Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]([N:16]1[C@H:20]([C:21](O)=[O:22])[CH2:19][CH:18]=[N:17]1)=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[F:29][C:30]1[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1>C(#N)C>[F:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:21]([C@H:20]2[N:16]([C:14](=[O:15])[C@@H:13]([CH2:12][N:3]([CH:1]=[O:2])[O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:17]=[CH:18][CH2:19]2)=[O:22])=[N:34][CH:35]=1
Reactant: Nc1ccc(F)cn1
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1N=CC[C@H]1C(=O)O
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of (5S)-1-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (100 mg, 0.26 mmol) and 5-fluoro-2-pyridinamine (37 mg, 0.33 mmol) in acetonitrile (10 mL) was added 4-methylmorpholine (39 mg, 0.39 mmol) and 2-chloro-4,6-bis(methyloxy)-1,3,5-triazine (49.5 mg, 0.28 mmol). The mixture was stirred at rt overnight. LCMS showed that the reaction was complete. The solvent was removed under vacuum and ethyl acetate was added. The mixture was washed with 10% KHSO4, sat. NaHCO3, brine, dried and concentrated. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (3:1 to 1:1) to provide the titled compound (108 mg, 85%) as a yellow oil.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1)#[N:2].N12CCCN=C1CC[CH2:19][CH2:18][CH2:17]2.IC(C)C>C(#N)C.C(OCC)C>[C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][CH:18]([CH3:19])[CH3:17])=[O:14])[CH2:5]1)#[N:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)O)O1
Solvent: CCOCC
Solvent: CC#N
Solvent: CC(C)I
Product: CC(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 0.6 g (3 mmol), in acetonitrile, 2 mL, is added 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), 0.45 mL (3 mmol), and 2-iodopropane, 0.33 mL (3.3 mmol). The solution is stirred overnight at room temperature, diluted with diethyl ether, washed with brine, and dried (magnesium sulfate). Flash chromatography provides 0.5 g of (±)-cis-1-methylethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][CH3:12])[CH:5]=1.[CH3:14][O:15][CH2:16][CH2:17]COS(C1C=CC(C)=CC=1)(=O)=O.[C:30]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[C:6]([O:11][CH2:12][CH2:17][CH2:16][O:15][CH3:14])[CH:7]=[C:8]([O:10][CH3:30])[CH:9]=1
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1cc(O)cc(OC)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCOc1cc(OC)cc(C(=O)OC)c1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a mixture of 3-methoxy-5-hydroxybenzoic acid methyl ester (23.2 g, 127 mmol), toluene-4-sulfonic acid 3-methoxy-propyl ester (40.7 g, 167 mmol) and Kl (2.23 g, 13.4 mmol) in DMF (350 mL), K2CO3 (53.1 g, 384 mmol) is added under N2. After stirring at 60° C. for 17 h, the reaction mixture is supplemented with H2O and extracted with Et2O. The combined organic phases are washed with H2O and dried (Na2SO4). Concentration under reduced pressure and silica gel flash chromatography give the title compound as colorless oil. MS: 255 [M+H]+; tR (HPLC, CombiScreen ODS-AM 50×4.6 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 2 min, flow 2.0 ml/min): 3.80 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[CH3:17][Si](C=[N+]=[N-])(C)C.[BrH:24]>C(#N)C>[Br:24][CH2:17][C:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)Cl
Reactant: Br
Solvent: CC#N
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbonyl chloride (from the previous step) was dissolved in ACN (30 mL) then trimethylsilyl-diazomethane (2M in Et2O, 16.38 mL, 32.76 mmol) was slowly added and the reaction stirred at room temperature for 2 hours. Hydrobromic acid (30% aq., 7 mL) was carefully added and the reaction stirred for an additional 1 hour. The mixture was submitted to standard aqueous workup then purified on silica gel (0-20% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[NH:19][C:20]1[N:24]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:23]2[CH:31]=[CH:32][C:33]([CH2:35][OH:36])=[CH:34][C:22]=2[N:21]=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][C:40]=1B(O)O.ClCCl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:25]1([N:24]2[C:23]3[CH:31]=[CH:32][C:33]([CH2:35][OH:36])=[CH:34][C:22]=3[N:21]=[C:20]2[NH:19][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:40]4[CH:41]=[N:42][CH:43]=[CH:44][C:39]=4[O:38][CH3:37])[CH:3]=3)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[N:6]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C[Si](C)(C)CCOCn1nc(Nc2nc3cc(CO)ccc3n2C2CCCCC2)c2cc(Br)ccc21
Reactant: COc1ccncc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(CO)ccc3n1C1CCCCC1)nn2COCC[Si](C)(C)C
Yield: 16.9 %

Procedure:
In a small microwave tube was added (2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-ylamino)-1-cyclohexyl-1H-benzo[d]imidazol-5-yl)methanol (164 mg, 0.000287 mol), 4-methoxypyridin-3-ylboronic acid (79.1 mg, 0.000517 mol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (47 mg, 0.000057 mol). To this mixture was added 1,4-dioxane (4.3 mL, 0.055 mol) and the resultant mixture was stirred under an argon atmosphere. To this mixtrure was then added 2 M sodium carbonate in water (700 uL) and the reaction mixture was microwaved for 21 minutes at 120° C. The reaction mixture filtered through a syringe filter cartridge and the cartridge washed 3 times with methanol. The residue after concentration was purified by flash chromatography using a 40 g silica gel cartridge and 10-60% ethyl acetate/hexane gradient. The product fractions were concentrated to give the title compound (29 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[C:3]2[C:10]([S:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(S)cc1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cn(COCC[Si](C)(C)C)c3ncnc(Cl)c23)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (110 mg, 0.27 mmol) was treated with 4-methoxybenzenethiol (50 μl, 0.40 mmol), copper(I) iodide (77 mg, 0.40 mmol) and potassium carbonate (74 mg, 0.54 mmol) in 2.2 mL dimethylformamide according to method described in Preparation 86 but stirring the reaction mixture at 50° C. overnight. The residue was purified using SP1® Purification System (0% to 15%, hexane-ethyl acetate) to give 57 mg (43% yield, 85% purity) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.ClC[C:28]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][N:29]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:28]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: COc1cccnc1CCl
Product: COc1cccnc1CSc1c(Cl)ccc2c1CCNCC2
Product: Cl

Procedure:
Use a method similar to the Example 315, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-chloromethyl-3-methoxypyridine to give, after deprotection by a method similar to the General Procedure 1-4, the title compound as a white solid (71 mg). MS (APCI+) m/z: 335 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:11]C1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1>N1C=CC=CC=1>[C:4]1([S:7]([NH2:11])(=[O:9])=[O:8])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1.32 mol (166 cm3) of benzenesulfochloride is added little by little at 45° C. with constant stirring to a solution of 1 mol (223 g) of 2-amino anthraquinone in 1800 cm3 of pyridine. When the addition is complete the reaction mixture is kept at 45° C. for 4 hours. It is then cooled to 0° C. Drying yields the crude product which is then washed successively in slightly hydrochloric water, in water, and in alcohol. 320 g of practically pure benzene-sulfonamide are thus obtained, which melt at 276° C. 12 g of slightly less pure benzene-sulfonamide may be recovered from the pyridine filtrate by dilution.
Reaction SMILES: O.[OH-].[Li+].[N:4]1([C:8]([C:10]2[N:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:34])[CH2:29][O:30][CH:31]([F:33])[F:32])[CH:26]=3)[C:20]([O:22]C)=[O:21])=[N:14][CH:15]=2)=[O:9])[CH2:7][CH2:6][CH2:5]1>O.C1COCC1>[N:4]1([C:8]([C:10]2[N:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:34])[CH2:29][O:30][CH:31]([F:32])[F:33])[CH:26]=3)[C:20]([OH:22])=[O:21])=[N:14][CH:15]=2)=[O:9])[CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@@H](C)COC(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.9 %

Procedure:
Lithium hydroxide monohydrate (48 mg, 1.13 mmol) in water (5 mL) was added to a solution of methyl 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)benzoate (0.33 g, 0.75 mmol) in THF (10 mL) and stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous layer washed with ethyl acetate (50 mL) to remove any impurities. The aqueous layer was acidified and extracted into ethyl acetate (2×50 mL), washed with brine, dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound as a white foam (0.26 g). m/z 424 (M+H)+
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:10]=1)C1C=CC=CC=1.[H][H]>[Ni].C(O)C>[CH3:22][Si:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][O:18][CH2:17][O:16][CH2:15][C:11]1[N:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCOCc1cccc(OCc2ccccc2)n1
Agent: [Ni]
Solvent: CCO
Product: C[Si](C)(C)CCOCOCc1cccc(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
7 g of Raney Nickel are added to a solution of 7 g of 2-benzyloxy-6-(2-trimethylsilanyl-ethoxymethoxy-methyl)pyridine in 75 ml of ethanol saturated with hydrogen. The suspension is stirred vigorously under a low hydrogen pressure at room temperature for 1 hour 30 minutes. The solid in suspension is removed by filtration on celite and then the ethanol is evaporated off. The title product is isolated by chromatography on a silica column (eluent: dichloromethane/methanol; 98:2). 4 g of a colorless oil are recovered.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[O:21]=[C:22]1[C:27](C(Cl)=O)=[CH:26][CH:25]=[C:24]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:23]1.[CH2:36]([N:38]([CH2:42][CH3:43])[CH2:39][CH2:40][NH2:41])[CH3:37]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([C:27]2[C:22](=[O:21])[O:23][C:24]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:26]=2)=[O:13])[C@H:8]([C:18]([NH:41][CH2:40][CH2:39][N:38]([CH2:42][CH3:43])[CH2:36][CH3:37])=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: CCN(CC)CCN
Product: C=CCON=C1C[C@@H](C(=O)NCCN(CC)CC)N(C(=O)c2ccc(CCCCC)oc2=O)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 93% purity by LC/MS. MS(ESI+): m/z=475.4.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21](=O)[C:22](OC)=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36]>C(O)C>[O:23]=[C:22]1[NH:36][C:31]2[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:29]=[C:21]1[C:18]1[C:17]2[CH:27]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:11])([F:9])[F:10])[N:2]([CH3:1])[C:3]3=[O:28])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1
Reactant: Nc1ccccc1N
Reactant: COC(=O)C(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Solvent: CCO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4nc5ccccc5[nH]c4=O)c3c2)c1=O
Reaction time: 16 h
Yield: 56.3 %

Procedure:
A mixture of methyl 5-[3-,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-glyoxylate (0.7500 g, 1.81 mmol), 1,2-diaminobenzene (0.200 g, 1.84 mmol) and ethanol is stirred 16 hours at reflux and filtered hot. The filtrate is concentrated in vacuo to afford the title compound as a light yellow solid (0.480 g, 56.3%, mp >250° C.) which is identified by NMR analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1.[C:11](O)(=[O:15])[C:12](O)=[O:13]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:9][C:11](=[O:15])[C:12](=[O:13])[NH:10]2)=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(N)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: Cc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
13.05 g (64.9 mmol) of 5-bromo-2,3-diaminotoluene and 6.42 g (1.1 eq.) of oxalic acid are stirred under reflux for 16 hours in 2N hydrochloric acid. The mixture is cooled, and the solid is filtered off and washed with water. The title compound is obtained as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[CH2:33][CH2:32][N:31]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:30]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(C2CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccc(F)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-fluorophenyl)pyrrolidine oxalate (15.3 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (3.3 mg). Calcd for C21H19FN2O2: 350.1431, found 350.1438.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:17]>C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:8]=2[NH:9][C:10](=[O:12])[CH3:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1ccccc1-c1ccccc1
Reactant: Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
2-Phenyl-N-acetylaniline (6.21 g, 29.40 mmol) was dissolved in acetic acid (70 mL). Thereto was dropwise added under ice bath a separately prepared solution of hydrogen bromide (6.14 g, 38.42 mmol) dissolved in carbon tetrachloride (19.21 mL) and the mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure, to the residue was added water (20 mL) and subsequently ethanol (30 mL), and the mixture was stirred under ice bath for 1 hour. The precipitate was collected by filtration, washed with ethanol/water (=1:1), dried under reduced pressure to obtain 2-phenyl-4-bromo-N-acetylaniline (7.79 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[CH3:13]N(CCN(C)C)C.[Li]CCCC.IC>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(c1)NC(=O)C2C
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a cooled solution (−78° C.) of 6-methoxy-1,3-dihydro-indol-2-one (840 mg, 5.2 mmol, see Quallich, G. J.; Morrissey, P. M. Synthesis 1993, 51-53) in THF (20 mL) is added dropwise TMEDA (1.57 mL, 10.4 mL) followed by dropwise addition of 2.5M n-BuLi (4.16 mL, 10.4 mmol). The mixture is stirred for 15 min then warmed to −25° C. Add dropwise iodomethane (405 μL, 6.5 mmol) and let stir for 20 min. The reaction is quenched with sat NH4Cl soln, warmed to room temp and diluted with EtOAc. The organic layer is washed with sat NH4Cl soln, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 45% ethyl acetate/hexanes) to give 679 mg of title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:35]([SH:36])=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[CH3:37]N(C)C=O.[H-].[Na+].IC>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:35]([S:36][CH3:37])=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cn2c(CC3CCN(CCn4c(S)nc5cncnc54)CC3)nc3ccccc32)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CSc1nc2cncnc2n1CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred mixture of 34.5 parts of 9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]-ethyl]-9H-purine-8-thiol and 180 parts of N,N-dimethylformamide were added portionwise 3.2 parts of a sodium hydride dispersion 50%. Upon completion, stirring was continued for 0.5 hours at room temperature. 11.5 parts of iodomethane were added dropwise. After complete addition, the whole was stirred for 1 hour. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 28.3 parts (80%) of 9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl)methyl]-1-piperidinyl]ethyl]-8-(methylthio)-9H-purine; mp. 133.1° C. (507).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[C:16]1([C@H:22]([CH3:26])[C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:23](=[O:24])[C@H:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:26])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(NC(=O)[C@@H](C)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a) (200 mg, 1 mmol), (S)-2-phenyl propionic acid (156 mg, 1 mmol), and PyBop (650 mg, 1.3 mmol) were added to DMF (4 mL) followed by triethylamine (0.3 mL, 2.1 mmol). The reaction stirred for 4 hours at room temperature under a nitrogen atmosphere then diluted with ethyl acetate (20 mL), washed with aqueous saturated NaHCO3 solution (2×15 mL) followed by aqueous saturated NaCl solution (15 mL). The organic phase was dried, filtered and concentrated on the rotovap. The crude product was re-suspended in methanol (3 mL) and purified by reversed phase HPLC (5%-95% ACN in H2O:25 minute gradient). The fractions containing the pure product were concentrated to afford (S)-N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-phenylpropanamide (200 mg, 60%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.36 (d, J=7.2, Hz, 3H), 2.09 (s, 3H), 2.36 (s, 3H), 3.71-3.66 (m, 1H), 5.05 (s, 2H), 7.33-7.17 (m, 5H), 7.37 (s, 1H), 7.90 (s, 1H), 10.05 (s, 1H). MS 325 (M+H). Melting point 108° C.-110° C.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=O)[CH2:3][CH2:2]1.[CH3:7][C:8]1([CH3:28])[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:1]1([CH2:4][CH2:5][N:25]2[CH2:26][CH2:27][N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH:10]3[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:8]([CH3:28])([CH3:7])[CH2:9]3)[CH2:23][CH2:24]2)[CH2:3][CH2:2]1
Reactant: O=CCC1CC1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC1(C)CC(c2ccccc2N2CCN(CCC3CC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of cyclopropylacetaldehyde in 1,2-dichloroethane (0.29 M, 5 mL) were added 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (25 mg, 0.0832 mmol) produced in Example (8b), sodium triacetoxyborohydride (22.9 mg, 0.108 mmol) and acetic acid (0.009 mL, 0.158 mmol), followed by stirring for 20 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed twice with ethyl acetate. The organic layer was concentrated and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 20.9 mg of 1-(2-cyclopropylethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless oil.