Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH2:24][OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=2)[C:11]([CH3:27])([CH3:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH:24]=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=2)[C:11]([CH3:26])([CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(CO)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCC(C=O)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.1 %

Procedure:
A solution of 7-(1-hydroxymethyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (1.27 g, 3.38 mmole) in 10 mL of dichloromethane was added to a suspension of 1.1 g of pyridinium chlorochromate in 15 mL of dichloromethane. The reaction mixture was stirred at room temperature for 6 hours, diluted with 50 mL of ether and filtered through a pad of Celite. The volatiles were removed in vacuo to give a brown oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to yield 0.91 g of 7-(1-formyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8](SC)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:13].C1C[O:17]CC1.C[O-].[Na+]>CCOC(C)=O>[NH2:13][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8](=[O:17])[S:9][C:10]=2[C:2]=1[Br:1]
Reactant: C1CCOC1
Reactant: CSc1nc2ccc(N)c(Br)c2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1ccc2[nH]c(=O)sc2c1Br
Temperature: 25 °C

Procedure:
To a round bottom flask was added 7-bromo-2-(methylthio)-1,3-benzothiazol-6-amine (13-1) (0.600 g, 2.180 mmol), THF (20 mL), and solid sodium methoxide (0.471 g, 8.72 mmol). The reaction mixture was then stirred at room temperature for several hours followed by heating to 60 C in a hot oil bath with stirring for several hours, then to 90 C for several hours. The reaction mixture was then suspended in EtOAc, washed with sat'd NaHCO3, then water, then brine. Organics were then dried over Na2SO4 filtered & concentrated to give 6-amino-7-bromo-1,3-benzothiazol-2(3H)-one (13-2) as a tan solid. HRMS (M+H)+: observed=244.9379, calculated=244.9379.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH2:16][OH:17].C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH2:16][OH:17])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in example 24, 2-oxo-4-phenylbutyric acid and L-serinyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-serinyl-L-proline.
Reaction SMILES: C(N)CN.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1.[O:39]1[CH2:43][CH2:42][NH:41][C:40]1=[O:44]>O1CCOCC1.[Cu]I>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([N:41]2[CH2:42][CH2:43][O:39][C:40]2=[O:44])=[CH:34][CH:33]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(I)cc2)c(Cl)c1
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Product: O=C1OCCN1c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
7 mg of copper(I) iodide, 2 mg of ethylenediamine and 155 mg of tripotassium phosphate are added, under argon, to a solution of 200 mg of 1,3-dichloro-5-(3,3-dichloro-allyloxy)-2-[3-(4-iodophenoxy)-propoxy]-benzene and 38 mg of 2-oxazolidinone in 4 ml of dioxane. After 17 hours at 110° C. the reaction mixture is filtered and concentrated. Purification over silica gel yields the title compound (compound 29.3).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][C:10]1[C:11](=[O:28])[C:12]2[CH:27]=[CH:26][CH:25]=[CH:24][C:13]=2[C:14]2[C:23]=1[S:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:15]=2>O.C(OCC)(=O)C>[OH:28][C:11]1[C:10]([CH3:9])=[C:23]2[C:14]([NH:15][C:16]3[C:21]([S:22]2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:13]2[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=12
Reactant: Cc1c2sc3ccccc3nc-2c2ccccc2c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c2c(c3ccccc3c1O)Nc1ccccc1S2
Reaction time: 2 h

Procedure:
A solution of sodium hydrosulfite (40 g) in water (0.5 l) was added to a suspension of 6-methyl-5H-benzo[a]phenothiazine-5-one (10.4 g) in ethyl acetate (1 l) and stirred for 2 hours. The organic layer was decanted, dried and evaporated to dryness. The resulting residue was triturated with ether and filtered to afford 5-hydroxy-6-methyl-12H-benzo[a]phenothiazine as an air sensitive solid.
Reaction SMILES: C[Si]1(C)O[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:4]=2[O:3]1.C[Si](C)(C)[O:17][C:18]1[CH:19]=[C:20]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH:21]=[CH:22][C:23]=1[O:24][Si](C)(C)C>>[OH:17][C:18]1[CH:19]=[C:20]([CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:4]=3[OH:3])=[CH:35][CH:36]=2)[CH:21]=[CH:22][C:23]=1[OH:24]
Reactant: C[Si](C)(C)Oc1ccc(CCc2ccc(N)cc2)cc1O[Si](C)(C)C
Reactant: Cc1ccc2c(c1)O[Si](C)(C)OC2=O
Product: Cc1ccc(C(=O)Nc2ccc(CCc3ccc(O)c(O)c3)cc2)c(O)c1
Temperature: 180 °C
Yield: 48.2 %

Procedure:
A mixture of 2,2,7-trimethyl-4H-1,3,2-benzodioxasilin-4-one (2.0 g, 10 mmole) and 4-[2-[3,4-bis[(trimethylsilyl)oxy]phenyl]ethyl]benzenamine (3.0 g, 8 mmol) is heated under argon to 180° C. After three hours the mixture is cooled, triturated with pentane and filtered. The collected solid is rinsed several times with pentane and dried. Recrystallization from isopropanol gave the pure product (1.4 g), mp 201°-202° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1/[CH:31]=[CH:32]/[CH:33]=O.C([BH3-])#N.[Na+]>ClCCl.CO>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1/[CH:31]=[CH:32]/[CH2:33][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1
Reactant: O=C/C=C/c1cc(F)ccc1F
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)N(CCN1CCC(NC/C=C/c3cc(F)ccc3F)CC1)C(=O)CO2
Yield: 30.9 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 58) (1.5 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde (202 mg, 1.2 mmol) (FR 2872164) (200 mg, 1.1 mmol) and sodium cyanoborohydride were reacted as described under Example 21. Chromatography on silica gel with dichloromethane/methanol gave 168 mg (25%) product
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[CH:5][CH:4]=1.CC(C)=[O:30].OS(O)(=O)=O.O=[Cr](=O)=O.C(OCC)(=O)C.O>CC(C)=O>[NH2:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([N:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([OH:30])=[O:1])=[CH:8][CH:7]=3)=[CH:10][C:11]([C:24]([F:25])([F:26])[F:27])=[N:12]2)=[CH:19][CH:18]=1)(=[O:22])=[O:21]
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(CO)cc2)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C(=O)O)cc2)cc1

Procedure:
To the product from Example 11 in 2 mL of acetone was added 1.33 M Jones reagent until an orange color persisted. The reaction was poured into 20 mL of ethyl acetate and 20 m of H2O and the organic layer separated, washed with saturated sodium bisulfite and dried over MgSO4. The crude was product was filtered through silica gel/Celite to afford the title compound as a yellow solid: HRMS m/z 411.0507 (calc'd for C17H12N3O4SF3, 411.0500).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>[Pd]>[C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]4[CH2:33][CH2:32][CH2:31][CH2:30][N:29]=4)=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCCCNc3ccccn3)ccc12
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCCCNC3=NCCCC3)ccc12

Procedure:
In accordance with Example 19, 200 mg of ethyl 3-phenyl-3-{6-[3-(pyridin-2-ylamino)propoxy]indol-3-yl}propionate 7 are hydrogenated in the presence of 2N hydrochloric acid and palladium/activated carbon (10%) to give 41.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[O:21]1[C:25]2([CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:27]3[CH2:28][CH2:29][C:25]4([O:21][CH2:22][CH2:23][CH2:24]4)[CH2:26]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1COC2(C1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC2(CCCO2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 1-oxa-7-azaspiro[4.4]nonane (176-12-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=394.5 [MH+].
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[S:8]/[C:9]/1=[N:10]\[C:11](=O)[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[CH2:2][CH2:3][CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>C1(C)C=CC=CC=1>[CH2:1]([C:5]1=[CH:6][N:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[S:8]/[C:9]/1=[N:10]\[C:11]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])=[S:27])[CH2:2][CH2:3][CH3:4]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Solvent: Cc1ccccc1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=S)c1cc(Cl)ccc1OC
Temperature: 82 °C
Yield: 35.3 %

Procedure:
To a solution of Example 1D (380 mg, 1 mmol) in toluene (25 mL) was added P2S5 (220 mg, 1 mmol) and the reaction mixture was heated at 82° C. for 75 minutes, concentrated under reduced pressure and purified via column chromatography (SiO2, 0-25% EtOAc in hexanes) to provide the title compound (0.14 g, 34% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.95 (t, J=7.3 Hz, 3H), 1.40 (dd, J=15.1, 7.5 Hz, 2H), 1.61-1.78 (m, 11H), 2.84-3.00 (m, 2H), 3.84 (s, 3H), 6.90 (d, J=8.7 Hz, 1H), 7.27-7.35 (m, 1H), 7.66 (d, J=2.8 Hz, 1H), 8.13 (s, 1H). MS (DCI/NH3) m/z 398 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][C:8]([CH3:10])=O>C(Cl)Cl>[CH3:7][C:8]1([CH3:10])[NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4]1
Reactant: CC(C)(N)CO
Reactant: CC(C)=O
Solvent: ClCCl
Product: CC1(C)COC(C)(C)N1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Into a 500 mL, three-necked flask with a reverse Dean-Stark trap is added 45 g (500 mmol) of 2-amino-2,2-dimethylethanol, 40 g (700 mmol) of acetone and 200 mL of methylene chloride. The reaction mixture is heated to reflux for 16 hours until no starting 2-amino-2,2-dimethylethanol is detected. The reaction mixture is allowed to cool to ambient temperature and is than concentrated under vacuum (200 mm Hg/30° C.) to give 50 g (77.5% yield) of a colorless liquid. The product is identified by mass spectroscopy (m/z=129) and 1Hnmr analysis.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[N+](C1C=C([N+]([O-])=O)C=CC=1C(NCC(OCC1C=CC=CC=1)=O)=O)([O-])=O.[N+:46]([C:49]1[CH:50]=[C:51]([CH:55]=[CH:56][C:57]=1[N+:58]([O-:60])=[O:59])[C:52](Cl)=[O:53])([O-:48])=[O:47]>>[N+:46]([C:49]1[CH:50]=[C:51]([CH:55]=[CH:56][C:57]=1[N+:58]([O-:60])=[O:59])[C:52]([NH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:53])([O-:48])=[O:47]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: NCC(=O)OCc1ccccc1
Agent: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)OCc1ccccc1

Procedure:
The reaction of 3,4-dinitrobenzoyl chloride (prepared from 3,4-dinitrobenzoic acid, 500 mg and SOCl2, 10 mL) with benzyl glycinate.PTS salt (794 mg, 2.358 mmol) in the presence of triethylamine (1.0 mL, 7.07 mmol) as described in intermediate 1 gave the title compound as an yellow color solid (780 mg, 92%), mp 150-152° C. 1H NMR (400 MHz, CDCl3): δ 8.37 (1H, br s), 8.17 (1H, d, J=8.0 Hz), 8.00 (1H, d, J=7.6 Hz), 7.39 (5H, s), 6.79 (1H, br s), 5.26 (2H, s), 4.31 (2H, d, J=4.0 Hz); LC-MS (negative ion mode): m/z 358 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].CC([O-])(C)C.[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH2:26])=[O:25])[CH:19]=1>CN(C=O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH2:26])=[O:25])[CH:19]=2)=[C:4]([F:9])[C:3]=1[F:10]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(N)c(F)c2F)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of 4-amino-2,3-difluorophenol (208 mg, 1.43 mmol) in DMF (4 mL) was added t-BuOK (257 mg, 2.29 mmol). The reaction was stirred at rt for 30 minutes, then 4-chloropicolinamide (249 mg, 1.59 mmol) was added. The mixture was microwaved at 120° C. for 3 hours, then cooled to rt and diluted with 25 mL of water. The resulted mixture was extracted with EtOAc (30 mL×3), and the combined organic phases were washed with brine (30 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as an orange solid (110 mg, 41.5%).
Reaction SMILES: C[O-].[Na+].C([O:7][CH:8]([CH:33]([O:46]C(=O)C)[CH:34]([O:42]C(=O)C)[CH:35]([O:38]C(=O)C)[CH2:36][OH:37])[C:9](=[O:32])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][NH:17][C:18]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])(=O)C>CO>[OH:7][CH:8]([CH:33]([OH:46])[CH:34]([OH:42])[CH:35]([OH:38])[CH2:36][OH:37])[C:9](=[O:32])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][NH:17][C:18]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19]
Reactant: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCNC(=O)COCCOCCOCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)COCCOCCOCC(=O)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO
Reaction time: 2 h

Procedure:
At room temperature, 100 μl of a 5.4 M sodium methoxide solution in methanol are added to a solution of 200 mg of {2-[2-({2-[2-(3,4,5,6-tetraacetoxy-7-hydroxy-2-oxo-heptyloxy)ethoxy]ethylcarbamoyl}methoxy)ethoxy]ethoxy}acetic acid (24) in 5 ml of methanol, and the mixture is stirred for 2 h. 1 g of Amberlite IR 120 is added to the reaction solution and the mixture is stirred for 10 min, filtered and concentrated, giving 26:
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:9][C@H:8]([CH2:10][OH:11])[C@H:7]2[CH2:12][OH:13])[C:4]2[N:14]=[C:15]([NH2:19])[N:16]=[C:17](N)[C:3]=2[N:2]=1.P([O-])([O-])([O-])=[O:21]>[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O>[CH:1]1[N:5]([C@@H:6]2[O:9][C@H:8]([CH2:10][OH:11])[C@H:7]2[CH2:12][OH:13])[C:4]2[NH:14][C:15]([NH2:19])=[N:16][C:17](=[O:21])[C:3]=2[N:2]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@H]3CO)c2n1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Product: Nc1nc(=O)c2ncn([C@@H]3O[C@H](CO)[C@H]3CO)c2[nH]1
Temperature: 37 °C
Reaction time: 50 h

Procedure:
After 2.0 g of 2-amino-OXT-A was dissolved in 300 ml of 1/10M phosphate buffer (pH 6.5), 200 units of 5'-adenylic acid deaminase (manufactured by Sigma Co., A-1907) were added to the solution followed by stirring at 37° C. for 50 hours. After the reaction solution was passed through a column packed with MCI® GEL CHP 20 (300 ml) and the reaction products were adsorbed onto it, the products were eluted by water. Fractions showing an Rf value of about 0.42 in silica gel TLC [developing solvent: n-butanol-acetic acid-water (4:1:2)] were collected and concentrated to dryness under reduced pressure to give 1.8 g of OXT-G as colorless crystals (yield, 90%).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:26][C:23]([F:24])([F:25])[C:20]1[N:19]=[CH:18][C:17]([C@H:9]2[CH2:8][C@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)=[CH:22][CH:21]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)nc1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3ccc(C(F)(F)F)nc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)-piperidine-1-carboxylate (60 mg, 0.16 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 1.27 mL, 7.27 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(6-(trifluoromethyl)pyridin-3-yl)piperidin-4-yl)isoxazol-3(2H)-one (11.4 mg, 23%), 1H NMR (400 MHz, dmso) δ 1.77-1.99 (m, 3H), 2.06-2.16 (m, 1H), 2.69-2.80 (m, 1H), 2.83-2.94 (m, 1H), 3.07-3.59 (m, 1H), 3.94 (d, 1H), 6.03 (s, 1H), 7.86 (d, 1H), 8.08 (d, 1H), 8.78 (s, 1H). HRMS Calculated for [C14H14F3N3O2+H]+: 314.1116. Found: 314.1122
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:31](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[OH:24])=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:31][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[OH:24])=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(C(O)c5ccccc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(C(O)c5ccccc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 91.5 %

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-yl]phenylmethanol is prepared as described in Example 179a starting with 0.105 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-yl]phenylmethanol instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.85 cm3 of 5N potassium hydroxide. 0.070 g Of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-yl]phenylmethanol is obtained, the characteristics of which are as follows:
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:43]I>CCCCCCC.CCOC(C)=O>[I:43][CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17]
Reactant: COc1ccc2c(c1)N(C[C@H](C)CO)C(=O)CO2
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Yield: 81.7 %

Procedure:
The compound (S)-4-(3-Hydroxy-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF34) (2.70 g, 12.0 mmol), triphenylphosphine (6.92 g, 26.4 mmol), Imidazole (1.96 g, 28.8 mmol) and I2 (8.53 g, 33.6 mmol) were mixed according to GP9. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (II 1MF36) (3.54 g, 82%). 1H NMR (CDCl3) δ 6.92 (d, J=8.4 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.53 (dd, J=2.8 Hz, J=8.8 Hz, 1H),4.54 (q, J=14.8 Hz, J=23.6 Hz, 2H), 3.92 (d, J=7.4 Hz, 2 H), 3.80 (s, 3H), 3.18 (dd, J=1.0 Hz, J=6 Hz, 2H), 2.17-2.08 (m, 1H), 1.05 (d, J=6.8 Hz, 3H); 13C NMR (CDCl3) δ 165.4, 155.6, 139.6, 129.4, 117.7, 108.0, 102.5, 68.0, 56.1, 46.1, 33.6, 18.9, 12.0.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:21][CH2:22][C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)=[C:10]([NH:12][C:13](=O)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].N>C(O)C>[C:14]1([C:13]2[N:21]([CH2:22][C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:11][C:10]=3[N:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc(CNc2ccc(N3CCCC3)cc2NC(=O)c2ccccc2)cc(OC)c1OC
Agent: Cl
Agent: N
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cn2c(-c3ccccc3)nc3cc(N4CCCC4)ccc32)cc(OC)c1OC
Temperature: 50 °C

Procedure:
To a suspension of N-(5-(pyrrolidin-1-yl)-2-(3,4,5-trimethoxybenzylamino)phenyl)benzamide in ethanol (20 mL) was added 4 N HCl. The reaction mixture was heated at 50° C. for 5 h, then cooled to room temperature. Excess acid was neutralized with ammonia hydroxide, and the resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organics were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuum. The residue was subjected to flash chromatography on silica gel to obtain 2-phenyl-5-(pyrrolidin-1-yl)-1-(3,4,5-trimethoxybenzyl)-1H-benzo[d]imidazole as a solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.75-7.72 (m, 2H, 2′,6′-H), 7.55-7.50 (m, 3H, 3′, 4′, 5′-H), 7.34 (d, J=8 Hz, 1H, 7-H), 7.75 (d, J=2 Hz, 1H, 4-H), 6.60 (dd, J=8, 2 Hz, 1H, 6-H), 6.29 (s, 2H, 2″, 6″-H), 5.38 (s, 2H, CH2), 3.56 (s, 9H, OCH3), 3.25-3.22 (m, 4H, 2′,5′-H), 1.97-1.94 (m, 4H, 3′,4′-H); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 152.9, 152.9, 152.5, 144.8, 144.0, 136.6, 132.7, 130.7, 129.4, 128.9, 128.9, 128.7, 128.7, 127.9, 111.1, 109.9, 103.7, 103.7, 99.9, 59.8, 55.7, 55.7, 47.9, 47.9, 47.7, 24.8, 24.8; EIMS: m/z 443 (M+).