Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[N:12]1([CH2:11][CH2:10][C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cccc(CCN2CCCC2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(CCN2CCCC2)c1

Procedure:
The mixture containing [2-(3-nitrophenyl)ethyl]pyrrolidine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 3-(2-pyrrolidinylethyl)phenylamine.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[CH3:16][NH:17][C:18]([CH3:23])([C:20]([OH:22])=[O:21])[CH3:19].C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:17]([CH3:16])[C:18]([CH3:23])([C:20]([OH:22])=[O:21])[CH3:19])=[O:14]
Reactant: O=C(Cl)CCCCCN1C(=O)C=CC1=O
Reactant: CNC(C)(C)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CCCCCN1C(=O)C=CC1=O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of #248 (600 mg, 2.61 mM) in 10 mL of dichloromethane, N,2-dimethylalanine (306 mg, 2.61 mM) was added followed by triethylamine (1.09 mL, 7.84 mM). The reaction was allowed to stir at room temperature for three hours. Dichloromethane was added to the reaction and the organic layer was washed three times with water and two times with brine. The organic layer was separated and then dried over sodium sulfate before being concentrated in vacuo. The crude residue was purified by silica chromatography (0-30% methanol in dichloromethane) on silica which had been previously neutralized with triethylamine yielding a white solid #249 (127 mg, 16%). LC-MS (Protocol Q): m/z 309.0 [M−H−], retention time=0.96 minutes.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][C:28]1[NH:29][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][CH:37]([CH3:40])[O:36][CH2:35]2)=[N:31][N:32]=1>>[CH3:27][C:28]1[N:29]=[C:30]2[N:33]([CH:34]3[CH2:39][CH2:38][CH:37]([CH3:40])[O:36][CH2:35]3)[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:31]2[N:32]=1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: Cc1nnc(NC2CCC(C)OC2)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(C)OC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 29.3 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.89 g) and 5-methyl-N-(6-methyltetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.18 g, 30%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25](Br)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([N:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][C:2]2=[O:1])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1cc(C(F)(F)F)ccn1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(C(F)(F)F)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 9 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-hydroxy-4-(trifluoromethyl)pyridine in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 9% yield: mp 197-198° C.; 1H NMR (300 MHz, CDCl3) δ 8.93 (d, J=7.8 Hz, 1H), 7.39-7.25 (m, 5H), 7.00 (d, J=0.6 Hz, 1H), 6.57-6.54 (m, 1H), 6.17 (s, 1H), 4.59 (d, J=5.7 Hz, 2H), 2.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 159.3, 152.4, 141.0, 137.5, 133.1, 128.8, 127.9, 127.8, 124.1, 119.1, 103.0, 44.2, 17.3; MS (ES+) m/z 394.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C([Li])CCC.CN([CH:18]=[O:19])C.Cl>C1COCC1.CCOCC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:18]=[O:19])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(F)ccc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
A −78° C. solution of 2-bromo-5-fluorotoluene (12.0 g, 63.5 mmol) in dry THF (60 mL) is treated with a 1.6 M hexanes solution of n-butyl lithium (59.5 mL, 95.3 mmol) and then stirred for 15 minutes at −78° C. under N2. The mixture is then treated with DMF (27.8 g, 0.381 mol) and warmed to rt. The reaction is acidified with 1 N HCl, diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using a gradient of 5/1 to 3/1 to hexanes/ethyl acetate to afford 6.24 g (71%) of the title compound. Rf=0.49 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH2:18][CH3:19])=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:18]([C:10]1[C:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1)[CH3:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1nn2ccccc2c1-c1cc(F)cc(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1nn2ccccc2c1-c1cc(F)cc(F)c1
Yield: 103.8 %

Procedure:
3-(3,5-Difluorophenyl)-2-ethylpyrazolo[1,5-a]pyridine (0.48 g, 1.8 mmol), N-bromosuccinimide (0.55 g, 3.1 mmol) and benzoyl peroxide (50 mg, 0.2 mmol) were stirred in carbon tetrachloride (20 mL). The mixture was heated to reflux for 2 hours. After removal of the solvent in vacuo, the residue was dissolved in dichloromethane, washed with water, saturated aqueous sodium sulfite, aqueous sodium bicarbonate and brine. The extracts were dried over sodium sulfate, filtered and concentrated to give the desired compound (0.63 g, 100%). LCMS for C15H12BrF2N2 (M+H)+: m/z=336.8, 338.8. 1H NMR (300 MHz, DMSO-d6): δ 8.78 (m, 1H), 7.70 (m, 1H), 7.30 (m, 4H), 7.02 (m, 1H), 5.63 (m, 1H), 2.17 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([C:18](=[O:20])[CH3:19])[CH:15]1[CH2:17][CH2:16]1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>C(O)C>[CH:21]1([NH:24][C:2]2[C:10](=[O:11])[C:9]3[N:8]([CH3:12])[N:7]=[CH:6][C:5]=3[C:4](=[O:13])[C:3]=2[N:14]([C:18](=[O:20])[CH3:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: CC(=O)N(C1=C(Cl)C(=O)c2c(cnn2C)C1=O)C1CC1
Solvent: CCO
Product: CC(=O)N(C1=C(NC2CC2)C(=O)c2c(cnn2C)C1=O)C1CC1

Procedure:
6-Chloro-5-(N-acetyl-N-cyclopropylamino)-1-methyl-1H-indazole-4,7 -dione (2 grams prepared as in Example III) and cyclopropylamine (2 grams) in ethanol (25 milliliters) were heated together under reflux for 10 minutes. The solvent was then removed under reduced pressure and the residual red oil purified by chromatography on alumina using methylene chloride as eluant to yield the desired product having a melting point of 75°-78° C.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][S+](C)C)=[O:6])[CH3:3].N12CCCN=C1CCCCC2.[C:22]1(=[O:27])[CH2:26][CH2:25][CH:24]=[CH:23]1>C(#N)C>[CH2:2]([O:4][C:5]([CH:7]1[CH:26]2[CH:25]1[CH2:24][CH2:23][C:22]2=[O:27])=[O:6])[CH3:3]
Reactant: CCOC(=O)C[S+](C)C
Reactant: O=C1C=CCC1
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C1C2CCC(=O)C21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a suspension of (ethoxycarbonylmethyl)dimethylsulfonium bromide (148.5 g, 0.648 mole) in acetonitrile (1170 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (97 ml, 0.648 mole) at 22° C. and stirring was continued for 45 min. The solution was treated with 2-cyclopenten-1-one (63 ml, 0.778 mole) and stirring was continued at 22° C. and light exclusion for 4 d. The mixture was evaporated to a volume of ca. 500 ml, partitioned between 1N aqueous HCl and diethylether, the organic layer was dried, evaporated and purified over silica (150 g) using cyclohexane/AcOEt (9:1). The material was dissolved in diethylether (50 ml) and n-pentane (50 ml), briefly cooled to −78° C. until the material precipitated, filtered and the residue was dried to give the title compound as white crystals.
Reaction SMILES: Br[CH:2]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1COCC1.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH:23]2[CH2:28][CH2:27][CH:26]([CH:29]=[O:30])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>[Zn].C(OCC)(=O)C>[F:8][CH:2]([CH:29]([OH:30])[CH:26]1[CH2:25][CH2:24][CH:23]([CH:20]2[CH2:21][CH2:22][CH:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]2)[CH2:28][CH2:27]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)Br
Reactant: CCCC1CCC(C2CCC(C=O)CC2)CC1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC1CCC(C2CCC(C(O)C(F)C(=O)OCC)CC2)CC1
Reaction time: 1 h
Yield: 127.7 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 1.1 g of well-dried zinc, 2.6 g of ethyl bromofluoroacetate (e-2) and 10 ml of THF were added, and the resultant mixture was cooled to 0° C. and stirred for 1 hour. The solution was slowly added dropwise in a temperature range of 20° C. to 25° C. to another reaction vessel under a nitrogen atmosphere in which 2.0 g of 4′-propyl-[1,1′-bi(cyclohexane)]-4-carboaldehyde (e-1) and 10 ml of THF were put, and the resultant mixture was further subjected to heating reflux for 4 hours. After cooling the resultant reaction mixture to 25° C., 100 ml of 1 N HCl aqueous solution and 100 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was isolated, and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 3.7 g of ethyl 2-fluoro-3-hydroxy-3-(4′-propyl-[1,1′-bi(cyclohexane)]-4-yl)propanoate (e-3) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=4)=[O:22])=[CH:16][C:14]=3[CH:15]=2)=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.Cl.[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[O:7])=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)=[O:22])=[CH:16][C:14]=2[CH:15]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc3sc(-c4cc(C(=O)O)cnc4N)cc3c2)c1
Reactant: COC(=O)CCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCNC(=O)c1cnc(N)c(-c2cc3cc(NC(=O)Nc4cccc(C)c4)ccc3s2)c1
Temperature: 50 °C

Procedure:
The reaction mixture of 6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinic acid (84 mg, 0.2 mmol, 1 eq), methyl 6-aminohexanoate hydrochloride (43.7 mg, 1.2 eq), DMAP (5 mg, 0.2 eq), and EDCI (46.1 mg, 1.2 eq) in anhydrous 1,2-dichloroethane (3 mL) was stirred and heated at 50° C. for 2 hours. It was then diluted with ethyl acetate, washed sequentially with aqueous NH4Cl, saturated aqueous NaHCO3, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the solid residue was triturated with EtOAc-Hex (3:1) yielding methyl 6-[({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)amino]hexanoate as a white solid in amount of 83 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][N+:5]#[C-:6].Cl[CH2:9][C:10]1[C:15]([CH2:16]Cl)=[CH:14][CH:13]=[CH:12][N:11]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1([N+:5]#[C-:6])[CH2:9][C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:16]1)=[O:7]
Reactant: ClCc1cccnc1CCl
Reactant: [C-]#[N+]CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: [C-]#[N+]C1(C(=O)OC)Cc2cccnc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isocyano-acetic acid methyl ester (112 mg, 1.13 mmol) and 2,3-bis-chloromethyl-pyridine (200 mg, 1.14 mmol) were dissolved in DMF. Potassium tert-butoxide (0.255 g, 2.27 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. The mixture was partitioned between EA and a saturated aqueous sodium hydrogencarbonate solution, the aqueous phase extracted with EA, and the organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to give 6-isocyano-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid methyl ester. This compound was added to a solution of thionyl chloride (147 mg, 1.23 mmol) in ethanol (1 ml) and refluxed overnight. The mixture was evaporated to dryness, and the residue was stirred with HEP, filtered and dried in vacuo. The obtained product was reacted with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 1 of example 15 and the title compound purified by preparative RP HPLC (water/ACN gradient).
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]2[C:9](=[O:19])[C:10]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=1)([O:3]C)=[O:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:21]=[CH:20][C:8]2[C:9](=[O:19])[C:10]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=3[CH:12]=[CH:13][C:7]=2[CH:6]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)CCc1c(F)cccc1C2=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc2c(=O)c3cccc(F)c3ccc2c1

Procedure:
A solution of 1.49 g. of 2-carbomethoxy-9-fluoro-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene and 0.94 g. of N-bromosuccinimide in 100 ml of carbon tetrachloride was refluxed and irradiated with a 100 W incandescent lamp for 22 hours. The cooled solution was filtered and evaporated, and the residue dissolved in 25 ml of dimethylformamide. 1.5 Ml of diazabicyclononene was added and the mixture heated to 80° for 1 hours, then poured into dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the extract washed, dried and evaporated. The residue was refluxed for 2 hours in 50 ml of water and 25 ml of methanol containing 1.5 g. of sodium hydroxide. The solution was cooled, acidified and filtered. The residue was recrystallized from aqueous dimethylformamide to yield 2-carboxy-9-fluoro-5-oxo-5H-dibenzo[a,d]cycloheptene, mp 340° (decomp.)
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[O:9][CH2:10][O:11][C:3]=12.[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][O:28][C:29]2[CH:38]=[C:37]3[C:32]([C:33](Cl)=[N:34][CH:35]=[N:36]3)=[CH:31][C:30]=2[O:40][CH3:41])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][O:28][C:29]2[CH:38]=[C:37]3[C:32]([C:33]([NH:1][C:2]4[C:7]([Cl:8])=[CH:6][N:5]=[C:4]5[O:9][CH2:10][O:11][C:3]=45)=[N:34][CH:35]=[N:36]3)=[CH:31][C:30]=2[O:40][CH3:41])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1c(Cl)cnc2c1OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Using a similar procedure to that described in Example 1, a solution of 4-amino-5-chloro-2,3-methylenedioxypyridine (0.193 g) in DMF (2 ml) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.048 g) in DMF (2 ml) and the mixture was stirred at ambient temperature for 15 minutes. A solution of 7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-chloro-6-methoxyquinazoline [International Patent Application WO 02/16352 (Note [24] within Example 2 thereof; 0.38 g] in DMF (4 ml) was added and the resultant mixture was stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 49:1 mixture of methylene chloride and methanol. There was thus obtained the title compound as a solid (0.24 g); NMR Spectrum: DMSOd6) 1.29 (m, 2H), 1.45 (s, 9H), 1.8 (m, 2H), 2.04 (m, 1H), 2.83 (m, 2H), 4.0 (m, 7H), 8.12 (br s, 2H), 7.17 (br s, 1H), 7.72 (m, 2H), 8.37 (br s, 1H), 9.37 (br s, 1H); Mass Spectrum: M+H+ 544 and 546.
Reaction SMILES: [C:1]([C:3]1[S:13][C:6]2[NH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:5]=2[CH:4]=1)#[N:2].Cl.[NH2:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)=[O:18]>>[CH2:24]([C@H:16]([NH:15][C:10]([C:8]1[NH:7][C:6]2[S:13][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH:9]=1)=[O:12])[C:17]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)=[O:18])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1
Reactant: N#Cc1cc2cc(C(=O)O)[nH]c2s1
Agent: Cl
Product: N#Cc1cc2cc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N3CC(O)C3)[nH]c2s1

Procedure:
2-Cyano-6H-thieno[2,3-b]pyrrole-5-carboxylic acid and (2S)-amino-1-(3-hydroxy-azetidin-1-yl)-3-phenyl-propan-1-one hydrochloride were coupled according to Procedure B.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]2([C:28]([OH:30])=O)[CH2:27][CH2:26]2)[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)[CH3:8]>ClCCl.CN(C=O)C>[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]2([C:28]([Cl:4])=[O:30])[CH2:27][CH2:26]2)[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)[CH3:8]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(C(=O)Cl)CC1
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.6 mL, 18 mmol) was added dropwise over a period of 5 minutes to a suspension of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-C]quinolin-1-yl]methyl}cyclopropanecarboxylic acid (2.0 g, 6.2 mmol) in dichloromethane (50 mL) containing one drop of DMF. The reaction mixture was stirred for two hours and then concentrated under reduced pressure to provide 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropanecarbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=[C:8]([OH:22])[CH:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=[C:8]([OH:22])[CH:7]=1
Reactant: COC(=O)C=Cc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reaction time: 7 h
Yield: 15 %

Procedure:
To a solution of 3-[5-hydroxy-2-(4-hydroxy-phenyl)benzofuran-7-yl]-acrylic acid methyl ester 59 (0.1 g, 0.32 mmol) in methanol (5 mL) and purged with nitrogen was added catalytic 10% palladium on carbon. The reaction vessel was evacuated and a balloon of hydrogen was added. After 7 hours, the reaction was filtered and the solvent removed in vacuo. The product was purified via flash chromatography on silica gel, eluting with 7% methanol in dichloromethane to give 0.015 g of 3-[5-hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-yl]-propionic acid methyl ester 60: Mp=167–170° C.; 1H NMR (DMSO-d6) δ 9.83 (s, 1 H), 9.08 (s, 1 H), 7.70 (d, 2 H, J=8.6 Hz), 7.00 (s, 1 H), 6.87 (d, 2 H, J=8.6 Hz), 6.73 (d, 1 H, J=2.3 Hz), 6.53 (d, 1 H, J=2.2 Hz), 3.59 (s, 3 H), 3.07 (t, 2 H, J=7.5 Hz), 2.77 (t, 2 H, J=7.6 Hz); MS 313 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[CH3:17][N:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[S:19]([C:22]1[C:27]([CH:28]=O)=[CH:26][CH:25]=[CH:24][N:23]=1)(=[O:21])=[O:20]>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:28][C:27]2[C:22]([S:19](=[O:21])(=[O:20])[N:18]([CH3:17])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:6]1[CH3:15]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: CN(c1ccccc1)S(=O)(=O)c1ncccc1C=O
Product: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)N(C)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 29a using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 3-formylpyridine-2-sulfonic acid methylphenylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15](O)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.C([O-])(=O)C.[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([NH2:23])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 3.75 h
Yield: 96.7 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]-benzazepine-4,10-(1H,9H)-dione (1 g, 3.44 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (0.64 mg, 3.95 mmol) in N,N-dimethylformamide (25 mL) was stirred for 64.5 hours. In one portion, ammonium acetate (0.796 mg, 10.33 mmol) was added, followed by additional N,N-dimethylformamide (15 mL). The solution was stirred for 3.75 hours at room temperature and concentrated in vacuo for 45 minutes. The residue was washed with water (63×20 mL). The insoluble material was filtered and dried to give the title compound (967 mg, 97% yield, m.p. 224-225° C.).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]Br)=[CH:3][CH:2]=1.[C:11]([OH:17])(=[O:16])[C:12](=[N:14][OH:15])[CH3:13]>>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][O:15][N:14]=[C:12]([CH3:13])[C:11]([OH:17])=[O:16])=[CH:3][CH:2]=1
Reactant: CC(=NO)C(=O)O
Reactant: Cc1ccc(CCBr)cc1
Product: CC(=NOCCc1ccc(C)cc1)C(=O)O
Yield: 41 %

Procedure:
2-p-Tolylethyl bromide and pyruvic acid oxime are reacted by the process of Example 1 and the reaction mixture is evaporated when the reaction is complete. The residue is taken up in a little water, washed with diethyl ether and the aqueous solution is acidified. The precipitate obtained is filtered off with suction and dried to give a yield of 41% of theory of 2-(2-p-tolylethyloxyimino)-propionic acid; m.p. 106°-108° C.