Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([NH:6][CH:7]([C:14]1([N:19]([CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCCCC>[Cl:1][C:2]1[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([NH:6][CH:7]([C:14]1([N:19]([CH2:21][CH2:22][OH:23])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN(CCO)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (±)-2-chloro-N-[{1-[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)(methyl)amino]cyclopentyl}(phenyl)methyl]-3-(trifluoromethyl)benzamide D30 (0.390 g; 0.685 mmol) in THF (10 ml) was added tetrabutylammonium fluoride (1M solution in THF 1.6 ml; 1.6 mmol). The reaction mixture was allowed to stir at room temperature for 4 h. The desired product was isolated by column chromatography on silica using 20% to 50% ether in n-pentane, the solvent was reduced in volume by evaporation in vacuo and loaded onto an SCX cartridge. Washing with DCM, then methanol followed by elution with 1M ammonia in methanol afforded the title product (170 mg, 73%). Mass Spectrum (Electrospray LC/MS). Found 455 (MH+). C23H2635ClF3N2O2 requires 454. Ret. time: 2.09 min.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[CH:4]1)[CH3:2].Cl.C(N(CC)CC)C.[N-:24]=[N+:25]=[N-:26].[Na+]>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[NH:26][N:25]=[N:24][N:15]=2)=[CH:4]1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1cc(C#N)c2ccc(OC)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCn1cc(-c2nnn[nH]2)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 45.2 %

Procedure:
A mixture of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00 g, 5.00 mmol) in toluene (30 mL) is treated with triethylamine hydrochloride (1.03 g, 7.50 mmol) and sodium azide (0.49 g, 7.50 mmol) and is heated at reflux for 16 h. After cooling to room temperature, the reaction mixture is diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer is then washed with additional NaHCO3 (2×). The combined aqueous phases are acidified to pH 2 with 6N HCl. The resultant thick precipitate is extracted with hot EtOAc (3×) and the combined organic phases are washed with saturated NaCl and dried and concentrated to give 0.55 g (45%) of 1-ethyl-6-methoxy-3-(1H-tetrazol-5-yl)-1H-indole as a yellow solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([CH3:14])[CH:5]=1.[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[OH-].[Na+].O>C(O)C>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:3][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=[C:6]([CH3:14])[CH:5]=2)=[CH:21][CH:20]=1)(=[O:17])=[O:18]
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(COc2ccc(S(C)(=O)=O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
To a solution of 7.23 g (29.6 mmol) of 4-chloromethyl-2-methylquinoline hydrochloride and 5.61 g (32.6 mmol) of 4-methylsulfonylphenol in ethanol (26 mL) was added 17.1 mL (68.1 mmol) of 4 N aqueous sodium hydroxide, followed by heating under reflux for 5 hours. After standing to cool, water (150 mL) and 4 N aqueous sodium hydroxide (2.5 mL) were added and stirred for 20 minutes at room temperature. The precipitates were collected by filtration, washed thoroughly with water and hexane, and then dried at 40° C. in vacuo in the presence of phosphorus pentoxide to give 9.06 g (yield 93.5%) of 4-(4-methanesulfonylphenoxymethyl)-2-methylquinoline (VI-1). Its physical properties are shown below.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:28][CH:27]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21]C(=O)C)[CH:15]=[CH:14]3)=[CH:7][C:6]=1[O:41][CH3:42])(=[O:4])=[O:3].C([O-])(O)=O.[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:28][CH:27]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][C:6]=1[O:41][CH3:42])(=[O:4])=[O:3]
Reactant: COc1cc(-c2ccc3cc(OC(C)=O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)ccc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)ccc1S(C)(=O)=O
Yield: 76.1 %

Procedure:
Dissolve the compound of Example 81 (210 mg, 0.36 mmol) in MeOH (4 mL). Add NaHCO3 (60 mg, 0.72 mmol) and stir the reaction mixture for 12 hours at room temperature. Filter and remove the solvent under reduced pressure. Purify the residue by flash column chromatography (silica gel, 2 to 10% MeOH—NH4OH (10/1, v/v)/CH2Cl2) to give 150 mg of 6-(4-methanesulfonyl-3-methoxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol (75%). Dissolve the free base (150 mg, 0.27 mm iol) in CH2Cl2 (5 mL) and cool to −78° C. Add 2M HCl in diethyl ether (0.2 mL) and stir the solution for 5 minutes. Remove the solvent under reduced pressure to give a solid. Dry the solid at room temperature overnight in vacuo to give 140 mg of the title compound (87%): mass spectrum (ion spray): m/z=548.1 (M+H—HCl).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[CH:9][C:10]=1Br)([CH3:3])[CH3:2].O1CCCC1.C([Li])CCC.[B:23](OCC)([O:27]CC)[O:24]CC>CCCCCC>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[CH:9][C:10]=1[B:23]([OH:27])[OH:24])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Br)c(OC(C)C)c1
Reactant: CCOB(OCC)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)c(OC(C)C)c1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
To a 125 mL 3N round-bottomed flask equipped with N2 inlet and septum were added 3.59 g (15.7 mmol) 3-isopropoxy-4-bromotoluene and 30 mL dry tetrahydrofuran. The solution was cooled to −70° C. and 7.5 mL (18.8 mmol) of a 2.5 M solution of butyl lithium in hexane was added over 5 minutes, and the solution stirred 5 minutes at −70° C. Then 3.2 mL (18.8 mmol) triethyl borate was added, followed by stirring for 5 minutes at −70° C. and then stirring at room temperature for 24 hours. The reaction was quenched with 1 N aqueous hydrochloric acid and extracted into ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated. The residue was triturated with hexane to a white solid, 1.7 g (56%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([CH:9]1[CH2:18][C:17](=[O:19])[C:16]2[C:11](=[C:12]([CH3:21])[N:13]=[C:14]([CH3:20])[CH:15]=2)[NH:10]1)[CH3:8].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[CH2:26]([O:25][C:23]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([CH3:20])=[N:13][C:12]=2[CH3:21])[C:17](=[O:19])[CH2:18][CH:9]1[CH2:7][CH3:8])=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CCC1CC(=O)c2cc(C)nc(C)c2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)N1c2c(cc(C)nc2C)C(=O)CC1CC

Procedure:
This compound can be obtained by reacting a suspension of K2CO3 (3-5 eqv) in THF with a solution of 2-ethyl-6,8-dimethyl-2,3-dihydro-1H-[1,7]naphthyridin-4-one in THF and ethyl chloroformate (1.5 to 2 eqv), typically at a temperature from about RT to about 50° C., followed by a typical workup procedure.
Reaction SMILES: [CH2:1]([C:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2].OO.C(=O)([O-])[O-:33].[K+].[K+].O>CS(C)=O>[CH2:1]([C:3]1([C:28]([NH2:29])=[O:33])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCC1(C(N)=O)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethyl-1-(2-((4-(morpholin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile (36 mg) obtained in Example 2 in dimethylsulfoxide (1 mL) were added a solution of 30% aqueous hydrogen peroxide (28 μL) and 2M aqueous potassium carbonate (0.14 mL), and the mixture was stirred overnight at room temperature. Water was added thereto in an ice bath, and the precipitated solid was collected by filtration. The obtained crude crystals were recrystallized (diisopropyl ether/ethanol) to give the title compound (13 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2].C(NCC)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]([CH2:20][CH3:19])[CH2:17][CH3:18])=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(CC)c1=O
Solvent: CCNCC
Solvent: CCO
Product: CCOC(=O)c1c(N(CC)CC)c2ccc(C)nc2n(CC)c1=O
Reaction time: 16 h

Procedure:
A mixture of 1.47 g. (0.005 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (Example 30) and 0.7 g. (0.01 mole) of diethylamine in 20 ml. of ethanol was heated in an autoclave placed in a steam bath for 16 hours. The solution was then evaporated in a rotary evaporator and the residue was triturated with 50 ml. of water and was extracted with 50 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated in a rotary evaporator. The residue was recrystallized from heptane. A second recrystallization from petroleum ether gave 0.4 g. of product, m.p. 79°-82° C.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][C@H:6]([C@H:11]([OH:13])[CH3:12])[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C1COCC1.CO>[CH2:5]([C@H:6]([C@H:11]([OH:13])[CH3:12])[C:7]([OH:9])=[O:8])[C:4]#[CH:3]
Reactant: COC(=O)[C@H](CC#C[Si](C)(C)C)[C@@H](C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C#CC[C@@H](C(=O)O)[C@@H](C)O
Temperature: 23 °C
Reaction time: 20 h
Yield: 85.9 %

Procedure:
To a solution of methyl (2R,3R)-2-(3-trimethylsilyl-2-propyne-1-yl)-3-hydroxybutanoate (5.6 g, 24.56 mmol) in THF-methanol (3:1, 160 mL) is added 2 M aqueous sodium hydroxide solution (40 mL, 36.8 mmol). The solution is stirred at 23° C. for 20 h, then concentrated and extracted with hexanes (100 mL). The aqueous layer is acidified to pH=3 with 1 M HCl and is extracted with two 100 mL portions of ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(2-propyne-1-yl)-3-hydroxybutanoic acid as an oil (3.0 g, 86% yield).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[CH2:15]([O:17][C:18]([C:20]1[N:21]=[C:22]([CH3:26])[S:23][C:24]=1I)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[N:21]=[C:22]([CH3:26])[S:23][C:24]=1[C:2]#[C:1][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])=[O:19])[CH3:16]
Reactant: CCOC(=O)c1nc(C)sc1I
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: CCOC(=O)c1nc(C)sc1C#Cc1c(-c2ccccc2)noc1C
Yield: 84 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (51 mg, 0.28 mmol) was converted (using 5-iodo-2-methyl-thiazole-4-carboxylic acid ethyl ester instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 83 mg, 84%) which was obtained as a light brown solid. MS: m/e=353.2 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[CH3:13][NH2:14]>C(O)C>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][NH:14][CH3:13]
Reactant: COc1ccccc1OCCBr
Reactant: CN
Solvent: CCO
Product: CNCCOc1ccccc1OC
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 1-(2-bromoethoxy)-2-methoxybenzene (7d) (7.7 g, 33 mmol) in a 33% solution of methylamine in ethanol was heated at 80° C. in a sealed tube for 16 h. After cooling to room temperature, the solvents were evaporated in vacuo. A 2N aqueous solution of sodium hydroxide was added to the remaining oil and the resulting slurry was extracted with ethyl acetate (2×250 mL). The collected organic phases were dried (Na2SO4) and the solvents evaporated in vacuo giving 5.9 g (98%) of the title compound as an oil: 1H NMR (CDCl3) δ 1.85 (broad s, 1H), 2.50 (s, 3H), 3.00 (t, 2H), 3.85 (s, 3H), 4.10 (t, 2H), 6.85-6.95 (m, 4H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2)(C(C)(C)C)(C)C.N1C=CC=CC=1.F.C(=O)([O-])O.[Na+]>C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2
Reactant: CC(C)C(O)(c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1)c1c[nH]cn1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 1-(6-tert-butyldimethylsilyloxynaphthalen-2-yl -1-(1H-imidazol-4-yl)-2-methylpropanol (1.60 g) in THF (10 mL) was added 70% aqueous solution of hydrogen fluoride-pyridine (3 ml) under ice cooling. The mixture was stirred for 30 min under ice cooling and for 2 h at room temperature. The mixture was neutralized with saturated solution of sodium hydrogencarbonate, extracted with dichloromethane and dried. The solvent was distilled off and the residue was purified by column chromatography (eluent, dichloromethane:methanol=10:1→5:1) to give the titled compound (856 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH2:19])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH:19][S:21]([CH3:20])(=[O:23])=[O:22])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CNS(C)(=O)=O)c2)cc2ccc(Cl)cc21

Procedure:
C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine and methanesulfonyl chloride are processed according to the method described in Example 186f to give N-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide. 1H NMR (400 MHz, MeOD) δ ppm 3.03 (s, 3H), 3.80 (s, 3H), 4.45 (s, 2H), 6.71 (s, 1H), 7.12 (dd, J=8.3, 1.8 Hz, 1H), 7.54 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 8.09 (t, J=2.2 Hz, 1H), 8.63 (d, J=2. Hz, 1H), 8.71 (d, J=2. Hz, 1H). HRMS (ESI) m/z 350.0728 [(M+H)+ Calcd for C16H17ClN3O2S: 350.0730].
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5].[CH3:23]O>S(Cl)(Cl)=O>[ClH:1].[NH2:2][CH:3]([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)[C:4]([O:6][CH3:23])=[O:5]
Reactant: CCCCCCCCc1ccc(CCC(N)C(=O)O)cc1
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCc1ccc(CCC(N)C(=O)OC)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-Amino-4-(4-octylphenyl)butanoic acid hydrochloride (20 g) in methanol (500 ml), thionyl chloride (7.2 ml) was added under ice-cooling and the mixture was left standing overnight. The reaction mixture was concentrated under reduced pressure to give the subject compound (16 g). MS: 305(M+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1>CN(C)C=O>[CH3:18][C:19]1[N:20]([C:2]2[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH:21]=[CH:22][N:23]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1cnc(C(=O)O)cn1
Temperature: 100 °C

Procedure:
A mixture of methyl 5-chloropyrazine-2-carboxylate (0.75 g), K2CO3 (1.8 g) and 2-methyl-1H-imidazole (1.3 g) in N,N-dimethylformamide (6 mL) is heated to 100° C. overnight. Analysis of the crude mixture by LCMS shows saponified product. The solvents are evaporated and the crude product is purified by HPLC. LC (method 20): tR=0.27 min; Mass spectrum (APCI): m/z=205 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[CH:9]=1.C1C(=O)N([Br:53])C(=O)C1>CC#N.C(Cl)Cl>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[C:9]=1[Br:53]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C2CCC(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (128 mg, 0.199 mmol) in CH3CN/DCM (3/1 mL) was added NBS (42.5 mg, 0.239 mmol) and stirred at rt for 30 min. TLC showed complete conversion. All the volatiles were removed under reduced pressure and the residue was purified by a SiO2 column (0-15% EtOAc/Hexanes, Rf=0.6 in 20% EtOAc) to afford 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone as a pale yellow oil (125 mg).
Reaction SMILES: [C:1]([CH:5]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])(=[O:4])[CH2:2][OH:3].[OH-].[K+].Cl>CO.O>[C:1]([CH:5]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])[CH2:2][OH:3]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)OCC)C(=O)CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(=O)CO

Procedure:
A clear, yellow solution of ethyl 8-glycoloyl-12 -hydroxyheptadecanoate (7.9 g., 0.02 mole) and potassium hydroxide (2.24 g., 0.04 mole) in 90% aqueous methanol (50 ml.) is stirred at 25° under nitrogen for 20 hours. The reaction solution is evaporated in vacuo at 40° leaving a residual red oil which is dissolved in water (200 ml.). The resulting solution is acidified with concentrated hydrochloric acid (10 ml.) and extracted with ether (2 × 200 ml.). The organic extract is washed with saturated brine (2 × 200 ml.), dried over sodium sulfate, filtered and evapoated in vacuo at 40°-50° providing the title compound as a slightly impure, deep yellow oil (6.3 g., 92%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:16])[NH:11]2.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C:10](=[O:16])[NH:11]3)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCc2c(cccc2OCCCCl)N1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: O=C1CCc2c(cccc2OCCCN2CCC(Cc3ccccc3)CC2)N1
Yield: 76 %

Procedure:
4.8 Grams of 5-(3-chloropropoxy)-3,4-dihydrocarbostyril and 4.2 g of 4-benzylpiperidine were mixed with 40 ml of toluene and the mixture was heated under refluxing condition for 24 hours. After cooling of the reaction mixture, the precipitates thus formed were obtained by filtration and washed with water, then recrystallized from ethanol to obtain 6.3 g (yield: 76%) of 5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril as in the form of colorless needle-like crystals. Melting point: 143°-145° C.
Reaction SMILES: [CH3:1][C@@:2]1([OH:21])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[CH:11]([CH2:12][CH:13]=[CH:14][CH2:15]1)[CH2:10][CH2:9]3.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>ClCCl>[CH3:1][C@@:2]1([OH:21])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[CH:11]([CH2:12][C@@H:13]2[O:30][C@@H:14]2[CH2:15]1)[CH2:10][CH2:9]3
Reactant: C[C@]12CC=CCC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(C)O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@]12C[C@H]3O[C@H]3CC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(C)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To a solution of compound 27 (120 mg, 0.43 mmol) in anhydrous dichloromethane (10 mL) was added m-CPBA (112 mg, 0.54 mmol) at 0° C. under an atmosphere of argon. The solution was stirred at 0° C. over a period of 3 h. The solution was subsequently diluted with dichloromethane (50 mL) and washed with an aqueous sodium bicarbonate solution (10%). The organic layer was dried with sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash chromatography (Hexanes/acetone: 95:5) to yield compound 28 (116 mg, 91%). 1H NMR (CDCl3) δ: 0.77 (s, 19-CH3), 0.83 (s, 18-CH3), 1.21 (s, 17α-CH3), 0.60-1.95 (residual CH and CH2), 3.11 (t, J=5.8 Hz, CH of epoxide) and 3.15 (broad s, 2×CH of epoxide).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)#[N:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([C:29]#[N:30])=[CH:32][CH:33]=3)[CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)c3ccc(C#N)cc3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 88, the title compound N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(4-cyano-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-cyanobenzoyl chloride instead of 4-fluorobenzoyl chloride and was obtained as a light brown oil. MS m/e: 542.1 [M+H]+.