Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[CH2:28][C:29](=[O:31])[CH3:30]>>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:28][C:29](=[O:31])[CH3:30])[CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:4]=2[CH:3]=1
Reactant: CC(=O)CCl
Reactant: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Solvent: CCN(CC)CC
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c([N+](=O)[O-])cc23)C1
Yield: 35.6 %

Procedure:
Prepared by the method described for example 26 from 1,2,3,4-tetrahydro-8-methyl-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.0 g, 0.008 moles), triethylamine (2.3 ml, 0.017 moles), and 1-chloro-2-propanone (0.7 g, 0.008 moles). Recrystallization from methanol gave the product (0.9 g), mp 166°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1)([CH3:14])[C:6](=[O:13])[NH:7]2.B(Br)(Br)Br.ClCCl>CO>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1)([CH3:14])[C:6](=[O:13])[NH:7]2
Reactant: COc1ccc(C2(C)C(=O)Nc3cc(Cl)cc(Cl)c3C2=O)cc1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC1(c2ccc(O)c([N+](=O)[O-])c2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Yield: 43.7 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 5,7-dichloro-3-(4-methoxy-3-nitro-phenyl)-3-methyl-1H-quinoline-2,4-dione (0.12 g, 0.30 mmol) and BBr3 (0.90 mL, 1.0 M dichloromethane solution). After normal workup, the objective compound (50 mg, 48%) was obtained as pale yellow solid by a flash column chromatography (dichloromethane:methanol=30:1): 1H NMR (200 MHz, DMSO-d6) δ 1.58 (s, 3H, CH3), 7.05-7.09 (m, 2H, ArH), 7.14-7.31 (m, 2H, ArH), 7.61 (d, J=2.4 Hz, 1H, ArH); m.p. 239-240° C.; MS(EI) m/e 380 [M+], 193, 165, 135; HRMS m/e cacld. for C16H10N2O5Cl2 379.9967, found 379.9968.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2cc(NCc3ccccc3)ccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
To a stirred solution of 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (350 mg, 1.41 mmol) in dichloromethane (15 ml) was added benzaldehyde (143 μl, 1.41 mmol), acetic acid (81 μl, 1.41 mmol) followed by sodium triacetoxyborohydride (418 mg, 1.97 mmol) and the reaction was stirred at room temperature for 16 hrs. The reaction mixture was quenched by cooling in ice batch and neutralising with aqueous sodium hydroxide 2M. The aqueous mixture was extracted using dichloromethane (3×50 ml) and the organics were combined, dried over sodium sulfate and then concentrated in vacuo. The crude residue was purified by column chromatography (1% methanol in dichloromethane) to afford the title compound as cream solid (320 mg, 67% yield). HPLC retention time 4.98 min. Mass spectrum (ES+) m/z 339 (M+H).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]CCCCC.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.CO>C1C=CC=CC=1>[CH3:8][O:23][C:22](=[O:24])[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([Br:14])=[CH:20][CH:19]=1)[OH:25]
Reactant: CCCCCC
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
A solution of trimethylsilyldiazomethane in hexane (2 M, 1.4 mL, 2.8 mmol) was added to a solution of 4-bromo-phenyl-hydroxy-acetic acid (506 mg, 2.19 mmol) in benzene (2.1 mL)-methanol (1.0 mL) under cooling with ice, and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (500 mg, 93%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[N:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:7]=2[C:6]1=[O:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:11][CH2:10][C:9](=[O:12])[C:8]4[N:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:7]=4[C:6]3=[O:18])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Cc1cn(C)c2c1C(=O)N(CCCCl)CCC2=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cn(C)c2c1C(=O)N(CCCN1CCN(c3ccc(F)cc3)CC1)CCC2=O
Yield: 80.2 %

Procedure:
Using Compound 13 (557 mg, 2 mmole), 1-(4-fluorophenyl)piperazine (541 mg, 3 mmole), potassium carbonate (415 mg, 3 mmole), sodium iodide (600 mg, 4 mmole) and acetonitrile (30 ml), the title compound (662 mg) was obtained in a similar manner as in Preparation Example 8 (yield: 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(N)c1ccc(F)cc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccc(F)cc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(4-fluorophenyl)acetate hydrochloride (prepared from 4-fluorophenylglycine (Fluka) and ethanol using General Procedure H), the title compound was prepared as a solid (mp=169-183° C.). The reaction was monitored by tlc (Rf=0.3 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.COC[O:20][C:21]1[C:22](=[O:38])[N:23](COC)[CH:24]=[C:25]([S:27][CH2:28][C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:26]=1>>[OH:20][C:21]1[C:22](=[O:38])[NH:23][CH:24]=[C:25]([S:27][CH2:28][C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:26]=1
Reactant: COCOc1cc(SCc2cnccn2)cn(COC)c1=O
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: O=c1[nH]cc(SCc2cnccn2)cc1O

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 12) from 3-(methoxymethoxy)-1-(methoxymethyl)-5-[(pyrazin-2-ylmethyl)sulfanyl]pyridin-2(1H)-one (Intermediate 29).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([C:36](=[O:41])[NH:37][CH:38]([CH3:40])[CH3:39])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:32]([C:36](=[O:41])[NH:37][CH:38]([CH3:39])[CH3:40])[CH2:31]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: CC(C)NC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Agent: Cl
Agent: [Li+]
Product: CC(C)NC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[(N-isopropyl)carbamoyl]piperazine hydrochloride
Reaction SMILES: [ClH:1].O1CCOCC1.[CH2:8]([C@H:12]1[N:19](C(OC(C)(C)C)=O)[CH2:18][C:15]2([CH2:17][CH2:16]2)[N:14]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:13]1)[CH:9]([CH3:11])[CH3:10]>O1CCOCC1>[ClH:1].[CH2:8]([C@H:12]1[NH:19][CH2:18][C:15]2([CH2:16][CH2:17]2)[N:14]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:13]1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)C[C@@H]1CN(C(=O)OCc2ccccc2)C2(CC2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@@H]1CN(C(=O)OCc2ccccc2)C2(CC2)CN1
Reaction time: 24 h

Procedure:
4 N hydrochloric acid/dioxane (8 ml) was added to a dioxane (10 ml) solution of the compound (0.57 g, 1.42 mmol) obtained in Step 4 above under ice cooling and the resulting mixture was gradually returned to room temperature while being stirred for 24 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[NH:4][CH2:5][C@H:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1.[C:28](O)(=O)C>C(OCC)(=O)C>[N:4]1([CH2:5][C@H:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[N:1]=[CH:28]1
Reactant: Cc1cccc(OC[C@H](CNc2ccccc2N)NC(=O)OC(C)(C)C)c1
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cccc(OC[C@H](Cn2cnc3ccccc32)NC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To the compound (85 mg) obtained in Step 2 were added methyl orthformate (1 ml) and acetic acid (50 μl), and the mixture was stirred at 60° C. for 1 hr. The mixture was diluted with ethyl acetate, and washed with 1N sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give the title compound (60 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([NH2:19])[CH:15]=[C:16]([NH2:18])[CH:17]=1.C(N(CC)CC)C>C1COCC1>[NH2:19][C:14]1[CH:15]=[C:16]([NH:18][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=[C:12]([F:11])[CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cc(N)cc(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1cc(F)cc(NC(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
Add slowly 4-fluorobenzoyl chloride (403 mg, 2.54 mmol) to a solution of 5-fluoro-benzene-1,3-diamine (Preparation 32 320 mg, 2.54 mmol) in triethylamine (514 mg, 0.71 mL, 5.08 mmol) and THF (10 mL) at 0° C. Stir the mixture overnight and gradually raise to room temperature. Quench the reaction with 0.1N NaOH solution, and extract the mixture with ethylacetate three times. Combine the organic layers and wash with saturated NaCl solution, dry over Na2SO4, filter and concentrate to give a solid. Purify by chromatography (silica gel, eluting with 25–40% ethylacetate in hexanes) gives 379 mg (60%) of N-(3-amino-5-fluoro-phenyl)-4-fluoro-benzamide.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:16][CH2:17][CH2:18][C:19]#[N:20])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.N.[H][H]>CO.[Ni]>[NH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:3]1([CH2:2][OH:1])[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:8]1
Reactant: [H][H]
Reactant: N#CCCNC1(CO)CCN(Cc2ccccc2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCNC1(CO)CCN(Cc2ccccc2)CC1
Yield: 86.2 %

Procedure:
A mixture of intermediate (14) (0.0159 mol) in methanol saturated with NH3 (150 ml) was hydrogenated at 14° C. with Raney nickel (½ spoon) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated, yielding 3.8 g of 4-[(3-aminopropyl)amino]-1-(phenylmethyl)-4-piperidinemethanol (intermediate 15).
Reaction SMILES: C([O:8][C:9]1[C:10]([O:39][CH3:40])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][C:30](=[O:37])[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:17]=4[CH2:18]3)[C:13]=2[CH:38]=1)C1C=CC=CC=1>[Ni].CO>[OH:8][C:9]1[C:10]([O:39][CH3:40])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][C:30](=[O:37])[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:17]=4[CH2:18]3)[C:13]=2[CH:38]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C1Cc3c(Cl)cc(OC)c(OC(=O)c4ccccc4)c3CN1CC2
Agent: [Ni]
Solvent: CO
Product: COc1cc2c(cc1O)C1Cc3c(Cl)cc(OC)c(OC(=O)c4ccccc4)c3CN1CC2
Reaction time: 1 h
Yield: 26.7 %

Procedure:
A product obtained in Example 3 (0.183 g, 0.33 mmol) was add CH3OH (15 ml) and Raney-Ni. The mixture was hydrogenated at room temperature for 1 hours. The mixture was filtered, and the filtrate was concentrated to give the product as yellow-green solide (0.16 g). The solide was recrystallized with ethyl acetate/petroleum ether to give pale yellow powder (0.041 g, 26.7%). mp 162˜164° C. 1HNMR (CDCl3) δ: 2.57˜2.71 (3H, m, CH2), 3.08˜3.12 (2H, m, CH2), 3.36˜3.58 (3H, m, CH2 and N—CH), 3.79 (3H, s, Ar—OCH3), 3.87 (3H, s, Ar—OCH3), 4.02 (1H, br, CH2), 5.55 (1H, s, Ar—OH), 6.59 (1H, s, ArH), 6.89 (1H, s, ArH), 6.95 (1H, s, ArH), 7.51˜7.56 (2H, m, PhH), 7.65˜7.67 (1H, m, PhH), 8.22˜8.24 (2H, m, PhH). MS (EI) m/z: 464 (M−1), 360, 344, 178, 105 (base), 77.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C@@:18]2([CH3:37])[C:22](=[O:23])[N:21]([C@@H:24]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20](=[O:36])[NH:19]2)=[CH:14][CH:13]=1>CN(C=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C@@:18]2([CH3:37])[C:22](=[O:23])[N:21]([C@@H:24]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:20](=[O:36])[N:19]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)N[C@@](C)(c2ccc(Br)cc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)N(Cc2ccccc2)[C@@](C)(c2ccc(Br)cc2)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
540 μl (4.4 mmol) of benzyl bromide and then, at 0° C., 140 mg of a 55-65% strength sodium hydride dispersion in oil were added to a solution of 1.75 g (4 mmol) of 169.2 in 20 ml of absolute DMF and the mixture was stirred at 0° C. for 15 min and at room temperature for 3 h. After allowing to stand overnight, the solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane/ethyl acetate=8/2. The product fractions were combined and the solvent was removed in vacuo. 1.97 g (93%) of 169.3 were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([CH2:28][O:29][CH3:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C([N:34]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([CH2:28][O:29][CH3:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:34])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COCc1ccc(Oc2cc(OC)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(Oc2cc(OC)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 42.6 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (160 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg), 1-hydroxybenzotriazole monohydrate (115 mg), 25% aqueous ammonium hydroxide solution (1 mL) and N,N-dimethylformamide (8 mL) was stirred at room temperature for 3.5 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100 to 8/92, volume ratio) to give a white amorphous solid. The amorphous solid was crystallized from ethyl acetate-diethyl ether to give white crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (68 mg, 43%) as colorless crystals. MS 427 (MH+). mp 135-136° C.
Reaction SMILES: OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[N+]([C:43]1[CH:44]=[C:45]([C:51]#[N:52])[C:46](=[CH:49][CH:50]=1)[C:47]#[N:48])([O-])=O.Cl>C1(C)C=CC=CC=1.CN1CCCC1=O>[C:51](#[N:52])[C:45]1[C:46](=[CH:49][CH:50]=[CH:43][CH:44]=1)[C:47]#[N:48]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1C#N
Temperature: 140 °C
Yield: 321.4 %

Procedure:
To a 250 mL, three-necked flask fitted with a thermometer, a Dean-Stark trap with condenser, and a nitrogen inlet were added bisphenol A (15.0 g, 65.7 mmol), 4,4′-dichlorobenzophenone (8.21 g, 32.7 mmol), powdered anhydrous K2CO3 (13.5 g, 97.8 mmol), (PPh3)3CuBr (50 mg), toluene (15 mL), and N-methylpyrrolidinone (NMP) (100 mL). Toluene was used to control the refluxing azeotropic removal of water and to control the temperature of the reaction content. The resulting mixture was degassed with nitrogen at ambient temperature and the Dean-Stark trap was filled with toluene. The mixture was refluxed at 135-145° C. under a nitrogen atmosphere for 6 hr or until no more water was observed being collected in the Dean-Stark trap. The toluene was then slowly distilled off causing the temperature to rise in the reaction vessel to enhance the yield of the intermediate hydroxyl salt and high conversion to this intermediate. The reaction mixture was heated above 180° C. for an additional 12 hr with a very small amount of toluene present to control the temperature and to totally remove the water formed as a by-product, so that the reaction could be pushed to completion and high conversion to the hydroxyl salt intermediate. The mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (11.7 g, 67.5 mmol) was added in one portion and the reaction mixture was heated at 80° C. for 6-8 hr. The mixture was allowed to cool to ambient temperature and poured into a 5% aqueous HCl solution resulting in the formation of a solid. The material was broken up and collected using a Büchner funnel. The white solid was washed with 200 mL of a 5% aqueous KOH solution, with 200 mL portions of distilled water until neutral, with 200 mL of a 5% aqueous HCl solution, and finally with 200 mL portions of water until neutral. The isolated solid was vacuum dried to yield the 2:1 oligomeric phthalonitrile (27.8 g, 95% yield). IR [cm−1]: ν 3075 (C═CH), 2232 (CN), 1650 (C═O), 1587 (C═C), 1477 (aromatic), 1306 (aromatic), 1308 (C—O), 1245 (CH3), 1160 (C—O), 929 (C—O), 845 (aromatic).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:21])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:5]=[CH:4][C:3]=1[C:22]#[N:23].[CH3:24][O-:25].[Na+]>CO>[C:22]([C:3]1[CH:4]=[CH:5][C:6]([N:8]([CH3:21])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[N:7][C:2]=1[O:25][CH3:24])#[N:23]
Reactant: C[O-]
Reactant: CN(c1ccc(C#N)c(Cl)n1)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Solvent: CO
Product: COc1nc(N(C)[C@@H]2CCN(C(=O)OC(C)(C)C)C2)ccc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-tert-butyl 3-((6-chloro-5-cyanopyridin-2-yl)(methyl)amino)pyrrolidine-1-carboxylate (0.45 mmol) in MeOH (20 mL) was added the solution of NaOMe (0.9 mmol) in MeOH (2 mL). The reaction mixture was stirred at room temperature for 3 hours, then heated to 50° C., stirred for another 2 hours, then stirred at reflux overnight. The mixture was concentrated, diluted with EtOAc, washed with brine, dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: O=C(c1ccccc1)C(O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccccc1)C(O)Cc1cccc(OCc2ccccc2)c1

Procedure:
20.8 g (86 mmole) 2,5-dihydroxy-β-phenylpropiophenone, 15.4 ml (130 mmole) benzyl bromide and 12.5 g (90 mmole) potassium carbonate were heated under reflux for 3 hours with 200 ml acetone. After distilling off the solvent, the residue was dissolved in ethylacetate and extracted three times with 150 ml each of 2N sodium hydroxide solution. Subsequently the organic phase was extracted with 150 ml 2N hydrochloric acid and then washed with water to neutrality. After that, the organic phase was separated, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol/acetone (2:1).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[C:14](=[O:16])[N:13]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH3:34])[CH:23]=2)[CH2:18][C:19](O)=[O:20])[CH2:12]3)=[O:5])[CH2:3][CH2:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:48][OH:49]>C1COCC1>[F:30][CH:29]([F:31])[O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:17]([N:13]2[C:14](=[O:16])[C:15]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:12]2)[CH2:18][C:19](=[O:20])[NH:48][OH:49])=[CH:23][C:24]=1[O:32][CH2:33][CH3:34]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 72.1 %

Procedure:
Cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide was prepared by the procedure of example 8 from 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.8 g, 1.7 mmol), CDI (0.41 g, 2.5 mmol) and hydroxylamine hydrochloride (0.23 g, 3.6 mmol) in THF (30 ml) to give cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.60 g, 80% yield): mp 116-118° C.; 1H NMR (CDCl3): δ 0.82 (m, 2H, c-CH2), 1.02 (m, 2H, c-CH2), 1.36 (t, J=6.8 Hz, 3H, OCH2CH3), 1.58 (m, 1H, c-CH), 2.86 (dd, J=5, 15 Hz, 1H, CH2), 3.15 (dd, J=10, 15 Hz, 1H, CH2), 3.30 (broad, 1H, NHOH), 4.01 (q, J=7.0 Hz, 2H, OCH2CH3), 4.02 (d, J=17.5 Hz, 1H, CH2N), 4.34 (d, J=17.5 Hz, 1H, CH2N), 5.42 (broad, 1H, NH2), 5.71 (m, 1H, CHN), 6.07 (broad, 1H, NHOH), 6.53 (t, JH-F=75 Hz, 1H, CF2H), 6.88 (m, 3H, Ar), 7.07 (d, J=7.5 Hz, 1H, Ar), 7.30 (t, J=7.5 Hz, 1H, Ar), 8.28 (d, J=8 Hz, 1H, Ar), 10.35 (s, 1H, NHCO). 13C NMR (CDCl3): δ 8.27, 8.39, 14.5, 16.0, 35.4, 47.3, 52.4, 64.8, 111.8, 113.3, 115.9, 116.9, 117.0, 118.9, 120.0, 122.6, 133.3, 136.6, 137.6, 140.0, 141.5, 150.8, 167.5, 169.7, 172.8; Anal. Calcd. for C24H25F2N3O6+0.34H2O: C, 58.16; H, 5.22; N, 8.48; Found: C, 58.25; H, 5.37; N, 8.58, 1.25H2O