Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[F:15][C:16]1[C:21](/[CH:22]=[CH:23]/[N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[F:15][C:16]1[C:21]([CH:22]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=3)[NH:12][CH:11]=2)[CH2:23][N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COCCOc1ccc2cc[nH]c2c1
Reactant: O=C(Nc1cccc(/C=C/[N+](=O)[O-])c1F)OCc1ccccc1
Solvent: C1CCOC1
Product: COCCOc1ccc2c(C(C[N+](=O)[O-])c3cccc(NC(=O)OCc4ccccc4)c3F)c[nH]c2c1
Temperature: 125 °C
Yield: 69.2 %

Procedure:
6-(2-Methoxyethoxy)-1H-indole (1.198 g, 6.26 mmol) and (E)-benzyl 2-fluoro-3-(2-nitrovinyl)phenylcarbamate (1.651 g, 5.22 mmol) were dissolved in THF (50 mL) and concentrated in vacuo, and the mixture was heated at 125° C. overnight. The reaction was cooled to room temperature, and the crude product was purified by flash chromatography (solid loading) using an ISCO 220 g column eluting with 15-75% EtOAc/hexanes to give the desired product (1.888 g, 3.61 mmol, 69.2% yield) as a light orange foam.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][NH:8][C:9]=1[C:10]([O:12]C)=O)=[O:4].[NH2:14][NH2:15]>CO>[NH:6]1[C:5]2[C:3](=[O:4])[NH:14][NH:15][C:10](=[O:12])[C:9]=2[N:8]=[CH:7]1
Reactant: NN
Reactant: COC(=O)c1nc[nH]c1C(=O)OC
Solvent: CO
Product: O=c1[nH][nH]c(=O)c2[nH]cnc12
Temperature: 115 °C
Yield: 60 %

Procedure:
1H-Imidazole-4,5-dicarboxylic acid dimethyl ester (592 mg, 3.21 mmol) is combined with hydrazine (600 mg, 18.8 mmol) and MeOH (10 mL). The reaction mixture is heated to 115° C. for 30 min. Cool and filter off the resulting precipitate. Wash with additional water. Combine the precipitate with hydrazine (1.38 mL) and reflux for 4 h. Pour the reaction mixture into ice water and adjust the to pH 2 with HCl (12 N). The new precipitate is isolated by filtration to afford the title product (293 mg, 60%)
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[O:25]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36](O)=[O:37])[C:26]1=[O:27].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:25]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:37])[C:26]1=[O:27]
Reactant: O=C(O)c1cc2ccccc2oc1=O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)c1cc2ccccc2oc1=O
Yield: 43.5 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), coumarin-3-carboxylic acid (2.7 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (2.0 g, 43%) as an oily product.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:33](=[O:34])[N:14]2[C:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[O:22])=[C:16]([CH2:19]Cl)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[O:22])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)COc4ccccc4)C(=O)N23)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=C1CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 97 %

Procedure:
To a solution of 48 ml of SmI2 in THF (0.1M), a solution of 1.1 g of p-methoxybenzyl 7β-phenoxyacetylamino-3-chloromethyl-3-cephem-4carboxylate in 100 ml of dry THF, was added by dropping at -78° C. The resulting mixture was allowed to warm to room temperature in 0.5 hours. Water was added, and the mixture stirred for further 0.2 hours at room temperature. After the usual work-up and column chromatography, the title produce was isolated in 97% yield.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].Cl.CN(C)CCCN=C=NCC.Cl.[CH2:27]([O:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][O:35][CH2:36][CH3:37])[CH3:28].C(N(C(C)C)CC)(C)C>ClCCl>[C:7]([O:9][CH2:10][C:11](=[O:13])[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[CH2:31][CH2:30][O:29][CH2:27][CH3:28])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: CCOCCNCCOCC
Reactant: COC(=O)/C=C/C(=O)OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCCN(CCOCC)C(=O)COC(=O)/C=C/C(=O)OC
Yield: 14.7 %

Procedure:
Following general procedure B2,2-[(2E)-3-(methoxycarbonyl) prop-2-enoyloxy]acetic acid (23) (0.80 g, 6.14 mmol) was activated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (1.40 g, 7.37 mmol) in 20 mL of dichloromethane (DCM) at ca. 0° C. bis(2-Ethoxyethyl)amine hydrochloride (1.18 g, 7.37 mmol) (1.18 g, 7.37 mmol) and diisopropylethylamine (DIEA) (1.34 mL, 0.99 g, 7.67 mmol) were added to the activated carboxylic acid. After work-up and isolation, and purification by silica gel flash column chromatography (Biotage) using ethyl acetate (EtOAc) and hexanes (1:1) afforded 0.30 g (15% yield) of the title compound (27) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.97 (d, J=15.6 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H), 5.01 (s, 2H), 3.80 (s, 3H), 3.56-3.43 (m, 12H), 1.19 (q, J=7.6 Hz, 6H). MS (ESI): m/z 332.20 (M+H)+.
Reaction SMILES: [CH:1]1([C@H:4]([OH:30])[CH2:5][O:6][C:7]2[C:25]([F:26])=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][C:8]=2[CH2:9][N:10]([CH3:21])[C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].N1C=CN=C1>CN(C=O)C>[Si:31]([O:30][C@@H:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][O:6][C:7]1[C:25]([F:26])=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][C:8]=1[CH2:9][N:10]([CH3:21])[C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1OC[C@@H](O)C1CC1)C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1OC[C@@H](O[Si](C)(C)C(C)(C)C)C1CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 73 %

Procedure:
To a solution of 21E (99 mg, 0.237 mmol) in DMF (3 mL), was added tert-butyldimethylsilyl chloride (178 mg, 1.183 mmol) and imidazole (81 mg, 1.183 mmol). The reaction mixture was stirred at rt for 60 h., then was quenched with water, extracted with EtOAc (2×). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography to give 21F (92 mg, 0.173 mmol, 73.0% yield). MS (ESI) m/z: 533.4 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:19]1[C:26]2[CH2:25][CH2:24][CH2:23][N+:22]=2[CH2:21][CH2:20]1>CCOCC.CCCCC>[CH3:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:26]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2
Reactant: Cc1ccncc1I
Reactant: C1CC2=[N+](C1)CCC2
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1ccncc1C12CCCN1CCC2
Temperature: -95 °C
Reaction time: 2 h
Yield: 6.5 %

Procedure:
3-Iodo-4-methylpyridine (330 mg, 3.10 mmol) was dissolved in Et2O and cooled to -95° C. A solution of t-BuLi (1.7M in pentane, 4.0 ml, 6.80 mmol) in pentane was added dropwise. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (960 mg, 4.60 mmol) was added, and the reaction mixture was allowed to warm to -10° C. with stirring for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford the title compound as an oil (41 mg, 6%): 1H NMR (CDCl3, 300 MHz) δ1.54-1.69 (m, 2H), 1.77-1.89 (m, 2H), 1.93-2.11 (m, 4H), 2.41 (s, 3H), 2.69-2.77 (m, 2H), 3.08-3.15 (m, 2H), 7.02 (d, J=4.8 Hz, 1H), 8.32 (d, J=4.8 Hz, 1H), 9.06 (s, 1H); MS (CI/NH3) m/z: 203 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:27](OC3C=CC([N+]([O-])=O)=CC=3)=[O:28])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:39]1[CH2:44][CH2:43][CH:42]([C:45]#[N:46])[CH2:41][CH2:40]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:45]([CH:42]1[CH2:43][CH2:44][N:39]([C:27]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:28])[CH2:40][CH2:41]1)#[N:46]
Reactant: O=C(NC1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: N#CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1CCN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1

Procedure:
115 mg (0.22 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxylate were initially charged in 3 ml of DMF, and 72 mg (0.65 mmol) of piperidine-4-carbonitrile and 30 mg (0.22 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 30 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 53 mg (48% of theory)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[C:22]([F:35])[C:21]=1[NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])[C:5]3[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=3[N:7]=2)[CH:23]=[C:22]([F:35])[C:21]=1[NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38]
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Reactant: CCNC(=O)Nc1c(F)cc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: CCNC(=O)Nc1c(F)cc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C)C3)cc1F
Yield: 9.2 %

Procedure:
Method as example 47 using (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) and 1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-ethylurea as starting materials. The reaction mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The crude material was then purified by prep. HPLC at high pH yielding the title compound (18.5 mg, 0.04 mmol, 9.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([S:35]([OH:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)(=O)C.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([S:35]([O-:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(O)c1ccccc1
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])c1ccccc1

Procedure:
3.790 g of Donepezil is dissolved in 70 ml of ethyl acetate. A solution (35 ml) of benzenesulfonic acid (1.852 g) in absolute ethanol is added slowly and drop-wisely. The solid precipitated is filtered under suction to give the title compound.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[OH-].[K+].[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13](F)[C:12]=1F>CS(C)=O.O>[F:10][C:11]1[C:12]2[N:1]3[CH2:7][CH2:6][CH2:5][CH:2]3[CH2:3][O:4][C:13]=2[CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: OC[C@@H]1CCCN1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(F)c2c(c1)OCC1CCCN21
Temperature: 65 °C
Yield: 92.9 %

Procedure:
To a suspension of prolinol (2.74 g, 27.11 mmol) and KOH (3.17 g, 56.47 mmol) in DMSO (30 mL) was added 1,2,3-trifluoro-5-nitrobenzene (4.00 g, 22.59 mmol) at rt. The reaction mixture was heated at 65° C. for 4 h. The mixture was diluted with water (150 mL) and extracted with CH2Cl2 (100 mL×2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (5.00 g, 93%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[C:8]([Cl:12])=[CH:7][N:6]=1>CO>[Cl:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[C:8]([Cl:12])=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
Sodium methoxide (295 mg, 5.45 mmol) was taken up in methanol (13.6 ml) and 2,4,5-trichloropyrimidine (500 mg, 2.73 mmol) was added. The mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The resulting residue was diluted with diethyl ether, washed with 1:1 water:saturated aqueous ammonium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by Combiflash (0-10% diethyl ether/hexanes) afforded 280 mg (1.56 mmol, 57%) of 2,5-dichloro-4-methoxypyrimidine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Clc1ccn2c(I)cnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Yield: 97 %

Procedure:
To a round bottomed flask add 7-chloro-3-iodo-imidazo[1,2-a]pyridine (3.0 g, 0.011 mol), add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.6 g, 1.1 equiv.), potassium carbonate (4.5 g, 3 equiv.), dioxane (40 mL), and water (20 mL). Deoxygenate this mixture thoroughly with N2 then add dichlorobis(triphenylphosphine)palladium (II) (0.23 g, 0.03 equiv.) and reflux the reaction overnight under N2. Concentrate the reaction to dryness and slurry in DCM. Filter this slurry thru Celite® and wash with DCM. Concentrate the filtrate then purify by silica plug (EtOAc to 5% MeOH: DCM to 10% MeOH: DCM) to give a pale grey solid (2.6 g, 100%). MS (ES), m/z 244 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[CH2:33][CH2:32]1>CN(C)C=O.O>[CH3:44][O:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[N:34]1[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][CH2:28][N:16]2[CH2:17][CH2:18][CH:13]([O:12][C:11]3[C:19]([F:26])=[C:20]([F:25])[C:21]([F:24])=[C:22]([F:23])[C:10]=3[F:9])[CH2:14][CH2:15]2)[CH2:36][CH2:35]1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCN2CCC(Oc3c(F)c(F)c(F)c(F)c3F)CC2)CC1
Temperature: 75 °C
Reaction time: 7 h
Yield: 51.4 %

Procedure:
A mixture of 10 g of potassium carbonate, 0.18 g of potassium iodide, 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 50 ml of dimethylformamide was treated with a solution of 4.56 g of 1-(3-chloropropyl)-4-(2-methoxyphenyl)piperazine in 25 ml dimethylformamide and stirred for seven hours at 75° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 7.5% methanol/dichloromethane). Evaporation of the appropriate fractions afforded 3.84 g of 1-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-4-(2,3,4,5,6-pentaflurophenoxy)piperidine as an oil. The oil was dissolved in isopropanol and acidified to pH 1 with etheral hydrogen chloride to precipitate the corresponding dihydrochloride salt. Recrystallization from isopropanol afforded 3.34 g (44.6%) of 1-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-4-(2,3,4,5,6-pentaflurophenoxy)piperidine hydrochloride, m.p. 261°-263° C.
Reaction SMILES: [C:1]([C:3]1[C:4](C2CCC2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[F:18]C1C(I)=CC(C(OC)=O)=C(C)C=1.C1(C2C(I)=CC(C(OC)=O)=C(C)C=2)CCC1>>[C:1]([C:3]1[C:4]([F:18])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(I)c(F)cc1C
Reactant: COC(=O)c1cc(C#N)c(C2CCC2)cc1C
Agent: COC(=O)c1cc(I)c(C2CCC2)cc1C
Product: COC(=O)c1cc(C#N)c(F)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 6.4, except methyl 4-fluoro-5-iodo-2-methylbenzoate (compound 101.2) was used in place of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 6.3).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:30]1[C:31]([N:50]2[CH2:54][CH2:53][C@@H:52]([OH:55])[CH2:51]2)=[N:32][CH:33]=[C:34]([CH:49]=1)[C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=1)=[O:36]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[OH:55][C@@H:52]1[CH2:53][CH2:54][N:50]([C:31]2[C:30]([C:11]3[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=[CH:9][CH:10]=3)=[CH:49][C:34]([C:35]([NH:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:42][CH:43]=3)=[O:36])=[CH:33][N:32]=2)[CH2:51]1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccnn2C2CCCCO2)c1
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (59.9 g, 214.4 mmol), K3PO4 (105.7 g, 498.1 mmol) and Pd(PPh3)4 (9.6 g, 8.30 mmol) were added to a suspension of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.2, 74 g, 165.8 mmol) in toluene (740 mL) and stirred at 110° C. for 2.5 h under argon. The mixture was then diluted with EtOAc (2 L), washed with water (2×1 L) and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the crude residue was purified by flash chromatography (Silica gel, 2 kg, DCM/MeOH 95:5). The resulting material was dissolved in a mixture of MeOH (500 mL) and THF (800 mL) and was treated with Si-Thiol (Biotage, 15 g, 19.5 mmol) at RT for 17 h. The mixture was filtered and the solvent was evaporated off under reduced pressure to give a residue which was crystallized from MeOH to give the title compound as a white crystalline solid. HPLC (Condition 5) tR=5.99 min, UPLC-MS (Condition 6) m/z=518.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.42 (br. s, 3H) 1.63-1.98 (m, 4H) 2.20-2.37 (m, 1H) 2.71-2.94 (m, 1H) 3.21 (d, J=6.65 Hz, 3H) 3.32-3.51 (m, 1H) 3.69-3.92 (m, 1H) 4.08-4.24 (m, 1H) 4.75-4.88 (m, 1H) 4.89-5.17 (m, 1H) 6.29-6.49 (m, 1H) 7.32 (d, J=8.99 Hz, 2H) 7.59 (s, 1H) 7.78-8.10 (m, 3H) 8.80 (t, J=2.54 Hz, 1H) 10.05-10.28 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:3][CH:2]=1.[C:16]([NH:24][NH2:25])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(=O)C>[C:10]1([CH2:9][C:7](=[N:25][NH:24][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1ccccc1)c1ccncc1
Reactant: NNC(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(NN=C(Cc1ccccc1)c1ccncc1)c1ccccc1

Procedure:
Following the general method of procedure 9 and making non-critical variations, except 12 drops of glacial acetic acid was used, 6.00 gm (0.0304 mole) of benzyl 4-pyridyl ketone and 4.14 gm (0.0304 mole) of benzhydrazide yield 8.90 gm (93%) of the title compound in two crops melting at 84.4° and 90.0°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:4]([CH2:5][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: COc1ccc(C=O)cc1Br
Reactant: CCOc1ccc(Br)cc1
Product: CCOc1ccc(Cc2ccc(OC)c(Br)c2)cc1

Procedure:
Preparation was performed in a similar manner as in Preparation Example 3 using 3-bromo-4-methoxybenzaldehyde and 4-bromophenetole.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[C:32]([CH3:39])[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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:29][C:30]1[CH:35]=[CH:34][C:33]([C:8]2[C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=3)[N:9]=2)=[C:32]([CH3:39])[CH:31]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3C)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (150 mg, 0.41 mmol) in dioxane (5.0 mL) and water (3 drops) was added (4-fluoro-2-methylphenyl)boronic acid (101 mg, 0.66 mmol), Pd(PPh3)4 (19.0 mg, 0.02 mmol), and K3PO4 (138.3 mg, 0.65 mmol). The reaction was stirred for 1 hour at 90° C. under a nitrogen atmosphere. The resulting solution was concentrated in vacuo, and then purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to provide (S)-methyl 2-(4-fluoro-2-methylphenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (120 mg, 78%).