Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:8]2[CH2:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Cl)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:40][C:36]4[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=4)=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[C:8]2[CH2:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:31][CH:32]=1
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3cccnc3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A suspension of ethyl 3-[1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-hydroxyindol-2-yl]-2,2-dimethylpropionate (3.0 g; 6.5 mmol), prepared as in step 4, 3-picolyl chloride hydrochloride (1.1 g; 6.5 mmol), and powdered potassium carbonate (2.7 g; 19.5 mmol) in 20 mL dimethylformamide (DMF) was stirred at ambient temperature for 4 days. The reaction mixture was diluted with brine and extracted with ethyl acetate. The extracts were dried over magnesium sulfate and concentrated. The resulting residue was subjected to flash chromatography on silica gel (70% diethyl ether in hexane) to give ethyl 3-[1-(p-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-(pyrid-3-ylmethoxy)indol-2-yl]-2,2-dimethylpropionate as a pale yellow oil containing a small amount of DMF.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C@@H:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C@@H:7]([OH:24])[C:6]1=[O:25].C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1>C1C=CC=CC=1>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C@@H:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C@@H:7]([O:24][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=2)[C:6]1=[O:25]
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: O=C(Cl)c1cccnc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2cccnc2)cc1

Procedure:
7 Grams (0.0188 mole) of the compound prepared under (A) were dissolved in 80 ml of anhydrous benzene, and the resulting solution was added with 8 ml (0.0574 mole) of triethylamine and 5 g (0.0281 mole) of nicotinoylchloride suspended in 20 ml of anhydrous benzene. The reaction mixture was heated for 24 hours on an oil bath at 55°-60° C. under stirring then, after cooling, it was twice washed with water and the organic phase was dried over sodium sulfate. The organic solvent was removed in vacuo until formation of a precipitate then, after complete precipitation, the obtained solid was recovered by filtration, washed with anhydrous diethyl ether and dried overnight at 70° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17][CH2:18][CH2:19][CH3:20])=[C:15]([C:21]([OH:23])=O)[CH:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:4].Cl.[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH:26]1[NH2:35])[CH2:32]2.C(SC1N(C2C=CC(C(OC)=O)=CC=2)N=CC=1C(N1CCC(C2C=CC=CC=2C(F)(F)F)C1)=O)CC>>[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH:26]1[NH:35][C:21]([C:15]1[CH:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:11][CH:10]=3)[C:16]=1[S:17][CH2:18][CH2:19][CH3:20])=[O:23])[CH2:32]2
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(CC(=O)OC)cc1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CCCSc1c(C(=O)N2CCC(c3ccccc3C(F)(F)F)C2)cnn1-c1ccc(C(=O)OC)cc1
Agent: Cl
Product: CCCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(CC(=O)OC)cc1

Procedure:
Prepared from 1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate #35) and 2-adamantylamine hydrochloride by the same procedure as used for Intermediate #6.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([C:17](OCC)=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[OH:18][CH2:17][C:4]1([CH2:3][O:2][CH3:1])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1(COC)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: COCC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl 4-(methoxymethyl)piperidine-1,4-dicarboxylate (2.05 g) in toluene (21 ml) was added 0.99 M solution of diisobutyl aluminum hydride in toluene (16.5 ml) under at 0° C. It was stirred at room temperature for 2 hours. Water was added and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4, evaporated off. The residue was purified by silica gel column to give tert-butyl 4-(hydroxymethyl)-4-(methoxymethyl)piperidine-1-carboxylate (0.95 g) as oil.
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])[C:8](=[O:14])[C:7](=[CH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:6]2.CO.C(Cl)Cl>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:7]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)C(=Cc1ccncc1)C2
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1)C2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.3 %

Procedure:
The mixture of 5,6-dimethoxy-2-(4-pyridyl)methylene-1-indanone (34 gm), methanol (325 ml), methylenedichloride (200 ml) and 5% palladium-charcoal (2 gm) is taken in a hydrogenation flask and subjected to hydrogenation under a hydrogen pressure of 2 bars for 3 hours. The catalyst is removed by filtration and the solvents are evaporated completely under vacuum to obtain a residue. Ethyl acetate (150 ml) is added to the residue and stirred for 20 minutes at 25° C. to 30° C. The contents are then cooled to 0° C., stirred for 30 minutes and filtered to give 34 gm of 5,6-dimethoxy-2-(4-pyridyl)methyl-1-indanone.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:7]=[C:8]([NH2:19])[CH:9]=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[N-:20]=[N+:21]=[N-].[Na+].C([O-])(=O)C.[Na+]>Cl>[N:19]([C:8]1[CH:7]=[C:6]([F:5])[C:11]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[C:10]([F:18])[CH:9]=1)=[N+:20]=[N-:21]
Reactant: Nc1cc(F)c(N2CCOCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Product: [N-]=[N+]=Nc1cc(F)c(N2CCOCC2)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
Sodium nitrite (0.91 g, 13.3 mmol) was added to an ice-cooled solution of 3,5-difluoro-4-morpholin-4-yl-phenylamine (0.95 g, 4.4 mmol), obtained in Preparation 6, in 6N HCl (30 mL) and the resulting yellow solution was stirred at 0° C. for 2 h. To this mixture was added an aqueous solution containing sodium azide (0.575 g, 8.86 mmol) and sodium acetate (57.5 g, 88.6 mmol). The reaction mixture was then extracted with ethyl acetate (50 mL×2) and the combined extracts were washed with 5% sodium bicarbonate solution followed by brine and dried over sodium sulfate. Evaporation of volatiles yielded the title compound as brown solid (1 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][C:22]1[CH2:26][CH2:25][CH2:24][C:23]=1Br.O>C1(C)C(CCO)=CC=CC=1>[CH3:11][O:10][C:8](=[O:9])[C:6]1[CH:5]=[C:4]([C:23]2[CH2:24][CH2:25][CH2:26][C:22]=2[Br:21])[CH:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: BrC1=C(Br)CCC1
Reactant: COC(=O)c1cc(N)cc(B(O)O)c1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cc(N)cc(C2=C(Br)CCC2)c1
Yield: 86.9 %

Procedure:
(3-amino-5-methoxycarbonylphenyl)boronic acid (2.66 g, 13.6 mmol), Pd(0) [PPh3]4 (1.57 g, 1.36 mmol), potassium carbonate (15 g, 108 mmol) and 1,2-dibromocyclopentene (12 g, 53 mmol) in toluene-ethanol (1:1 60 mL) were stirred at 90° C., under nitrogen, for 2 hrs. Upon cooling, the reaction mixture was poured into water and extracted with ethyl acetate (40×3 mL). The combined organic layers were dried over MgSO4 and concentrated. Purification was carried out on a Biotage® using isohexane containing a gradient of ethyl acetate (0–20%) to give the required product as yellow solid (3.5 g, 87%). 1H NMR (CDCl3):1.96–2.0 (2H,m), 2.50 (2H,t,J=7.4), 2.67 (2H,t,J=7.4), 3.80 (2H,bs), 3.88 (3H,s), 7.14 (1H,s), 7.28 (1H,s), 7.59 (1H,s). LC/MS[MH+]=296, 298 Rt=3.38.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]2[NH:28][CH2:29][CH2:30][N:31]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[N+:34]([C:37]1[CH:47]=[CH:46][C:40]([CH2:41][O:42][C:43](Cl)=[O:44])=[CH:39][CH:38]=1)([O-:36])=[O:35].C(O)(=O)C>O1CCCC1.ClCCl>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]2[N:28]([C:43]([O:42][CH2:41][C:40]3[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:47][CH:46]=3)=[O:44])[CH2:29][CH2:30][N:31]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C2=NCCN2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C2=NCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 107.6 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-(2-imidazolin-2-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (930 mg) in tetrahydrofuran (20 ml) was added sodium hydride (62.8% suspension in oil, 103 mg), and to this mixture was dropwise added a solution of 4-nitrobenzyloxycarbonyl chloride (531 mg) in dichloromethane (15 ml) at 0° C. After stirring at 0° C. for 1.5 hours, acetic acid (0.18 ml) was added thereto. The mixture was evaporated, extracted with ethyl acetate, and washed with saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated, the obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and acetone (9:1, V/V) to give (2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl)-2-imidazolin-2-yl]pyrrolidine (1.4 g).
Reaction SMILES: [Al].[C:2]([C:8]1[N:9]=[C:10]([Cl:17])[C:11]2[CH:16]=[CH:15][NH:14][C:12]=2[N:13]=1)(=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[I:18]N1C(=O)CCC1=O>C1COCC1>[C:2]([C:8]1[N:9]=[C:10]([Cl:17])[C:11]2[C:16]([I:18])=[CH:15][NH:14][C:12]=2[N:13]=1)(=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)C(=O)c1nc(Cl)c2cc[nH]c2n1
Agent: [Al]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1nc(Cl)c2c(I)c[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a 100 ml round bottom flask covered with aluminum foil was charged 1.50 g (5.94 mmol) of 2-pivaloyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine dissolved in 30 ml of anhydrous THF, followed by the addition of 1.47 g (6.5 mmol) of N-iodosuccinimide. The dark brown solution was stirred at RT under a nitrogen atmosphere for 1 h. The solvent was removed in vacuo, and the residue was dissolved in CHCl3, washed with water, dried over Na2SO4, and removed in vacuo. The crude residue was then flash chromatographed on silica gel eluting with a gradient of 100% CHCl3 to 2% MeOH/CHCl3. After collecting the correct fractions, the solvents were removed in vacuo to give 1.86 g (83%) of 2-pivaloyl-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine as a
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OS(C)(=O)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere 4-methanesulfonyloxy-benzoic acid methyl ester (2.3 g, 10 mmol) was dissolved in dry THF (50 mL) and LiAlH4 (0.28 g, 10 mmol) was added at 0° C. After the addition was completed the ice bath was removed and stirring was continued at r.t. for 2 h. The mixture was cooled down to 0° C. again and excess LiAlH4 was hydrolyzed by the addition of MeOH, H2O and aq. HCl (2N). After extracting DCM the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to afford the crude but mainly pure product as an oil which was used in the next step without further purification (1.95 g, 96.4%). 1H NMR (400 MHz, CDCl3): δ 7.35-7.37 (d, 2H), 7.21-7.23 (d, 2H), 4.65 (s, 2H), 3.09 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(O)C>O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(F)c(OCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Charge methyl 4-fluoro-3-hydroxybenzoate (519 mg, 3.05 mmol), 4-(bromomethyl)-1-fluorobenzene (577 mg, 3.05 mmol), K2CO3 (843 mg, 6.10 mmol) and ethanol (10 mL) to a flask. The mixture was then stirred at room temperature overnight. Water was added to the reaction mixture at 0° C., filtered, and the solid dried and purified by flash column chromatograph to give 571 mg of the title compound (67%). 1H NMR (400 MHz, CDCl3): δ 3.90 (3H, s), 5.13 (2H, s), 7.06-7.15 (3H, m), 7.41-7.45 (2H, m), 7.63-7.67 (1H, m), 7.71 (1H, dd, J=2.0 Hz, 8.4 Hz).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18]>>[C:1]([N:9]1[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: NO
Agent: Cl
Product: O=C(c1ccccc1)N1CCC(=NO)CC1

Procedure:
1-Benzoyl-piperidin-4-one oxime was prepared from 1-benzoyl-piperidin-4-one and hydroxylamine hydrochloride using conditions of General Method 1. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (1H, br. s.), 7.29-7.54 (5H, m), 3.49-3.81 (4H, m), 2.44-2.66 (2H, m), 2.17-2.42 (2H, m).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]2[C:27](=[O:28])[NH:26][N:25]=[CH:24][C:13]3=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][C:16]([CH:17]=1)=[C:12]23>CN(C)C=O.CO>[O:28]=[C:27]1[C:11]2[C:12]3[C:13](=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][C:16]=3[CH:17]=[C:9]([NH:8][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH:10]=2)[CH:24]=[N:25][NH:26]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)CCC(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Temperature: 22 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
Succinic anhydride (3 eq, 0.022 g) was added to a solution of the title compound of Example 7 (0.02 g, 0.072 mmol) in N,N-dimethylformamide (0.7 M, 1 mL) and methanol (2.5 M, 0.3 mL). The reaction mixture was stirred at 22° C. for 24 hours and concentrated under reduced pressure. The yellow solid was triturated with methanol (1.0 mL) and collected by filtration. Following washes with methanol (4 mL) and diethyl ether (5.0 mL), the title compound (21 mg) was obtained in 77% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[CH3:14]
Reactant: CCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(F)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-4-nitrophenol (1.57 g, 10.0 mmol) in 20 mL of dry DMF was added bromoethane (540 mg, 5.0 mmol) and K2CO3 powder (500 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H2O, extracted with diethyl ether (100 mL×2). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 4-ethoxy-2-fluoro-1-nitrobenzene as a pale yellow oil: MS (ESI) 186 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[N:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:30]=[CH:29][C:21]([O:22][CH2:23][CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[C:20]([O:31][CH3:32])[CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[N:15]=[CH:14][N:13]([C:18]3[CH:30]=[CH:29][C:21]([O:22][CH2:23][CH:24]([CH:26]4[CH2:27][CH2:28]4)[OH:25])=[C:20]([O:31][CH3:32])[CH:19]=3)[C:12](=[O:16])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(CSc2ccc(Cl)cc2)nc[nH]1
Reactant: COc1cc(Br)ccc1OCC(O)C1CC1
Product: COc1cc(-n2cnc(CSc3ccc(Cl)cc3)cc2=O)ccc1OCC(O)C1CC1

Procedure:
N-arylation of 6-((4-chlorophenylthio)methyl)pyrimidin-4(3H)-one Part B of Procedure 10 with 2-(4-bromo-2-methoxyphenoxy)-1-cyclopropylethanol Part C to generate G-2 was achieved using the procedure described in Part C of Procedure 10. LC/MS 459 (M+H)+, tR 0.97 min (method 5). 1H NMR (400 MHz, Chloroform-D) δ ppm 8.14 (1H, s), 7.26-7.40 (4H, m), 7.03 (1H, d), 6.80-6.91 (2H, m), 6.45 (1H, s), 4.20 (1H, dd, J=9.54, 2.76 Hz), 4.03 (1H, t, J=8.91 Hz), 3.96 (2H, s), 3.87 (3H, s), 3.36 (1H, td, J=8.34, 2.64 Hz), 0.91-1.06 (1H, m), 0.51-0.67 (2H, m), 0.40-0.50 (1H, m), 0.26-0.37 (1H, m).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[N:18]=3)[N:16]=[C:10]2[CH:9]1[C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:35][CH:36]=1)C1C=CC=CC=1.C(O)(=O)C.[H][H].C(OCC)(=O)C>CO.[OH-].[Pd+2].[OH-]>[C:33]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:35][CH:36]=[C:31]([CH:9]2[NH:8][CH2:13][CH2:12][N:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]5)=[C:19]([O:29][CH3:30])[N:18]=4)[N:16]=[C:10]23)[CH:32]=1
Reactant: [H][H]
Reactant: COc1nc(-c2nc3n(n2)CCN(Cc2ccccc2)C3c2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1nc(-c2nc3n(n2)CCNC3c2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Yield: 9.9 %

Procedure:
To a solution of 7-benzyl-8-biphenyl-3-yl-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine (541 mg) and acetic acid (1.32 ml) in methanol (52 ml) was added 20% palladium hydroxide (743 mg) and the reaction mixture was stirred at room temperature in a hydrogen atmosphere for 4 days. After the reaction atmosphere was replaced with nitrogen, ethyl acetate was added to the reaction mixture. The catalyst was removed by filtration by Celite. The filtrate was concentrated under reduced pressure and the residue was purified by NH silica gel column chromatography to obtain the title compound (45 mg) and the raw material. (291 mg)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C:4]2[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:3]1=2.O1C2C(=CC=C(O)C=2)CCC1.[O:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[C:31]1=[O:40].C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:39][C:32]1([C:9]2[C:10]([OH:12])=[CH:11][C:3]3[N:2]([CH3:1])[CH2:7][CH2:6][O:5][C:4]=3[CH:8]=2)[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]([CH2:29][C@H:25]2[CH2:26][CH2:27][CH2:28][O:24]2)[C:31]1=[O:40]
Reactant: O=C1C(=O)N(C[C@H]2CCCO2)c2ccccc21
Reactant: CN1CCOc2ccc(O)cc21
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: Oc1ccc2c(c1)OCCC2
Product: CN1CCOc2cc(C3(O)C(=O)N(C[C@H]4CCCO4)c4ccccc43)c(O)cc21

Procedure:
Following the procedure as described in PREPARATION 14A, and making non-critical variations using 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ol (McMurtrey, K. D., et al., J. Org. Chem. (1970), 35(12):4252-3) to replace chroman-7-ol, and 1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-indole-2,3-dione to replace 1-(diphenylmethyl)indoline-2,3-dione, 3-hydroxy-3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one was obtained (92%) as a pale brown solid: 1H NMR (300 MHz, CDCl3) δ9.21 (d, J=13.6 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.36 (dd, J=7.8, 7.8 Hz, 1H), 7.17 (dd, J=7.5, 7.2 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 6.40 (s, 1H), 6.18 (s, 1H), 4.25-4.06 (m, 3H), 3.87-3.63 (m, 4H), 3.27-3.17 (m, 2H), 2.87 (s, 3H), 2.02-1.74 (m, 3H), 1.71-1.57 (m, 2H); 13C NMR (75 MHz, CDCl3) δ179.8, 179.7, 151.54, 151.52, 143.1, 143.0, 138.0, 137.4, 130.12, 130.10, 129.32, 129.29, 126.1, 126.0, 123.8, 114.8, 114.6, 113.1, 113.0, 110.4, 110.3, 103.5, 79.11, 79.06, 76.9, 76.7, 68.32, 68.26, 64.6, 48.9, 44.6, 38.5, 29.3, 29.1, 25.7, 25.6; MS (ES+) m/z 418.9 (M+23).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH2:31][C:32](=[O:38])[NH:33]2>>[F:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[C:31](=[CH:19][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)[C:7](=[O:18])[C:6]=3[C:2]=1[CH3:1])[C:32](=[O:38])[NH:33]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 33.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 33.3%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](C[C@@H](C([O-])=O)N)=[CH:5][CH:4]=1.[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:28]([OH:30])=[O:29])[CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.COC1C=CC(O)=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([O:29][C:28](=[O:30])[C@H:26]([CH3:27])[NH:25][C:23]([O:22][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(C[C@H](N)C(=O)[O-])cc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COc1ccc(O)cc1
Product: COc1ccc(OC(=O)[C@H](C)NC(=O)OCc2ccccc2)cc1
Yield: 57 %

Procedure:
4-Methoxyphenylalaninate was first prepared by reacting N-benzyloxycarbonyl-(S)-alanine (10.9 g, 0.049 mole) with 4-methoxyphenol and 1,3-dicyclohexylcarbodiimide to give 9.2 g (57%) of N-benzyloxycarbonyl-(S)-alanine 4-methoxyphenyl ester, mp 128°-129° C.; [α]D25 -18.98° (c=0.769, CHCl3); IR (KBr): 3320, 1750 and 1660 cm-1 ; NMR (δ): 1.52 (3H, d, J=7.4 Hz), 3.72 (3H, s), 4.48 (1H, q, J=7.4 Hz), 5.08 (2H, s), 5.36-5.48 (1H, broad, signal disappeared in D2O), 6.68-7.48 (9H, m). Anal. for C18H19NO5 : Calcd: C, 65.65; H, 5,77; N, 4.25. Found: C, 65.74; H, 5.91; N, 4.31.