Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=3)[O:15][CH2:14][C@H:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][CH:7]=1.Cl>[OH-].[K+].CO>[OH:22][C:18]1[CH:17]=[C:16]2[C:21]([C@H:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:11][CH:10]=3)[C@H:13]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:14][O:15]2)=[CH:20][CH:19]=1
Reactant: COC(=O)COc1ccc([C@H]2c3ccc(O)cc3OC[C@H]2c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1ccc([C@H]2c3ccc(O)cc3OC[C@H]2c2ccccc2)cc1
Reaction time: 1 h

Procedure:
(+,−) cis [4-(7-Hydroxy-3-phenyl-chroman-4-yl)-phenoxy]-acetic acid methyl ester (30 mg, 0.077 mmol) was stirred in 2N potassium hydroxide in methanol (1 ml) for 120 min. The reaction mixture was acidified by 1 N hydrochloric acid (2.5 ml), and stirring continued for 60 min. The precipitated product was filtered, washed with water and vacuum dried with sicapent (Merck) at 50° C. overnight.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13]([NH2:15])=[O:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:28](=O)([O-])[O-].[Na+].[Na+].CI>C(#N)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[N:17]2[CH3:28])[C:13]([NH2:15])=[O:14])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(N=NC(C(N)=O)=C2NC(C)(C)Cc3ccccc32)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: CI
Product: CC(=O)c1ccc(N=NC(C(N)=O)=C2c3ccccc3CC(C)(C)N2C)cc1
Temperature: 25 °C

Procedure:
2-(4-acetyl-phenylazo)-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene) acetamide (Asinex Corp., Russia) and sodium carbonate are added to acetonitrile, and an acetonitrile solution of methyl iodide is slowly dropped and refluxed. The refluxed product is cooled to room temperature and, then, the solvent is removed by reducing a pressure; the residue is dissolved in dichloromethane and washed with distilled water. Thereafter, the product is dried with anhydrous sodium sulfate and filtered and, then, the solvent is removed by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.[BH4-].[Na+]>CO.O>[OH:16][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]=2)=[CH:9][CH:10]=1)[CH3:15]
Reactant: CC(=O)c1ccc(C2=CCC(C)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1CC=C(c2ccc(C(C)O)cc2)CC1
Reaction time: 4 h

Procedure:
8.8 g of para-(4-methyl-1-cyclohexenyl)-acetophenone are stirred portionwise into a solution, cooled to 0°C, of 1.8 g of sodium borohydride in 80 ml of methanol and 15 ml of water. Stirring is continued at 5°-10°C for an hour and a half and at room temperature for 4 hours, 200 ml of water are added, and the batch then extracted with 3 × 100 ml of methylene chloride. The methylene chloride residue is recrystallized from petroleum ether and yields 1-hydroxy-1-[para-(4-methyl-1-cyclohexenyl)-phenyl]-ethane of melting point 65°-67°C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:20][CH2:21][O:22][Si](C(C)C)(C(C)C)C(C)C)[CH2:10][N:11](C)[C:12](=O)OC(C)(C)C)=[CH:5][CH:4]=1)#[N:2].Cl>C1COCC1>[OH:22][CH2:21][CH2:20][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:10][NH:11][CH3:12]
Reactant: CC(C)[Si](OCCC(CN(C)C(=O)OC(C)(C)C)c1ccc(C#N)cc1)(C(C)C)C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CNCC(CCO)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl {2-(4-cyanophenyl)-4-[(triisopropylsilyl)oxy]butyl}methylcarbamate (0.37 g) was dissolved in THF (8 mL) at 0° C. Hydrochloric acid (8 ml of 6M solution) was added and the mixture stirred overnight at room temperature. The volatiles were removed by evaporation and then removed azeotropically after the addition of methanol (5×50 mL). The residue was dissolved in water and the solution alkalised to pH 8-9 by the addition of Na2CO3 (s) and then extracted thrice with ethyl acetate (100 mL). The organic solution was dried over Na2SO4 and then the solvent was evaporated. The product was purified by flash chromatography (CH2Cl2-MeOH—NH4OH, 9:1:0.1). There was obtained 0.10 g, 60%) of 4-{3-Hydroxy-1-[(methylamino)methyl]propyl}benzonitrile as a solid. 1H NMR (300 MHz, CDCl3): 1.9-2.0 (m, 2H), 2.5 (s, 3H), 2.8-2.9 (m, 3H), 3.4-3.7 (m, 3H), 3.7 (m, 1H), 7.3 (d, 2H), 7.6 (d, 2H); LCMS: m/z 205 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][CH:16]([CH:30]([CH3:32])[CH3:31])[CH2:17][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]3[CH2:21][O:20]3)[CH:13]=2)[N:8]([CH3:33])[CH:7]=1>C(O)(C)C.C(N)(C)C>[OH:20][CH:19]([CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH2:17][CH:16]([CH2:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:33])[CH:7]=[C:6]2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:30]([CH3:31])[CH3:32])[CH2:21][NH:8][CH:9]([CH3:14])[CH3:10]
Reactant: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C3CO3)C(C)C)cc12
Solvent: CC(C)O
Solvent: CC(C)N
Product: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CNC(C)C)C(C)C)cc12

Procedure:
A solution of 0.032 g of tert-butyl {3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methyl-1-oxiranylpentyl}carbamate in 1 ml of isopropanol and 0.044 ml of isopropylamine is stirred at 70° C. On completion of reaction (TLC monitoring), the reaction mixture is concentrated by evaporation, and the residue is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[N:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1>C1COCC1>[C:1]1([N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClN1C=Cc2ccccc2C1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: C1=CN(c2ccccc2)Cc2ccccc21
Reaction time: 0.83 h
Yield: 56.5 %

Procedure:
A solution of phenylmagnesium bromide (1M in THF, 3.6 mL, 3.6 mmol) is added to a solution of 2-chloro-isoquinoline (258 mg, 1.57 mmol)) and Fe(acac)3 (28 mg, 0.078 mmol) in THF (10 mL) at −30° C. After stirring for 50 min at that temperature, the reaction is quenched with brine, the aqueous layer is extracted with Et2O, the combined organic phases are dried over Na2SO4 and evaporated, and the residue is purified by flash chromatography (hexane/ethyl acetate, 10:1). After eluting a first fraction containing biphenyl (60 mg), one obtains 2-phenyl-isoquinoline as a colorless solid (184 mg, 57%). 1H NMR (300 MHz, CD2Cl2) δ 8.60 (d, 1H), 8.11 (d, 1H), 7.91 (d, 1H), 7.66–7.72 (m, 4H), 7.48–7.57 (m, 4H); 13C NMR (75 MHz, CD2Cl2) δ 160.9, 142.6, 140.1, 137.2, 130.3, 130.2, 128.8, 128.5, 127.7, 127.5, 127.3, 127.0, 120.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20].[NH4+].[Cl-]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Clc1ccc2c(I)n[nH]c2c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 77.3 %

Procedure:
To a solution of 6-chloro-3-iodo-1H-indazole (337 mg, 1.21 mmol) in dry tetrahydrofuran (20 mL) was added drop-wise isopropylmagnesium chloride (1.33 mL, 2M in THF, 2.66 mmol) at −16° C. under N2 atmosphere. After stirring for 20 minutes, tributylchlorostannane (472 mg, 1.45 mmol) was added drop-wise at −16° C., and then it was warmed to 20° C. for 2 h. Then NH4Cl solution (2 mL) was added and product extracted with dichloromethane (15 mL), organic phase was washed with water (2×20 mL) and brine (2×20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford 6-chloro-3-(tributylstannyl)-1H-indazole (413 mg, crude) as yellow oil which was used to next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[C:13]([CH3:14])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32](=[O:45])[C@@H:33]([CH2:35][CH2:36][CH2:37][NH:38][C:39]([NH2:44])=[N:40][N+:41]([O-:43])=[O:42])[NH2:34])=[CH:26][CH:25]=1)=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:19][C:20]([NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32](=[O:45])[C@@H:33]([CH2:35][CH2:36][CH2:37][NH:38][C:39]([NH2:44])=[N:40][N+:41]([O-:43])=[O:42])[NH:34][C:15]([C:11]2[CH:12]=[C:13]([CH3:14])[C:6]3[N:5]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:8]([CH3:9])[C:7]=3[CH:10]=2)=[O:17])=[CH:28][CH:29]=1)=[O:21]
Reactant: Cc1cc(C(=O)O)cc2c1nc(C1CC1)n2C
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: Cc1cc(C(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc2ccc(CNC(N)=O)cc2)cc2c1nc(C1CC1)n2C
Yield: 51 %

Procedure:
Prepared analogously to Example 69a) from 2-cyclopropyl-1,4-dimethyl-1H-benzimidazole-6-carboxylic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamide-hydrochloride and TBTU in a yield of 51% of theory.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.II.[CH3:13][N:14]([CH3:22])[CH2:15][C@H:16]([CH3:21])[C:17](=[O:20])[CH2:18][CH3:19]>O1CCCC1>[CH3:13][N:14]([CH3:22])[CH2:15][C@H:16]([CH3:21])[C@:17]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1)([OH:20])[CH2:18][CH3:19]
Reactant: CCC(=O)[C@@H](C)CN(C)C
Reactant: COc1cccc(Br)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC[C@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Temperature: 71.5 °C
Yield: 79.77 %

Procedure:
In a dry flask charged magnesium turning (41.0 gm 1.70 M) in tetrahydrofuran (200 ml). Under nitrogen atmosphere charged 3-Bromo anisole (20.0 gm; 0.106 M), iodine crystal (0.2 gm). Stirred and heated the reaction mass to 68-75° C. After initiation of the reaction the remaining quantity of 3-Bromo anisole (307 gm, 1.641 M) was added maintaining the reaction at reflux. Stirred and maintained the reaction mass at refluxed for 1 hrs, cooled to 25-30° C. Slowly added (2S)-1-(dimethylamino)-2-methylpentan-3-one (100.0 gm, 0.699 M) maintaining the temperature of the reaction at 25-30° C. The reaction mass was maintained for 12 hour at 25-30° C. and then quenched the reaction mass in ice cold D. M. water (1.0 Liter). Stirred and adjusted the pH of the reaction mass to 3-4 with acetic acid. Further adjusted the pH to 9-10 using ammonia solution. Stirred the reaction mass 30 minutes and extracted the reaction solution with diisopropyl ether. Combined diisopropyl ether was dried over anhydrous sodium sulphate and concentrated under reduced pressure below 40° C. to get the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:17]([O-])=O)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[H][H]>[Ni].C(O)C>[NH2:17][C:9]1[C:10]([F:16])=[C:11]([F:15])[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c([N+](=O)[O-])c2c1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(N)c2c1=O
Yield: 34.7 %

Procedure:
A suspension of 1.9 g (5.3 mmoles) of ethyl 1-cyclopropyl-5-nitro-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 0.5 g of Raney nickel and 100 ml of ethanol was shaken in a hydrogen atmosphere at pressures of 42.5-50 psi and temperatures of 24°-26.5° C. for ten hours. The mixture was filtered through Celite and some insoluble product was dissolved in tetrahydrofuran with filtration. The combined filtrates were evaporated in vacuo and the residue was chromatographed on silica gel to give 600 mg of the title compound, mp 223°-225° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C([Li])CCC.B(F)(F)F.CCOCC.[CH:21]([C:23]([CH3:25])=[O:24])=[CH2:22]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:22][CH2:21][C:23](=[O:24])[CH3:25]
Reactant: C#CCCCCl
Reactant: C=CC(C)=O
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)CCC#CCCCCl
Reaction time: 0.25 h

Procedure:
14.85 Parts of 5-chloropent-1-yne is dissolved in 250 parts by volume of toluene and the resulting solution is cooled to approximately -40°. To that solution is then added 62.8 parts by volume of 2.31 M ethereal butyl lithium and stirring is continued for approximately 15 minutes. 6.87 Parts of boron trifluoride etherate is added and the reaction mixture is stirred for about 2 hours, then allowed to stand for about 16 hours at -5° to -10°. At the end of that time 10.14 parts of methyl vinyl ketone is added at -40° and the reaction mixture is stirred for about 4 hours, then is quenched with water. 50 Parts by volume of 3 N hydrochloric acid is added and the mixture is kept at room temperature for about 16 hours, at the end of which time the aqueous and organic layers are separated. The aqueous layer is extracted with toluene and the organic layer with water. The organic solutions are combined, washed successively with aqueous sodium hydroxide and water, then dried over anhydrous sodium sulfate and stripped to dryness under reduced pressure, thus affording the crude product. This material is purified by distillation under reduced pressure to afford 9-chloro-5-nonyn-2-one, boiling at about 80°-92° at a pressure of 0.11-0.06 mm.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[O:29][CH:28]=[N:27][CH:26]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:36]>CO.C(OCC)(=O)C>[ClH:36].[NH2:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[O:29][CH:28]=[N:27][CH:26]=1)=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3cnco3)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(-c3cnco3)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
Tert-butyl[2-isobutyl-6-(1,3-oxazol-5-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.14 g, 0.30 mmol) was dissolved in methanol (4 mL) and a solution (10 mL) of 4N hydrogen chloride in ethyl acetate were added thereto. This mixture was stirred at room temperature for 1 h and the precipitated crystals were collected by filtration to give the title compound (0.084 g, 69%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:33])[O:30][CH2:31][CH3:32]>CC1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:15][CH2:14][N:13]([C:29]([O:30][CH2:31][CH3:32])=[O:33])[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(F)cc1)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C(=O)c2ccc(F)cc2)(c2ccccc2)CC1
Reaction time: 5 h

Procedure:
To a stirred mixture of 79 parts of (4-fluorophenyl)[4-phenyl-1-(phenylmethyl)-4-piperidinyl]methanone and 630 parts of methylbenzene were added dropwise 32 parts of ethyl carbonochloridate at room temperature. Upon completion, stirring was continued for 5 hours at reflux temperature. The reaction mixture was evaporated and the (chloromethyl)benzene was distilled in vacuo (pump). The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and a small amount of petroleumether, yielding 35.5 parts of ethyl 4-(4-fluorobenzoyl)-4-phenyl-1-piperidinecarboxylate; mp. 91.7° C. (intermediate 15).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.[CH3:27][O:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][N:30]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:29]([O:28][CH3:27])=[N:30]3)[N:3]=2)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:12])([CH3:18])[CH3:17]
Reactant: COc1n[nH]c2ccccc12
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1nn(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2ccccc12
Temperature: 125 °C
Yield: 80 %

Procedure:
To a stirred solution of 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 338 μmol), 3-methoxy-1H-indazole (50.1 mg, 338 μmol) in dioxane (2 mL) was added sodium tert-butoxide (71.5 mg, 744 μmol) and bis(tri-tert-butylphosphine)palladium(0) (17.3 mg, 33.8 μmol). The mixture was degassed then heated in sealed tube at 125° C. for 15 h. The mixture was cooled, filtered through celite, and the filter cake washed with ethyl acetate. The combined filtrates were concentrated in vacuo and the crude residue purified by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(3-methoxy-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (138 mg, 80%).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12]C)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6](C(OC(C)(C)C)=O)[CH2:7]2.B(Br)(Br)Br>ClCCl>[OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: COc1ccc2c(c1O)CCN(C(=O)OC(C)(C)C)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(c1O)CCNC2
Temperature: 0 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (70 mg, 0.25 mmol, 1.00 equiv) and dichloromethane (30 mL). This was followed by the addition of BBr3 (187 mg) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at 0° C. in a water/ice bath. The resulting mixture was concentrated under vacuum. This resulted in 100 mg (crude) of 5,6-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide as a light yellow solid. MS (ESI) m/z 166 ([M+H-HBr]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:30])[CH2:13][CH2:12][N:11]([C:14]([C@H:16]3[CH2:19][CH2:18][C@H:17]3[NH:20]C(=O)OC(C)(C)C)=[O:15])[CH2:10][C:9]2([CH3:29])[CH3:28])=[CH:4][CH:3]=1.O1CCOCC1>Cl>[ClH:1].[NH2:20][C@H:17]1[CH2:18][CH2:19][C@H:16]1[C:14]([N:11]1[CH2:12][CH2:13][C@@:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:30])[C:9]([CH3:29])([CH3:28])[CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H]1C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CN(C(=O)[C@@H]2CC[C@@H]2N)CC[C@]1(O)c1ccc(Cl)cc1

Procedure:
A solution of tert-butyl (±)-(cis)-2-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)cyclobutylcarbamate (160 mg, 0.366 mmol) in 4 M HCl in dioxane (5 mL, 20.00 mmol HCl) was stirred at room temperature for 3 hours. After this time, the mixture was concentrated in vacuo, then concentrated 3× from methylene chloride to remove residual HCl and dioxane, to yield the title compound as a colorless solid which was used without purification in the next step. MS (ESI+)=327.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:13]([O:15]CC)=[O:14])=[C:8]([CH:10]([OH:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+]>>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:13]([OH:15])=[O:14])=[C:8]([CH:10]([OH:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCc1nc(C(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 84.6 %

Procedure:
Following a procedure similar to that described in Example 36, 0.54 g of ethyl 2-butyl-4-(1-hydroxyethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 43(b)] was hydrolyzed, using 245 mg of lithium hydroxide monohydrate, to give 0.43 g of the title compound as a powder, melting at 214°-217° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=O)[CH:7]=1.[CH3:17][NH:18][NH2:19]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:18]([CH3:17])[N:19]=[C:8]2[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CNN
Reactant: O=C(c1cccnc1)c1cc(Br)ccc1F
Solvent: C1COCCO1
Product: Cn1nc(-c2cccnc2)c2cc(Br)ccc21
Temperature: 100 °C

Procedure:
A heavy wall pressure flask was charged with (5-bromo-2-fluorophenyl)(pyridin-3-yl)methanone (3.417 g, 12.2 mmol) and dioxane (30 mL). Methylhydrazine (1.4 mL, 26.6 mmol) was then added, and the mixture was heated to 100° C. for 16 hours. The crude mixture was concentrated, and purified by column chromatography (gradient 0 to 55% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 9.19 (d, J=2.1 Hz, 1H), 8.65 (dd, J=4.9, 1.5 Hz, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 7.54 (dd, J=8.9, 1.7 Hz, 1H), 7.49 (dd, J=8.0, 4.9 Hz, 1H), 7.35 (d, J=8.9 Hz, 1H), 4.15 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:38]=[N+:39]=[N-])(=O)=O)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[N+:38](=[C:13]([C:5]1[CH:4]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1)[C:14]([O:16][CH3:17])=[O:15])=[N-:39]
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To methyl 3,5-bis(trifluoromethyl)phenylacetate (43.5 g, 160 mmol), in dry acetonitrile (250 ml), cooled to -5° C., was added 2,4,6-triisopropyl benzenesulfonyl azide (52.7 g). To the resulting solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (25.5 ml), and the mixture was stirred at -5° C. for 1 hour. The mixture was warmed to room temperature, and then stirred for 0.5 hour. The solvents were evaporated at reduced pressure and the residue purified by chromatography on silica gel (eluant 5% diethyl ether/petroleum ether), to afford the the title compound as yellow prisms. I.R (film, NaCl) 1740, 2140 cm-1.