Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(C)=O.[CH2:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH3:18].Cl>[OH-].[Na+]>[CH2:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:24])=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCc1ccc(C(=O)N[C@H](Cc2ccccc2)C(=O)O)cc1
Yield: 84.1 %

Procedure:
D-Phenylalanine 2 g (12 mmole) was dissolved in 10% aqueous sodium hydroxide solution (10 ml), and acetone (10 ml) was added. An acetone (5 ml) solution of 4-ethyl benzoyl choride (2.5 g, 15 mmole) and a 10% aqueous sodium hydroxide solution were added dropwise to the mixture obtained above while stirring and cooling with ice over 20 minutes, the reaction solution being maintained at pH 10. The reaction solution was returned to the room temperature, stirred for 3 hours, and made an acidic with a dilute hydrochloric acid solution to precipitate crystals. The crystals were filtered, washed with water and recrystallized from ethyl acetate to obtain N-(4-etylbenzoyl)-D-phenylalanine (3.0 g, yield 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[O:9])=[CH:4][C:3]=1[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1.Cl[C:31](=[O:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>C(Cl)Cl>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][C:31](=[O:38])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[O:9])=[CH:4][C:3]=1[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH3:37]
Reactant: Nc1ccc(C(=O)c2nc(-c3ccccc3)cs2)cc1C(=O)c1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1ccc(C(=O)c2nc(-c3ccccc3)cs2)cc1C(=O)c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
A mixture of intermediate (16) (0.048 mol) in DCM (200 ml) was cooled on an ice bath. 3-chloro-3-oxo-propanoic acid, ethyl ester (0.105 mol) was added dropwise. The mixture was stirred at a low temperature for 30 min, then stirred and refluxed for 1 hour and poured out into water. The organic layer was separated, washed with K2CO3 10%, dried (MgSO4), filtered and the solvent was evaporated till dryness. The product was used without further purification, yielding (quant.) N-[2-(3-chlorobenzoyl)-4-[(4-phenyl-2-thiazolyl)carbonyl]phenyl]-3-oxo-β-alanine ethyl ester (intermediate 17).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][CH3:13])[CH:11]=1)[O:8][C:7]([CH:24]1[CH:29]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:27][CH:26]([CH3:33])[CH2:25]1)([CH:14]1[CH:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH2:17][CH:16]([CH3:23])[CH2:15]1)[CH2:6][C:5]2([CH:44]1[CH:49]([CH:50]([CH3:52])[CH3:51])[CH2:48][CH2:47][CH:46]([CH3:53])[CH2:45]1)[CH:34]1[CH:39]([CH:40]([CH3:42])[CH3:41])[CH2:38][CH2:37][CH:36]([CH3:43])[CH2:35]1.[CH3:54][Si:55]([C:58]#[CH:59])([CH3:57])[CH3:56].C(N(CC)CC)C.O1CCCC1>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:12]([C:10]1[CH:11]=[C:2]([C:59]#[C:58][Si:55]([CH3:57])([CH3:56])[CH3:54])[CH:3]=[C:4]2[C:9]=1[O:8][C:7]([CH:14]1[CH:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH2:17][CH:16]([CH3:23])[CH2:15]1)([CH:24]1[CH:29]([CH:30]([CH3:31])[CH3:32])[CH2:28][CH2:27][CH:26]([CH3:33])[CH2:25]1)[CH2:6][C:5]2([CH:34]1[CH:39]([CH:40]([CH3:42])[CH3:41])[CH2:38][CH2:37][CH:36]([CH3:43])[CH2:35]1)[CH:44]1[CH:49]([CH:50]([CH3:52])[CH3:51])[CH2:48][CH2:47][CH:46]([CH3:53])[CH2:45]1)[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: CCc1cc(Br)cc2c1OC(C1CC(C)CCC1C(C)C)(C1CC(C)CCC1C(C)C)CC2(C1CC(C)CCC1C(C)C)C1CC(C)CCC1C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCc1cc(C#C[Si](C)(C)C)cc2c1OC(C1CC(C)CCC1C(C)C)(C1CC(C)CCC1C(C)C)CC2(C1CC(C)CCC1C(C)C)C1CC(C)CCC1C(C)C

Procedure:
Following general procedure D and using 6-bromo-8-ethyl-2,2,4,4-tetramenthyl chroman (Intermediate 46, 0.5 g, 1.61 mmol), (trimethylsilyl)acetylene (1.57 g, 16.1 mmol), triethyl amine (8 mL), anhydrous tetrahydrofuran (10 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol), followed by flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.137 g, 27%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>[OH-].[Na+]>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:23])=[O:22])=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 8-aminooctanoic acid in 10% sodium hydroxide solution was treated with 4-nitrobenzenesulphonyl chloride in the manner of Example 2 to give the title compound which, on recrystallisation from aqueous ethanol, had a melting point of 126°-7° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[N:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1.[H-].[Na+]>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)=[N:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(OCCCOCc3ccccc3)cn2)C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(OCCCOCc3ccccc3)cn2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
A solution of 40 mg (0.09 mmol) of tert-butyl (3RS,4RS)-4-[5-(3-benzyloxy-propoxy)-pyrimidin-2-yl]-3-hydroxy-piperidine-1-carboxylate and 23 mg (0.1 mmol) of 2-bromomethyl-naphthalene in 5 ml of N,N-dimethylformamide was treated with 5 mg (0.1 mmol) of sodium hydride (50% dispersion in oil) and stirred at room temperature for 18 hours. For the working-up, the reaction mixture was evaporated under reduced pressure, the residue obtained was taken up in 3 ml of methylene chloride and the solution was chromatographed directly on silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 40 mg (76% of theory) of tert-butyl (3RS,4RS)-4-[5-(3-benzyloxy-propoxy)-pyrimidin-2-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as an oil; MS: 584 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][O:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][O:29][CH2:30][C:31]([OH:33])=[O:32])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)COCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCOCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
To a solution of ethyl ({2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}oxy)acetate (D104) (20 mg) in THF (5 mL) was added aqueous NaOH (2 M, 1 mL). The reaction was stirred at 20° C. for 4 h. The mixture was acidified with aqueous HCl (2 M) to pH 4-5. After concentration, the residue was partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford ({2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}oxy)acetic acid (E79) (11 mg). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.98 (2H, t), 3.63 (3H, s), 3.74 (2H, t), 4.05 (2H, s), 4.89 (1H, m), 7.17 (1H, t), 7.26 (1H, s), 7.44 (2H, m), 7.81 (1H, dd), 8.13 (1H, dd), 8.19 (1H, d), 12.57 (1H, br s). MS (ES): C24H24ClN3O6 requires 469; found 470.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=S)[C:3]=1[NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[N:20]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCNc1c(N)cccc1NC(=S)Nc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(N)c21
Yield: 75.9 %

Procedure:
To a solution of ethyl N-[2-amino-6-({[(2,4-dichlorophenyl)amino]carbonothioyl}amino)phenyl]-beta-alaninate (Reference Example 26; 174 mg, 0.407 mmol) in tetrahydrofuran (4 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (234 mg, 1.22 mmol) at room temperature. The resultant mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give the title compound as an oil (122 mg, 0.309 mmol, 76%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]([CH2:38][C:39]([O:41]CC)=[O:40])[CH2:32][C:33]([O:35]CC)=[O:34])(=[O:30])=[O:29])(=[O:21])=[O:20])[CH:6]=[C:7]([CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]([NH2:16])=[NH:15].C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[CH3:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]([CH2:32][C:33]([OH:35])=[O:34])[CH2:38][C:39]([OH:41])=[O:40])(=[O:30])=[O:29])(=[O:20])=[O:21])[CH:6]=[C:7]([CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]([NH2:16])=[NH:15]
Reactant: CCOC(=O)CN(CC(=O)OCC)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(CC(=O)O)CC(=O)O)c1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield from 3-[5-methyl-3-(2-(N,N-bis(ethoxycarbonylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride, as prepared in step b of Example 57, in a manner analogous to Example 27. 1H-NMR (300 MHz, DMSO-d6) δ 8.29 (d, J=7.0 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.97 (t, J=7.6 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.63 (br s, 4H), 6.72 (s, 1H), 6.58 (s, 1H), 6.49 (s, 1H), 4.13 (s, 4H), 3.97 (t, J=6.3 Hz, 2H), 3.90 (t, J=6.3 Hz, 2H), 2.23 (s, 3H), 2.03 (pentet, J=6.2 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C21H26N4O11S2: 575.1 (M+H), 597.1 (M+Na), 613.1 (M+K). Found: 575.1, 597.0, 613.1.
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=[O:9])[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.Cl.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:1]1([CH2:7][C:8]([CH:25]2[CH:26]3[CH:22]([C:21](=[O:27])[CH2:20][CH2:19][C:18]3([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][NH:24]2)=[O:9])[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1
Reactant: O=C(O)CC1=CCC=CC1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2C1CNC2C(=O)CC1=CCC=CC1
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
N,N'-Carbonyldiimidazole (3.6 g) is added to a solution of (cyclohexa-1,4-dien-1-yl)acetic acid (2.35 g) in dry dichloromethane (50 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of 7,7-diphenyl-4-perhydroisoindolone hydrochloride (6.55 g) and triethylamine (5.6 cc) in dichloromethane (30 cc) is then added. The reaction mixture is stirred for 1 hour at +5° C. and then for 16 hours at 20° C. and is washed with normal hydrochloric acid (150 cc) and an aqueous saturated sodium chloride solution (150 cc). The organic phase is dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 6 cm, height 30 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture (3 liters) of cyclohexane and ethyl acetate (50/50) and then with ethyl acetate (2 liters) and collecting 100 cc fractions. Fractions 10 to 48 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from acetonitrile (15 cc). The crystals are drained, washed with acetonitrile (5 cc) and isopropyl ether (25 cc) and dried. (3aRS,7aRS)-2-(cyclohexa-1,4-dien-1-yl)-acetyl-7,7-diphenyl-4-perhydroisoindolone (5.7 g) is obtained. m.p.=186° C.
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH2:11][CH:12]([CH2:17][CH2:18][C:19]([O-])=[O:20])[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=[C:7]([O:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:24])[CH:6]=1)(=O)C.[NH3:34]>CO>[OH:4][C:5]1[C:10]2[CH2:11][CH:12]([CH2:17][CH2:18][C:19]([NH2:34])=[O:20])[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=[C:7]([O:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:24])[CH:6]=1
Reactant: CC(=O)Oc1cc(OC(C)CCCc2ccccc2)cc2c1CC(CCC(=O)[O-])C(C)(C)O2
Reactant: N
Solvent: CO
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)OC(C)(C)C(CCC(N)=O)C2
Reaction time: 8 h

Procedure:
Methyl dl-3-[5-acetoxy-2,2-dimethyl-7-(5-phenyl-2-pentyloxy)-3,4-dihydro-2H-benzopyran-3-yl]propionate, 4.68 g (0.01 mole), is dissolved in methanol and anhydrous ammonia is passed through the mixture at room temperature. The resulting mixture is heated at reflux for two hours while passing ammonia through it. After standing overnight the volatiles are removed by evaporation and the residue purified by column chromatography on silica gel to provide dl-3-[5-hydroxy-2,2-dimethyl-7-(5-phenyl-2-pentyloxy)-3,4-dihydro-2H-benzopyran-3-yl]propionamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:22]
Reactant: NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Product: COc1ccc(C(=O)NCCc2ccc(-c3ccc(O)cc3)cc2)c(OC)c1
Yield: 80 %

Procedure:
4-[2-(2,4-Dimethoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl was prepared analogous to Example I from 4-[2-amino-ethyl]-4'-hydroxy-biphenyl and 2,4-dimethoxybenzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].C(N(C(C)C)CC)(C)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([C:39](O)=[O:40])=[C:36]([CH3:42])[C:35]=2[CH:43]=1.CCCP(O)(O)=O.C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:39]([C:37]3[O:38][C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:43][C:35]=4[C:36]=3[CH3:42])=[O:40])=[CH:16][CH:17]=2)[C:9]=1[CH3:10]
Reactant: Cc1c(C(=O)O)oc2ccc(F)cc12
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C
Agent: CCCP(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cc1c(C)nn(Cc2ccc(NC(=O)c3oc4ccc(F)cc4c3C)cc2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
To a solution of [1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (400 mg, 1.46 mmol) in 5 mL dichloromethane are added diisopropylethylamine (1.5 mL, 8.8 mmol) and 5-fluoro-3-methyl-1-benzofuran-2-carboxylic acid (369 mg, 1.9 mmol). After stiffing at room temperature for 10 minutes a 50% solution of 1-propylphosphonic acid cyclic anhydride in ethyl acetate (1.725 mL, 2.93 mmol) is added with cooling and the mixture is stirred at room temperature for 12 hours. The solvent is evaporated in vacuo and the residue is purified by MPLC (dichloromethane/methanol 98:2) to yield 410 mg of (1-{4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=450; TLC: Rf=0.56 (dichloromethane/methanol 95:5, silicagel 60 F254)). b) To a solution of (1-{4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (410 mg, 0.91 mmol) in dioxane/water (10 mL/10 mL) is added 1 M NaOH (2.3 mL) and the mixture is stirred at room temperature for 24 hours. The mixture is diluted with water and acidified with hydrochloric acid (1 M, 3.25 mL). The precipitate is filtered, washed with water and dried to yield 338 mg of the title compound (ESI mass spectrum: [M+H]+=436; Retention time HPLC: 0.85 min (method D).
Reaction SMILES: [CH3:1][C:2](=O)[CH:3]([S:7][C:8]1[N:12]=[CH:11][NH:10][N:9]=1)[C:4](=[O:6])[CH3:5].Cl.NO.C([N:19](CC)CC)C>C(O)C>[CH3:1][C:2]1[C:3]([S:7][C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([CH3:5])[O:6][N:19]=1
Reactant: CC(=O)C(Sc1nc[nH]n1)C(C)=O
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CCO
Product: Cc1noc(C)c1Sc1nc[nH]n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 3-(2,4-pentanedion-3-yl)thio-1H-1,2,4-triazole (2 g), hydroxylamine hydrochloride (0.7 g), triethylamine (1.4 ml) and ethanol (10 ml) was heated and stirred for 5 hours on an oil bath at 100° C. The reaction solution was concentrated under reduced pressure, and then extracted with ethyl acetate-water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to a silica-gel column chromatography with 10 to 30% (20% 2-propanol/ethyl acetate)/hexane, followed by recrystallization in ethyl acetate-hexane to yield the title compound (440 mg).
Reaction SMILES: [N:1]1([C:7]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][NH:10]2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[N:1]1([CH2:7][CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C1NCCc2sccc21)N1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1cc2c(s1)CCNC2CN1CCCCC1

Procedure:
Prepared as Description No. 4, from 1.7 g (6.8 mmoles) of 4-(piperidin-1-yl)carbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 600 mg (15.79 mmoles) of lithium aluminium hydride in 50 ml of dry THF.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].CCN(CC)CC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26]
Reactant: NCc1ccccc1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccccc1O
Yield: 29.5 %

Procedure:
To a mixture of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (194 mg, 0.69 mmol) and 2-aminomethyl-phenol hydrochloride salt (110 mg, 0.69 mmol) in N,N-dimethylformamide (DMF) (5 mL) is added Et3N (0.145 mL, 1.04 mmol). The precipitate is filtered to give 76 mg (30%) of the title compound as a beige solid. MS (ESI) m/z 371.0 (M−H)−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[O:17]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24](Cl)=O)=[CH:18]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>C(OCC)(=O)C>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[O:17]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:6]3[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:16]=2)=[CH:18]1
Reactant: O=C(Cl)/C=C/c1ccoc1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1ccoc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-(3-furyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate-hexane yielded the titled compound. MW: 407.39; mp: 196.0-198.0° C.; 1H-NMR (DMSO) δ: 8.75-8.73 (1H, m), 8.16 (1H, td, J=7.7, 1.8 Hz), 8.04 (1H, br.s), 7.76-7.58 (4H, m), 7.33 (1H, d, J=8.8 Hz), 7.23 (1H, d, J=2.2 Hz), 6.90-6.80 (3H, m), 3.82 (3H, s).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([CH3:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[O:35][N:34]=[C:33]([CH3:36])[CH:32]=4)[CH:26]=3)[CH2:22][C:21](=[O:37])[NH:20][C:9]=2[CH:10]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from [4-methyl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example M84) (0.33 g, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (163 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=3)[N:20]([CH3:28])[CH:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[CH:7]=1.[OH-].[Na+]>C1COCC1.Cl>[Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=3)[N:20]([CH3:28])[CH:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2cn(C)c3cc(F)ccc23)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Nc2cc(F)c(CC(=O)O)cc2Cl)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.2 %

Procedure:
In THF (17 ml) was dissolved ethyl (5-chloro-2-fluoro-4-((6-fluoro-1-methyl-3-indolylcarbonyl)amino)phenyl)acetate (665 mg, 1.63 mmol). To the resulting solution was added 0.25N NaOH (9.81 ml, 2.45 mmol) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured in 1N HCl (3.0 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give (5-chloro-2-fluoro-4-((6-fluoro-1-methyl-3-indolylcarbonyl)amino)phenyl)acetic acid (600 mg, 97%) as a brown solid.