Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[CH2:19]([N:6]1[C:5]2[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=[C:2]1[Cl:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1cc2nc(Cl)n(Cc3ccccc3)c2cc1Cl
Reaction time: 48 h
Yield: 96.3 %

Procedure:
2,5,6-Trichlorobenzimidazole (5, 50 mg, 0.0002 moles) was dissolved in 15 ml of CH3CN, and K2CO3 (33 mg, 0.0002 moles) was added. The mixture was stirred at room temperature for one hour, at which time benzyl bromide (0.024 ml, 0.0002 moles) was added. The mixture was then stirred for two days. TLC analysis showed the formation of a new compound with a higher Rf than starting material. The mixture was then concentrated and a liquid-liquid extraction was done using CHCl3, and H2O. The CHCl3 layer was kept, dried with MgSO4, filtered, and then concentrated. Column chromotograpy was then performed using 2% MeOH/CHCl3 to elute the compounds. The fractions were collected and those containing the compound were concentrated. The compound was recrystallized from MeOH, giving 60 mg of 1-benzyl-2,5,6-trichlorobenzlmtdazole (181) (96.2%). 1H NMR (CDCl3): d 3.49 ppm (s,3H), 7.13 (m, 2H), 7.32 (m, 4H), 7.78 (s, 1H). 13C NMR (CDCl3): d 43.20 ppm, 106.25, 115.78, 121.62, 122.24, 122.66, 123.50, 124.15, 129.05, 129.16, 135.97, 137.68. GC-MS: m/e 310, 273, 239, 221,197, 170, 168, 135, 120, 100, 91, 77, 65, 51, 39. m.p: 175°-176° C. Elemental Analysis: (C14H9Cl3N2): Calculated: C, 53.85; H, 2.68; N, 8.97. Found: C, 53.92; H, 2.85; N, 8.89. UV lmax nm (e×104): (pH 7) 263 (0.080), 290 (0.102), 299 (0.154); (pH 1) 224 (0.412), 255 (0.157), 290 (0.155), 299 (0.166).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>COCCOC>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[CH:12][CH:13]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(I)cc1
Reactant: OB(O)c1ccc(Br)cc1
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
tert-Butyl[2-(4-iodophenyl)ethoxy]dimethylsilane (7.1 g, 19.6 mmol), (4-bromophenyl)boronic acid (4.8 g, 23.9 mmol), tripotassium phosphate n-hydrate (10.4 g, 49.0 mmol) and a [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.80 g, 0.98 mmol) were suspended in 1,2-dimethoxyethane (150 mL), followed by stirring at room temperature for 4 hours under a nitrogen atmosphere. After the reaction solution was filtered with celite, the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane), and a fraction corresponding to the Rf value=0.90 (hexane/ethyl acetate=19/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (2.0 g, 5.1 mmol) as a white solid (yield 26%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][S:15]([C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][NH:24][CH:25]2[CH3:28])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:26](=[CH:27][C:18]([S:15]([CH3:14])(=[O:16])=[O:17])=[CH:19][CH:20]=4)[CH:25]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(S(C)(=O)=O)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(S(C)(=O)=O)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Methanesulfonyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[H-].[Na+].C[O:21][C:22](=O)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>C1COCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:22](=[O:21])[CH2:14][C:13]([C:11]2[N:10]=[N:9][N:8]([CH2:7][C:6]3[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:12]=2)=[O:15])=[CH:25][CH:26]=1
Reactant: COc1ccc(Cn2cc(C(C)=O)nn2)cc1
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(=O)CC(=O)Cc3ccc(F)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of 1-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]ethanone (1.0 g, 4.30 mmol) in anhydrous THF (25 mL) was added NaH (0.38 g, 9.5 mmol) at 0° C. The mixture was stirred at RT for 1 hour, and (4-fluoro-phenyl)-acetic acid methyl ester (1.67 g, 10.0 mmol) was added at 0° C. and the mixture was refluxed overnight. The reaction mixture was evaporated and the residue was purified via column chromatography (silica gel, EtOAc/Petroleum ether 1:5) to yield the title compound (0.6 g, 38.0%) as a colorless oil.
Reaction SMILES: C[C:2]1([OH:30])[CH:7]([OH:8])C2C=C3C(=O)C4C(=C(O)C=C(OC)C=4)C(=O)C3=[C:12]([OH:13])[C:5]=2[CH:4]([OH:27])[CH:3]1[O:28]C.CN(C)C=[O:34]>>[O:13]=[CH:12][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:7][OH:8])[OH:30])[OH:28])[OH:27])[OH:34]
Reactant: COc1cc(O)c2c(c1)C(=O)c1cc3c(c(O)c1C2=O)C(O)C(OC)C(C)(O)C3O
Reactant: CN(C)C=O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Steffimycinol (50 mg/l), as a milled aqueous suspension or dimethylformamide solution, is added aseptically at the time of inoculation.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)=[O:26])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1nccs1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Product: CCN(Cc1nccs1)C(=O)CN(c1ccc2cn[nH]c2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[C:33](Cl)(=[O:42])[CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([NH:11][C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:33](=[O:42])/[CH:34]=[CH:35]/[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[S:3][C:4]=3[N:5]=2)[CH:13]=1)=[O:32])([CH3:29])[CH3:28])#[N:31]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)/C=C/c3ccccc3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 338 μmol) produced in Example D25(iii) in pyridine (4 mL) was added cinnamoyl chloride (141 mg, 845 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=30/70→10/90), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (108 mg, 56%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[N:8][C:9](Cl)=[CH:10][C:5]=2[NH:4][N:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[O:18].CC([O-])(C)C.[K+].C1COCC1>>[Cl:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:19][C:17]([NH:16][CH2:15][CH2:14][O:13][CH3:12])=[O:18])=[CH:10][C:5]=2[NH:4][N:3]=1
Reactant: COCCNC(N)=O
Reactant: Clc1cc2[nH]nc(Cl)c2cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCNC(=O)Nc1cc2[nH]nc(Cl)c2cn1
Temperature: 60 °C
Yield: 25.6 %

Procedure:
A mixture of 3,6-dichloro-1H-pyrazolo[4,3-c]pyridine (583.6 mg, 3.10 mmol), 1-(2-methoxyethyl)urea (550 mg, 4.66 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (248 mg, 0.310 mmol) and 1.78 M KOtBu in THF (5231 μl, 9.31 mmol) was degassed and then THF (0.5 mL) was added. The reaction mixture was heated to 60° C. overnight. The reaction was diluted with ethyl acetate and washed with water. The combined organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC (0-30% MeOH-DCM) gave 1-(3-chloro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(2-methoxyethyl)urea (214 mg, 0.794 mmol, 25.6% yield). MS ESI calc'd. for C10H13ClN5O2 [M+H]+ 270, found 270.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH2:25])[CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=2)=[N:7]1.C1C[O:29][CH2:28]C1>>[O:12]=[C:11]1[N:6]([CH2:5][C:4]2[CH:22]=[CH:23][C:24]3[NH:25][C:28](=[O:29])[NH:1][C:2]=3[CH:3]=2)[N:7]=[C:8]([C:13]2[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=2)[CH:9]=[CH:10]1
Reactant: Nc1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)ccc2=O)cc1N
Reactant: C1CCOC1
Product: O=c1[nH]c2ccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)cc2[nH]1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1 g (2.89 mmol) of 2-(3,4-diaminobenzyl)-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one are dissolved in 10 ml of THF, 702 mg (4.33 mmol) of 1,1″-carbonyldiimidazole (CDI) are added, and the mixture is stirred at room temperature. After 15 h, the precipitate formed is filtered off with suction, washed with THF and dried in vacuo.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(CC)C(C)C)(C)C.[N:14]([CH2:17][CH:18]([S:32][S:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:19][C@H:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:21]([OH:23])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[C:3]([CH2:2][O:23][C:21](=[O:22])[C@@H:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH:18]([S:32][S:33][C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:17][N:14]=[N+:15]=[N-:16])#[N:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)O
Reactant: N#CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
Bromoacetonitrile (62 μl, 0.911 mmol) and N,N-diisopropylethylamine (79 μl, 0.456 mmol) were added to a solution of (S)-5-azido-2-tert-butoxycarbonylamino-4-tert-butyldisulfanyl-pentanoic acid (Compound 40a) (115 mg, 0.304 mmol) in acetonitrile (1 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate/saturated ammonium chloride, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-5-azido-2-tert-butoxycarbonylamino-4-tert-butyldisulfanyl-pentanoic acid cyanomethyl ester (Compound 41) (120 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O=S(Cl)Cl.C(Cl)Cl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccccc1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(4-fluorophenyl)acetic acid (5.0 g, 32.5 mmol, 1.00 equiv) in SOCl2 (30 mL) was heated for 3 hr at reflux in a 50-mL round-bottom flask. Most of SOCl2 was removed under vacuum, and the residue was added dropwise into a solution of AlCl3 (12.8 g, 96.2 mmol, 3.00 equiv) and fluorobenzene (6.1 g, 63.54 mmol, 2.00 equiv) in DCM (20 mL) at 0° C. The resulting solution was allowed to react, with stirring, for 2 hrs at room temperature.
Reaction SMILES: C(O[C:6]1[C:19](C)=[C:18](C)[C:17]2[O:16][C:15]3[C:10](=[C:11](C)[C:12](OCC4OC4)=[C:13](C)[C:14]=3C)[CH:9](C3C=CC=CC=3)[C:8]=2[C:7]=1C)C1OC1.C(OC1C=CC(C2C=CC(OCC3OC3)=CC=2)=CC=1)C1OC1.OC1C=CC(C2C=CC(O)=CC=2)=CC=1.[OH:73][C:74]1[CH:79]=[CH:78][C:77]([C:80]([C:83]2[CH:88]=[CH:87][C:86]([OH:89])=[CH:85][CH:84]=2)([CH3:82])[CH3:81])=[CH:76][CH:75]=1>>[CH:11]1[C:10]2[CH2:9][C:8]3[C:17](=[CH:18][CH:19]=[CH:6][CH:7]=3)[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.[OH:73][C:74]1[CH:75]=[CH:76][C:77]([C:80]([C:83]2[CH:84]=[CH:85][C:86]([OH:89])=[CH:87][CH:88]=2)([CH3:82])[CH3:81])=[CH:78][CH:79]=1
Reactant: Cc1c(C)c2c(c(C)c1OCC1CO1)C(c1ccccc1)c1c(C)c(OCC3CO3)c(C)c(C)c1O2
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: c1cc(-c2ccc(OCC3CO3)cc2)ccc1OCC1CO1
Product: c1ccc2c(c1)Cc1ccccc1O2

Procedure:
In the same manner as in Synthesis Example 3, except that 1.555 g (manufactured by DAINIPPON INK & CHEMICALS Co., Ltd., “EXA7335”, 3.2 mmol) of 2,7-diglycidyloxy-1,3,4,5,6,8-hexamethyl-9-phenylxanthene, 0.238 g (0.8 mmol) of 4,4′-diglycidyloxybiphenyl and 0.67 g (3.6 mmol) of 4,4′-dihydroxybiphenyl, were replaced by 1.944 g (manufactured by DAINIPPON INK & CHEMICALS Co., Ltd., “EXA7335”, 4.0 mmol) of 2,7-diglycidyloxy-1,3,4,5,6,8-hexamethyl-9-phenylxanthene and 0.821 g (3.6 mmol) of bisphenol A, a xanthene-bisphenol A copolymer type linear epoxy resin was obtained. The amount of the resulting xanthene-bisphenol A copolymer type linear epoxy resin was 2.69 g and the yield was 97%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl[Si](C)(C)C.CO>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][C@@H:12]([C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)cc1[C@H]1CN(Cc2ccccc2)C(=O)CO1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Br)cc1[C@H]1CN(Cc2ccccc2)CCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of (6S)-4-benzyl-6-(5-bromo-2-methoxyphenyl)-morpholin-3-one (67.2 g, 179 mmol) in tetrahydrofuran (200 ml) was added to an ice-cooled mixture of lithium borohydride (8.55 g, 393 mmol) and chlorotrimethylsilane (99.7 ml, 785 mmol) in tetrahydrofuran (500 ml) over 45 minutes and the solution was stirred at same temperature for one hour and then at room temperature for 5 hours. After careful addition of methanol (60 ml) to the ice-cooled solution, solvent was removed under reduced pressure and the residue in 10% aqueous sodium hydroxide (280 ml) was stirred at 90° C. for 3 hours. The solvents were removed under reduced pressure and the residue was partitioned between water and diethyl ether. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by silica gel column chromatography (hexane/ethyl acetate) gave (2S)-4-benzyl-2-(5-bromo-2-methoxyphenyl)-morpholine (46.1 g, 71%, 2 steps) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH2:16][CH3:17])=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:18]1([Mg]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:18]1([CH:14]([C:12]2[C:11]([CH2:16][CH3:17])=[N:10][N:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[CH:13]=2)[OH:15])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCc1nn(-c2cc(F)cc(F)c2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: CCc1nn(-c2cc(F)cc(F)c2)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution (10 mL) of 1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazole-4-carbaldehyde (1.5 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (12.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.9 g, quantitative) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COCCN(C)C(=O)CCl
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COCCN(C)CCOc1ccc(CN(c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 33.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.2 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:13][CH2:12][C:5]2([NH:9]C(=O)N[C:6]2=[O:11])[CH2:4][CH2:3]1.[OH2:14].O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[NH2:9][C:5]1([C:6]([OH:11])=[O:14])[CH2:4][CH2:3][N:2]([CH3:1])[CH2:13][CH2:12]1
Reactant: CN1CCC2(CC1)NC(=O)NC2=O
Reactant: O
Agent: [Ba+2]
Agent: [OH-]
Product: CN1CCC(N)(C(=O)O)CC1
Yield: 2215.5 %

Procedure:
1 -methylpiperidine-4-spiro-5'-hydantoin (9.75 g., 0.0533 mole) and barium hydroxide octahydrate (28.8 g., 0.00913 mole) in water (150 ml.) were heated at 160° C. in an autoclave for three hours. The contents of four such batches were combined and the precipitated barium carbonate was filtered off. The filtrate was neutralized with solid carbon dioxide and the precipitate was removed by filtration. The filtrate was concentrated to a small volume to give 4-amino-1-methylpiperidine-4-carboxylic acid (32.0 g., 95% yield), m.p. 275°-280° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].FC(F)(F)S(O[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])(=O)=O.CC1C=CC=C(C)N=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH2:11][O:12][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(CO)cc1F
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](OCc1ccc([N+](=O)[O-])c(F)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a 3-L round-bottomed flask was added (3-fluoro-4-nitrophenyl)methanol (4.7 g, 27.5 mmol) and DCM (47 mL). To the mixture was added triisopropylsilyl trifluoromethanesulfonate (9.26 g, 30.2 mmol) and 2,6-dimethylpyridine (3.53 g, 33.0 mmol). The resulting mixture was stirred for 3 hours at RT, and washed with NH4Cl (5-250 mL) and H2O (5-250 mL). The organic layer was collected and dried over sodium sulfate and concentrated to afford (3-fluoro-4-nitrobenzyloxy)triisopropylsilane (8.9 g, 99% yield) as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:12]1([C:9]2[CH:10]=[CH:11][C:5]3[O:4][C:3]([CH2:2][O:21][C:18](=[O:20])[CH3:19])=[N:7][C:6]=3[CH:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1nc2cc(-c3ccccc3)ccc2o1
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1nc2cc(-c3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromomethyl-5-phenyl-benzoxazole 49 (440 mg, 1.53 mmol) and cesium acetate (585 mg, 3.06 mmol) in 5 ml DMF was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, dried, filtered and concentrated to yield acetic acid 5-phenyl-benzoxazole-2-ylmethyl ester 50.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7]([N-:10]Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Na+].II.[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[CH2:20]>[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.O>[C:4]1([S:7]([N:10]2[CH2:20][CH:19]2[C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([Br:15])[CH:17]=2)(=[O:9])=[O:8])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: C=Cc1cccc(Br)c1
Reactant: O=S(=O)([N-]Cl)c1ccccc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: II
Agent: [Cl-]
Solvent: O
Product: O=S(=O)(c1ccccc1)N1CC1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a stirred suspension of chloramine B (CAS [127-52-6], 2.97 g), iodine (0.353 g) and trioctylmethylammoniumchloride (Aliquat 336, 0.562 g) in water (40 mL) under argon was added 3-bromostyrene (5.09 g). The mixture was stirred for 2 h at room temperature and subsequently extracted with ethyl acetate. The org. phase was washed with water, dried (MgSO4), filtered and concentrated. The product was purified using column chromatography (SiO2, cyclohexane/ethyl acetate 1:0=>4:1) to give 1-benzenesulfonyl-2-(3-bromo-phenyl)-aziridine (3.18 g) as a light brown oil.