Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>>[OH:29][CH2:28][CH:27]([NH:26][C:22]([C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:25])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:17])([CH3:16])[C:10]=2[CH:18]=1)=[O:24])[CH2:30][OH:31]
Reactant: NC(CO)CO
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(C(=O)NC(CO)CO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-aminopropane-1,3-diol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=3[O:22][CH3:23])[O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:27].[K+]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[O:22][CH3:23])=[C:9]([CH:10]=1)[C:8]([OH:27])=[O:11]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(C(F)(F)F)ccc1C1OC(=O)c2cc(Br)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1cc(C(F)(F)F)ccc1C(=O)c1ccc(Br)cc1C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a stirred mixture of 6-bromo-3-(2-methoxy-4-(trifluoromethyl)phenyl)isobenzofuran-1(3H)-one (2.06 g, 5.32 mmol) in KOH (21.3 mL, 5.32 mmol, 25% aqueous solution) and pyridine (10.6 mL) in a pressure tube was added powder potassium permanganate (1.26 g, 7.98 mmol). The reaction was heated at 100° C. After 4 h, the reaction was cooled to RT and the mixture was filtered, and the residue was washed with water. The filtrate was acidified with concentrated HCl until a pH of about 2. The white solid that precipitated out of the solution was filtered off with the aid of water and dried to afford 5-bromo-2-(2-methoxy-4-(trifluoromethyl)benzoyl)benzoic acid (2.16 g, 100% yield). This material was carried on to the next step. m/z (ESI) 405.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O[CH:13](OCC)[CH2:14][NH2:15])C>>[Cl:1][C:2]1[CH:9]=[C:8]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[N:15][CH:14]=[CH:13]2
Reactant: CCOC(CN)OCC
Reactant: O=Cc1ccc(Cl)cc1
Product: Clc1ccc2cnccc2c1

Procedure:
Commercially available 4-chlorobenzaldehyde (10 g) was cyclized with aminoacetaldehyde diethyl acetal according to the procedure of Hendrickson, et. al., J. Org. Chem., 48, 3344 (1983), to give 6-chloroisoquinoline (600 mg). Nitration of the obtained product using the procedure of Campbell et. al., J. Am. Chem. Soc., 68, 1559 (1946) gave 6-chloro-5-nitroisoquinoline (700 mg). Substitution of 6-chloro for thiomethoxide according to the procedure of Massie, Iowa State Coll, J. Sci., 21, 41 (1946) (Ca 41:3033 g) gave 6-methylthio-5-nitroisoquinoline (632 mg). This material (200 mg) was reduced using stannous chloride (2.0 g) and concentrated hydrochloric acid (30 ml) to give 5-amino-6-(methylthio) isoquinoline (143 mg). This material (140 mg) was coupled with 2-hexylthiodecanoic acid (prepared according to the procedures described in Examples 1 and 3) using the procedure described in Example 25 to give the title compound (80 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CNc1cccc(C(=O)c2ccccc2)c1
Yield: 66 %

Procedure:
4.5 g Ethyl N-(3-benzoylphenyl)-glycinate, obtained at a 66% yield from 3-aminobenzophenone and ethyl bromoacetate by an analogous procedure to that of Example 1, are heated in the presence of 10 ml dimethyl sulphate and 2 ml water to 100° C. for 11/2 hours.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4](=[CH2:6])[CH3:5].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.C(OCC)(=O)C>[CH2:8]([O:7][CH2:3][C:4]([CH3:6])=[CH2:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: C=C(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)COCc1ccccc1
Reaction time: 0.5 h

Procedure:
Under nitrogen stream, 50 % sodium hydride (5.28 g; 0.11 mole) was added to dry tetrahydrofuran (50 ml), and a solution of methallyl alcohol (7.2 g;0.1 mole) in dry tetrahydrofuran (20 ml) was portionwise added thereto with ice-cooling, followed by stirring for 30 minutes. A solution of benzyl bromide (17.1 g; 0.1 mole) in dry tetrahydrofuran (20 ml) was added thereto to quench the reaction. The reaction mixture was diluted with ethyl acetate and washed successively with lN hydrochloric acid, water and an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 1-benzyloxy-2-methyl-2-propene.
Reaction SMILES: ClCCC1C=C(F)C=[CH:6][C:5]=1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1CCCl)(=[O:13])=[O:12].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[F:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([CH2:5][CH2:6][N:34]2[CH2:33][CH2:32][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:35]2)(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: O=S(=O)(c1ccc(F)cc1CCCl)c1ccc(F)cc1CCCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloroethyl-4-fluorophenyl sulfone (2.5 g), N-(t-butoxycarbonyl)piperazine (2.3 g) and triethylamine (1.7 ml) were dissolved in tetrahydrofuran (30 ml) and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried, and evaporated. The residue was purified by Cromatorex NH silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (4.4 g, quantitatively) as a colorless oil.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[C:15]([F:22])=[CH:14][C:10]=1[C:11](O)=[O:12].S(Cl)([Cl:25])=O>CN(C=O)C>[F:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[C:15]([F:22])=[CH:14][C:10]=1[C:11]([Cl:25])=[O:12]
Reactant: C#CCOc1cc(F)c(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOc1cc(F)c(C(=O)Cl)cc1F

Procedure:
To 20 ml of toluene were added 1.4 g of 2,5-difluoro-4-(2-propynyloxy)benzoic acid, 0.8 ml of thionyl chloride and 10 mg of DMF, and the mixture was heated to reflux for 2 hours. Then, the reaction mixture was concentrated under reduced pressure, and 1.5 g of 2,5-difluoro-4-(2-propynyloxy)benzoyl chloride was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:14](=[O:25])[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:7]1.ClC1C=C(C=CC=1Cl)CN1CCO[C@H](CN)C1.C1C([N+]([O-])=O)=CC=C([Cl-]C([O-])=O)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:14](=[O:25])[O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH2:7]1
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Agent: NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Intermediate 14 was prepared in an analogous manner to Intermediate 10 from Intermediate 12 (0.21 g) and 4-nitrophenylchloroformate (0.17 g) to yield the title compound (0.23 g).
Reaction SMILES: COC1C=CC([N:9]([C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)[C:10]([NH2:12])=[O:11])=CC=1.[CH3:21]S(O)(=O)=O>COCCOCCOC>[NH:9]1[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21][NH:12][C:10]1=[O:11]
Reactant: COc1ccc(N(C(N)=O)c2ccc(OC)cc2)cc1
Reactant: CS(=O)(=O)O
Solvent: COCCOCCOC
Product: O=C1NCc2ccccc2N1

Procedure:
A solution of 144 mg (0.53 mmol) 1,1-bis-(4-methoxy-phenyl)-urea, 160 μl (1.06 mmol) cumic aldehyde and 16 μl (0.27 mmol) methane sulfonic acid in 1 ml diglyme is heated for 4 d at 100°. The reaction mixture is extracted with water/dichloromethane and the intermediate dihydro-quinazolinone is isolated by preparative HPLC. Oxidation with ruthenium trichloride and sodium periodate, as described above, furnishes 4-(4-isospropyl-phenyl)-6-methoxy-1-(4-methoxy-phenyl)-1.H.-quinazolin-2-one.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl.[Cl:11][C:12]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:13]=1[CH:14]=O>O.C(O)C>[ClH:11].[Cl:11][C:12]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:13]=1[CH:14]=[N:5][NH:6][C:7]([NH2:9])=[NH:8]
Reactant: O=Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: O
Solvent: CCO
Product: N=C(N)NN=Cc1c(Cl)ccc([N+](=O)[O-])c1Cl

Procedure:
Aminoguanidine hydrogen carbonate (1.24 g, 9.1 mmol) was added to a solution of concentrated hydrochloric acid (0.8 cm3, 9.3 mmol) in water (3 cm3). After diluting the resulting solution with ethanol (20 cm3), 2,6-dichloro-3-nitrobenzaldehyde (2.0 g, 9.1 mmol) was added and the mixture heated under reflux for 7 h. The solution was evaporated under reduced pressure and the residual solid suspended in refluxing ethanol, basified (pH 11) by addition of dilute sodium hydroxide solution and cooled to yield a white solid which was collected. This solid was dissolved in hot methanol and the solution acidified (pH 2) with ethanolic hydrogen chloride, diluted with diethyl ether and cooled to yield (2,6-dichloro-3-nitrobenzylideneamino)-guanidine hydrochloride as a white solid, m.p. 186°-7° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])[CH:8]=2)[N:3]=1.[CH2:27]([Mg]Br)[CH2:28][CH3:29].C1COCC1>>[NH:21]=[C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:18]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[CH:10]2)[CH2:27][CH2:28][CH3:29]
Reactant: CCC[Mg]Br
Reactant: Cc1cccc(C#N)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Solvent: C1CCOC1
Product: CCCC(=N)c1cccc(C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 60 °C

Procedure:
To a sealed vessel containing 2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylbenzonitrile (0.040 g, 0.116 mmol) under N2 atmosphere was added a solution of propylmagnesium bromide, 2.0M in THF (0.232 mL, 0.465 mmol) via syringe at ambient temperature. The mixture was sonicated until all solids were in solution and then warmed vessel to 60° C. for 7 h. The mixture was concentrated, diluted with MeOH and purified on HPLC (10-100% MeCN/H2O with 0.1% TFA modifier) to afford 6-(2-(1-iminobutyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine as white solid. MS (ESI, pos. ion) m/z: 389 (M+1).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])#[N:16].O>CN(C)C(=O)C>[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:28][CH:27]=1)(=[O:25])=[O:24])#[N:16]
Reactant: N#Cc1ccccc1S(=O)(=O)c1ccc(N)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2C#N)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.82 g, 5.2 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.62 g, 5.2 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4-[(2-Cyanophenyl)sulfonyl]benzeneamine (1.00 g, 3.8 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured-into water and the aqueous solution decanted from an oily solid which was purified by flash column chromatography (5% v/v ethyl acetate/methylene chloride). Recrystallization from methylene chloride/hexane yielded the title propanamide as a white solid (1.08 g, 72%); mp 156°-158° C. 1H-NMR (250 MHz, d6-DMSO): 1.58 (s, 3H, CH3) 7.59 (s, 1H, OH) 7.88-8.13 (m, 7H, aromatic) 8.31 (d, 1H, J=6.9 Hz, aromatic) 10.50 (s, 1H, OH). MS (CI, CH4): 399 (M+1).
Reaction SMILES: Cl.[CH2:2]([C:9]1([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O>[CH2:2]([C:9]1([N:19]([CH3:20])[CH3:21])[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reaction time: 24 h
Yield: 76.5 %

Procedure:
200 ml of hydrochloric acid (32 wt. %) were diluted with 120 ml of water; 78.4 g of crude (8-benzyl-1,4-dioxa-spiro[4.5]dec-8-yl)-dimethyl-amine were added to this approximately six molar hydrochloric acid, and stirring was carried out for 24 hours. The reaction mixture was washed three times using 100 ml of diethyl ether each time, rendered alkaline (pH>10) with 100 ml of sodium hydroxide solution (32 wt. %) while cooling with an ice bath, and extracted three times using 100 ml of dichloromethane each time. The extracts were combined, dried over sodium sulfate, filtered and concentrated. 50.4 g of 4-benzyl-4-dimethylamino-cyclohexanone were obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([I:24])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](OCN1C2C(Cl)=NC(CCCC)=NC=2C(I)=C1C)C1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([I:24])=[C:11]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(N)c2c(n1)c(I)cn2COCc1ccccc1
Reactant: CCCCc1nc(Cl)c2c(n1)c(I)c(C)n2COCc1ccccc1
Product: CCCCc1nc(N)c2c(n1)c(I)c(C)n2COCc1ccccc1

Procedure:
Prepared similarly to Intermediate 6 from 5-((benzyloxy)methyl)-2-butyl-4-chloro-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidine
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].[BH4-].[Na+].Cl>COCCOC.O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH2:15][OH:16])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc2ccccc2c1-c1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 81.4 %

Procedure:
3-(2-Methyl-1-naphthyl)benzaldehyde (2.39 g, 9.70 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (10 mL) and tetrahydrofuran (10 mL), and sodium borohydride (0.189 g, 5.00 mmol) was added under ice-cooling. The mixture was stirred at the same temperature for 3 hr. Dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-30% ethyl acetate/hexane) to give the title compound (1.96 g, yield 81%) as a colorless viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)NCC2

Procedure:
A suspension of 21.9 gm (0.1 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one and 1.5 gm of 10% palladium-on-charcoal in 200 ml of glacial acetic acid was hydrogenated at 50° C. and at a hydrogen pressure of 5 bar. After the catalyst had been filtered off, the solvent was evaporated in vacuo, and the residue was taken up in methylene chloride. After the solution had been extracted with an aqueous sodium bicarbonate solution and washed with water, it was dried over magnesium sulfate, evaporated and purified over silica gel with methylene chloride and then with increasing amounts of methanol (up to 10%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:20][CH:21]=2)[C:16]([CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:15]1)=[O:11]>ClCCl>[C:25]([CH2:24][CH2:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:14]([CH2:13][CH2:12][C:10]([O:9][CH3:8])=[O:11])[CH:15]=[C:16]2[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)([OH:27])=[O:26]
Reactant: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCC(=O)OC(C)(C)C)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCC(=O)O)ccc21
Reaction time: 18 h
Yield: 86.5 %

Procedure:
Trifluoroacetic acid (15 ml) was added to a stirred solution of t-butyl 1-(2-methoxycarbonylethyl)-3-(3-pyridylmethyl)-1H-indole-5-propanoate (7.60 g) in dry dichloromethane (100 ml) at room temperature, and stirringwas continued for 18 hours. The solution was evaporated and the residue wasazeotroped with toluene and then dissolved in ethyl acetate. Saturated sodium bicarbonate solution was added slowly with shaking until the pH of the aqueous layer was 4-5. The organic layer was then separated, washed with water and dried (MgSO4). The solvent was evaporated and the residue was triturated with ether to give the title compound (5.70 g), m.p. 108°-110° C. Found: C,68.80; H,6.16; N,7.57%. C21 H22N2O4 requires: C,68.83; H,6.05; N,7.65%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C:14]([CH2:18][C:19]([OH:21])=O)([CH3:17])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C:14]([CH3:17])([CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC1(CC(=O)O)CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccccc1
Product: CC1(CC(=O)Nc2ccccc2)CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 74.2 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-5-methyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (100 mg, 0.28 mmol) and aniline (28 μL, 0.31 mmol) to give 89 mg of the title compound (73%): mp 155°~162° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ812.00 (s, 1H), 9.92 (s, 1H), 7.46 (d, 2H, J=8 Hz), 7.23 (t, 2H, J=8 Hz), 7.14 (bs, 2H), 6.99 (t, 1H, J=8 Hz), 3.63 (d, 1H, J=15 Hz), 2.90 (d, 1H, J=15 Hz), 2.80~2.90 (m, 2H), 2.25~2.40 (m, 1H), 1.85~2.00 (m, 1H), 1.68 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])[CH:6]=[CH:7][CH:8]=1.[OH:32][CH:33]([CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])[C:34]([NH:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][C:44](O)=[O:45])=[O:35].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][C:44]([CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][NH:36][C:34](=[O:35])[CH:33]([OH:32])[CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])=[O:45])=[CH:18][CH:17]=1
Reactant: O=C(O)COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO
Reactant: NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO)NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1

Procedure:
21 is prepared similarly to 18 starting from 100 mg of 4-(3-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (15), 122 mg of {2-[2-(2,3,4,5,6-pentahydroxyhexanoylamino)ethoxy]ethoxy}acetic acid (20), 93 μl of diisopropylcarbodiimide and 65 mg of hydroxybenzotriazole in 2 ml of dimethylformamide. This gives 21: C37H45F2N3O11 (745.78) MS (ESI) 746 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.N1C(=O)CC[C@H]1C(O)=O.C(Cl)Cl>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1)=[O:23]
Reactant: Oc1ccc(-c2cc3cc(O)ccc3o2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(-c2cc3cc(OC(=O)C(C)(C)C)ccc3o2)cc1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A solution of 75 (8.2 g, 36.3 mmol) in CH2Cl2/Pyr was treated with pivaloyl chloride (9.63 g, 79.9 mmol) and stirred at rt until TLC indicated that the reaction was complete. The reaction was worked up by diluting with additional CH2Cl2 and washing with 2 N HCl aq. The CH2Cl2 layer was washed with satd NaHCO3 aq, brine and dried over MgSO4. Filtration and concentration yielded 9.3 g of the crude solid that was used as is for the next reaction.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C@@H:19]1[C@@H:27]([CH2:28][OH:29])[O:26][C@H:25]2[C@H:21]([N:22]=[C:23]([N:30]([CH3:32])[CH3:31])[S:24]2)[C@H:20]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@@H:19]1[C@@H:27]([CH:28]=[O:29])[O:26][C@H:25]2[C@H:21]([N:22]=[C:23]([N:30]([CH3:32])[CH3:31])[S:24]2)[C@H:20]1[O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)O[C@@H]2S1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A solution of DMSO (14.6 g, 187 mmol) in dichloromethane (300 mL) was treated with oxalyl dichloride (17.7 g, 140 mmol) at −78° C. for 1 hour, then a solution of ((3aR,5R,6S,7R,7aR)-6,7-bis(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methanol (10 g, 23 mmol) in dichloromethane (30 mL) was added slowly. The resulted solution was kept for 4 hours at −20° C., followed by the addition of triethylamine (28.3 g, 280 mmol) at −78° C. After additional 1 hour at −50° C., the reaction was quenched by water (300 mL) and extracted with dichloromethane (2×200 mL). The organic layers combined, washed with brine (3×100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrates were concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 20% ethyl acetate in dichloromethane to give compound 95 as a yellow syrup (8.1 g, 80%). (ES, m/z): [M+H]+ 426.7; 1H NMR (300 MHz, CDCl3) δ 9.62 (s, 1H), 7.28-7.39 (m, 10H), 6.27-6.34 (m, 1H), 4.41-4.84 (m, 6H), 4.10-4.17 (m, 1H), 3.86-3.94 (m, 1H), 3.02 (s, 6H).