Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.CO.C[O-].[Na+].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([C:31](Cl)=[O:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]>ClCCl>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:31]([C:29]1[O:30][C:26]([C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=3)=[CH:27][CH:28]=1)=[O:32])[CH2:5]2
Reactant: O=C(Cl)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: NC1CN2CCC1CC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1CN2CCC1CC2)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1

Procedure:
A mixture of (±)3-aminoquinuclidine dihydrochloride, methanol (250 ml), sodium methoxide (5.1 g, 95 mmol) was stirred at reflux for 1 hour. The mixture was evaporated and was mixed with methanol (150 ml) and dichloromethane (100 ml) was added and cooled on ice, and 5-(4-nitrophenyl)-2-furoyl chloride (11.2 g, 44.5 mmol), solved in dichloromethane (200 ml) was added drop-wise at 0° C. The mixture was stirred at room temperature for 21 hours. The mixture was evaporated, water (200 ml) was added and the pH was adjusted to 8.5 with triethylamine. The mixture was extracted with ethyl acetate (3×200 ml) and the pure product was isolated as free base. Yield 5.0 g (33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[N:56][C:55]([CH3:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)[C:13]([NH:51][C:52]2[CH:57]=[N:56][C:55]([CH3:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Reactant: Cc1cnc(N)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)[C@H](CC2CCC(=O)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.1 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 263 mg, 0.73 mmol) and triphenylphosphine (250 mg, 0.95 mmol) in methylene chloride (5.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (167 mg, 0.95 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-methylpyrazine (160 mg, 1.46 mmol) and 2,6-lutidine (0.36 mL, 2.92 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution 1×20 mL), a saturated aqueous sodium bicarbonate solution 1×20 mL) and water 1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 3/7 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-methyl-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (158 mg, 48%) as a white foam: [α]23589=−41.52° (c=0.33, chloroform); EI-HRMS m/e calcd for C20H21Cl2N3O4S (M+H)+ 450.1249. found 450.1253.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][C:22]1[C:27]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@@H](N5CCC[C@H]5C)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 17A for the product of Example 1E and substituting the product of Example 2A for pyrimidine-5-boronic acid. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (d, J=8.29 Hz, 1H) 7.76 (d, J=1.84 Hz, 1H) 7.45 (d, J=7.67 Hz, 1H) 7.38 (dd, J=8.44, 1.69 Hz, 1H) 7.06 (d, J=7.36 Hz, 1H) 3.57-3.70 (m, 1H) 3.14-3.29 (m, 1H) 2.99-3.13 (m, 1H) 2.73-2.85 (m, 1H) 2.59 (s, 3H) 2.49 (s, 3H) 2.28-2.67 (m, 5H) 1.91-2.01 (m, 1H) 1.77-1.88 (m, 1H) 1.59-1.73 (m, 1H) 1.43-1.53 (m, 1H) 1.15 (s, 3H). MS: (M+H)+=378.
Reaction SMILES: C1(C[O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH2:23])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)C=CC=CC=1.[H][H].[ClH:26]>CO.[Pd]>[ClH:26].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([NH2:23])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: NC(Cc1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(Cc1ccccc1)c1ccc(O)cc1

Procedure:
To a solution of 1-[4-(phenylmethoxy)phenyl]-2-phenylethylamine (4.5 g, 0.013 mol) in methanol (200 mL) and 1N hydrochloric acid (50 mL) was added 5% palladium on carbon (0.8 g). The mixture was shaken on a Parr apparatus under a pressure of 35-40 psi of hydrogen for 3 h. The catalyst was removed by filtration, and the filtrate concentrated under vacuum to give a white solid. This solid was recrystallized from 2-propanol (75 mL) and ether (50 mL) and vacuum dried at 80° C. for 48 h to give 2.31 g of 1-(4-hydroxyphenyl)-2-phenylethylamine hydrochloride; mp 203°-204° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:35]1([C:38](O)=[O:39])[CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:35]1([C:38]([NH:2][C@@H:3]2[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)[CH2:5][CH2:4]2)=[O:39])[CH2:37][CH2:36]1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C3CC3)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 98.3 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by cyclopropanecarboxylic acid (23 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-[cis-4-(Cyclopropanecarbonyl-amino)-cyclohexyl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (106 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C)(C)Br
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)(C)Oc1cc(C)cc(C)c1C
Reaction time: 36 h
Yield: 87.2 %

Procedure:
To a solution of 2,3,5-trimethylphenol (20.0 g, 147 mmol) in dimethylsulfoxide (100 ml) was added methyl 2-bromoisobutyrate (52.2 g, 288 mmol) and potassium carbonate (40.0 g, 289 mmol) at room temperature. The mixture was stirred for 36 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using basic silica gel column chromatography (hexane/ethyl acetate=50/1) to obtain 30.3 g (yield 87%) of oily title compound.
Reaction SMILES: N#N.C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[CH3:24][O:25][C:26]([CH:28]1[CH2:32][O:31][C:30]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]3([CH3:45])[O:44][CH2:43][CH2:42][O:41]3)[CH:35]=2)=[N:29]1)=[O:27]>C(Cl)Cl.[Cu](Br)Br>[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]3([CH3:45])[O:44][CH2:43][CH2:42][O:41]3)[CH:35]=2)[O:31][CH:32]=1)=[O:27]
Reactant: COC(=O)C1COC(Cc2cccc(C3(C)OCCO3)c2)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: N#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1coc(Cc2cccc(C3(C)OCCO3)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), hexamethylenetetramine (1.10 g, 7.79 mmol) and DBU (1.17 mL, 7.75 mmol) were added to a stirred suspension of copper (II) bromide (1.73 g, 7.75 mmol) in deoxygenated dry CH2Cl2 (15 mL). After 20 min, a deoxygenated solution of 2-[3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (951 mg, 3.12 mmol) in CH2Cl2 (15.0 mL) was added and the reaction mixture was stirred at rt for 45 min. The solvent was removed under reduced pressure and the residue was partitioned between EA (50 mL), and 50 mL of a 1:1 mixture of sat. aq. NH4Cl and 25% aq. NH4OH. The aq. layer was extracted with EA (50 mL) and the combined organic layers were washed with 50 mL of a 1:1 mixture of sat. aq. NH4Cl and 25% aq. NH4OH followed by 10% citric acid (50 mL), sat. aq. NaHCO3 (50 mL) and brine (50 mL). The organic phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1:1 hept-EA)=0.37. LC-MS-conditions 02: tR=0.93 min, [M+H]+=304.34.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:21][CH2:22][CH2:23][CH2:24]Br>CC(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[O:11][CH2:24][CH2:23][CH2:22][Cl:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(C)=O)ccc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(C(C)=O)ccc1OCCCCl
Temperature: 25 °C

Procedure:
A stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl]ethanone (7.7 g, 40 mmol). K2CO3 (5.7 g), 3-chloro-1-bromopropane (8.9 g, 56 mmol and acetone (100 ml) was refluxed for 16 hours. The reaction was allowed to cool to ambient temperature and filtered. Concentration of the filtrate yielded 8.5 g of a white solid. The solid was recrystallized from toluene and then from ethanol to afford 6.5 g or an off-white solid. A 3.3 g sample of this material was flash chromatographed on silica gel with ethyl acetate as eluent. Concentration of the appropriate fractions afforded 2.8 g of a solid. The solid was recrystallized from toluene and then from ethanol water to yield 2.2 g (51%) of a solid, m.p.=124°-126° C. ANALYSIS: Calculated for C13H18ClNO3: 57.89%C 5.98%H 5.19%N Found: 57.08%C 5.85%H 5.13%N
Reaction SMILES: Br.[NH:2]([C:4]1[NH:5][CH2:6][CH2:7][N:8]=1)[NH2:3].Br.[OH:10][C@H:11]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@:17]3([OH:35])[CH2:18][CH2:19][C@@H:20]2/[CH:21]=[C:22](\[CH3:25])/[CH:23]=O)[CH2:12]1>O.O1CCOCC1>[NH:8]1[CH2:7][CH2:6][N:5]=[C:4]1[NH:2]/[N:3]=[CH:23]/[C:22](/[CH3:25])=[CH:21]/[C@H:20]1[CH2:19][CH2:18][C@:17]2([OH:35])[C@H:16]3[C@H:29]([CH2:28][CH2:27][C@:26]12[CH3:34])[C@:30]1([CH3:33])[C@@H:13]([CH2:12][C@@H:11]([OH:10])[CH2:32][CH2:31]1)[CH2:14][CH2:15]3
Reactant: NNC1=NCCN1
Reactant: C/C(C=O)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CC(/C=N/NC1=NCCN1)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 72 h

Procedure:
A solution of 0.55 g of 2-hydrazino-2-imidazoline hydrobromide in 10 ml of water and 30 ml of dioxane was made acid to pH 3 with 0.1N HBr. A solution of 1.00 g of (E)-3β,14β-dihydroxy-21-methyl-5β-pregn-20-ene-21-carboxaldehyde (Prepn, 1) in 10 ml of dioxane was added at room temperature. After 3 days, the solution was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 90/10/1 as the eluant: the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with ethyl acetate and ethanol to give 0.85 g of the title compound (I-ab) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH3:15])=[O:5].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=2[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH3:15])=[O:5])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1nccn1CCCNC(=O)c1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Cc1nccn1CCCNC(=O)c1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Amino-N-[3-(2-methylimidazol-1-yl)propyl]benzamide (10.5 g) was dissolved in pyridine (50 ml) and 4-chlorobenzenesulphonyl chloride (12.35 g) was added in portions during five minutes. The temperature of the reaction mixture rose to 45° C. The solution was stirred at room temperature for 4 hours and the pyridine was evaporated in vacuo to give a brown oil. The oil was chromatographed on silica gel, eluting with a mixture of chloroform and methanol (19:1) to give 2-(4-chlorobenzenesulphonamido)-N-[3-(2-methylimidazol-1-yl)propyl]benzamide in the form of a white solid (7 g), m.p. 122°-123° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([O:8][C:9](=[O:31])[C@H:10]([C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)[CH2:11][C:12]#[C:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=O)[CH3:7])=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][NH2:48])=[CH:43][CH:42]=1>C1COCC1>[CH2:1]([O:3][C:4]([CH:6]([O:8][C:9](=[O:31])[C@H:10]([C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)[CH2:11][C:12]1[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:47]([C:44]2[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][CH:43]=2)[N:48]=1)[CH3:7])=[O:5])[CH3:2]
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)C(C)OC(=O)[C@@H](CC#CC(=O)c1ccc(Cl)c(Cl)c1)c1cccc(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)OC(=O)[C@@H](Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (S)-6-(3,4-dichloro-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid 1-ethoxycarbonyl-ethyl ester from Example 502 (15.5 g, 0.0336 mol) in THF (150 mL) was added Cs2CO3 (8.8 g, 0.027 mol) followed by 4-methoxyphenyl hydrazine HCl (6.5 g, 0.037 mol). The resulting slurry was stirred at rt overnight and then slowly quenched with 1 N HCl until pH 2-3. The mixture was transferred to a separatory funnel and extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to an oil. The crude oil was purified by pad filtration on silica gel using EtOAc/hexanes to obtain the pyrazole as mixture of two regioisomers in 4:1 ratio (18.6 g, 95%). Chiral HPLC (Method S): Rt (R,S)=5.6 min; (S,S)=6.3 min. 1H NMR (400 MHz, CDCl3): 7.31-7.07 (m, 8H), 6.91-6.86 (m, 3H), 6.23 (s, 1H), 5.13 (dd, J=10.4, 7.0 Hz, 1H), 4.16 (m, 1H), 4.07 (dd, J=14.4, 7.2 Hz, 2H), 3.82 (s, 3H), 3.51 (dd, J=14.9, 9.6 1H), 3.04 (dd, J=14.9, 6.3 Hz, 1H), 2.37 (s, 3H), 1.42 (d, J=7.0 Hz, 3H), 1.12 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:4]1)[CH3:2].C(OCC)C.[C:29]([OH:38])(=[O:37])[C@H:30]([C@@H:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31]>O1CCCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:4]1)[CH3:2].[C:34]([CH:32]([CH:30]([C:29]([O-:38])=[O:37])[OH:31])[OH:33])([O-:36])=[O:35]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: CCN1CCCC(NC2c3ccccc3Oc3ccccc32)C1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 1.1 g. of N-(N-ethyl-3-piperidinyl)-9-xanthenylamine in 8 ml. of tetrahydrofuran and 50 ml. of diethyl ether at -5° C. was added 538 mg. of levo tartaric acid in 32 ml. of tetrahydrofuran. The resulting precipitate was allowed to stand one hour, filtered off, washed twice with 100 ml. portions of ether and air-dried to give N-(N-ethyl-3-piperidinyl)-9-xanthenylamine, tartrate, hydrate m.p. 146°-148° C. (dec.)
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[C:19]([C:21](=[O:31])[NH:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:24])[CH:18]=[CH:17][C:16]=3[S:32][C:33]3[CH:38]=[CH:37][C:36]([NH:39]C(=O)OC(C)(C)C)=[CH:35][CH:34]=3)=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(Cl)Cl.FC(F)(F)C(O)=O>>[NH2:39][C:36]1[CH:35]=[CH:34][C:33]([S:32][C:16]2[CH:17]=[CH:18][C:19]([C:21]([NH:22][C@H:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH3:24])=[O:31])=[CH:20][C:15]=2[NH:14][C:8]2[C:7]3[C:12](=[CH:13][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[N:11]=[CH:10][N:9]=2)=[CH:38][CH:37]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(N)cc3)ncnc2c1
Yield: 72.5 %

Procedure:
The product of Example 91G (36 mg, 0.0568 mmol) was treated with 1:1 v/v methylene chloride/trifluoroacetic acid (3 mL) at room temperature for one hour then concentrated by rotary evaporation. The residue was dissolved in ethyl acetate (50 mL), washed with saturated aqueous sodium hydrogencarbonate (25 mL), water (25 mL), and brine (25 mL) then dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel flash chromatography eluting with 3:97 methanol/methylene chloride afforded the title compound as a white solid (22 mg, 0.0412 mmol, 73%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31 (d, J=6.99 Hz, 6 H) 1.45 (d, J=7.35 Hz, 3 H) 3.01-3.20 (m, 1 H) 5.07-5.26 (m, 1 H) 5.57 (s, 2 H) 6.61 (d, J=8.46 Hz, 2 H) 6.83 (d, J=8.46 Hz, 1 H) 7.11 (d, J=8.82 Hz, 2 H) 7.17-7.43 (m, 5 H) 7.54-7.64 (m, 2 H) 7.69 (dd, J=8.46, 1.10 Hz, 1 H) 7.89 (d, J=1.47 Hz, 1 H) 8.43 (t, J=4.23 Hz, 2 H) 8.74 (d, J=7.72 Hz, 1 H) 9.88 (s, 1 H); MS (ESI+) m/z 534 (M+H)+, 1067 (2M+H)+; MS (ESI−) m/z 532 (M−H)−.
Reaction SMILES: C[Sn](C)C.C[Sn](C)C.[F:9][C:10]1[CH:11]=[CH:12][C:13](Br)=[N:14][CH:15]=1.Br[C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])=[CH:20][CH:19]=1>ClCCl.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>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:18]2[O:22][C:21]([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])=[CH:20][CH:19]=2)=[N:14][CH:15]=1
Reactant: N#Cc1cccc(-c2ccc(Br)o2)c1
Reactant: Fc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: ClCCl
Product: N#Cc1cccc(-c2ccc(-c3ccc(F)cn3)o2)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
In a similar fashion, Pd(PPh3)4 (25 mg, 0.022 mmol) was added to a solution of hexamethylditin (163 mg, 0.50 mmol) and 5-fluoro-2-bromopyridine (87 mg, 0.49 mmol) in toulene (4 mL) under argon. The resulting solution was stirred at 80° C. for 15 h. After cooling to room temperature, a second portion of Pd(PPh3)4 (25 mg, 0.022 mmol) and 3-(5-bromofuran-2-yl)-benzonitrile (105 mg, 0.42 mmol) were added and the resulting solution was stirred at 110° C. for 48 h. After cooling to room temperature, the mixture was diluted with dichloromethane and passed through a 1 g silica gel SPE tube using dichloromethane to elute the product. Flash chromatography (silica gel, 50–100% dichloromethane in hexane) afforded 48.4 mg (43%) of 3-(5-(5-fluoro-2-pyridyl)-2-furyl)-benzonitrile (pure by GC/MS). 1H-NMR (CDCl3), δ (ppm): 8.48 (d, 1H), 8.03 (s, 1H), 7.95 (m, 1H), 7.81 (m, 1H), 7.51 (m, 3H), 7.11 (d, 1H), 6.87 (d, 1H).
Reaction SMILES: O[CH2:2][CH:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CO>[O:45]=[C:43]1[C:42]2[C:41](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:40](=[O:50])[N:44]1[CH2:2][CH:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC(CO)C(C)(C)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CN1C(=O)c2ccccc2C1=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of 1,1-dimethylethyl [1-(hydroxymethyl)-2-methyl-2-phenylpropyl]carbamate (775 mg, 2.8 mmol), triphenylphosphine (915 mg, 3.5 mmol) and phthalimide (499 mg, 3.4 mmol) in THF (15 mL) at 25° C. was added diethyl azodicarboxylate (0.54 mL, 3.4 mmol). After stirring at RT for 1 h, MeOH was added (5 mL) and the reaction solution was adsorbed onto silica then purified via column chromatography(1% MeOH in DCM) affording the title compound (723 mg, 64%) as a white solid: LCMS (ES) m/z 409 (M+H)+.