Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:31](=[O:46])[CH2:32][C@@H:33]([C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[C:34]1[CH:38]=[CH:37][O:36][N:35]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:36]1[CH:37]=[CH:38][C:34]([C@H:33]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:2][C:3]3[S:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)=[CH:41][CH:40]=2)[CH2:32][C:31]([N:26]2[C@@H:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:29][O:28][C:27]2=[O:30])=[O:46])=[N:35]1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)s2)cc1
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(C[C@@H](c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A mixture of 61.4 (0.19 mmol), 7.5 (62 mg, 0.16 mmol), and Cs2CO3 (155 mg, 0.48 mmol) in DMF (1.6 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (25-50% EtOAc/hexane) to afford 61.5 (76 mg, 54%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, 1H), 7.69 (d, 2H), 7.64 (d, 2H), 7.35 (m, 2H), 7.28 (m, 4H), 7.21 (m, 2H), 7.11 (d, 1H), 6.98 (d, 2H), 6.16 (d, 1H), 5.22 (s, 2H), 4.78 (dd, 1H), 4.64 (m, 1H), 4.16 (m, 2H), 4.05 (dd, 1H), 3.56 (dd, 1H), 3.22 (dd, 1H), 2.78 (dd, 1H).
Reaction SMILES: [BH4-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([O:27][CH3:28])[CH:19]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].CO>O.O.O.O.O.O.[Ni](Cl)Cl.C1COCC1>[C:3]([N:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([O:27][CH3:28])[CH:19]=3)[CH2:14][CH2:13]2)[CH2:10][CH2:11]1)(=[O:5])[CH3:4]
Reactant: COc1cc(N2CCC(N3CCN(C(C)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(C(C)=O)CC3)CC2)ccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
NaBH4 (0.190 g, 5.06 mmol) was added carefully in portions (exothermic) to a suspension of 1-acetyl-4-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (0.52 g, 1.45 mmol), nickel(II)chloride hexahydrate (0.170 g, 0.72 mmol), MeOH (8 mL) and THF (4 mL) at 0° C. The ice bath was removed and the reaction mixture was stirred at rt overnight (˜16 h). The solvent was evaporated and the residue was suspended in DCM and filtered through celite. Flash chromatography afforded the title compound of step B (0.36 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ 6.50-6.45 (m, 2H), 6.30-6.25 (m, 1H), 4.18 (bs, 2H), 3.71 (s, 3H), 3.45-3.36 (m, 6H), 2.45-2.38 (m, 3H), 2.31-2.23 (m, 1H), 1.96 (s, 3H), 1.82-1.74 (m, 2H), 1.58-1.44 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:2]1([NH:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(CNc2ccccc2)cc1
Yield: 91 %

Procedure:
According to the general procedure A, chlorobenzene (58 mg, 0.51 mmol) reacted with benzylamine (68 mg, 0.64 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (59 mg, 0.60 mmol) in toluene at 100° C. for 5 h to give the title compound (85 mg, 92%) as an oil. GC/MS(EI): m/z 183 (M+), 184.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl>[C:38]([N:26]1[CH2:27][CH2:28][C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[C@H:24]([OH:29])[CH2:25]1)(=[O:40])[CH3:39]
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCNC[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC[C@@H](n2cnc3c(cc(Cc4ccc(Cl)nc4)c4ccccc43)c2=O)[C@H](O)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4R)-3-hydroxypiperidin-4-yl]benzo[h]quinazolin-4(3H)-one (Example 35, 0.050 g, 0.11 mmol) in 2 mL of dichloromethane at 0° C. was added triethylamine (0.023 mL, 0.16 mmol) and acetic anhydride (0.013 mL, 0.14 mmol). The reaction was stirred at 0° C. for 5 h, quenched with water, and concentrated in vacuo. The resultant residue was subjected to purification via reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 462.9 for M+H+: 1H NMR (400 MHz, CDCl3) δ 9.01-9.00 (m, 1H), 8.37 (s, 1H), 8.37 (s, 1H), 7.96 (d, J=7.1 Hz, 1H), 7.88 (s, 1H), 7.72-7.68 (m, 2H), 7.41 (d, J=8.7 Hz, 1H), 7.22-7.20 (m, 1H), 5.07-5.01 (m, 1H), 4.92-4.67 (m, 2H), 4.44 (s, 2H), 4.23-3.98 (m, 3H), 3.34-3.24 (m, 1H), 3.20-3.11 (m, 1H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14](=[O:31])[C:15]2[CH:20]=[C:19]([F:21])[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][C:16]=2[F:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][C:16]=2[F:30])[OH:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](C(=O)c2cc(F)c(OCc3ccccc3)cc2F)C1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@H](C(O)c2cc(F)c(OCc3ccccc3)cc2F)C1
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
To a solution of 7.5 g of (S)-2-(4-benzyloxy-2,5-difluoro-benzoyl)-morpholine-4-carboxylic acid tert-butyl ester in methanol (90 ml) was added with cooling (0-5° C.) sodium borohydride (660 mg) in small portions. Stirring continued for 15 minutes with cooling before sodium bicarbonate (150 mL, saturated) was added. Organic material was partitioned into ethyl acetate (3×), organic phases were pooled, washed with brine and dried with Na2SO4 before being concentrated in vacuo to give 7.5 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH:44]3[CH2:46][CH2:45]3)=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH:44]3[CH2:45][CH2:46]3)=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J36) (239 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow solid (274 mg, 63%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=O)=[CH:27][CH:26]=1)#[N:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([N:21]([CH3:22])[C:33](=[O:35])[CH2:32][CH2:31][C:28]4[CH:27]=[CH:26][C:25]([C:23]#[N:24])=[CH:30][CH:29]=4)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Reactant: CNc1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C(=O)CCc1ccc(C#N)cc1)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[2-(4-cyanophenyl)-ethyl]-1-methyl-5-methylamino-benzimidazole (0.9 g, 3.1 mmol), 3-(p-cyanophenyl)-propionic acid (0.6 g, 3,4 mmol) and 0.5 mL of N-methylmorpholine are taken up in 10 mL of dimethylformamide. TBTU (1.2 g, 3.7 mmol) is added and the mixture is stirred for 16 h at ambient temperature. After dilution with 75 mL of ethyl acetate the mixture is washed with dilute aqueous NaOH or saturated NaHCO3 solution and with water, dried and evaporated down. The product is crystallised from ethyl acetate/diethylether.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:24][CH2:25][N:26]([S:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[O:41][CH3:40])(=[O:50])=[O:49])[CH2:27][CH2:28]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: COc1ccccc1S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3ccccc3OC)CC2)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 102 mg, 0.237 mmol) and N,N-diisopropylethylamine (124 μL, 0.711 mmol) in methylene chloride (6.0 mL) was added 2-methoxybenzenesulfonyl chloride (98 mg, 0.474 mmol). After stirring for ˜10 minutes at 0° C., the light yellow reaction mixture was allowed to warm to room temperature and then was stirred for 4 hours at room temperature under nitrogen. During this time, some solvent had evaporated. Additional methylene chloride was added. The reaction mixture was diluted with water (˜25 mL) and extracted with methylene chloride (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. Silica gel chromatography (20-33% ethyl acetate/hexanes) afforded {6-fluoro-4-[1-(2-methoxy-benzenesulfonyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (64 mg, 55%). MS cald. for C26H29FNO5S [(M+H)+]: 486, obsd. 486.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[CH2:7]2.CO.[BH4-].[Na+]>C(O)(=O)C>[C:2]1([OH:1])[C:3]2[CH2:4][CH2:5][CH:6]([OH:12])[CH2:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCc2c(O)cccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1cccc2c1CCC(O)C2
Reaction time: 2.5 h

Procedure:
A 3.7 g. (0.0235 mole) sample of 5-hydroxy-3,4-dihydro-2(1H)-naphthalenone in 125 ml. of methanol is added to a cooled solution of 1.0 g. (0.025 mole) of sodium borohydride in 25 ml. of methanol. After 150 minutes at 0°, 7.2 g. of acetic acid is added and the solvent removed in vacuo. Partitioning between water and methylene chloride gives 3.54 g. of crude product after further extraction, drying and solvent removal. Recrystallization from hexane-ethyl acetate gives 2.92 g., m.p. 126°-128.5°. (lit. m.p. 127°-128°) JACS, 80, 2887 (1958).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1.[C:20]([O-])(O)=[O:21].[Na+].C(Cl)(Cl)=O>ClCCl>[CH2:11]([O:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:2]=[C:20]=[O:21])=[CH:19][CH:18]=1)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C([O-])O
Reactant: NCc1ccc(C(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C=NCc1ccc(C(=O)OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 94 %

Procedure:
To 4-(aminomethyl)benzoic acid, benzyl ester, hydrochloride salt, prepared as in Example 5, step C (288 mg, 1.04 mmol) at 0° C. was added saturated aqueous NaHCO3 (15 ml) and dichloromethane (20 ml). After 20 minutes stirring was ceased and the two layers were allowed to separate. Phosgene (20% solution in toluene, 1.1 ml, 2.18 mmol) was added rapidly to the lower layer and stirring resumed immediately. After 1 hour the organic layer was isolated. The aqueous layer was extracted with dichloromethane (3×20 ml). The four organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give the title compound (261 mg, 94%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=2)[N:19]=[C:18]([C:27]([O-:29])=O)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].C(OC(C)C)(C)C>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=2)[N:19]=[C:18]([C:27]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:29])[N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2nc(C(=O)[O-])nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Reactant: COCCN
Solvent: CO
Solvent: CC(C)OC(C)C
Product: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(C)ccc2n1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a suspension of 15.0 g of ethyl 4-({(1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino-6-methylquinazolin-2-carboxylate in 15 ml of methanol, 7.89 g of 2-methoxyethylamine was added, and the mixture was stirred at 50° C. for 15 hours. After the reaction solution was cooled to room temperature, 45 ml of diisopropyl ether was added thereto, and the mixture was stirred at 0° C. for 30 minutes. The deposited crystal was collected by filtration, washed with diisopropyl ether and dried under reduced pressure, whereby 12.2 g of a desired compound was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=1)=O.[OH-].[K+].O.NN.Cl>O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C(=O)c3cccc(OC)c3)cc(OC)c21
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cc3cccc(OC)c3)cc(OC)c21
Temperature: 190 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
A mixture of 125 mg (0.233 mmol) [4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-(3-methoxy-phenyl)-methanone (example 26o), 45 mg KOH pellets, 3.2 ml hydrazine-monohydrate, 0.5 ml water and 13 ml ethyleneglykol is stirred at 190° C. for 2 h. After that the reaction mixture is poured on 4N HCl-solution and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 20 mg of the title compound as an off-white crystalline solid.
Reaction SMILES: [Na].[C:2]([O:13]CC1C=CC=CC=1)(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]CCl)=[O:8].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CC(C)=O.[Pd]>[OH2:8].[C:2]([OH:13])(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(CCCCC(=O)OCc1ccccc1)OCCl
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)CCCCC(=O)O
Reaction time: 1 h
Yield: 417.1 %

Procedure:
To 400 ml acetone is added 48.5 g (0.19 mole) sodium, 1,1-dioxopenicillanate, 48.0 g (0.17 mole) benzyl chloromethyl adipate and 19.3 g (0.06 mole) tetrabutylammonium bromide. The mixture is heated at reflux under nitrogen overnight, filtered, washed with acetone and the filtrate evaporated. The residue is taken up in 500 ml ethyl acetate, washed alternately with brine and water, 250 ml portions, brine again and dried (MgSO4). Evaporation of solvent in vacuo afforded 89.6 g light yellow oil. The oil is taken up in 250 ml ethyl acetate, 20.0 g 10% Pd/C added and the mixture is hydrogenated at 3.52 kg/cm2 for one hour. After adding 15 g of fresh catalyst the hydrogenation is continued for 2.5 hours. The catalyst is removed by filtration, the cake washed with acetone (1500 ml) and the combined filtrate and washings evaporated in vacuo to obtain a viscous oil. The oil is taken up in 150 ml acetone and water added slowly to start crystallization, then continued until 800 ml water is added. After stirring 30 minutes, the crystalline product is recovered by filtration, washing with water and air dried to obtain 58.2 g of the title carboxylic acid. Recrystallization from ethyl acetate affords the crystalline monohydrate, m.p. 100°-102° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1)(=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>ClC1C=CC=CC=1Cl.ClCCl.[Cu].C1COCC1>[C:11]([N:14]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)(=[O:13])[CH3:12]
Reactant: CC(C)c1ccc(I)cc1
Reactant: CC(=O)Nc1ccc(C(C)C)cc1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(C(C)C)cc1)c1ccc(C(C)C)cc1
Reaction time: 48 h

Procedure:
4-Isopropyliodobenzene (29.2 g, 118 mmol), N-acetyl-4-isopropylaniline (21.0 g, 118 mmol), copper powder (15.0 g, 237 mmol), potassium carbonate (65.4 g, 474 mmol) and 18-crown-6 (2.9 g, 12 mmol) are heated to reflux in 200 ml of 1,2-dichlorobenzene. The reaction is monitored by thin-layer chromatography (eluent: 10% THF in dichloromethane). After 48 h, the still-hot reaction mixture is filtered, the filter residue is washed thoroughly and the solvent is removed on a rotary evaporator. The crude product is chromatographed on silica gel using 10% THF in dichloromethane. The product fractions are concentrated to dryness, recrystallized from hexane and dried under reduced pressure.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][OH:16].O>CS(C)=O>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: OCCn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
KOH (571 mg, 10.2 mmol) was stirred in 5 mL of anhydrous DMSO at room temperature. 6-Bromoindole (500 mg, 2.55 mmol) was added as solid. After 30 min, 2-bromoethanol (181 μL, 2.55 mmol) was added to the green solution, which was then stirred at room temperature overnight. Water was then added and the reaction mixture was extracted with ethyl acetate (2×25 mL). The organic layer was then washed with water and brine, dried over Na2SO4, evaporated in vacuo. MPLC purification of the crude product provided the titled compound as a light brown oil (344 mg, 56% yield).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]3[O:37][CH2:36]3)[C:30]([O:32]C)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]([OH:37])[CH2:36][S:1][C:2]3[NH:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=3)[C:30]([OH:32])=[O:31])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc4ccccc4[nH]3)C(=O)O)cc2)cc1

Procedure:
Example 28 is prepared from 2-mercaptobenzimidazole and 1d using the procedure described for compound 20.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH3:2].[C:16]12([NH:26][C:27](=[O:35])[NH:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.CCN=C=NCCCN(C)C.CN(C1C=CN=CC=1)C>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][NH:28][C:27]([NH:26][C:16]12[CH2:17][CH:18]3[CH2:19][CH:20]([CH2:21][CH:22]([CH2:24]3)[CH2:23]1)[CH2:25]2)=[O:35])[CH3:2]
Reactant: O=C(O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)CCCCCCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: CCOC(=O)CCCCCCCCCOC(=O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Yield: 60 %

Procedure:
A mixture of 10-hydroxydecanoic acid (0.25 g, 1.33 mmol; 11-hydroxyundecanoic acid for compound 881 and 12-hydroxydodecanoic acid for compound 882), ethyl bromide (0.16 g, 1.46 mmol), and lithium carbonate (0.11 g, 1.46 mmol) in DMF (25 mL) was stirred at 70 C for 6 h. Then the product was extracted with ether (30 mL), and the ether solution was washed with 1 N NaOH aqueous solution (20 mL) and water (30 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (3:1) to give 10-hydroxydecanoic acid ethyl ester (80 mg, 28%). This alcohol was coupled with 4-(3-adamantan-1-yl-ureido)butyric acid 822 by using EDCI/DMAP coupling reagent to give 880 (0.11 g, 60%) as a solid: 1H NMR (CDCl3) 1.24-1.32 (13H, m), 1.62-1.68 (10H, m), 1.80 (2H, quint, J=6.9 Hz), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.28 (2H, t, J=6.9 Hz), 2.36 (2H, t, J=6.9 Hz), 3.16 (2H, q, J=6.9 Hz), 4.05-4.14 (5H, m), 4.25 (1H, s); LC-MS (ESI) m/z calcd for C27H46N2O5 [M+H]+ 479.34. found [M+H]+ 479.29; mp 60-61 C. Anal. Calcd for C27H46N2O5: C, 67.75; H, 9.69; N, 5.85. Found: C, 68.33; H, 9.92; N, 5.97.