Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH2:12]([CH2:27]/[C:28](/[CH3:37])=[CH:29]/[CH2:30][CH2:31]/[C:32](/[CH3:36])=[CH:33]/[CH2:34]Br)[CH:13]=[C:14]([CH2:16][CH2:17][CH:18]=[C:19]([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH3:20])[CH3:15]>C1COCC1>[CH2:12]([CH2:27]/[C:28](/[CH3:37])=[CH:29]/[CH2:30][CH2:31]/[C:32](/[CH3:36])=[CH:33]/[CH2:34][NH:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)[CH:13]=[C:14]([CH2:16][CH2:17][CH:18]=[C:19]([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH3:20])[CH3:15]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Reactant: NCc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCC/C(C)=C/CC/C(C)=C/CNCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
In 40 ml of THF was dissolved 7.56 g of piperonylamine, a solution of 2.11 g of farnesylgeranyl bromide in 10 ml of THF was added dropwise at room temperature and stirred at room temperature for 12 hours. Then, the THF was concentrated under reduced pressure. The concentrate was dissolved in chloroform and then washed with a 5% sodium hydroxide solution. After the chloroform layer was concentrated under reduced pressure, the concentrate was dissolved in acetonitrile and extracted with hexane (150 ml×2). The hexane layer was washed with acetonitrile (50 ml×2) and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (using ethyl acetate as a developing solvent) to give 2.0 g of N-farnesylgeranylpiperonylamine as a yellow oily substance.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:1]([NH:8][C:9]1[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: NC(=O)c1cnc(Cl)nc1NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1cnc(Nc2ccccc2)nc1NCc1ccccc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 68.7 %

Procedure:
A 1 ml portion of THF solution containing 7.9 mg of 4-benzylamino-2-chloropyrimidine-5-carboxamide and 3.7 mg of aniline, followed by stirring at 90° C. for 20 hours, which was then mixed with 60 mg of PS-tosyl chloride (mfd. by Argonaut Technologies, 2.44 mmol/g), followed by stirring at room temperature for 3 hours. The reaction mixture was mixed with 2 ml of saturated sodium bicarbonate aqueous solution and extracted with 2 ml of chloroform. By evaporating the solvent under a reduced pressure, 6.6 mg of 4-benzylamino-2-phenylaminopyrimidine-5-carboxamide was obtained.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:8][C@@H:9]1[C@@H:26]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:25][C@@:24]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][C@H:17]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:18]2=[O:34])[CH2:10]1)(=[O:7])[CH:4]([CH3:6])[CH3:5].O>C(Cl)Cl.CO>[C:3]([O:8][C@@H:9]1[C@@H:26]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:25][C@@:24]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][C@H:17]([N:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)[C@@H:18]2[OH:34])[CH2:10]1)(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)[C@@H](N5CCCCC5)C[C@@H]34)[C@@]2(C)C[C@@H]1N1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)C(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)[C@@H](N5CCCCC5)C[C@@H]34)[C@@]2(C)C[C@@H]1N1CCCCC1
Yield: 40.5 %

Procedure:
Sodium borohydride (16 g) was added to a stirred solution of 3α-isobutyroxy-2β,16β-dipiperidino-5α-androstan-17-one (51.6 g) in methylene dichloride (150 ml) and methanol (150 ml) and the reaction mixture was stirred for a further hour. Water was added, the product extracted with ether, and the extract washed well with water and dried. Concentration of the ether solution yielded 2β,16β-dipiperidino-5α-androstan-3α,17β-diol 3-isobutyrate (21 g) which was recrystallised from ether.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[O:10][C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH:7]=1.[CH3:23]C1C(C)=CC=CC=1NC(=O)C.NC1C=CC(C)=C(NC(=O)C)C=1>>[CH3:22][C:5]1[C:4]([CH3:23])=[CH:3][CH:2]=[CH:7][C:6]=1[NH:8][C:9]1[O:10][C:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:12][N:13]=1
Reactant: CC(=O)Nc1cccc(C)c1C
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Agent: CC(=O)Nc1cc(N)ccc1C
Product: Cc1cccc(Nc2ncc(-c3ccc(C#N)cc3)o2)c1C
Yield: 91 %

Procedure:
The same procedure outlined above in the preparation of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However N-(2,3-dimethylphenyl)-acetamide was used instead N-(5-amino-2-methyl-phenyl)-acetamide. Yield=91%.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([NH2:7])=[S:6])=[S:3].[CH2:8](Br)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>COCCO>[CH2:8]([SH:3]=[C:2]([NH:4][C:5]([NH2:7])=[S:6])[NH2:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCBr
Reactant: NC(=S)NC(N)=S
Solvent: COCCO
Product: CCCCCCCC[SH]=C(N)NC(N)=S
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The S-octyldithiobiuret was prepared as follows: To 135 g of dithiobiuret in 300 ml ethyleneglycol monomethyl ether were added 210 g of n-octyl bromide dropwise at 70°C. After 12 hours the solvent was distilled off at 12 mm. The residue was dissolved in toluene and hexane was added after which the mixture was cooled at 0°C. The solvent was decanted from the semicrystalline precipitate which was dissolved again in glacial acetic acid. The solution was poured on icewater and stirred for 2 hours. The solid was filtered, stirred with hexane in a beaker until it had completely crystallized, filtered and dried. The product had a melting point of 75°-77°C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)OC)cc1
Temperature: 50 °C

Procedure:
To a solution of methyl 4-hydroxybenzoate (22-1) (9.72 g, 64.36 mmol) in 100 mL of DMF was added 24.8 g (76.0 mmol) of Cs2CO3 followed by 5.0 mL (58.5 mmol) of allyl bromide. The resulting solution was then heated at 50° C. for 5 h. The solvent was distilled under reduced pressure and the residue was taken up in 200 mL of EtOAc. The organic phase was extracted with 1N NaOH (2×50 mL), water (5×50 mL) and brine (50 mL), dried (MgSO4) and concentrated to afford product 22-2 as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17]=1[SH:25].[OH-].[Na+]>C(O)C>[CH3:15][O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S:25][C:17]2[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]=2)[C:8]=1[CH3:9]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COCCCOc1ccnc(CCl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (26.6 g (100 mmol)), denatured ethanol (160 ml), 2-benzimidazolethiol (15.0 g (100 mmol)), and sodium hydroxide (13.4 g (335 mmol)) were added together, and reaction was carried out for approximately 2 hours at 50° C. After it had been confirmed by TLC that the starting material had disappeared, vacuum concentration was carried out, and toluene (300 ml) and water (168 ml) were then added. After stirring and then leaving to stand, the aqueous layer was separated off. The organic layer was washed with a 10% sodium hydroxide aqueous solution (50 ml), and twice with water (50 ml), and then vacuum concentration was carried out, thus obtaining crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (34.8 g) (HPLC purity 98.7%, yield 101%).
Reaction SMILES: C([N:8]([C@@H](C1C=CC=CC=1)C)[C@@H:9]1[CH2:13][CH2:12][CH2:11][C@:10]1([OH:18])[C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1.C(O)=O>CO.[Pd]>[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@:10]1([OH:18])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@@]1(O)CCC[C@H]1N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: COC(=O)[C@@]1(O)CCC[C@H]1N
Temperature: 40 °C
Reaction time: 3 h
Yield: 124.1 %

Procedure:
To a solution of methyl (1R,2R)-2-{benzyl[(1R)-1-phenylethyl]amino}-1-hydroxycyclopentanecarboxylate (0.75 g, 2.1 mmol) in methanol (30 mL) was added formic acid (1.44 mL) and 10% Pd/C (0.5 g). The mixture was purged with nitrogen followed by hydrogen and allowed to stir at 40° C. for 3 h under 1 atmosphere of hydrogen. The reaction mixture was then filtered through celite. Hydrochloric acid (1 mL, 12 M) was added to the filtrate, which was then concentrated and chased three times with methanol/benzene (1:1) to afford methyl (1R,2R)-2-amino-1-hydroxycyclopentanecarboxylate as a white solid (0.415 g, 100%). MS: 160.1 (M+H)+
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N+:15]([O-:17])=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].C(Cl)[Cl:22]>CO.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([Cl:22])=[N:15][OH:17])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCc1ccc(CC[N+](=O)[O-])cc1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCOCc1ccc(CC(Cl)=NO)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 99 %

Procedure:
To a solution of 1-butoxymethyl-4-(2-nitroethyl)-benzene (55 mg, 0.23 mmol) described in Manufacturing Example 4-1-3 in methanol (2 mL) was added sodium methoxide (1.49 M methanol solution, 47.3 μL, 0.23 mmol) at 0° C. The reaction solution was stirred for 35 minutes at room temperature, and concentrated under a reduced pressure. To a solution of the residue in methylene chloride (2 mL) was added titanium (IV) chloride (28 μL, 0.23 mmol) under nitrogen atmosphere at −78° C., which was then stirred for 30 minutes at 0° C. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the magnesium sulfate was removed by filtration. The organic layer was filtered with silica gel, and the filtrate was evaporated under a reduced pressure to obtain the title compound (59 mg, 99%) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([NH2:31])=O)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]#[N:31])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCC(CC)N1C(=O)[C@@](C)(CC#N)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2.75 h

Procedure:
To an ice-cooled solution of 1.15 g (2.49 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetamide (Example 82, Step A) in THF (21 mL) was added 1.73 mL (12.4 mmol) of triethylamine and 865 μL (6.22 mmol) of TFA. The resulting tan solution was stirred at 0° C. for 2.75 h, then was warmed to room temperature and stirred for an additional 2 h. The reaction was recooled to 0° C., quenched with 1 N citric acid, and then extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The combined organic layers were washed with saturated aqueous sodium chloride (1×), then were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (5 to 35% EtOAc/hexanes, gradient elution) provided the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:5]=1[CH2:25][CH3:26])(=O)[CH3:2]>O1CCCC1>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[C:4]([CH2:1][CH3:2])=[C:5]1[CH2:25][CH3:26]
Reactant: CCc1c(C(C)=O)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Solvent: C1CCOC1
Product: CCc1c(CC)n(Cc2ccccc2Cl)c2cc(C(=O)OC)ccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of methyl 3-acetyl-1-(2-chlorobenzyl)-2-ethylindole-6-carboxylate (110 mg) in tetrahydrofuran (5 ml) was added 1M solution of boran in tetrahydrofuran (0.6 ml) in one portion at 0° C. The mixture was stirred at 20° C. for 1 hour, then quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (2:1) to give methyl 1-(2-chlorobenzyl)-2,3-diethylindole-6-carboxylate (42 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].C(OC([NH:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)=O)(C)(C)C>>[NH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:21])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: NCC(F)(F)F
Product: NCc1ccc(C(=O)NCC(F)(F)F)cc1
Yield: 94 %

Procedure:
Use the General Procedure 6-1, using 2,2,2-trifluoroethylamine (197 mg, 2 mmol) and 4-(tert-butoxycarbonylamino-methyl)-benzoic acid, to give the title compound as a clear oil (440 mg, 94%). MS (ES+) m/z: 233 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[C:26](=[O:39])[N:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:28]=[CH:29][C:30]=1I)=[O:24].[CH3:40][NH2:41]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[C:26](=[O:39])[N:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:28]=[CH:29][C:30]=1[NH:41][CH3:40])=[O:24]
Reactant: CN
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4c(I)ccn(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Product: CNc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(-c3cnn(C)c3)c2)cc1F
Yield: 36 %

Procedure:
A mixture of Example A5 (100 mg, 0.155 mmol) in a methanolic solution of MeNH2 (10 mL) was heated at 80° C. for 3 h. The mixture was concentrated to dryness and purified by HPLC to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamide (31 mg, 36%). 1H-NMR (400 MHz, CD3OD): δ 8.64 (br, s, 1H), 8.49 (br, s, 1H), 8.42 (br, s, 1H), 8.13 (br, s, 1H), 7.64 (br, s, 3H), 7.56 (br, s, 2H), 7.37-7.16 (m, 4H), 6.33 (br, s, 1H), 3.98 (s, 3H), 3.09 (s, 3H); MS (ESI) m/z: 547.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([CH2:13][CH2:14]O)[NH:8][CH2:7][CH2:6]2.[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[O:19].C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([CH2:13][CH2:14][Br:24])[NH:8][CH2:7][CH2:6]2.[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[O:19]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc2c(c1)CCN[C@@H]2CCO
Agent: NC(=O)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN[C@@H]2CCBr
Yield: 93.4 %

Procedure:
To a solution of 6-methoxy-1-(R)-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide (330mg, 1.09 mmol) obtained in step (b) of Example 190 and carbon tetrabromide (542 mg, 1.63 mmol) in dichloromethane (5 ml) was added gradually triphenyl phosphine (343 mg, 1.31 mmol) with stirring under cooling in a water bath. The resulting mixture was further stirred at room temperature, and after confirming the disappearance of the starting material by thin layer chromatography, the reaction mixture was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (80:20) as the eluent to afford the title compound (390 mg, yield: 98%) as a colorless oil.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:24]([O:31][C:32]1[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1.[C:1]([NH:18][C@H:19]([C:21]([O-:23])=[O:22])[CH3:20])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)O
Agent: Oc1ccc(OCc2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)[O-]
Reaction time: 1 h

Procedure:
16.4 g (0.05 mol) of N-hexadecanoyl-(l)-alanine and 8.1 g (0.05 mol) of 1,1-carbonyldiimidazole are dissolved in 100 ml of dimethylformamide, the solution is stirred at 5° for 1 hour, 10 g (0.05 mol) of 4-benzyloxyphenol in 50 ml of dimethylformamide are run in, the mixture is stirred for 18 hours and evaporated and the residue is then taken up with chloroform. After washes with water and dilute sodium hydroxide solution and drying, the title derivative is obtained in the pure state, m.p.=77°/9°, and only shows a single spot of Rf(i)=0.76 in TLC.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[N:10]=1)=[O:8]>>[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Cl:3])[N:10]=1)=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cccc(CO)n1
Product: COC(=O)c1cccc(CCl)n1
Reaction time: 1 h

Procedure:
5 ml of thionyl chloride is slowly added to 2.50 g of 6-(hydroxymethyl)-2-pyridinecarboxylic acid methyl ester at 0° C. under nitrogen and stirred for 1 hour. The reaction mixture is concentrated by evaporation in a vacuum. The thus obtained residue is mixed with 15 ml of saturated sodium bicarbonate solution and extracted three times with 25 ml of toluene each. After the drying on sodium sulfate and filtration, it is concentrated by evaporation in a vacuum. 2.37 g of the title compound is obtained, which is further used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I-].[K+].II>C(O)C.O.C(OCC)(=O)C>[C:14]1([S:20][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:10][CH2:11][CH2:12][OH:13])[NH:1][CH:2]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCCc1cccc2[nH]ccc12
Reactant: Sc1ccccc1
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: OCCCc1cccc2[nH]cc(Sc3ccccc3)c12
Temperature: 65 °C
Yield: 71.3 %

Procedure:
To a solution of 3-(1H-indol-4-yl)propan-1-ol (0.91 g, 5.19 mmol) and thiophenol (0.53 mL, 5.19 mmol) in absolute ethanol (30 mL) was added a solution of potassium iodide (0.862 g, 5.19 mmol) and iodine (1.318 g, 5.19 mmol) in ethanol (7.5 mL) and water (22.5 mL) over 5 minutes, and the reaction was then heated at 65° C. for 5.5 hours. The cooled reaction mixture was diluted with ethyl acetate (250 mL), washed with 5% aqueous Na2S2O3 solution (250 mL), water (250 mL) and brine (250 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford an off-white solid. Purification by flash chromatography (25 to 75% ethyl acetate/hexane) afforded a white solid. The product was recrystallized from 3:1 v/v hexane:ethyl acetate (60 mL) to afford the title compound as a white crystalline solid (1.048 g, 71%). MS (ES+) m/z 284.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[CH3:12])#[N:2].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(=O)O)ccc1C#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Cl)ccc1C#N
Reaction time: 3 h

Procedure:
The crude product of 4-cyano-3-methylbenzoic acid (1.0 g) was suspended in dichloromethane. To the mixture, oxalyl chloride (1.2 g) and an catalytic amount of N,N-dimethylformamide (2 to 3 drops) were added under ice cooling. After adjusting to room temperature, the reaction solution was stirred for three hours. The solvent was distilled off under reduced pressure to obtain 4-cyano-3-methylbenzoyl chloride as a crude product (1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH:10]=2)=[CH:5][CH:4]=1>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=CCCc3ccccc32)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2CCCc3ccccc32)cc1
Yield: 92.5 %

Procedure:
1-(4-Methoxyphenyl)-3,4-dihydro-naphthalene (12 g., 0.051 mole) was added to a mixture of 10% Pd on carbon catalyst (1.0 g.) and ethanol (250 ml.) and hydrogenated for 4 hours at room temperature and 50 psi of H2. The reaction mixture was then filtered and evaporated under vacuum to an oil, which was used in the next step without further purification (11.2 g., 92.5% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.CO>C(Cl)Cl>[OH:3][CH2:4][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1ccc(-c2cccc3cncn23)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: OCc1ccc(-c2cccc3cncn23)cc1
Reaction time: 1 h

Procedure:
1 g of 5-(p-ethoxycarbonylphenyl)imidazo[1,5-a]pyridine is dissolved in 26 ml of methylene chloride at -78° under nitrogen, and then 6.6 ml of diisobutylaluminium hydride in toluene (11.4 mmole) is added dropwise. After stirring for 1 h, 1.5 ml of methanol is added, the cold bath is removed and 15 ml of water is added. The salts are filtered off, the organic phase is dried over sodium sulfate and evaporated to yield the title compound, m.p. 137°-138°.