Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:28][Si](C)(C)C>CC(CC)=O>[ClH:28].[CH3:27][N:2]([CH3:1])[C:3]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCc2ccccc2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexylidene)-N-phenylethylacetamide (225 mg, 0.62 mmol) was dissolved in ethyl methyl ketone (12 ml) with gentle heating and chlorotrimethylsilane (0.118 ml, 0.93 mmol) was added. After 2 h the product was isolated as a colourless solid in a yield of 86% (213 mg).
Reaction SMILES: OP([O-])(O)=O.[K+].[C:7]([C:9]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)([CH2:16][CH3:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:8].[OH-].[Na+]>>[C:7]([C@:9]([C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)([CH2:16][CH3:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:8]
Reactant: CCC(C#N)(CCC(=O)OC)c1ccc([N+](=O)[O-])cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Product: CC[C@@](C#N)(CCC(=O)OC)c1ccc([N+](=O)[O-])cc1
Temperature: 37 °C
Yield: 50.3 %

Procedure:
A 1 l jacketed biotransformation vessel was charged with 0.05M KH2PO4, pH 7.5 (500 ml) and methyl 4-cyano-4-(4-nitrophenyl)hexanoate (20 g, 72 mmol). α-Chymotrypsin (ex. Aldrich; 4 g) was introduced and the mixture was agitated using an overhead stirrer. Temperature was maintained at 37° C. with the aid of a thermocirculator and the pH controlled by a probe linked to an autotitrator. The biotransformation was allowed to proceed until 18 ml of 1M NaOH had been added (equivalent to 50% conversion). This took about 68 hours, with addition of more α-chymotrypsin (1 g portions) after 24 hours and 50 hours. At this point, the biotransformation was quenched by the addition of NaCl (50 g) and the resulting mixture was extracted with diethyl ether (500 ml×3). The extracts were pooled, dried and concentrated under reduced pressure, yielding 10 g (50%) of (R)-methyl 4-cyano-4-(4-nitrophenyl)hexanoate, enriched in the (R)-enantiomer, 70% ee by chiral HPLC analysis.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:15])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10](Cl)[CH:9]=2)=[CH:5][C:4]([C:16]([O:18][CH3:19])=[O:17])=[CH:3]1.CN1C=CC(C(O)=O)=C1>>[CH3:1][N:2]1[C:6]([C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:15])=[CH:5][C:4]([C:16]([O:18][CH3:19])=[O:17])=[CH:3]1
Reactant: COC(=O)c1cc(C(=O)c2cccc(Cl)c2)n(C)c1
Agent: Cn1ccc(C(=O)O)c1
Product: COC(=O)c1cc(C(=O)C2CCCCC2)n(C)c1

Procedure:
Belgian Pat. No. 870,910 (published Mar. 29, 1979) discloses preparation of analogous 1-alkyl-5-acylpyrrole-3-carboxylates, specifically exemplifying preparation of methyl 1-methyl-5-(3-chlorobenzoyl)pyrrole-3-carboxylate by Friedel-Crafts acylation of 1-methylpyrrole-3-carboxylic acid followed by esterification and separation from the 4-acyl isomer.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:26][CH:27]1[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1.C(=O)([O-])[O-]>C(Cl)Cl>[NH:29]1[CH2:30][CH:27]([NH:26][C:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][C:11]4[N:17]([N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[CH:10]=4)[C:16]=3[CH:19]=2)=[O:25])[CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)NC3CNC3)ccc1OCC2
Reaction time: 1.5 h

Procedure:
Following the procedure for 126, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 1,1-dimethylethyl 3-aminoazetidine-1-carboxylate then the crude product was suspended in DCM and treated with MP carbonate resin and stirred for 1.5 h. The mixture was filtered, the filtrate concentrated in vacuo and the resultant residue triturated in diethyl ether to give 156 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.11 (d, J=6.84 Hz, 1 H); 8.46 (d, J=2.18 Hz, 1 H); 8.05 (t, J=0.64 Hz, 1 H); 7.90-7.85 (m, 1 H); 7.37-7.30 (m, 1 H); 6.92 (s, 1 H); 5.62-5.53 (m, 1 H); 4.82-4.73 (m, 1 H); 4.57 (t, J=5.76 Hz, 2 H); 3.95-3.81 (m, 4 H); 3.25 (t, J=5.78 Hz, 2 H); 1.50 (d, J=6.58 Hz, 6 H). LCMS RT=6.45 min, M+H+=394
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[N:10]([CH2:13][CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]=O)=[N+:11]=[N-:12]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:17]/[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][N:10]=[N+:11]=[N-:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CC=O)CCN=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C/C=N/CC(=O)OC(C)(C)C)CCN=[N+]=[N-]
Yield: 98.9 %

Procedure:
Step C In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.32 g, 2.45 mmol) was reacted with 5-azido-3,3-dimethyl-pentanal (0.38 g, 2.45 mmol) in CH2Cl2 at room temperature for 18 h to give [5-azido-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (0.65 g, 100%).
Reaction SMILES: C([O:4][C:5]1[C:6]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:7][C:8]2[O:12][C:11]([CH2:14][O:15][C:16]3[CH:27]=[CH:26][C:19]([CH:20]=[N:21][NH:22][C:23]([NH2:25])=[NH:24])=[CH:18][CH:17]=3)([CH3:13])[CH2:10][C:9]=2[C:28]=1[C:29]([CH3:32])([CH3:31])[CH3:30])(=O)C.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1>[C:29]([C:28]1[C:9]2[CH2:10][C:11]([CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([CH:20]=[N:21][NH:22][C:23]([NH2:25])=[NH:24])=[CH:26][CH:27]=3)([CH3:13])[O:12][C:8]=2[CH:7]=[C:6]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:5]=1[OH:4])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COc1ccc(C=NNC(=N)N)cc1)O2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(COc2ccc(C=NNC(=N)N)cc2)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
Under a nitrogen atmosphere, 2.0 g of 1-{4-[(5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methoxy]benzylideneamino}guanidine was dissolved in 100 ml of tetrahydrofuran, and 10 ml of n-butyl lithium (1.6 M in n-hexane) was added and the mixture was stirred at room temperature for 30 minutes. After reaction, the reaction solution was combined with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with chloroform containing 10% methanol to give 0.46 g of 1-{4-[(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)methoxy]benzylideneamino}guanidine as a pale yellow solid (yield 25%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1.[CH2:25]([NH:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([N:29]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1)[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]
Reactant: O=C1c2ccccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)no1
Yield: 68.4 %

Procedure:
1.15 g (3.5 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 1.29 g (10 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.04 g (68%) of (S)-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](O)=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([C:26]1([NH2:35])[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](=[O:19])[NH:35][C:26]3([C:24]([O:23][CH2:21][CH3:22])=[O:25])[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CN(C(=O)OC(C)(C)C)CC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of 3,4-dihydro-1H-isoquinoline-2,8-dicarboxylic acid 2-tert-butyl ester (2.0 g, 7.2 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (1.5 g, 7.2 mmol), HATU (3.3 g, 8.6 mmol) in anhydrous DMF (70 mL) is added DIPEA (1.4 mL, 8.6 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (150 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (200 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (217) as white solid (3.3 g, 99%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:7]=[CH:6][N:5]([CH2:8]O)[N:4]=1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:8][N:5]1[CH:6]=[N:7][C:3]([C:2]([F:11])([F:10])[F:1])=[N:4]1
Reactant: OCn1cnc(C(F)(F)F)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ncn(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.52 g of 3-(trifluoromethyl)-1H-1,2,4-triazole 1-ylmethanol was dissolved to 50 ml of dichloromethane, and 2.7 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.36 g of 1-(chloromethyl)-3-(trifluoromethyl)-1H-1,2,4-triazole.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[O:5][C:6]=1[C:7](=[O:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Li+].[BH4-].[NH4+].[Cl-].C(OCC)(=O)C>CO>[CH3:1][C:2]1[N:3]=[C:4]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=2)[O:5][C:6]=1[CH:7]([OH:15])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(O)Cc1ccccc1
Yield: 90.5 %

Procedure:
To a solution of 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethanone (1.2 g, 3.5 mmol) in 50 mL MeOH at 0° C. is added LiBH4 (0.086 g, 3.50 mmol) portionwise. After gas evolution had ceased a tic indicated that the reaction is complete and 50 mL of NH4Cl (aq.) is added and the resultant solution extraxted with ethyl acetate (3×50 mL). The combined organics are dried (Na2SO4), filtered and concentrated under vacuo. The resultant crude oil is purified by flash column chromatography (10%–20%) ethyl acetate/hexane to provide 1.1 g 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethanol. To a solution of 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethanol (0.50 g, 1.44 mmol), 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.28 g, 1.44 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.54 g, 2.16 mmol) in 15 mL toluene is added tributylphosphine (0.5 mL, 2.16 mmol). After 1 hr the volatiles are removed and the crude ester purified by flash column chromatography (10%–25%) ethyl acetate/hexane to provide 0.34 g (45%) of 3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethoxy}-phenyl)-propionic acid methyl ester as the racemate. The ester is separated by HPLC utilizing a chiral column with ethanol as the eluent. This enatiomerically pure ester (0.097 g, 0.18 mmol) is hydrolyzed in the usual manner 3 eq. 1N LiOH in 0.5 mL 3:2:1 solution of THF:MeOH:H2O to provide 0.09 g (93%) of the title compound. MS (M++1) 510.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[CH2:19][C:18]1=[O:26]>>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[C:19]2[C:20]3[C:25](=[N:24][CH:23]=[CH:22][CH:21]=3)[NH:17][C:18]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1C1CCCCC1
Reactant: O=C1Cc2cccnc2N1
Product: COc1ccc(C=C2C(=O)Nc3ncccc32)cc1C1CCCCC1

Procedure:
3-Cyclohexyl-4-methoxybenzaldehyde was condensed with 7-aza-2-oxindole to give 0.25 g of 3-(3-Cyclohexyl-4-methoxybenzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: CO[C:3]([CH:5]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:8](=[O:15])(=[O:14])[N:7]([CH3:16])[C:6]1=[O:17])=[O:4].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C1(C)C(C)=CC=CC=1>[CH3:16][N:7]1[C:6](=[O:17])[CH:5]([C:3](=[O:4])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:8]1(=[O:14])=[O:15]
Reactant: COC(=O)C1C(=O)N(C)S(=O)(=O)c2ccsc21
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1C
Product: CN1C(=O)C(C(=O)Nc2ccccn2)c2sccc2S1(=O)=O

Procedure:
0.3 G. of 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine 1,1-dioxide and 0.13 g. of 2-aminopyridine are dissolved in 30 ml. of absolute xylene and the solution is heated for 1 hour under reflux. After cooling, the crystals are removed by filtration and recrystallized from glacial acetic acid. 3,4-Dihydro-2-methyl-3-oxo-4-(2-pyridyl-carbamoyl)-2H-thieno[2,3-e]1,2-thiazine 1,1-dioxide, melting point 255° C. to 256° C. (decomposition), is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:20](=[O:21])[NH:19][CH2:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.ClC(Cl)(Cl)C(O)=[O:27].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:20](=[O:21])[NH:19][CH:18]([OH:27])[C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: O=C1NCC2=C1c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NC(O)C2=C1c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In one portion, 0.7 g (2 mmol) of 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepin-1(2H)-one was added to an ice-cooled solution of 2.6 g (15.8 mmol) of trichloroacetic acid and 2.0 g(4.4 mmol) of lead tetraacetate in 30 ml of methylene chloride. After stirring for 1 hour, the mixture was neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a yellow residue. Purification of the residue by column chromatography (silica gel, 10 g; eluent, 5% methanol in methylene chloride) followed by crystallization from ether gave 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-3-hydroxypyrrolo[3,4-d][2]benzazepin-1(2H)-one as pale yellow prisms, mp 221°-222° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:7][C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:3]=[N:2]1.[CH2:13]([Mg]Br)[CH3:14].C(OCC)C>C1COCC1>[NH:2]1[CH:3]=[C:4]([C:6]2[S:7][C:8]([CH:11]([OH:12])[CH2:13][CH3:14])=[CH:9][N:10]=2)[CH:5]=[N:1]1
Reactant: CC[Mg]Br
Reactant: O=Cc1cnc(-c2cn[nH]c2)s1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1cnc(-c2cn[nH]c2)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A solution of 2-(1H-pyrazol-4-yl)thiazole-5-carbaldehyde (245 mg, 1.3 mmol) in THF (15 mL) was cooled to 0° C., a 3M solution of ethyl magnesium bromide in diethyl ether (0.9 mL, 2.7 mmol) slowly added at 0° C., and the reaction mixture stirred for 2 hours at 0° C. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered and the organic solvent was concentrated under reduced pressure to obtain crude product. The crude product was purified by flash chromatography (60-120μ; 3% methanol in dichloromethane) to afford 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)propan-1-ol as pale yellow liquid (180 mg, 63% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.19 (br s, 1H), 8.25 (s, 1H), 7.88 (s, 1H), 7.51 (s, 1H), 5.59 (d, 1H), 4.71 (q, 1H), 1.97-1.64 (m, 2H), 0.86 (t, 3H); LC-MS m/z calculated for [M+H]+ 210.06. found 210.1.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]([CH2:20][CH2:21][CH3:22])[CH:7]1[CH2:19][C:10]2=[CH:11][C:12]3[C:13](=[O:18])[NH:14][CH2:15][C:16]=3[CH:17]=[C:9]2[CH2:8]1)[CH2:4][CH3:5].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1.Cl>CN(C=O)C>[CH2:20]([N:6]([CH2:3][CH2:4][CH3:5])[CH:7]1[CH2:19][C:10]2=[CH:11][C:12]3[C:13](=[O:18])[N:14]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=4)[CH2:15][C:16]=3[CH:17]=[C:9]2[CH2:8]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(C#N)cc1)C3
Temperature: 84 °C
Reaction time: 24 h

Procedure:
To a slurry of washed NaH (0.05 g, 1.32 mmol) in DMF (5 mL) was added a slurry of 6-(Dipropylamino)-3,5,6,7-tetrahydrocyclopent[f]isoindol-1(2H)-one (94, 0.30 g, 1.10 mmol) in DMF (10 mL). The slurry was heated to 84° C. and after 40 min, was treated with a solution of alpha-bromo-p-tolunitrile (0.43 g, 2.20 mmol) in DMF (10 mL). After 24 h, the reaction was quenched with H2O and extracted with CH2Cl2. The organic layers were washed with brine, dried (MgSO4), and concentrated on hi-vac. The reside was purified on silica gel, eluting with CH2Cl2 /MeOH to give an oil that was converted to an HCl salt and recrystallized to afford 133 as a white solid (m.p. 141-145° C.).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[C:10]([CH2:13][CH2:14][CH3:15])[CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Ni]>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][CH3:15])[CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(C=O)=CC=Cc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Product: CCCC(CO)CCCc1ccccc1
Reaction time: 20 h
Yield: 89.7 %

Procedure:
395 g of 5-Phenyl-2-n-propyl-penta-2,4-dienal from Synthesis Example 1.1 were combined with 14 g of Raney-Ni and hydrogenated at a hydrogen pressure of 20 bar and at a temperature of 120° C. After 20 hours the reaction was finished. The catalyst was removed and the product distilled. 365 g (content 96%) of 5-phenyl-2-n-propyl-pentanol are obtained. Yield: 93.6% of theoretical.
Reaction SMILES: Cl.[F:2][C:3]([F:11])([F:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:13]1[CH:45]=[CH:44][C:16]([CH2:17][N:18]2[C:22]3[CH:23]=[C:24]([O:27][CH2:28][C:29]4[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=4)[CH:25]=[CH:26][C:21]=3[N:20]=[C:19]2[CH2:35][C:36]([CH2:42][CH3:43])([CH2:40][CH3:41])[C:37]([OH:39])=[O:38])=[C:15]([F:46])[CH:14]=1.FC(F)(F)C1CCNCC1>>[CH2:40]([C:36]([CH2:35][C:19]1[N:18]([CH2:17][C:16]2[CH:44]=[CH:45][C:13]([N:7]3[CH2:8][CH2:9][CH:4]([C:3]([F:11])([F:10])[F:2])[CH2:5][CH2:6]3)=[CH:14][C:15]=2[F:46])[C:22]2[CH:23]=[C:24]([O:27][CH2:28][C:29]3[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=3)[CH:25]=[CH:26][C:21]=2[N:20]=1)([CH2:42][CH3:43])[C:37]([OH:39])=[O:38])[CH3:41]
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(Br)cc1F)C(=O)O
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Product: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(N2CCC(C(F)(F)F)CC2)cc1F)C(=O)O

Procedure:
The title compound was prepared in a manner analogous to that in Example 152 substituting 4-(trifluoromethyl)piperidine hydrochloride and 2-((1-(4-bromo-2-fluorobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)methyl)-2-ethylbutanoic acid and 4-(trifluoromethyl)piperidine. MS (ESI): mass calcd. for C32H37F4N5O3, 615.28; m/z found, 615.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.68 (d, J=9.0, 1H), 7.56 (d, J=2.3, 1H), 7.40 (d, J=2.3, 1H), 7.26 (dd, J=9.0, 2.3, 1H), 7.24-7.18 (m, 1H), 6.80-6.73 (m, 2H), 6.33 (d, J=2.3, 1H), 5.68 (s, 2H), 5.09 (s, 2H), 3.88 (s, 3H), 3.87-3.84 (m, 2H), 3.46 (s, 2H), 2.80 (td, J=12.7, 2.6, 2H), 2.43-2.30 (m, 1H), 1.97-1.88 (m, 2H), 1.87-1.68 (m, 4H), 1.68-1.53 (m, 2H), 0.88 (t, J=7.4, 6H).
Reaction SMILES: [CH2:1]([N:4]([CH2:17][C:18]([OH:20])=O)[NH:5][C:6](=[O:16])[NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[CH:2]=[CH2:3].[NH2:21][C@@H:22]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:24]>>[CH2:1]([N:4]([CH2:17][C:18]([NH:21][C@@H:22]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:24])=[O:20])[NH:5][C:6]([NH:7][C@@H:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9])=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)O)NC(=O)N[C@H](C)c1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: C=CCN(CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC)NC(=O)N[C@H](C)c1ccccc1
Yield: 85.1 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, (R)-2-(1-allyl-2-(1-phenylethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-4) 133 mg (0.48 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxy-propan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 203 mg (0.4 mmol) and purified on silica gel column chromatography (n-hexane:Ethyl acetate=90:10 to 80:20) to obtain the title compound 261 mg (85%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:40])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:20])([F:18])[F:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[C:36]([CH3:38])[N:35]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M115) (0.52 g, 0.91 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (337 mg, 82%).