Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.P(Br)(Br)[Br:11]>C(Cl)Cl>[Br:11][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Clc1cc(CBr)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
(2-chloropyridin-4-yl)methanol (1.1 g, 7.3 mmol) is dissolved in 20 mL DCM; flushed with argon and cooled to 0° C. PBr3 (0.76 mL; 8.1 mmol) is added drop wise via a syringe (solution turned cloudy) and reaction mixture is stirred at RT for 3 h. Cooled to 0° C. and quenched with 5 mL water. The reaction mixture is adjusted to pH 7 by the addition of 2M K2CO3. The aqueous and organic layer are separated and the aqueous layer is extracted 3× with EtOAc. The organic layers are combined, dried over anhydrous sodium sulfate, filtered and deposited on silica. Column chromatography on silica gel (pre-washed with 1% NEt3), using a solvent gradient from hexanes to EtOAc lead to the isolation of the product as pale pink crystals (700 mg, 50% yield based on recovered starting material).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:3]=12>S(Cl)(Cl)=O>[Cl:1][C:2]1[C:7]([C:8]2[O:10][C:4]([CH:3]([CH3:13])[CH3:2])=[N:11][N:12]=2)=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:3]=12
Reactant: CCn1ncc2c(Cl)c(C(=O)O)cnc21
Solvent: O=S(Cl)Cl
Product: CCn1ncc2c(Cl)c(-c3nnc(C(C)C)o3)cnc21
Temperature: 95 °C
Reaction time: 1 h
Yield: 151.6 %

Procedure:
Intermediate 11 (0.05 g) was dissolved in thionyl chloride (1 ml) and the mixture was heated at reflux (95° C.) with stirring for 1 h. After cooling to room temperature, excess thionyl chloride was removed by evaporation under reduced pressure and the resultant solid dissolved in anhydrous acetonitrile (0.5 ml). This solution was added to a solution of isobutyric acid hydrazide (0.025 g) and diisopropylethylamine (0.058 ml) in anhydrous acetonitrile (1 ml), and the mixture stirred for a further 1.5 h. The mixture was concentrated in vacuo and the residue treated directly with phosphorus oxychloride (2 ml). The resultant solution was stirred and heated at reflux (120° C.) for 2 h, then allowed to cool and concentrated in vacuo. The residue was applied to an SPE cartridge (silica, 5 g) which was eluted sequentially with a gradient of EtOAc:cyclohexanI (i) 1:16, (ii) 1:8, (iii) 1:4, (iv) 1:2, (v) 1:1 and (vi) 1:0. Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 13 (0.049 g). LCMS showed MH+=292; TRET=2.96 min.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]=[C:16]2[CH2:21][CH2:20][CH2:19][CH:18]=[C:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:31]CCl>C(O)C>[ClH:31].[C:22]1([C:17]2[C:16](=[N:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[CH2:21][CH2:20][CH2:19][CH:18]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCON=C2CCCC=C2c2ccccc2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCON=C2CCCC=C2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above ester (0.4 g, 1.1 mmol) was dissolved in ethanol (10 ml) and 4N sodium hydroxide (1 ml) was added. The mixture was stirred at ambient temperature for 3 h and excess concentrated hydrochloric acid was added followed by dichloromethane (400 ml). The suspension was dried (MgSO4) and the solvent evaporated in vacuo. The residue was re-evaporated with acetone, dissolved in acetone (10 ml) and left for crystallisation. This afforded 0.17 g of the title compound as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:55])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]4[N:29]=[CH:28][N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:26]=4)[CH:23]=3)[N:18](C3CCCCO3)[N:17]=2)[CH:11]=1)=[O:8]>Cl.O1CCOCC1>[NH:27]1[CH:28]=[N:29][C:25]([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[C:12]2[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:55])[CH:15]=[CH:14][CH:13]=2)=[N:26]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C(=O)c1ccco1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
2-(2-Furyl)-2-oxo-N-(3-{1-perhydro-2H-pyran-2-yl-5[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)acetamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature for 4 h. After neutralization with aqueous NaHCO3, the crude product was extracted in ethyl acetate and purified by preparative HPLC (0.0048 g, 5% yield over 2 steps): 1H NMR (CD3OD) δ 8.80 (s, 1H), 8.43 (d, 1H), 8.11 (br s, 1H), 8.10 (d, 1H), 8.01 (s, 1H), 7.94 (d, 1H), 7.87 (d, 1H), 7.72 (br d, 1H), 7.58 (t, 1H), 6.77 (dt, 1H); ES-MS (m/z) 399.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([Sn](CCCC)(CCCC)CCCC)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)S(O[C:31]1[CH:32]2[CH2:37][CH:34]([CH2:35][CH:36]=1)[C:33]2([CH3:39])[CH3:38])(=O)=O>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:31]2[CH:32]3[CH2:37][CH:34]([CH2:35][CH:36]=2)[C:33]3([CH3:39])[CH3:38])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OCC)cc1
Reactant: CC1(C)C2CC=C(OS(=O)(=O)C(F)(F)F)C1C2
Product: CCOC(=O)c1ccc(C2=CCC3CC2C3(C)C)cc1

Procedure:
4-(Tri-n-butyl-stannyl)-benzoic acid ethyl ester of Example 15, Step A (1.45 g, 3.30 mmol) and 6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl trifluoromethanesulfonate (0.981 g, 3.63 mmol) were reacted in the manner of Example 15, Step B. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 5% ethyl acetate in hexane afforded the crude title compound a yellow oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:14](=N)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
Hydrochloride of methyl ester of L-phenylalanine (5.95 g) and benzophenoneimine (5.00 g) were added to methylene chloride (100 ml), and they were stirred at room temperature overnight. A solid thus formed was filtered out of the reaction mixture. The filtrate was concentrated under reduced pressure. Diethyl ether (100 ml) was added to the residue. A solid thus formed was again filtered out of the reaction mixture. The ether layer was washed with water (100 ml) and then dried over anhydrous magnesium sulfate. Magnesium sulfate was removed, and the solution in ether was concentrated to obtain the intended methyl ester of N-(diphenylmethylene)-L-phenylalanine (9.44 g) in a yield of 99.6%.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1>OS(O)(=O)=O>[CH3:20][N:2]([CH2:3][C:4]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][C:7](=[O:8])[CH2:12][CH2:13]1)[CH3:1]
Reactant: CN(C)CC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: O=S(=O)(O)O
Product: CN(C)CC1(c2ccccc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound of step 5 (5.40 g, 19.6 mmol) was dissolved in 5% H2SO4 (300 mL) and stirred for 1 d at RT. The solution was then washed with ether three times and the ether phase discarded. The aqueous phase was made alkaline with 5N NaOH with ice cooling and extracted with dichloromethane three times. The organic phase was washed with a little water, dried over Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([C:7](=[O:14])[CH2:8][O:9][CH2:10]2)=[CH:5][CH:4]=1.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18].C[O-].[Na+].CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([C:7](=[O:14])[CH:8]([C:17](=[O:18])[C:16]([F:23])([F:22])[F:15])[O:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc2c(c1F)COCC2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1F)COC(C(=O)C(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A solution of 7-methoxy-8-fluoro-isochroman-4-one from Step 2 (370 mg, 1.76 mmol) and ethyl trifluoroacetate (290 mg, 2.04 mmol) in 8 mL of anhydrous tetrahydrofuran was treated with a solution of 25% sodium methoxide in methanol (570 mg, 2.64 mmol). The solution was stirred at room temperature for 16 hours, treated with excess 3N hydrochloric acid, and extracted with ether. The ethereal extract was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 450 mg (88%) of pure 7-methoxy-8-fluoro-3-(trifluoroacetyl)isochroman-4-one which was used directly in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9]([O:11]CC)=[O:10])[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1CCO>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9]([OH:11])=[O:10])[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccccc1N1CCOCC1
Agent: OCCC1CCCO1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccccc1N1CCOCC1

Procedure:
Ethyl 2-morpholinobenzoate prepared in the manner described in Tetrahedron, 53:7557, (1997) was refluxed with 10N NaOH in tetrahydrofuran-ethanol (8:2) for 1.5 hrs to give 2-morpholinobenzoic acid, mp 156-157° C. A 1.8 g, sample of this compound in 5 ml of CH2Cl2 (chilled) was added to a solution of 7.9 ml of oxalyl chloride in CH2Cl2 (2M) followed by the addition of 0.058 ml of N,N-dimethylformanide. The solution was stirred at room temperature for 6 hrs and the solvent removed. Toluene was added (2 times) and removed to give 2-(4-morpholino)benzoyl chloride as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36](O)=[O:37])[CH:30]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.ClCCl.CCOCC.ClCCl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH:19][C:36](=[O:37])[CH2:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Cc1cccnc1)NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.4 %

Procedure:
The [6-[(4-chlorophenylsulfonyl) (2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (30 mg, 0.073 mmol) obtained in Example 351, 3-pyridylacetic acid hydrochloride (16 mg, 0.092 mmol), 4-(dimethylamino)pyridine (5 mg, 0.04 mmol) and triethylamine (0.025 ml, 0.18 mmol) were dissolved in dichloromethane (5 ml). To the resulting solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17 mg, 0.089 mmol). After stirring at room temperature for 14 hours, a saturated aqueous solution (0.1 ml) of sodium bicarbonate was added to the reaction mixture. The residue obtained by concentration of the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. A fraction obtained from the elution portion with dichloromethane:methanol 30:1 was concentrated under reduced pressure, whereby a white solid was obtained. The white solid was washed with ether, whereby the title compound (35 mg, 0.066 mmol, 90%) was obtained as a white powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[C:14](B(O)O)=[CH:13][CH:12]=[CH:11][N:10]=1.Br[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[O:35][CH3:36])[C:22]#[N:23]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][C:26]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[C:14]2[C:9]([O:8][CH3:7])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:29]([O:35][CH3:36])[CH:30]=1
Reactant: COc1cc(Cl)ccc1Oc1ccc(C#N)cc1Br
Reactant: COc1ncccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(Cl)ccc1Oc1ccc(C#N)cc1-c1cccnc1OC
Temperature: 70 °C
Yield: 86.1 %

Procedure:
Potassium carbonate (0.232 g, 1.68 mmol) and (2-methoxypyridin-3-yl)boronic acid (0.215 g, 1.26 mmol) were added to a solution of 3-bromo-4-(4-chloro-2-methoxyphenoxy)benzonitrile (Preparation 3, 0.284, 0.839 mmol) in dioxane (10 mL). The reaction was degassed three times, then tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol) was added and the mixture was degassed three further times. The resulting mixture was heated at 70° C. over for 72 hours, then the reaction was cooled to room temperature. Then (2-methoxypyridin-3-yl)boronic acid (0.072 g, 0.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol) were added and the reaction was heated at 90° C. for 3 hours. The reaction was allowed to cool to room temperature and the solvent removed in vacuo to give a black oil which was absorbed onto silica and purified by silica gel chromatography (Biotage®, SNAP cartridge 50 g, DCM 6CV then 99/1, DCM/MeOH 5 CV and then 9/1, DCM/MeOH 6 CV) to afford the title compound as a white solid (0.265 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@H:11]([CH2:28][N:29]2[CH2:33][CH2:32][C@@H:31]([OH:34])[CH2:30]2)[CH2:10]1)(=[O:8])=[O:7].S1C=CC=C1S(N1CCN(C2C=CC([C@](O)(C)C(F)(F)F)=CC=2)[C@@H](CN2CC[C@@H](O)C2)C1)(=O)=O.S1C=CC=C1S(N1CCN(C2C=CC([C@@](O)(C)C(F)(F)F)=CC=2)[C@@H](CN2CC[C@@H](O)C2)C1)(=O)=O.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C@:21]([OH:27])([CH3:26])[C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=2)[C@H:11]([CH2:28][N:29]2[CH2:33][CH2:32][C@@H:31]([OH:34])[CH2:30]2)[CH2:10]1)(=[O:7])=[O:8]
Reactant: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CN2CC[C@@H](O)C2)cc1)C(F)(F)F
Agent: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CC[C@@H](O)C2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CC[C@@H](O)C2)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CN2CC[C@@H](O)C2)cc1)C(F)(F)F

Procedure:
(3R)-1-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyrrolidinol; (3R)-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyrrolidinol; (3R)-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyrrolidinol. 1H NMR (400 MHz, DMSO-d6) δ 8.07-8.05 (m, 1H), 7.69-7.67 (m, 1H), 7.38-7.36 (d, J=9.1 Hz, 2H), 7.32-7.29 (m, 1H), 6.90-6.86 (d, J=9.1 Hz, 2H), 4.71-4.67 (m, 1H), 4.17-4.12 (m, 3H), 3.46-3.41 (m, 2H), 3.17-3.04 (m, 1H), 2.99-3.92 (m, 2H), 2.63-2.59 (m, 1H), 2.48-2.38 (m, 3H), 1.95-1.89 (m, 2H), 1.61 (s, 3H), 1.55-1.50 (m, 1H). m/z (ESI, +ve ion) 520.1 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.50 μM.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:27]2[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=3)=[N:30][N:29]=[N:28]2)C=CC=CC=1>>[CH2:1]([C:5]1[N:6]([CH2:44][C:41]2[CH:42]=[CH:43][C:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:39][CH:40]=2)[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(-n2cccc2)c(C(=O)OCC)[nH]1
Product: CCCCc1nc(-n2cccc2)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the method described in Example 15, ethyl 2-butyl-4-(1H-pyrrol-1-yl)imidazole-5-carboxylate (Example 21) and N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 12) are reacted and deprotected to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[N:4][CH:3]=1.[CH:11]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([CH3:13])[CH3:12]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([O:14][CH:11]([CH3:13])[CH3:12])[CH:16]=2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(Cl)c1cncc(Cl)n1
Reactant: CC(C)Oc1cccc(N)c1
Solvent: ClCCl
Product: CC(C)Oc1cccc(NC(=O)c2cncc(Cl)n2)c1

Procedure:
The product from Example 15B was reacted with 3-isopropoxyaniline and TEA in CH2Cl2 as described in Example 15C to afford the title compound. MS (DCI/NH3) m/z 309 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[C:13]#[CH:14]>C(O)C>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:13]([C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:14][N:3]=[N:2]2)=[CH:11][CH:10]=1)#[N:9]
Reactant: N#Cc1ccc(N=[N+]=[N-])cc1
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnnn1-c1ccc(C#N)cc1
Yield: 7.3 %

Procedure:
A solution of 4-azidobenzonitrile (5.3 g, 36.77 mmol, 1.00 equiv) and ethyl prop-2-ynoate (10.82 g, 110.30 mmol, 3.00 equiv) in ethanol (160 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to give 650 mg (7%) of ethyl 1-(4-cyanophenyl)-1H-1,2,3-triazole-5-carboxylate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.54 (s, 1H), 8.11 (d, J=8.0 Hz, 2H), 7.90 (d, J=8.0 Hz, 2H), 4.27-4.22 (m, 2H), 1.20 (t, J=6.8 Hz, 3H) ppm. LCMS (method C, ESI): RT=0.87 min, m/z=243.1 [M+H]+ and 2.4 g (26%) of ethyl 1-(4-cyanophenyl)-1H-1,2,3-triazole-4-carboxylate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.66 (s, 1H), 8.24 (d, J=8.8 Hz, 2H), 8.13 (d, J=8.8 Hz, 2H), 4.41-4.36 (m, 2H), 1.36 (t, J=7.2 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.71 min, m/z=243.1 [M+H]+.
Reaction SMILES: NC1C=CC(C)=C2C=1C(=O)NC2.NC1C=CC=C2C=1C(=O)NC2.[I-].[K+].II.[N+]([O-])(OC(C)(C)C)=O.[I:36][C:37]1[CH:38]=[CH:39][C:40](C)=[C:41]2[C:45]=1[C:44](=[O:46])[NH:43][CH2:42]2>C(#N)C.[Cu](I)I>[I:36][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:45]=1[C:44](=[O:46])[NH:43][CH2:42]2
Reactant: Cc1ccc(I)c2c1CNC2=O
Agent: I[Cu]I
Agent: CC(C)(C)O[N+](=O)[O-]
Agent: Cc1ccc(N)c2c1CNC2=O
Solvent: CC#N
Product: O=C1NCc2cccc(I)c21
Yield: 50 %

Procedure:
In a similar manner to Step 4 of Example 140, a mixture of 7-amino-4-methylisoindolinone and 7-aminoisoindolinone (10/1, 57.4 mg, 0.357 mmol) was dissolved in acetonitrile (4.6 mL), and the solution was treated with potassium iodide (78 mg, 0.47 mmol), copper iodide (90 mg, 0.47 mmol), iodine (120 mg, 0.471 mmol) and tert-butyl nitrate (0.128 mL, 1.07 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=5/1) to obtain a mixture of 7-iodo-4-methylisoindolinone and 7-iodoisoindolinone (44.8 mg, ratio 10/1, yield 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:25])[N:16]4[CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:12]([C:26](O)=[O:27])[N:11]=3)[C:6]=2[CH:29]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:25])[N:16]4[CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:12]([C:26]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:27])[N:11]=3)[C:6]=2[CH:29]=1
Reactant: C1CCNCC1
Reactant: O=C(O)c1nc(-n2cnc3ccc(F)cc32)nc2c1[nH]c(=O)n2C1CCOCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(c1nc(-n2cnc3ccc(F)cc32)nc2c1[nH]c(=O)n2C1CCOCC1)N1CCCCC1
Reaction time: 24 h

Procedure:
To a solution of 2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-6-carboxylic acid (25 mg, 0.063 mmol) in THF (2 mL) at 0° C. was added piperidine (8 mg, 0.09 mmol) and triethyl amine (0.052 mL, 0.37 mmol), followed by a solution of triphenylphosphine (0.056 mL, 0.18 mmol) in ethyl acetate. The reaction mixture was allowed to reach room temperature and stirred for 24 h. The solvent was evaporated and a saturated solution of sodium bicarbonate was added to the residue. The solid formed was filtered and dried to give the desired compound as a white solid. Yield: 10 mg, 34%. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 11.89 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.82 (dd, J=4.8, 4.8 Hz, 1H), 7.24 (t, J=6.94 Hz, 1H), 4.58 (m, 1H), 4.03 (t, J=2.2 Hz, 2H), 3.68 (m, 2H), 3.68-3.48 (m, 4H), 2.64-2.55 (m, 2H), 1.79 (d, J=11.6 Hz, 2H), 1.66 (m, 4H), 1.55 (m, 2H); LCMS (EI) m/z 466 (MH)+.
Reaction SMILES: C(O[C:4](=[O:19])[CH2:5][C:6](=[O:18])[C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[N:20]12[CH2:27][CH2:26]N(CC1)CC2>>[CH3:13][CH:12]([C:7]1[CH:6]=[CH:5][CH:4]=[C:26]([CH:9]([CH3:10])[CH3:8])[C:27]=1[NH:20][C:4](=[O:19])[CH2:5][C:6](=[O:18])[C:7]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:17]
Reactant: C1CN2CCN1CC2
Reactant: CCOC(=O)CC(=O)C1(c2ccccc2)CCCC1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)C1(c2ccccc2)CCCC1

Procedure:
The title compound was prepared from β-oxo-1-phenylcyclopentanepropanoic acid ethyl ester (8.0 g, 0.03 mol), 1,4-diazabicyclo[2.2.2]octane (34.4 g, 0.30 mol) and xylenes (54.8 ML, 15.0 eq) using the procedure described in Example 3, Step B. 1H NMR (ppm, CDCl3): 1.62-1.73 (m, 4H), 1.85-1.90 (m, 2H), 1.93 (s, 3H, CH3), 2.43-2.52 (m, 2H), 7.20-7.36 (m, 5H).