Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.C(OC1C=CC(C=O)=CC=1)C1C=CC=CC=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:16]([O:15][C:13]([NH:12][CH2:11][C:7]1[CH:6]=[C:5]([CH:4]([OH:20])[C:3]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][CH:2]=2)[CH:10]=[CH:9][CH:8]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1ccc(N)c(C(O)c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Agent: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(C(O)c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
In methanol (6 ml) were dissolved 2-amino-α-(3-tert-butoxycarbonylaminomethylphenyl)-5-methyloxybenzyl alcohol (0.18 g), 4-benzyloxy-benzaldehyde (0.12 g) and acetic acid (0.02 g). To the solution was added sodium cyano borohydride (0.02 mg). The mixture was stirred for 30 minutes at 60° C. The reaction mixture was concentrated, to which were added ethyl acetate (30 ml) and water (50 ml). The mixture was shaken. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-(4-benzyloxybenzyl)-α-(3-tert-butoxycarbonylaminomethylphenyl-5-methyloxybenzyl alcohol as a colorless crystalline product (0.17 g). m.p.:86-87° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)#[N:2].I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=[C:14]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=3)[C:22]=12
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc(CC#N)cc2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of (4-Cyanomethylphenyl)boronic acid (18 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA45. ESI-MS (M+H)+ m/z calcd 293.1, found 293.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].[CH3:13][CH:14]([CH2:18][CH2:19][Cl:20])[C:15](Cl)=[O:16]>C1C=CC=CC=1>[Cl:20][CH2:19][CH2:18][CH:14]([CH3:13])[C:15]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8])=[O:16]
Reactant: CC(C)(C)c1csc(N)c1C#N
Reactant: CC(CCCl)C(=O)Cl
Solvent: c1ccccc1
Product: CC(CCCl)C(=O)Nc1scc(C(C)(C)C)c1C#N
Yield: 56.6 %

Procedure:
A mixture of 4.0 g of 2-amino-3-cyano-4-(1,1-dimethylethyl)thiophene and 4.0 g of 2-methyl-4-chlorobutyryl chloride dissolved with 100 ml benzene was refluxed for about 72 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed while eluting with a 90/10 mixture of Skellysolve B/ethyl acetate. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford 3.75 g of 4-chloro-N-[3-cyano-4-(1,1-dimethylethyl)-2-thienyl]-2-methylbutanamide. mp=115°-116° C. Yield 57%.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:5]=1[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:8]=1>C(O)C>[F:3][C:4]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:5]=1[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=1
Reactant: CCOC(=O)c1cc(Cc2cc(F)ccc2F)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A solution of sodium hydroxide 1M (28 mL; 28 mmol) was added to a solution of ethyl 5-(2,5-difluorobenzyl)isoxazole-3-carboxylate (2.50 g; 9.36 mmol) in ethanol (3 mL). The mixture was stirred at room temperature. After 1 hour, a precipitation occurred and The reaction mixture was allowed to stir for 30 minutes. The solution was acidified to pH 1 by addition of a solution of hydrochloric acid 6N. The precipitate was collected by filtration and dried under reduced pressure to give 1.90 g (84%) of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([B:35]4[O:39]C(C)(C)C(C)(C)[O:36]4)=[CH:31][CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.C1(B(O)O)C=CC=CC=1.Cl>O1CCCC1>[CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([B:35]([OH:36])[OH:39])=[CH:33][CH:34]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: OB(O)c1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B(O)O)cc3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.3 %

Procedure:
A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide (152 mg, 0.251 mmol), polymer-supported benzeneboronic acid (480 mg, 1.255 mmol), and aqueous 5N HCl (0.35 mL, 1.757 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 48 hours. The solution was filtered, concentrated to dryness, and purified by reverse phase HPLC to afford 4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronic acid (45 mg, 0.086 mmol, 34% yield) as a white solid. 1H NMR (METHANOL-d4) δ: 7.98 (d, 1H), 7.96 (d, 1H), 7.87 (S, 1H), 7.66 (d, 2H), 7.46 (d, 2H), 7.32-7.26 (m, 3H), 3.33 (s, 3H), 2.99 (s, 3H), 2.22-2.18 (m, 1H), 1.10-0.37 (m, 4H). LCMS (m/z, ES+)=523 (M+H+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10][NH2:11])=[CH:13][CH:14]=1
Reactant: NCCC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: NCCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propylamine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B3) Rt 2.54 [M+H]+ 312.04. 1H NMR (Me-d3-OD) δ 2.39 (2H, m), 2.84 (2H, t), 4.06 (1H, t), 7.27-7.33 (6H, m), 7.54 (2H, d), 7.91 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5](=[O:7])[CH3:6].C[O-].[Na+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]([F:26])([F:25])[F:24])=[O:15]>C1COCC1>[CH3:1][O:2][C:3](=[O:8])[CH:4]([CH2:13][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]([F:24])([F:25])[F:26])[C:5](=[O:7])[CH3:6]
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CBr)c1ccccc1OC(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)c1ccccc1OC(F)(F)F)C(C)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 71.6 %

Procedure:
To a solution of 2.6 g of 3-oxo-butyric acid methyl ester in THF (50 ml) and 4.6 ml of a solution of sodium methoxide (5.4 M in methanol) was added over 15 minutes a solution of 6.7 g of 2-bromo-1-[2-(trifluoromethoxy)phenyl]-ethanone in 30 ml of THF. The reaction mixture was allowed to stir at room temperature for 17 hours. The solvent was removed, the residue was diluted in diethyl ether and washed several times with water. The organic phase was dried with sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel; heptane/ethyl acetate) to give 5.1 g of the title compound. MS (EI) 319.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[C:6]([CH3:12])[C:3]=1[CH2:4]Cl.[NH2:13][CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:15].C1C=CC=CC=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[C:6]([CH3:12])[C:3]=1[CH2:4][NH:13][CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:15]
Reactant: CCCCCC(C)N
Reactant: Cc1cc(C)c(C)c(CCl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CO
Product: CCCCCC(C)NCc1c(C)c(C)cc(C)c1C

Procedure:
36.5 g (0.2 mol) of 2,3,5,6-tetramethylbenzyl chloride, 46.0 g (0.4 mol) of 2-aminoheptane and 100 ml of benzene are refluxed for 2 hours. The solvent is then removed in vacuo. A solution of 8 g (0.2 mol) of sodium hydroxide in methanol is then added to the residue to liberate the free base. The reaction product is separated from the precipitated sodium chloride by means of a suction filter, and the excess of 2-aminoheptane is removed by vacuum distillation. The 2-(2,3,5,6-tetramethylbenzyl)aminoheptane obtained is then treated with ethereal hydrochloric acid to convert it into the hydrochloride which is recrystallised from methanol/ethyl acetate. The melting point of the hydrochloride is 155° C.
Reaction SMILES: [NH2:1][CH:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:3]1.[C:18]([O:22][C:23](NC(C1C=CC=CC=1)C#N)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([NH:1][CH:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C@@H:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH2:3]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: C[C@H](c1ccccc1)N1CC(N)C2(CCC2)C1
Reactant: CC(C)(C)OC(=O)NC(C#N)c1ccccc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC(NC(=O)OC(C)(C)C)C2(CCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To an ice-cooled solution of 2.9 g of 8-amino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane in 30 ml of tetrahydrofuran there was added 3.3 g of 2-(tertbutoxycarbonyl-amino)-2-phenylacetonitrile and the resulting mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, and ethyl acetate was added to the resulting residue. The mixture was washed with a 1N sodium hydroxide aqueous solution three times and then dried. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography using 50 g of silica gel. The column was eluted with chloroform, chloroform containing methanol and 4.1 g of the titled compound was obtained from a eluate when the eluant was chloroform containing 1% (v/v) of methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10]O.P(Br)(Br)[Br:13].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][Br:13]
Reactant: OCc1c(Cl)cc(Cl)cc1Br
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cc(Cl)c(CBr)c(Br)c1
Reaction time: 8 h

Procedure:
3.1 g of the benzyl alcohol 35.4 were dissolved in 40 ml of dry dichloromethane and admixed dropwise at 5° C. with a solution of 0.455 ml of phosphorus tribromide in 10 ml of dichloromethane. The reaction mixture was stirred overnight and then neutralized with 5 ml of a saturated aqueous sodium carbonate solution. The organic phase was removed, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with n-heptane as the eluent. 2-Bromo-4,6-dichlorobenzyl bromide 35.3 was obtained.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:48])[C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41]>>[CH3:38][N:39]([CH3:48])[C:40]([N:42]1[CH2:43][CH2:44][N:45]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:46][CH2:47]1)=[O:41]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)N(C)C)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with piperazine-1-carboxylic acid dimethylamide (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C36H45Cl2N6O3 [(M+H)+] 679.2925, observed 679.2927.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4](C2C=CC(CCC)=CC=2)[CH2:3]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH:25]=2)=[CH:20][CH:19]=1>>[O:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([C:21]2[CH:22]=[CH:23][C:18]([N:4]3[CH2:5][CH2:6][NH:7][C@H:2]([CH3:1])[CH2:3]3)=[CH:19][CH:20]=2)=[CH:25]1
Reactant: CCCc1ccc(N2CCN[C@H](C)C2)cc1
Reactant: Brc1ccc(-c2coc3ccccc23)cc1
Product: C[C@@H]1CN(c2ccc(-c3coc4ccccc34)cc2)CCN1
Yield: 21 %

Procedure:
The title compound was prepared following the procedure of Intermediate 17, but starting from 3-(4-bromophenyl)-1-benzofuran (obtained as described in Malamas et al., 2000, J. Med. Chem., 43, 1293-1310). Purification by chromatography (DCM/MeOH 80/20) afforded the title compound as beige solid (21%). HPLC (Condition A), Rt: 3.0 min (HPLC purity: 93.4%). M+(ESI): 293.2
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:28]5[C:27]6[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=6)[C:21](=[N:29]O)[C:20]=5[CH:19]=[CH:18][CH:17]=4)[NH:13][C:12]=3[CH:31]=2)[CH2:4][CH2:3]1>[Ni].C(O)C.O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:28]5[C:27]6[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=6)[CH:21]([NH2:29])[C:20]=5[CH:19]=[CH:18][CH:17]=4)[NH:13][C:12]=3[CH:31]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc3nc(-c4cccc5c4-c4ccccc4C5=NO)[nH]c3c2)CC1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(c2ccc3nc(-c4cccc5c4-c4ccccc4C5N)[nH]c3c2)CC1
Yield: 89.7 %

Procedure:
The procedure used in Example 6 is followed, but starting from 1.5 g of 4-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, and 229 mg of Raney nickel in 35 ml of ethanol and 35 ml of tetrahydrofuran for 48 hours at 60° C. under an initial hydrogen pressure of one bar. After filtration of the catalyst, concentration to dryness under reduced pressure and purification by formation of a paste in diisopropyl ether, in this way we obtained 1.3 g of 4-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-9H-fluoren-9(R,S)-ylamine, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.N1C=CC=CC=1.[CH3:18][O:19][C:20]([C:22]1[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C@H:30]([NH:34][C:35](=[O:61])[C@H:36]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[CH:55]=2)[NH:37][C:38](=[O:52])[CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:31]([NH2:33])=O)[N:23]=1)=[O:21]>CCOC(C)=O>[CH3:18][O:19][C:20]([C:22]1[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C@H:30]([NH:34][C:35](=[O:61])[C@H:36]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[CH:55]=2)[NH:37][C:38](=[O:52])[CH:39]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:31]#[N:33])[N:23]=1)=[O:21]
Reactant: COC(=O)c1ccn(CCC[C@H](NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)C(N)=O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccn(CCC[C@@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (0.082 mL, 0.94 mmol) is added dropwise to DMF (20 mL), and the resulting solution is cooled to 0° C. After the solution becomes clear, pyridine (0.15 mL, 1.88 mmol) is added, followed by N-[4-(3-methoxycarbonyl-1H-pyrazol-1-yl)-1(S)-(aminocarbonyl)butyl]-3-methyl-Nα-(2,2-diphenyl-acetyl)-L-phenylalaninamide (0.28 g, 0.47 mmol), in one portion. The yellow reaction solution is stirred at 0° C. for 1.5 hours, after which time it is diluted with EtOAc (50 mL), and washed with saturated NaHCO3 (1×50 mL), saturated LiCl (1×50 mL), dried over MgSO4, and evaporated. The residue is chromatographed (silica, 66% EtOAc/hexane) to yield N-[4-(3-methoxycarbonyl-1H-pyrazol-1-yl)-1(S)-cyanobutyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)=[CH:12][N:11]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)=[CH:12][N:11]=1
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Reactant: CCCCCCBr
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCCCCC)c(F)c3F)nc2)cn1
Yield: 73 %

Procedure:
The etherification of 2.4 mmol of 2-(2,3-difluoro-4-hydroxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine using 2.7 mmol of 1-bromohexane is carried out analogously to the procedure indicated in Example 3. Corresponding purification gives 0.88 g (73%) of colorless crystals, X 81.5 S3 75.5 SC 165.6 SA 174 I.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[C:13](=[O:23])[C:14](=[C:20]([CH3:22])[CH3:21])[O:15]3)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:45]=[CH:44][C:34]([C:35]([NH:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:36])=[CH:33][CH:32]=1>CN(C)C=O>[F:30][C:31]1[CH:45]=[CH:44][C:34]([C:35]([NH:37][CH:38]2[CH2:43][CH2:42][N:41]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]4[CH:19]=[CH:18][CH:17]=[C:16]5[C:12]=4[C:13](=[O:23])[C:14](=[C:20]([CH3:22])[CH3:21])[O:15]5)=[CH:5][CH:4]=3)[CH2:40][CH2:39]2)=[O:36])=[CH:33][CH:32]=1
Reactant: CC(C)=C1Oc2cccc(OCc3ccc(CCl)cc3)c2C1=O
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=C1Oc2cccc(OCc3ccc(CN4CCC(NC(=O)c5ccc(F)cc5)CC4)cc3)c2C1=O
Temperature: 60 °C
Yield: 20.2 %

Procedure:
A mixture of 570 mg 4-(4-chloromethyl-phenylmethoxy)-2-isopropylidenecoumaran-3-one (preparation 2), 240 mg potassium carbonate, 400 mg 4-(4-fluorobenzamido)piperidine and 15 ml dimethylformamide is warmed to 60° C. for 3 hours, then evaporated, mixed with water and extracted with ethyl acetate. After evaporation of the extract, the residue (0.6 g) is purified by silica gel chromatography (eluent ethyl acetate) to give 180 mg (19%) of the desired compound, m.p. 205-208° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](O)=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[H-].[Na+].[CH3:15][C:16]([CH2:18]Br)=[CH2:17]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([CH2:17][C:16]([CH3:18])=[CH2:15])=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: CC(O)c1cc(I)c(O)c(Cl)n1
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)Cc1c(I)cc(C(C)O)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A solution of 2-chloro-3-hydroxy-4-iodo-6-(1-hydroxyethyl)-pyridine (4.49 g, 15 mmol) in 25 mL of N,N-dimethylformamide at 0° C. is treated with 600 mg (60% in oil, 15 mmol) of sodium hydride and stirred at room temperature for 1 h. The reaction is treated with 1.7 mL (16.5 mmol) of 2-methyl-3-bromopropene and stirred for 2 h. The mixture is diluted with 150 mL of ethyl acetate and washed with 4×50 mL of 1:1 50% saturated sodium chloride/sodium bicarbonate, and dried over potassium carbonate. The crude material is chromatographed over 150 g of silica gel (230-400 mesh), eluting with 25% ethyl acetate/hexanes to give 3.94 g (74%) of 2-chloro-3-(2-methyl-1-propen-3-yl)-4-iodo-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=C\CCCCCCCC>OO>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: OO
Product: CCCCCCCCC(=O)O
Reaction time: 5 h
Yield: 69 %

Procedure:
The apparatus used in Example 3 was loaded with the following reagents: 103 g of crude oleic acid (purity=80%, linoleic acid content=9.9%), 2.0 g of H2WO4 and 2.0 g of Arquad 2HT. 105 cm3 of 60% H2O2 were gradually added to the mixture which was stirred continuously and kept at a temperature of between 100° and 109° C. for a period of about 5 hours. Treatment was carried out as described in Example 3 and 39.8 g of pelargonic acid (total yield 86%) and 46.8 g of azelaic acid (total yield 76% ) were obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]1[C:19](=[O:34])[CH2:20][C:21]1[NH:26][C:25](=[O:27])[CH:24]=[C:23]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:22]=1.O.ClCCl>C(Cl)(Cl)Cl>[Br:1][C:24]1[C:25](=[O:27])[NH:26][C:21]([CH2:20][C:19]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18][C@@H:10]2[CH3:9])=[O:34])=[N:22][C:23]=1[N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: C[C@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C[C@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)c(Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
100 mg of N-bromosuccinimide are added to a solution of 200 mg of 2-{2-[(2S)-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one in 4 ml of chloroform. The reaction medium is stirred at ambient temperature for 2 hours. 5 ml of water and 30 ml of dichloromethane are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 99/01 to 96/04 dichloromethane/methanol gradient, so as to give 93 mg of 5-bromo-2-[2-((S)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one, the characteristics of which are the following: