Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=O)[CH:18]=2)[NH:13][C:12]=1[C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:63]([NH:65][CH2:66][CH3:67])[CH3:64]>>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:22])[N:65]([CH2:66][CH3:67])[CH2:63][CH3:64])[CH:18]=2)[NH:13][C:12]=1[C:23]1[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)N(CCCCc1cccnc1)CCc1c(-c2cc(Cl)cc(Cl)c2)[nH]c2ccc(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCN(CC)C(=O)c1ccc2[nH]c(-c3cc(Cl)cc(Cl)c3)c(CCN(CCCCc3cccnc3)C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-{2-[tert-butoxycarbonyl-(4-pyridin-3-yl-butyl)amino]ethyl}-2-(3,5-dichlorophenyl)-1H-indole-5-carboxylic acid (63 mg in 6 mL methylene chloride) was added 24.2 mg 1-hydroxybenzotriazole followed by 26.7 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture stirred at room temperature. After 30 minutes, 0.06 mL of diethylamine was added and the mixture stirred at room temperature for 16 hours. The reaction was then concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (63 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:37]=1[CH:38]=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:38]/[C:37]2[C:36]([Cl:35])=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:44])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/c2c(Cl)cccc2Cl)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.89 g, 6.9 mmol) and Ph3P (1.82 g, 6.9 mmol) in DMF (35 mL) was heated at 100° C. for 1 h then 2,6-dichlorobenzaldehyde (1.2 g, 6.9 mmol) was added followed by K2CO3 (1.9 g, 13.75 mmol). The resulting deep-red mixture was stirred at 100° C. for 18 h then was allowed to cool to ambient temperature. To this was added water and the mixture was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography using methylene chloride as eluent to give 4-[(E)-2-(2,6-dichlorophenyl)-vinyl]-3-nitrobenzoic acid methyl ester as a pale-yellow solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([CH2:28][N:29]([CH3:31])[CH3:30])[CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:31][N:29]([CH2:28][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:20]1)[CH3:30]
Reactant: CN(C)CC1CNc2ccccc21
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN(C)CC1CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2ccccc21
Yield: 61.5 %

Procedure:
The product is prepared according to the procedure described in example 5, using 220 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 300 mg of (2,3-dihydro-1H-indol-3-ylmethyl)dimethylamine and 210 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.14 ml of pyridine and 2.5 ml of N,N-dimethylformamide. 206 mg of 2-[2-(3-dimethylaminomethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[C:7]([N+:13]([O-])=O)[CH:6]=1)(=[O:4])=[O:3].CCOC(C)=O>CC(O)=O.[Fe]>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][C:7]=1[NH2:13])[CH3:12]
Reactant: C=Cc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCc1ccc(S(C)(=O)=O)cc1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 4-(methylsulfonyl)-2-nitro-1-vinylbenzene (Intermediate 121; 3.60 g; 15.8 mmol) in AcOH (100 mL) was treated with a solution of iron (15.9 g; 285 mmol) in AcOH (20 ml) and the reaction mixture was stirred at 60° C. for 1 h. EtOAc was added and the solution was filtered, the solvents removed under reduced pressure. The residue was taken up in EtOAc, washed with a sat. NaHCO3 solution in water, then with brine. The organic layer was dried, filtered and concentrated to give the title compound.
Reaction SMILES: NC1SC2C3C(CC=2[C:3]=1[C:14](N)=[O:15])=CC=CC=3.[NH2:17][C:18]1[S:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[C:19]=1[C:32]([NH2:34])=[O:33])=[CH:27][C:26]([Br:31])=[CH:25][CH:24]=3>>[C:14]([NH:17][C:18]1[S:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[C:19]=1[C:32]([NH2:34])=[O:33])=[CH:27][C:26]([Br:31])=[CH:25][CH:24]=3)(=[O:15])[CH3:3]
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Reactant: NC(=O)c1c(N)sc2c1CCc1cc(Br)ccc1-2
Product: CC(=O)Nc1sc2c(c1C(N)=O)CCc1cc(Br)ccc1-2

Procedure:
The title compound was prepared by the same procedure as Example 3 except that 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide was replaced with 2-amino-7-bromo-4,5-dihydro-naphtho[1,2-b]thiophene-3-carboxylic acid amide to give the above title compound as light grey solid. ESMS m/z: 366 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>CCCCCC.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH3:15])[C:9](=[O:14])[CH2:10][C:11]2([CH3:12])[CH3:13]
Reactant: CC(C)=CC(=O)N(C)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: CN1C(=O)CC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
N-(4-bromophenyl)-N-methyl-3-methyl-2-butenamide (Intermediate 54, 6.42 g, 24 mmol) was heated to 130° C. and aluminum chloride (5 g, 37.4 mmol) was added in portions over 0.5 h. The reaction mixture was stirred for 1 hour at the same temperature and then cooled to room temperature. Ice was added cautiously to the solid, followed by ˜200 mL of iced water. The reaction mixture was then extracted with ether (×2) and dichloromethane (×1) and the combined organic phase was dried over anhydrous magnesium sulfate and evaporated in vacuo to yield a brown solid. The solid was treated with hexane-dichloromethane and filtered to afford 1.7 g of product. The mother liquor was evaporated and purified by flash column chromatography on silica gel (230-400 mesh) to afford 2.9 g of the title compound as a solid (total 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1>[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([C:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:7])=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl[Fe](Cl)Cl
Product: O=C(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 69 %

Procedure:
FIG. 5 shows the synthetic route for the chlorophenyl-substituted precursor polymer (Cl-DP-PPV) 19. See H. V. Huynh et al., Organometallics 27, 2231 (2008); X. Jing et al., Synth. Commun. 39, 492 (2009); and W. C. Wan et al., Macromolecules 30, 6567 (1997). As an example, commercially available benzimidazole 10 was reacted with two equivalents of octyl bromide to produce the benzimidazolium salt 11 in 46% yield, which was used as a condensation catalyst in the following reaction. Coupling 4-chlorobenzaldehyde 12 in the presence of the condensation catalyst 11 under basic aqueous conditions followed by oxidation with iron trichloride produced 4,4′-dichlorobenzil 13 in 69% yield. The benzil derivative 13 was then condensed with diethyl 1,3-acetonedicarboxylate to afford the cyclopentanone derivative 14 in 64% yield. A Diels-Alder reaction with norbornadiene produced the terephthalate derivative 15 in 89% yield. Reduction of hindered diesters is typically carried out using LiAlH4; however, a complex mixture of products was obtained as a result of the partial reduction of the phenyl chlorines. Better results were obtained with LiBH4, which produced the desired diol 16 in 93% yield, but required long (36 h) reaction times. The monomer 17 was obtained in 95% yield after stirring the diol 16 in thionyl chloride for 16 h. The chlorophenyl-substituted precursor polymer 18 was afforded in 37% yield by reaction of the monomer 17 with 1 equivalent of t-BuOK. The fully conjugated polymer 19 can be prepared by heating the precursor polymer to high temperatures.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][CH2:16][CH3:17])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=O)C>O.NN>[CH2:16]([O:15][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([NH2:4])=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13])[CH3:17]
Reactant: CCOC(C(=O)O)c1ccc(NC(C)=O)cc1
Agent: NN
Solvent: O
Product: CCOC(C(=O)O)c1ccc(N)cc1
Yield: 37 %

Procedure:
2-(4-Acetamidophenyl)-2-ethoxyacetic acid (7.54 g, 31.8 mmol) was heated with hydrazine monohydrate (40 ml) for 16 hr, the mixture cooled then concentrated in vacuo The residual oil was then purified by silica column chromatography (20-40% methanol in CH2Cl2 eluent) to give (±)-2-ethoxy-2-(4′-aminophenyl)-acetic acid (2.3 g, 37%) as a white foam.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][OH:13])[CH3:8])=[CH:3][CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[O:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCNCC1)=O)=NC(N1CCNCC1)=O>>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[O:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH3:8])=[CH:3][CH:2]=1
Reactant: O=C1OC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(-c2ccccc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCNCC1)N1CCNCC1
Product: CC(=NOCCOc1ccc(CC2OC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccccc2)cc1
Yield: 50.7 %

Procedure:
Following a procedure similar to that described in Example 3(a), but using 0.23 g of 2-[1-(4-biphenylyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 15), 0.40 g of 5-(4-hydroxybenzyl)-3-trityloxazolidine-2,4-dione, 0.40 g of tributylphosphine and 0.50 g of 1,1'-(azodicarbonyl)dipiperazine, 0.31 g of the title compound was obtained as a crystalline powder, melting at 193°-195° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:23]1[CH:24]=[CH:25][C:26]([O:31][CH2:32][C:33]([CH2:35]I)=[CH2:34])=[C:27]([CH:30]=1)[CH:28]=O)(=[O:22])[CH3:21].C[O-].[Na+].O>C(#N)C.CO>[CH2:34]=[C:33]1[CH:35]=[CH:28][C:27]2[CH:30]=[C:23]([C:20](=[O:22])[CH3:21])[CH:24]=[CH:25][C:26]=2[O:31][CH2:32]1
Reactant: C=C(CI)COc1ccc(C(C)=O)cc1C=O
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Solvent: CC#N
Product: C=C1C=Cc2cc(C(C)=O)ccc2OC1
Reaction time: 14 h
Yield: 57.9 %

Procedure:
973 mg (3.575 mmol) of triphenylphosphine are added under argon to 1.118 g (3.25 mmol) of 5-acetyl-2-{[2-(iodomethyl)-2-propenyl]oxy}benzaldehyde in solution in 30 ml of acetonitrile. The medium is brought to reflux and is stirred for 14 hours. After cooling the solution, 0.743 ml (3.25 mmol) of a 25% solution of sodium methoxide in methanol is added. The medium is stirred at ambient temperature for 3 hours and then water is added. After concentrating the solution under vacuum, dichloromethane is added. The phases are then separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed, are then dried and are finally concentrated under vacuum. The crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 10/90) to give 377 mg (58%) of 1-(3-methylene-2,3-dihydro-1-benzoxepin-7-yl)ethanone in the form of a white solid; 1H NMR (300 MHz, CDCl3): 7.86 (d, J=2.1 Hz, 1H), 7.75 (dd, J=2.1 Hz and 8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.51 (d, J=11.7 Hz, 1H), 6.38 (d, J=11.7 Hz, 1H), 5.28 and 5.11 (2s, 2H), 4.61 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4](Cl)=[C:5]([F:21])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]2=[O:20])#[N:2].[C@@H:23]12[CH2:31][NH:30][CH2:29][C@@H:28]1[CH2:27][CH2:26][CH2:25][NH:24]2.N12CCN(CC1)CC2>C(#N)C>[C:1]([C:3]1[C:4]([N:30]2[CH2:31][C@@H:23]3[C@@H:28]([CH2:27][CH2:26][CH2:25][NH:24]3)[CH2:29]2)=[C:5]([F:21])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]2=[O:20])#[N:2]
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Reactant: COC(=O)c1cn(C2CC2)c2c(C#N)c(Cl)c(F)cc2c1=O
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COC(=O)c1cn(C2CC2)c2c(C#N)c(N3C[C@@H]4CCCN[C@@H]4C3)c(F)cc2c1=O

Procedure:
200 mg (0.625 mmol) of methyl 8-cyano-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 86 mg (0.683 mmol) of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane and 150 mg (1.34 mmol) of 1,4-diazabicyclo[2.2.2]-octane are stirred in 6 ml of acetonitrile at room temperature for 48 hours. Thereafter, the mixture is evaporated and the residue is partitioned between 15 ml of chloroform and 20 ml of saturated sodium carbonate solution. The organic phase is separated off, the aqueous phase is extracted again with chloroform and, after drying with sodium sulfate, the combined extracts are evaporated. For purification, the residue is chromatographed over silica gel with ethyl acetate/ethanol/25% strength aqueous ammonia solution.
Reaction SMILES: Cl.[CH2:2]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:18][C:17]([NH:19][C:20](=[O:35])[N:21]([CH:28]3[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]3)[CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH3:3].[F:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>>[CH2:2]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:18][C:17]([NH:19][C:20](=[O:35])[N:21]([CH:22]3[CH2:27][CH2:26][N:25]([C:41](=[O:42])[C:40]4[CH:44]=[CH:45][C:37]([F:36])=[CH:38][CH:39]=4)[CH2:24][CH2:23]3)[CH:28]3[CH2:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH2:33]3)=[N:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:5])=[O:6])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCNCC3)C3CCC(C)CC3)s2)CC1
Agent: Cl
Product: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCC(C)CC3)C3CCN(C(=O)c4ccc(F)cc4)CC3)s2)CC1
Yield: 86.1 %

Procedure:
Prepared as described in general procedure (N) using 3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1-(4-methyl-cyclohexyl)-1-piperidin-4-yl-urea hydrochloride (46 mg, 0.075 mmol), TEA (26 μL, 0.19 mmol) and 4-fluorobenzoyl chloride (10 μL, 0.083 mmol) and to afford 41 mg (86%) of the desired product after purification.
Reaction SMILES: [CH3:1][N:2]([CH:15]([N:18]1[C:24](=O)[CH2:23][C:22]2[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:21]=2[CH:20]=[CH:19]1)[CH2:16][CH3:17])[CH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][N:2]([CH:15]([N:18]1[CH2:24][CH2:23][C:22]2[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:21]=2[CH:20]=[CH:19]1)[CH2:16][CH3:17])[CH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCC(N1C=Cc2cc(OC)c(OC)cc2CC1=O)N(C)C(C)c1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(N1C=Cc2cc(OC)c(OC)cc2CC1)N(C)C(C)c1cccc2ccccc12

Procedure:
Prepared from 3-[N-methyl-N-((naphth-1-yl)-eth-2-yl)-amino-prop-3-yl]-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one and lithium aluminium hydride analogously to Example 8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:16]2)=[O:10])=[CH:4][C:3]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:9]2=[O:10])=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc(NC(=O)NNC(=O)C[C@@H]2CCN(C(=O)C3CC3)C2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(-n2c(C[C@@H]3CCN(C(=O)C4CC4)C3)n[nH]c2=O)ccc1Br
Temperature: 115 °C

Procedure:
N-[4-bromo-3-(methyloxy)phenyl]-2-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide (500 mg, 0.911 mmol) and potassium carbonate (445 mg, 3.22 mmol) were added to a round-bottom flask and suspended in water (50 mL). The mixture was refluxed overnight at 115° C. Analysis by LCMS indicated formation of desired product (and other major by-products). A white solid (that was not desired product) had collected at the bottom of the flask and was filtered off. The pH of the filtrate was adjusted to ˜6 with 1N aq HCl and was partitioned with ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to an oil. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, then 0-30% isopropanol/ethyl acetate). The desired fractions were combined and concentrated in vacuo to afford the title product as an off-white solid (151 mg, 38%). MS(ES)+ m/e 421.0, 422.9 M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O.C(Cl)(=O)C(Cl)=O.[CH3:25][O:26][CH2:27][C:28]([C:31]1[CH:35]=[C:34]([NH2:36])[O:33][N:32]=1)([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[S:12][C:13]([CH3:18])([CH3:17])[C:14]([NH:36][C:34]1[O:33][N:32]=[C:31]([C:28]([CH3:30])([CH3:29])[CH2:27][O:26][CH3:25])[CH:35]=1)=[O:16]
Reactant: CC(C)(Sc1ccc(S(C)(=O)=O)cc1F)C(=O)O
Reactant: COCC(C)(C)c1cc(N)on1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCC(C)(C)c1cc(NC(=O)C(C)(C)Sc2ccc(S(C)(=O)=O)cc2F)on1
Temperature: 50 °C
Yield: 43 %

Procedure:
Activation of 336 mg (1.15 mmol) of 2-(2-fluoro-4-methanesulfonyl-phenylsulfanyl)-2-methyl-propionic acid as its acid chloride is achieved by treatment with oxalyl chloride (0.3 mL, 3.45 mmol) and DMF (1 drop) in DCM (15 mL) at room temperature for 3 h. The solvent is removed under reduced pressure and the crude acid chloride is dissolved in toluene (5 mL) and added to a solution of 196 mg (1.15 mmol) of 3-(2-methoxy-1,1-dimethyl-ethyl)-isoxazol-5-ylamine and N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) in toluene. The reaction is heated to 50° C. for 18 h. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate (20 mL) and washed with 1M aqueous HCl solution (2×10 mL), water (2×10 mL), saturated aqueous NaHCO3 solution (2×10 mL), brine (10 mL). The organic layer is dried (Na2SO4), filtered and the filtrate is concentrated under reduced pressure. The residue is purified twice by column chromatography (silica, eluent: heptanes, 20-50% ethyl acetate, followed by heptanes, 10% ethyl acetate) to afford 220 mg of 2-(2-fluoro-4-methanesulfonyl-phenylsulfanyl)-N-[3-(2-methoxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-propionamide. Yield: 43%, ES-MS: m/z 445 [M+H]
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH3:22]O>>[CH3:22][O:12][C:11](=[O:13])[CH2:10][CH2:9][C:8]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:14]
Reactant: CO
Reactant: CC(CCC(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1
Product: COC(=O)CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C

Procedure:
To a solution in methanol (120 mL) of 4,4-bis(4-hydroxyphenyl)pentanoic acid (Aldrich Chemical Co., 12 g, 42 mmol) was added concentrated H2 SO4 (0.5 mL) and the mixture was heated to reflux for 3 hours. After cooling to room temperature the mixture was concentrated in vacuo and dissolved in ether (300 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×150 mL) and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide a thick oil which was crystallized from ether/hexane to give 4,4-bis(4-hydroxyphenyl)pentanoic acid methyl ester as an off-white color solid (11.8 g, 94%), mp 130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccc(F)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and commercial 4-fluoroacetophenone, 3-(4-chlorophenyl)-1-(4-fluorophenyl)prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([C:8]1[CH:23]=[CH:22][C:11]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][C:18]([OH:21])=[CH:19][CH:20]=3)[NH:14][C:10]=2[CH:9]=1)([CH3:7])[CH3:6])=[O:2].O.[OH-].[K+].[CH3:27]I>C(O)C>[CH:1]([NH:3][CH2:4][C:5]([C:8]1[CH:23]=[CH:22][C:11]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:27])=[CH:19][CH:20]=3)[NH:14][C:10]=2[CH:9]=1)([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(CNC=O)c1ccc2nc(-c3ccc(O)nc3)[nH]c2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc3ccc(C(C)(C)CNC=O)cc3[nH]2)cn1
Reaction time: 24 h

Procedure:
To a solution of 3.5 g. of the 5-(2-formylaminomethylprop-2-yl)-2-(6-hydroxypyridin-3-yl)-benzimidazole (prepared in Example 4d) in 20 ml. water and 13.6 ml. 1N potassium hydroxide solution in ethanol is added 0.85 ml. methyl iodide, while cooling with water. After 24 hours, it is filtered off with suction and purified by column chromatography (silica gel, elution agent dichloromethane:methanolic ammonia=20:1 v/v). Appropriate fractions are combined, the solvent is removed in a vacuum and the residue is digested with ethanol/water. After filtering off with suction, there are obtained 2.2 g. (57% of theory) of the title compound which, per mole, still contains 0.75 mole of water, as colourless crystals which, in the air, become reddish coloured; m.p. 217°-221° C.