Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.Br[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[N:6]([CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[N:3]=1
Reactant: CC(C)=CCBr
Reactant: COC(=O)c1nc(Br)[nH]c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(Br)n(CC=C(C)C)c1C(=O)OC
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 12.20 g (46 mmol) dimethyl 2-bromo-imidazole-4,5-dicarboxylate, 7.16 g (48 mmol) 1-bromo-3-methyl-2-butene and 7.19 g (52 mmol) potassium carbonate in 150 ml of dimethylformamide were stirred for two hours at 50° C. Then 100 ml of water were added, and the mixture was extracted three times with ethyl acetate. The extracts were dried and evaporated down. The crude product thus obtained was purified by column chromatography (silica gel; eluant: cyclohexane/ethyl acetate 4:1->2:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13]/[C:12](=[N:14]\[C:15]([C:17]23[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]4)[CH2:18]2)[CH2:24]3)=[O:16])/[N:11](COCC[Si](C)(C)C)[CH:10]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)=[O:16])=[N:11][CH:10]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(F)cc2F)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ncc(-c2ccc(F)cc2F)s1)C12CC3CC(CC(C3)C1)C2

Procedure:
A solution of Example 200B in trifluoroacetic acid was heated at 50° C. for 3 hours then concentrated. The residue was diluted with saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered and concentrated to afford the title compound MS (ESI) m/z 375 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>CO.[Pt](=O)=O>[NH2:8][C:6]1[CH:5]=[C:4]([CH2:11][OH:12])[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cc(CO)c1
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1cc(Br)cc(CO)c1
Reaction time: 1 h

Procedure:
(3-Bromo-5-nitrophenyl)methanol (3.9 g, 16.8 mmol) in methanol (35 mL) was flushed with nitrogen, and treated with platinum (IV) oxide (390 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen for 1 h. The reaction was flushed with nitrogen, filtered through celite, and concentrated to afford 3.1 g (94%). 1H-NMR (CDCl3, 300 MHz) δ 6.95 (s, 1H), 6.80 (s, 1H), 6.79 (s, 1H), 4.61 (s, 2H). Mass spec.: 203.96 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[C:12]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH2:21])([CH3:20])[CH3:19])(=[O:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([C:15]1[CH:16]=[C:17]([C:18]([NH:21][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:20])[CH3:19])[CH:22]=[CH:23][CH:24]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cccc(C(C)(C)N)c1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(C(C)(C)NC(=O)Cc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
4-Chlorophenylacetylchloride (106 mg, 0.56 mmol) in dichloromethane was added to a solution of 3-acetyl-α, α-dimethylbenzylamine 24 (100 mg, 0.56 mmol) and triethylamine (120 μL, 0.86 mmol) in dichloromethane over a period of 5 to 10 min at 0° C. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with dichloromethane (20 mL) and washed with 1 N HCl, water and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by column chromatography using hexane/ethyl acetate as eluent to give 26 (146 mg, 80%). 1H NMR (CDCl3, 400 MHz) δ 1.61 (s, 6H), 2.53 (s, 3H), 3.46 (s, 2H), 5.68 (s, 1H), 7.19 (d, J=7.2 Hz, 2H), 7.30-7.38 (m, 3H), 7.46 (d, J=8 Hz, 1H), 7.75 (d, J=7.2 Hz, 1H), 7.87 (s, 1H); 13C NMR (DMSO-d6 100 MHz) δ 27.26, 29.89, 42.54, 55.34, 124.71, 126.76, 128.74, 128.98, 130.23, 131.45, 131.63, 136.22, 137.19, 148.96, 169.54, 198.59; ESI-HRMS for C19H21NO2Cl (M+H)+ calcd. 330.1261. found 330.1270.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8](=[O:15])[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12].Cl.O1CCOCC1>C(=O)(O)[O-].[Na+]>[F:12][C:11]([F:13])([F:14])[CH2:10][CH2:9][C:8](=[O:15])[CH2:7][CH2:6][CH:2]=[O:1]
Reactant: O=C(CCC1OCCO1)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=CCCC(=O)CCC(F)(F)F
Yield: 69 %

Procedure:
Crude 1-[1,3]dioxolan-2-yl-6,6,6-trifluoro-hexan-3-one (18 g, prepared above) in 1:1 2N HCl-dioxane (80 ml) was heated to reflux for 20 minutes, then neutralized with aqueous sodium bicarbonate (100 ml), then extracted with ethyl acetate (3×75 ml). The combined organics were washed with brine (2×50 ml), then concentrated under reduced pressure to provide crude 7,7,7-trifluoro-4-oxo-heptanal (10 g), which may be used without further purification. 1H NMR (CDCl3) δ 9.80 (1H, s), 2.85-2.70 (6H, m), 2.47-2.35 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH3:18]I>CN(C=O)C>[CH3:18][NH:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(C(=O)OC)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A solution of dimethyl 5-aminoisophthalate (0.250 g, 1.17 mmol, 1 eq) dissolved in 3 mL anhydrous DMF was added dropwise to a stirred suspension of NaH (60% dispersion in mineral oil, 0.14 g, 3.5 mmol, 3 eq) in 2 mL anhydrous DMF at 0° C. under Ar. MeI (0.23 mL, 0.53 g, 3.7 mmol, 3.2 eq) was added dropwise to the resulting mixture. The reaction was stirred at 0° C. to room temperature overnight. The reaction was poured into ice water to quench. The aqueous mixture was extracted with EtOAc (×2), and the combined organic extracts were washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography on silica gel yielded 0.14 g (0.63 mmol, 54% yield) of dimethyl 5-(methylamino)isophthalate.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][CH:17]([F:30])[CH2:18][O:19][C:20]1[C:21]([CH3:29])=[CH:22][C:23]([CH:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:22]=[C:21]([CH3:29])[C:20]([O:19][CH2:18][CH:17]([F:30])[F:16])=[CH:25][N:24]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)ncc1OCC(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (360 mg, brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (390 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (350 mg, 1.4 mmol, Amine-59, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[C:9]1[C:18](=[O:19])[CH2:17][CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10]1=[O:20])[CH2:7][CH3:8])[CH:2]=[CH2:3].[OH-].[Na+].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O.O>[CH2:1]([O:4][N:5]=[C:6]([C:9]1[C:10](=[O:20])[CH:11]2[CH:16]([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:17][C:18]=1[O:19][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCONC(CC)=C1C(=O)CC2CCCCC2C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C=CCON=C(CC)C1=C(OC(=O)c2ccccc2)CC2CCCCC2C1=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(1-allyloxyaminopropylidene)decaline-1,3-dione (2 g) in acetone (30 ml), sodium hydroxide (0.2 g) in water (1 ml) was added at room temperature and then benzoylchloride (0.7 g) was added. After stirring for 5 hours, the reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with one normal sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo and an oily substance (1.8 g) was obtained.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[S:18][CH:17]=[N:16][C:15]=1[CH3:19])SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[S:18][CH:17]=[N:16][C:15]=1[CH3:19])#[N:4]
Reactant: CN
Reactant: CSC(=NCCSCc1scnc1C)NC#N
Solvent: CCO
Product: CNC(=NCCSCc1scnc1C)NC#N
Reaction time: 2.5 h

Procedure:
A solution of 75 ml. of 33% methylamine in ethanol is added to a solution of the N-cyano-N'-[2-(4-methyl-5-thiazolylmethylthio)ethyl]-S-methylisothiourea prepared above in 30 ml. of ethanol. The reaction mixture is set aside at ambient temperature for 2.5 hours, and the precipitate is collected to give N-cyano-N'-methyl-N"-[2-(4-methyl-5-thiazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[C:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:10][C:9]=2[Br:19])[C:3]1=[O:20].[C:21]([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][N:28]2[C:32]([CH:33]=O)=[CH:31][N:30]=[CH:29]2)=[CH:25][C:24]=1[F:37])#[N:22].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[Br:19][C:9]1[CH:10]=[CH:11][C:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=1[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:33][C:32]2[N:28]([CH2:27][C:26]3[CH:35]=[CH:36][C:23]([C:21]#[N:22])=[C:24]([F:37])[CH:25]=3)[CH:29]=[N:30][CH:31]=2)[C:3]1=[O:20]
Reactant: CS(=O)(=O)Oc1ccc(Br)c(CN2CCC(N)C2=O)c1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)Oc1ccc(Br)c(CN2CCC(NCc3cncn3Cc3ccc(C#N)c(F)c3)C2=O)c1
Reaction time: 0.5 h

Procedure:
3-Amino-1-(2-bromo-5-methanesulfonyloxybenzyl)-2-oxopyrrolidine, as described above in Step E, (640 mg, 1.12 mmol), 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described above in Example 1, Step G, (333 mg, 1.45 mmol) were stirred in MeOH (8 mL) and the solution was acidified to pH≈5 to 6, as judged by wetted pH indicator paper, with acetic acid. Stirring was continued for 30 min, then NaCNBH3 (118 mg, 1.88 mmol) was added. Stirring was continued for 18 hours, then the reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (20 mL). The aqueous layer was extracted further with EtOAc (2×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2—1% to 5% MeOH, to yield the desired product.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.Cl.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:38])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[C:34]([F:37])([F:36])[F:35])=[CH:21][CH:20]=1.O>CCOCC>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[C:6](=[O:12])[NH:7]4)=[CH:24][CH:23]=2)=[O:38])=[C:28]([C:34]([F:35])([F:36])[F:37])[CH:29]=1
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2C(F)(F)F)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1)c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
To a suspension of 83 (135 mg, 0.59 mmol) in ether (10 mL) was added HCl (1.17 mL, 1.00 M, 1.17 mmol) in ether. The mixture was stirred for 3 h and the solvent was removed under vacuo. A suspension of this HCl salt in NMP (3 mL) was added N-(4-aminophenyl)-4-fluoro-2-(trifluoromethyl)benzamide (209 mg, 0.70 mmol). The mixture was stirred at 150° C. for 3 h. After cooling to room temperature, H2O was added. The resulting product precipitate and the solid was filtered, washed with H2O and MeOH, and dried under vacuum to provide 378 (210 mg, 73% yield) as pale solid.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[NH2:13]>C(O)(=O)C.CCOCC>[F:9][C:10]1[C:16]([C:17]([F:18])([F:19])[F:20])=[CH:15][C:14]([I:1])=[C:12]([CH:11]=1)[NH2:13]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1cc(F)c(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6.16 g of N-iodosuccinimide (27 mmol) were slowly added to a solution of 4.9 g of 3-fluoro-4-(trifluoromethyl)-aniline (27 mmol) in 20 ml acetic acid. After the reaction mixture had been stirred for 1.5 h at rt it was diluted with ether and washed with a 2 molar solution of Na2S2O3 and with brine. The ether layer was then dried with magnesium sulfate, filtered and the solvent was evaporated. 5-Fluoro-2-iodo-4-trifluoromethyl-aniline was isolated from the remaining residue by chromatography (silica gel; cyclohexane/EtOAc 4:1). This yielded 3.27 g (39%) of 5-fluoro-2-iodo-4-trifluoromethyl-aniline as a dark red liquid. 1H-NMR (CDCl3, 300 MHz): δ 4.52 (br s, 2H), 6.49 (d, J=12 Hz, 1H), 7.79 (d, J=8 Hz, 1H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)[OH:22].N([O-])=O.[Na+].F[B-](F)(F)F.[Na+]>O>[OH:22][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: Nc1ccccc1Sc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=S(=O)(O)O
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Sc1ccccc1O
Reaction time: 0.33 h

Procedure:
Suspend 10.15 g (35 mmoles) of the amino acid of Step A in 75 ml of water and add 4 ml concentrated sulfuric acid (7.36 g, 75 mmoles, 140 meq.). Cool the mixture in an ice-bath and add 3.657 g (53 mmoles) of sodium nitrite in portions at 0°-5° C. Stir the suspension in the cold for 20 minutes. Add 10 g (91 mmoles) of sodium fluoroborate and stir for an additional 20 minutes. Separate the precipitated crude diazonium fluoroborate, suspend tne precipitate in 250 ml of 50% sulfuric acid and heat in an oil bath at 90°-100° C. for 45 minutes. Cool the mixture and separate the precipitate. (Yield: 7.76 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([O:18][C@@H:19]4[O:45][C@H:44]([CH2:46][O:47]C(=O)C(C)(C)C)[C@@H:36]([O:37]C(=O)C(C)(C)C)[C@H:28]([O:29]C(=O)C(C)(C)C)[C@H:20]4[O:21]C(=O)C(C)(C)C)[C:10]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].C(O)(=O)C>CO>[C@@H:19]1([O:18][C:17]2[C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:15][N:16]=2)[O:45][C@H:44]([CH2:46][OH:47])[C@@H:36]([OH:37])[C@H:28]([OH:29])[C@H:20]1[OH:21]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccccc4)c23)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 5 h
Yield: 64.3 %

Procedure:
To a solution of 4-(2-phenylethyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo-[3,4-b]pyridine (0.26 g) in methanol (5 mL) was added sodium methoxide (28% methanol solution, 0.067 mL), and the mixture was stirred at 50° C. for 5 hours. To the reaction mixture was added acetic acid (0.04 mL), and the resulting mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (91 mg)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][CH:6]2[C:16]([O:18][CH3:19])=[O:17])#[N:2].C([O-])([O-])=O.[K+].[K+].[Cl:26][C:27]1[CH:44]=[CH:43][C:30]([CH2:31][CH2:32][NH:33][C:34](=[O:42])[C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)=[CH:29][CH:28]=1>CN1CCCC1=O>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH2:32][NH:33][C:34]([C:35]2[CH:40]=[CH:39][C:38]([O:41][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:7][C:8]([CH3:15])([CH3:14])[O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:37][CH:36]=2)=[O:42])=[CH:43][CH:44]=1
Reactant: COC(=O)C1CC(C)(C)Oc2cc(F)c(C#N)cc21
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CC(C)(C)Oc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Temperature: 110 °C
Yield: 5.4 %

Procedure:
Methyl 6-cyano-7-fluoro-2,2-dimethylchroman-4-carboxylate (19 mg, 0.072 mmol) was diluted with N-methylpyrrolidone (2 mL) followed by the addition of K2CO3 (25 mg, 0.18 mmol) and N-(4-chlorophenethyl)-4-hydroxybenzamide (20 mg, 0.072 mmol). The reaction was bubbled with argon for 10 minutes and then heated at 110° C. for 6 hours. After cooling, the reaction mixture was loaded directly onto a Biotage 25 column and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (2.0 mg, 5.3% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([NH:17][CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(C)(C)C.Cl>O>[CH:11]1([N:17]([CH3:18])[C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CNC1CCCCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: O
Solvent: CC(C)(C)O
Product: CN(c1ncnc2[nH]ccc12)C1CCCCC1
Yield: 87.8 %

Procedure:
A mixture of 200 mg (1.30 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (prepared by the method of Davoll, J. Am. Chem. Soc., (1960). 82, 131), the product from Method A (589 mg/5.21 mmol) and 3 mL of tert-butanol was stirred in a sealed tube at 100° C. for 24 h. The reaction mixture was added to water, acidified to pH 1 with 1 N HCl (aq), washed twice with diethylether (ether) and basified to pH 14 with 1 N sodium hydroxide (NaOH). The resulting precipitate was filtered and dried in vacuo to obtain 263 mg (88%) of the title compound, mp 177-180° C. 1H NMR (400 MHz, CDCl3): δ1.11-1.22 (m, 1H), 1.43-1.63 (m, 4H), 1.73 (br d, 1H, J=13.3 Hz), 1.83-1.90 (m, 4 H), 3.23 (s, 3H), 4.69 (br, 1H), 6.53 (d, 1H, J=3.5 Hz), 7.03 (d, 1H, J=3.5 Hz), 8.30 (s, 1H), 10.6 (br, 1H). LRMS: 231 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH3:22][C:23]#[N:24]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:22][C:23]#[N:24])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: N#CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Yield: 999.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (6.0 g, 2.7 mmol), NaHCO3 (2.5 g, 3.0 mmol) chloroacetonitrile (2.5 g, 3.3 mmol) and CH3CN (150 mol) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2D and the aqueous solution was extracted with EtOAc. The EtOAc extract was washed with H2O, washed with brine, dried with MgSO4 and concentrated to yield 7.0 g of a tan solid. A 1.3 g sample was recrystallized from EtOAc to yield 0.65 g of a beige solid, m.p. 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[S:16])[NH:11][CH2:12][C:13](N)=[O:14].[CH2:17](I)[CH3:18]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][N:11]=[C:10]1[S:16][CH2:17][CH3:18]
Reactant: Cc1cccc(Cl)c1NC(=S)NCC(N)=O
Reactant: CCI
Agent: Cl
Product: CCSC1=NCC(=O)N1c1c(C)cccc1Cl

Procedure:
The title compound was prepared by the procedure described in Example 6 using 12.9 g of 2-[3-(2-chloro-6-methylphenyl)-thioureido]-acetamide, and 18.0 g of ethyl iodide. The hydrochloride salt was prepared in ethereal hydrogen chloride. Crystallization from ethyl acetate afforded the title compound as the mono-hydrochloride as a light yellow solid (4.9 g), m.p. 152°-154° C. (dec.). Anal. Calcd. for. C12H13Cl N2O S . HCl: C, 47.22; H, 4.62; N, 9.18. Found: C, 46.99; H, 4.60; N, 9.16. Mass spectrum (+FAB, [M+H]+) m/z 269/271. 1H-NMR (DMSO-d6 ; 400 MHz) δ8.28 (broad s, 2 H), 7.51 (m, 1 H), 7.44 (t, 1 H), 7.39 (m, 1 H), 4.51 (q, 2 H), 3.12 (q, 2 H), 2.17 (s, 3 H), and 1.27 ppm (t, 3 H).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.O1C[CH2:37][CH2:36][CH2:35]1>O>[CH:21]1([CH2:20][NH:19][N:16]2[C:17](=[O:18])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:1])(=[O:28])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH2:22][CH2:37][CH2:36][CH2:35][CH2:23]1
Reactant: C1CCOC1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NCC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.12 g, 0.26 mmol) in tetrahydrofuran (5 mL) and methanol (0.021 mL, 0.52 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.195 mL, 0.39 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 97:3 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (m, 2 H) 1.23 (m, 3 H) 1.52 (m, 1 H) 1.68 (m, 3 H) 1.87 (m, 2 H) 2.69 (m, 2 H) 5.95 (t, J=7.17 Hz, 1 H) 7.07 (d, J=5.52 Hz, 1 H) 7.19 (d, J=8.09 Hz, 1 H) 7.26 (t, J=7.72 Hz, 1 H) 7.53 (t, J=7.17 Hz, 1 H) 7.65 (d, J=6.99 Hz, 1 H) 7.78 (d, J=5.15 Hz, 1 H) 15.91 (s, 1 H). MS (APCI+) m/z 459 (M+H)+.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(CC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)C1CCC(Cc2ccc3cc(CN4CCC(C(=O)O)CC4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a solution of ethyl 1-((6-((4-(tert-butyl)cyclohexyl)methyl)naphthalen-2-yl)methyl)piperidine-4-carboxylate (150 mg, 0.33 mmol) in MeOH (5 mL) was added NaOH (68 mg, 1.7 mmol, 5.0 eq) and H2O (0.5 mL). The reaction mixture was stirred at 80° C. for 4 h. The pH of the solution was adjusted to 6 with 3 N HCl. The mixture was filtered and the yellow solid was purified by prep-HPLC (CH3CN: H2O/0.05% TFA=0-95%) to afford the desired product 1-((6-((4-(tert-butyl)cyclohexyl)methyl)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid (120 mg, 85%). ESI-MS (M+1)+: 422.3. 1H NMR (400 MHz, CD3OD) δ: 7.89 (s, 1H), 7.84˜7.81 (m, 1H), 7.77-7.74 (m, 1H), 7.58 (d, J=10 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.35˜7.32 (m, 1H), 4.36 (s, 2H), 3.50˜3.46 (m, 2H), 3.22-3.20 (m, 2H), 2.77-2.75 (m, 1H), 2.58-2.56 (m, 2H), 2.15-2.11 (m, 2H), 1.91 (br, 1H), 1.75-1.66 (m, 3H), 1.56-1.25 (m, 6H), 1.00-0.88 (m, 2H), 0.81 (s, 9H). HPLC: 96.20%