-128° C. of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Cl)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-chlorophenol: ESMS m/e: 509.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19](O)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(OCC1C=CC=CC=1)N.O[N:38]1C2C=CC=CC=2N=[N:39]1.CN1CCOCC1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH:38][NH2:39])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H](C(=O)NN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A solution of 19 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in 220 ml of dimethylformamide was cooled to 0° C. and was treated in succession with 9.22 g of benzyl carbamate, 8.43 g of 1-hydroxybenzotriazole, 7.05 ml of N-methylmorpholine and 11.7 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The mixture was allowed to warm to room temperature and was then stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The ethyl acetate layer was washed with 5% sodium hydrogen carbonate and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the ethyl acetate was evaporated and the residue dissolved 200 ml of methanol and 2.5 g of 10% palladium-on-charcoal added. The mixture was shaken in a hydrogen atmosphere for 4 hours and then the catalyst was removed by filtration. The methanol was evaporated and the residue stirred with hexane and filtered. There was obtained 17.41 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.S(Cl)(Cl)=O.[CH3:29]O>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:21]([C:22]([O:24][CH3:29])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: CO
Reactant: O=C(O)c1cccc2nc(-c3ccc(C4CCCN4)cc3F)oc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2nc(-c3ccc(C4CCCN4)cc3F)oc12
Temperature: 70 °C
Yield: 38 %

Procedure:
2-(2-Fluoro-4-(pyrrolidin-2-yl)phenyl)benzo[d]oxazole-7-carboxylic acid (500 mg, 1.53 mmol) was dissolved in methanol (20 mL) at −5° C.-0° C., thionyl chloride (0.2 mL, 2.40 mmol) was added dropwise. The mixture was heated at 70° C. for 3 h., then evaporated and the residue was adjusted to pH=9 by NaHCO3, and extracted with ethyl acetate. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate and evaporated to give methyl 2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)benzo[d]oxazole-7-carboxylate (200 mg, yield 38%) as white solid. LC-MS (ESI) m/z: 341 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][C:25]1[N:20]2[CH:21]([CH3:40])[C:22](=[O:39])[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:24]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:17]2[CH:18]=[C:19]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][C:25]2[N:20]3[CH:21]([CH3:40])[C:22](=[O:39])[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[N:24]=2)[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(Br)cc3N21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(N4C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]4C)cc3N21
Temperature: 100 °C
Yield: 19.1 %

Procedure:
A mixture of (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 7.00 mmol), 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #1, Step E, 1.990 g, 4.67 mmol), Pd(OAc)2 (0.210 g, 0.933 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisoproplylbiphenyl (0.667 g, 1.400 mmol) and t-BuONa (0.897 g, 9.33 mmol) in toluene (120 mL) was heated at 100° C. for 3 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-50% EtOAc in petroleum ether) to give (2S,5R)-2,5-dimethyl-4-[4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 19%) as a solid. LC/MS (Table 1, Method 25) Rt=1.072 min.; MS m/z: 560 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[NH:8][C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.[BrH:29].[NH+]1C=CC=CC=1>C1COCC1>[NH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[NH:8][C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[C:20]([Br:29])[CH:19]=1
Reactant: NCCOc1c(-c2ccc(N3CCCC3)cc2)[nH]c(=O)c2cc(F)ccc12
Reactant: Br
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: NCCOc1c(-c2ccc(N3CCCC3)c(Br)c2)[nH]c(=O)c2cc(F)ccc12
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-(2-aminoethoxy)-7-fluoro-3-(4-pyrrolidin-1-yl-phenyl)-2H-isoquinolin-1-one hydrochloride [(I), cpd. 7, R=R1=R2=H, R3=4-pyrrolidin-1-yl, R4=H](15 mg, 0.037 mmol) in dry THF (0.3 mL), kept at room temperature, pyridinium hydrobromide perbromide (13 mg, 0.04 mmol) were added. The reaction mixture was stirred for 1 hour, the volatiles were then evaporated in vacuo and the resulting crude was purified through preparative HPLC on a Phenomenex Gemini C18 (21×250 mm, 10 μm) column, using a Waters FractionLynx System equipped with a 2996 PDA detector and ZQ2000 single quadrupole mass spectrometer, with electrospray ionization (positive and negative mode). Mobile phase A was 0.05% NH3/ACN 95/5, and mobile phase B was ACN. Gradient from 5 to 95% B in 25 min, hold 95% B 3 min. Flow rate 20 mL/min.
Reaction SMILES: Br[C:2]1[C:3]([Cl:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.COCCOC>ClCCl.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:3]1[C:2]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[N:7]2[CH3:11]
Reactant: CN1C(=O)Cc2c1ccc(Br)c2Cl
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)Cc2c1ccc(-c1cccnc1)c2Cl
Temperature: 100 °C

Procedure:
To 5-bromo-4-chloro-1-methyl-1,3-dihydro-indol-2-one (78 mg, 0.3 mmol) was added 3-pyridine boronic acid (CAS#1692-25-7, 50.2 mg, 0.41 mmol), 1,2-dimethoxyethane (2.5 mL) and 2 M aqueous sodium carbonate (0.410 mL, 0.82 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.09 mmol/g loading, (167 mg, 0.015 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 75 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane and saturated aqueous sodium carbonate, and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 40 to 100%) to afford 4-chloro-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 259.0636 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.27 (s, 3H), 3.62 (s, 2H), 6.85 (d, J=8.1 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.38-7.48 (m, 1H), 7.85 (d, J=7.8 Hz, 1H), 8.64 (dd, J=4.9, 1.6 Hz, 1H), 8.69 (d, J=2.3 Hz, 1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:30]([O:32][C:33]1[CH:47]=[CH:46][C:36]([O:37][CH2:38][CH:39]2[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]2)=[C:35]([F:48])[C:34]=1[F:49])[CH3:31].O>C1COCC1>[CH2:30]([O:32][C:33]1[CH:47]=[CH:46][C:36]([O:37][CH2:38][CH:39]2[CH2:44][CH2:43][C:42](=[CH:2][O:3][CH3:4])[CH2:41][CH2:40]2)=[C:35]([F:48])[C:34]=1[F:49])[CH3:31]
Reactant: CCOc1ccc(OCC2CCC(=O)CC2)c(F)c1F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(OCC2CCC(=COC)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
In a reactor under nitrogen atmosphere, 50 mL of THF was added to 14.7 g of methoxymethyltriphenylphosphonium chloride, and the mixture was cooled to −20° C., to which 4.8 g of t-BuOK was added, followed by stirring for 1 hour. A solution containing 8.1 g of 4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexanone obtained in the fifth step dissolved in 100 mL of THF was added dropwise thereto, followed by stirring for 1 hour. The temperature of the reaction mixture was increased to room temperature, and 200 mL of water was added to the reaction mixture, which was extracted three times with 300 mL of toluene. The resulting organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated to about 200 mL under reduced pressure, and the concentrated solution was placed in 1,000 mL of n-hexane, followed by removing the deposited solid matters. The solvent was distilled off from the resulting solution under reduced pressure, and the residue was purified by silica gel column chromatography to provide 8.3 g of 1-ethoxy-2,3-difluoro-4-(4-methoxymethylenecyclohexylmethoxy)benzene.
Reaction SMILES: OO.[C:3]1([O:13][CH3:14])[C:4](=[CH:6][CH:7]=[C:8]([CH:12]=1)[CH:9]=[CH:10][CH3:11])[OH:5].S(=O)(=O)(O)[OH:16].C1(C)C=CC=CC=1>C(O)=O>[CH3:11][C:10]([CH2:9][C:8]1[CH:7]=[CH:6][C:4]([OH:5])=[C:3]([O:13][CH3:14])[CH:12]=1)=[O:16]
Reactant: CC=Cc1ccc(O)c(OC)c1
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: O=CO
Solvent: Cc1ccccc1
Product: COc1cc(CC(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of 30% aqueous hydrogen peroxide (9 ml, 85.5 mm) and formic acid (16 ml, 88%) is added to a solution of isoeugenol (8.1 gm, 50 mm) in formic acid (4 ml). The reaction mixture is stirred at 35° C.-40° C. under nitrogen atmosphere for 3 hours. The resulting 1-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol-monoformate is treated with 10% aqueous sulfuric acid (125 ml.) and toluene (125 ml.). After refluxing with mixing for 6 hours, the reaction mixture is cooled to room temperature, and the toluene layer separated. The aqueous layer is extracted with fresh toluene and the toluene layers are combined, washed with saturated aqueous sodium sulfate, dried over anhydrous sodium sulfate and concentrated to give methylvanillyl ketone in 48% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:10])=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(C)ccc2C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cc(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
Sulfur trioxide pyridine complex (800 mg, 5.0 mmol) was added to a solution of 3-[3-(2,5-dimethylphenylsulfonyloxy)-5-methylphenoxy]propanol (600 mg, 1.7 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.4 mL, 5.6 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (60 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (530 mg, 89%). 1H-NMR (300 MHz, CDCl3) δ 9.82 (s, 1H), 7.68 (s, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.29 (s, 1H), 6.60 (s, 1H), 6.45 (s, 1H), 6.35 (s, 1H), 4.17 (t, J=6.1 Hz, 2H), 2.85 (t, J=6.1 Hz, 2H), 2.70 (s, 3H), 2.33 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([N:13]([CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)[CH3:14])=[O:19]
Reactant: CNCCC#Cc1cccc(CF)n1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Product: CN(CCC#Cc1cccc(CF)n1)C(=O)c1c(Cl)cccc1Cl
Yield: 5.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (180 mg, 0.93 mmol) and 2,6-dichlorobenzoyl chloride (255 mg, 1.22 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 18.5 mg of 2,6-dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide as a yellow oil (Yield: 5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][C:13]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:16](OCC)=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C(OCC)(=O)C>C(OCC)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][C:13]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([CH2:16][OH:17])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)C1(CCc2ccccc2)CCN(Cc2cccnc2OC)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: COc1ncccc1CN1CCC(CO)(CCc2ccccc2)CC1
Temperature: -20 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
After dissolving 247 mg of ethyl 1-(2-methoxy-3-pyridinylmethyl)-4-(2-phenylethyl)piperidine-4-carboxylate in 10 ml of diethyl ether, the solution was cooled to −20° C. and 1 ml of diisobutylaluminium hydride (1.5 M, toluene solution) was added dropwise. The mixture was stirred for 4 hours while slowly raising the temperature to room temperature, and then approximately 10 ml of a saturated aqueous solution of potassium sodium (+)-tartrate tetrahydrate and approximately 10 ml of ethyl acetate were added and the mixture was stirred for 10 minutes at room temperature. The organic layer was separated off and the aqueous layer was extracted With ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (173 mg, 79% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=[C:10]([C:12]([O:14]C)=[O:13])[N:11]=1)([CH3:6])[CH3:5])[CH3:2].C(OC(C1N(COCC[Si](C)(C)C)C=C(C(OCC)=O)N=1)(C)C)C>>[CH2:1]([O:3][C:4]([C:7]1[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)([CH3:5])[CH3:6])[CH3:2]
Reactant: CCOC(C)(C)c1nc(C(=O)OC)cn1COCC[Si](C)(C)C
Agent: CCOC(=O)c1cn(COCC[Si](C)(C)C)c(C(C)(C)OCC)n1
Product: CCOC(C)(C)c1nc(C(=O)O)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 58(e) starting from the mixture of methyl 2-(2-ethoxypropan-2-yl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-imidazole-4-carboxylate and ethyl 2-(2-ethoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (90 mg). Yield 70 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.02 (s, 9H), 0.87 (t, 2H), 1.06 (t, 3H), 1.57 (s, 6H), 3.12 (q, 2H), 3.58 (t, 2H), 5.53 (s, 2H), 7.93 (s, 1H), 12.28 (bs, 1H).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:21]=[C:22]([C@H:27]2[N:35]3[C@@H:30]([CH2:31][CH2:32][CH:33](P(=O)(OCC)OCC)[C:34]3=[O:36])[CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1.C(O)C>O1CCCC1>[F:26][C:24]1[CH:23]=[C:22]([C@H:27]2[N:35]3[C@@H:30]([CH2:31][CH2:32]/[C:33](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:34]3=[O:36])[CH2:29][CH2:28]2)[CH:21]=[C:20]([F:19])[CH:25]=1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3cc(F)cc(F)c3)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4cc(F)cc(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 88.2 %

Procedure:
Lithium hydroxide (56.8 mg) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.12 g) and diethyl [(3S,8aR)-3-(3,5-difluorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (0.25 g) in tetrahydrofuran (1.0 mL)-ethanol (4.0 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.22 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C)=[O:13].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.O>CC(C)=O>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:13])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1ccc([N+](=O)[O-])s1

Procedure:
To a solution of 5-nitro-2-thiopenecarboxaidehyde (1.00 g, 6.24 mmol) in acetone (50 ml) was added Jones reagent (8N in acetone, 8.12 ml), 65 mmol) at −20° C. After stirring for 1H, 30 ml of isopropanol was added to the mixture. H2O was added to the mixture and extracted with CH2Cl2. The extract was washed with water, brine, dried (Na2So4), and concentrated to give 967 mg (90%) of yellow amorphous.