Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].C(N(CC)CC)C.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.Cl.C(N(CC)CC)C>CCOCC>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[CH:16][CH:17]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CNS(=O)(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)Nc1ccc(C(C)=O)cc1
Temperature: -50 °C

Procedure:
Methylsulfamoyl chloride (42.5 g., 0.33 mole) is added dropwise to a mixture of triethylamine (33.4 g., 0.33 mole) and p-aminoacetophenone (40.5 g., 0.30 mole )in ether (1.5 1.) at -50° C. The mixture is stirred at -50° C. and then allowed to warm to -10° C. The mixture is filtered to give a mixture of product and triethylamine hydrochloride. Washing with water and recrystallization from isopropanol furnishes 30.6 g. (40%) of the above pure intermediate, m.p. 159°-159.5° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11]C)[C:5]([OH:7])=O.[NH2:14][C:15]1[CH:20]=[C:19]([O:21]C)[CH:18]=[C:17]([Br:23])[C:16]=1O>>[Br:23][C:17]1[C:16]2[O:7][C:5]([C:4]3[CH:8]=[C:9]([F:13])[C:10]([OH:11])=[C:2]([F:1])[CH:3]=3)=[N:14][C:15]=2[CH:20]=[C:19]([OH:21])[CH:18]=1
Reactant: COc1cc(N)c(O)c(Br)c1
Reactant: COc1c(F)cc(C(=O)O)cc1F
Product: Oc1cc(Br)c2oc(-c3cc(F)c(O)c(F)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 21, from 3,5-difluoro-4-methoxybenzoic acid, and 2-amino-6-bromo-4-methoxyphenol, and was obtained as a white solid, m.p. 270–272° C.; MS m/e 340 (M−H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]CCCC.C(C1C=[C:17](C(C)(C)C)[CH:16]=[C:14]([OH:15])[C:13]=1[OH:23])(C)(C)C.[OH2:24]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:1][C:2]1([CH3:3])[O:23][CH2:13][CH:14]2[CH:16]([O:15]2)[CH2:17][O:24]1
Reactant: CCCCCCC
Reactant: CC(C)(C)c1cc(O)c(O)c(C(C)(C)C)c1
Reactant: O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CC1(C)OCC2OC2CO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Heptane (2 ml) was added to 3,5-di-t-butylcatechol (617 mg), and titanium tetraisopropoxide (Ti(OPri)4, 818 μl) was added under a nitrogen atmosphere. The mixture was stirred for 20 min at room temperature. (R)-1-phenethylamine (1.79 ml), water (20 μl) and 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (compound [1′], 2.0 g) obtained by a known method were successively added with stirring, and the mixture was stirred at room temperature for 20 hr. Heptane (4.6 ml) was added to the reaction mixture and the mixture was stirred under ice-cooling for 1 hr. The resulting crystals were collected by filtration to give (5R,6S)-2,2-dimethyl-6-[(R)-1-phenethylamino]-1,3-dioxepan-5-ol (compound [3′], 2.14 g, yield 57%).
Reaction SMILES: [Zn:1].[Br:2]CCBr.Cl[Si](C)(C)C.Br[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=1>C1COCC1>[Br-:2].[F:23][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=1)[CH2:12][Zn+:1]
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Reactant: [Zn]
Reactant: BrCCBr
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Fc1cc(C[Zn+])cc(C(F)(F)F)c1
Product: [Br-]
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
In a dried flask was zinc powder (1.526 g, 23.34 mmol) suspended in anhydrous THF (12.5 mL) under nitrogen. The resulting suspension was warmed to 60° C., then 1,2-dibromoethane (0.084 mL, 0.97 mmol) was added and stirred at that temperature for 15 min. It was cooled to room temperature, then chlorotrimethylsilane (0.099 mL, 0.78 mmol) was added and stirred at room temperature for 20 min. Then, 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (5 g, 19.45 mmol) dissolved in anhydrous THF (12.5 mL) was added over 7 min and stirring continued at room temperature for 1 h, then stirring was switched off to let the solids settle. The supernatant was used in the next transformation.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24](Br)=[O:25].[F:27][C:28]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:29]=1[CH2:30][NH2:31]>>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:23][C:24]([NH:31][CH2:30][C:29]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:28]=1[F:27])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cc(F)ccc1F
Reactant: COc1cc2c(cc1OC)C(Cc1ccccc1)NCC2
Reactant: O=C(Br)CBr
Product: COc1cc2c(cc1OC)C(Cc1ccccc1)N(CC(=O)NCc1cc(F)ccc1F)CC2

Procedure:
prepared by reaction of 1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2,5-difluorobenzylamine
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]2=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].P(Br)(Br)[Br:25]>C1COCC1>[Br:25][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)[CH2:19][CH2:20][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc2c(c1)CCC(c1ccc(S(C)(=O)=O)cc1)C2=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(c1ccc(S(C)(=O)=O)cc1)=C2Br
Temperature: 25 °C
Yield: 74 %

Procedure:
Add 2-(4-methanesulfonyl-phenyl)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (1.0 eq.); hyflo (20 wt %), and toluene (7.5 vols) to a three neck flask with a reflux condenser and nitrogen vent purge. While stirring at room temperature, add PBr3 (1.75 eq.) in one portion. Heat the reaction to reflux (˜110° C.) overnight allowing it to vent through a caustic scrubber. After refluxing for 15 hours, cool the yellow solution to 45° C. and slowly add THF (20 vols). Stir this mixture for 30 minutes at 45° and filter it, while warm, over a pad of Hyflo. Wash the pad with 45° C. THF (2×2 vols). Concentrate the filtrate at reduced pressure to remove all of the THF. Carefully add water (7.5 vols) to the remaining mixture keeping the temperature below 40° C. Cool the slurry to room temperature and stir it for 2 to 3 hours. Filter the slurry over a polypropylene pad and wash it with water (2×2 vols). Dry the resulting filter cake in a vacuum oven overnight at 50° C. to provide the title compound (74%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.Cl.[NH2:33][C:34](N)=[NH:35].O>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:1][C:34]([NH2:35])=[NH:33])=[N:11][C:10]2[C:5]([N:4]=1)=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N
Reactant: N=C(N)N
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(=N)N
Temperature: 70 °C
Reaction time: 24 h
Yield: 10.8 %

Procedure:
A mixture of 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (445a, 10 mg, 0.33 mmol), DIEA (0.29 mL, 1.68 mmol), and guanidine hydrochloride (0.025 mL, 0.37 mmol) in DMSO (3 mL) was stirred at 70° C. for 24 h. The reaction mixture was cooled, H2O was added, and extracted with DCM (3×). The extracts were dried over Na2SO4, concentrated and purified by reverse phase HPLC. The pure fractions were concentrated, dissolved in MeOH, and neutralized by Stratosphere SPE (PL-HCO3 MP-resin) to give the title compound (12 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (1H, br. s.), 9.95 (1H, br. s.), 8.53-8.39 (3H, br. s.), 7.84 (1H, br. s.), 7.73 (1H, br. s.), 7.02 (1H, br. s.), 6.77 (1H, s), 3.38-3.52 (2H, t, J=6.8 Hz), 2.87 (2H, t, J=6.8 Hz), 2.73 (3H, s). m/z (ESI, +ve) 336 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1([C:23]([OH:25])=O)[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:34])[C@H:29]([C@@H:31]([CH3:33])[OH:32])[NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C:8]1([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:23](=[O:25])[NH:30][C@@H:29]([C@H:31]([OH:32])[CH3:33])[C:28]([O:27][CH3:26])=[O:34])=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OCc1ccccc1)N1CCCC1(Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
To a suspension of compound 3 (1.0 g, 2.94 mmol), L-threonine methyl ester (471 mg, 3.53 mmol) in DMF (20 mL) was added HATU (1.12 g, 2.94 mmol) and DIPEA (1.58 mL, 8.84 mmol) at 5° C. The reaction mixture was stirred at RT for 16 h. It was diluted with EtOAc (150 mL) and washed with water (2×30 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography 50% EtOAc/Hexane as eluent to yield compound 4 (1.0 g, 74%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]2[CH:13]([CH2:24][Cl:25])[CH2:14][N:15]([C:18](=[O:23])[C:19](F)(F)F)[C:16]=2[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:36][O:37][C:38]1[CH:48]=[CH:47][C:41](/[CH:42]=C/C(Cl)=O)=[CH:40][CH:39]=1>CN1CCCC1=O.O.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]2[CH:13]([CH2:24][Cl:25])[CH2:14][N:15]([C:18](=[O:23])/[CH:19]=[CH:42]/[C:41]3[CH:47]=[CH:48][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)[C:16]=2[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc2c(c3ccccc13)C(CCl)CN2C(=O)C(F)(F)F
Reactant: COc1ccc(/C=C/C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc(NC(=O)OC(C)(C)C)c2ccccc32)cc1
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 48.5 %

Procedure:
A stirred solution of the above 5-(tert-butyloxycarbonylamino)-1-(chloromethyl)-3-trifluoroacetyl-1,2-dihydro-3H-benz[e]indole (100 mg, 0.23 mmol) in N-methylpyrrolidone (2.5 mL) was treated dropwise at 20° C. with a solution of Cs2CO3 (650 mg) in water (1.5 mL). the mixture was stirred for a further 45 min at 20° C. then diluted with water (20 mL) and extracted with benzene (2×15 mL). The combined organic extracts were washed with water (2×), dried (Na2SO4) and concentrated under reduced pressure below 30° C. The residue was dissolved in pyridine (2 mL), cooled to -5° C. and treated with (E)-4-methoxycinnamoyl chloride (46 mg, 0.23 mmol) followed by DMAP (15 mg). The mixture was stirred for a further 30 min at 20° C., then diluted with KHCO3 solution. The precipitated solid was collected, washed with water, dried and chromatographed on silica gel. Elution with CH2Cl2 /EtOAc gave the crude product which was recrystallised from CH2Cl2 /petroleum either to give 5-(tert-butyloxycarbonylamino)-1-(chloromethyl)-3-[(E)-4-methoxycinnamoyl]-1,2-dihydro-3H-benz[e]indole (55 mg, 48%), mp 185-185.5° C. 1H NMR [(CD3)2SO] δ 9.28 (br s, 1 H, NH), 8.64 (br s, 1 H, H-4), 8.01 (d, J=8.1 Hz, 1 H, H-6), 7.92 (d, J=8.3 Hz, 1 H, H-9), 7.78 (d, J=8.6 Hz, 2 H, H-2',6'), 7.66 (d, J=15.3 Hz, 1 H, PhCH=CH), 7.54 (t, J=7.6 Hz, 1 H, H-8), 7.42 (t, J=7.7 Hz, 1 H, H-7), 7.10 (d, J=15.2 Hz, 1 H, PhCH=CH), 7.01 (d, J=8.7 Hz, 2 H, H-3',5'), 4.60-4.44 (m, 2 H, H-2), 4.41-4.28 (m, 1 H, H-1), 4.02 (dd, J=11.1, 3.0 Hz, 1 H, CHHCl), 3.92 (dd, J=11.1, 7.2 Hz, 1 H, CHHCl), 3.82 (s, 3 H, OCH3), 1.51 (s, 9 H, C(CH3)3).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH:25][C@@H:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:28]([CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:27]1.O>CN(C=O)C>[CH3:44][O:43][C:41](=[O:42])[CH2:40][CH2:39][C@@H:28]1[CH2:27][C@H:26]([O:25][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)=[C:9]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:31][CH2:30][N:29]1[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: COC(=O)CC[C@@H]1C[C@H](O)CCN1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC[C@@H]1C[C@H](Oc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)CCN1C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Dissolve 631.7 mg (1.87 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 490 mg (1.71 mmol) of tert-butyl(2R,4R)-4-hydroxy-2-(3-methoxy-3-oxopropyl)piperidine-1-carboxylate in 1 ml of DMF, cool to −10° C. and add 1.02 ml (2.05 mmol) of phosphazene base P2-t-Bu (approx. 2 M solution in THF). Stir the reaction mixture at 0° C. for 1 h and then add to water. Extract three times with dichloromethane, combine the organic phases, wash with satd. sodium chloride solution and dry over magnesium sulphate. After concentrating under reduced pressure, purify the product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1→3:1). 420 mg (38.1% of theory) of the target compound are obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[H][H].[O:10]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24]Br)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O>[O:10]([C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][CH2:24][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:26][CH:27]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1c[nH]cn1
Reactant: [H][H]
Reactant: BrCCCOc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccc(OCCCn3ccnc3)cc2)cc1
Temperature: 80 °C
Yield: 82.2 %

Procedure:
1.98 g of 80% strength sodium hydride is added in portions to a solution of 4.25 g of imidazole in 70 ml of dimethylformamide. Upon completion of hydrogen evolution the mixture is stirred for a further 3 hours at 60° C., after which a solution of 18.42 g of 3-[4-(phenoxy)-phenoxy]-1-bromopropane in 40 ml of dimethylformamide is added. The mixture is heated for 8 hours at 80° C. and then poured into 2.5 liters of ice water. The solid which separates out is filtered off in a desiccator, dried over calcium chloride and purified by filtration over silica gel. There is obtained 14.5 g (82%) of N-[(p-phenoxyphenoxy)-n-propyl]-imidazole; m.p.: 54.5°-55.5° C.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].Cl.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:3](=[O:4])[C:5]3[NH:6][C:7]4[CH:8]=[C:9]([Cl:20])[CH:10]=[CH:11][C:12]=4[C:13](=[O:19])[C:14]=3[C:15]([OH:17])=[N:30]2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(Br)cc3)nc(O)c12
Temperature: 25 °C
Yield: 62.8 %

Procedure:
To a stirred suspension of dimethyl-7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (1.90 g, 6.40 mM) and 4-bromophenylhydrazine hydrochloride (10.0 g, 44.7 mM) in ethanol (35 mL) was added triethylamine (7.1 mL, 51.1 mM). The resulting brown solution was refluxed for 22 hours during which time a tan precipitate formed. This mixture was cooled to room temperature and filtered to give the 4-bromophenylhydrazine salt of the title compound as a white powder (1.69 g). This material was refluxed in glacial acetic acid (20 mL) for 3 hours and cooled to room temperature. The resulting tan suspension was filtered and the solids washed with glacial acetic acid and then ether to give the title compound (1.15 g, 43%) as a tan powder, mp 393-394° C.; MS(CI): 420 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.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>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Br)nc1
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: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
2,5-Dibromopyridine (0.948 g, 4 mmol), phenylboronic acid (0.488 g, 4 mmol) and tetrakis(triphenylphosphine)palladium (0.116 g, 0.1 mmol) were dissolved in anhydrous tetrahydrofuran (6 mL) and a solution of sodium carbonate (0.848 g, 8 mmol) in water (6 mL) was added. The mixture was put under nitrogen and stirred at 75° C. for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in water (10 mL) and extracted with dichloromethane (3×5 mL). The combined organic extracts were dried with anhydrous sodium sulphate. Column chromatography of the residue (silica gel Fluka 60, hexanes/dichloromethane 1:1) afforded 3-bromo-6-phenylpyridine as a white crystalline product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[N:18]=[C:19]([CH2:34][CH3:35])[C:20]([NH:25][C@H:26]2[C@@H:30]([O:31][CH2:32][CH3:33])[CH2:29][NH:28][CH2:27]2)=[N:21][C:22]=1[CH2:23][CH3:24]>>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[N:18]=[C:19]([CH2:34][CH3:35])[C:20]([NH:25][C@H:26]2[C@@H:30]([O:31][CH2:32][CH3:33])[CH2:29][N:28]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:27]2)=[N:21][C:22]=1[CH2:23][CH3:24]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Reactant: Brc1cccnc1
Product: CCO[C@H]1CN(c2cccnc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrzin-2-amine but substituting 3-bromopyridine and starting with 5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.17, 1.26–1.33, 2.51, 2.73, 3.39, 3.57, 3.76, 3.78, 3.86, 3.93, 4.31, 4.91, 5.26, 6.89, 7.04, 7.25, 8.00; IR (diffuse reflectance) 2970, 2430 (w), 2054 (w), 1914 (w), 1603, 1584, 1566 (s), 1481 (s), 1434, 1396, 1372, 1287, 1228, 1122, 1044 cm−1 HRMS (ESI) calcd for C26H32N5O2Cl+H1 482.2322. found 482.2311.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([O:23][Si](C(C)(C)C)(C)C)[C:9]2[N:13]([CH3:14])[C:12]([S:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[N:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].FC1C=C(C(O[Si](C(C)(C)C)(C)C)C2N(C)C(Cl)=NC=2)C=CC=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[N:13]([CH3:14])[C:12]([S:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[N:11][CH:10]=2)[OH:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(Sc2ncc(C(O[Si](C)(C)C(C)(C)C)c3cccc(F)c3)n2C)CC1
Agent: Cn1c(C(O[Si](C)(C)C(C)(C)C)c2cccc(F)c2)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Sc2ncc(C(O)c3cccc(F)c3)n2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{5-[(3-Fluoro-phenyl)-(tert-butyl-dimethyl-silanyloxy)-methyl]-1-methyl-1H-imidazol-2-ylsulfanyl}-1-methyl-piperidine. To a 0° C. solution of 1-methyl-piperidine-thiol (1.5 equivalents) in THF (0.2 M) is added NaH (60% dispersion in oil, 1.5 equivalents). After 30 min, 5-[(3-fluoro-phenyl)-(tert-butyl-dimethyl-silanyloxy)-methyl]-2-chloro-1-methyl-1H-imidazole (1 equivalent) in THF (1 M) is added dropwise. The mixture is heated at reflux until HPLC analysis shows consumption of the starting material. The reaction mixture is cooled to rt, quenched with satd. aq. NH4Cl, and extracted with EtOAc (2×). The combined organic extracts are washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude material is purified by HPLC or flash column chromatography to provide the desired product. Step C. (3-Fluoro-phenyl)-[3-methyl-2-(1-methyl-piperidin-4-ylsulfanyl)-3H-imidazol-4-yl]-methanol. A solution of 4-{5-[(3-fluoro-phenyl)-(tert-butyl-dimethyl-silanyloxy)-methyl]-1-methyl-1H-imidazol-2-ylsulfanyl}-1-methyl-piperidine (1 equiv.) in THF (0.2 M) is treated with tetrabutylammonium fluoride (1.2 equiv.). When the reaction is complete, the solution is diluted with satd. aq. NaHCO3 and extracted with EtOAc. The organic layer is dried over anhydrous Na2SO4. The crude material is purified by chromatography or recrystallization. This material can then be oxidized to form the corresponding sulfoxide (A3 is S(O)), or sulfone (A3 is S(O2)) as described in Example XVI, Scheme XI.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](Cl)=[O:14])[CH3:11]>>[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](=[O:14])[O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:11]
Reactant: CCN(CC)C(=O)Cl
Reactant: Oc1ccc(F)c(Cl)c1
Product: CCN(CC)C(=O)Oc1ccc(F)c(Cl)c1

Procedure:
3-Chloro-4-fluorophenol was acylated with diethylcarbamoyl chloride to produce 3-chloro-4-fluorophenyl diethylcarbamate, which was converted to 3-chloro-4-fluoro-2-iodophenyl diethylcarbamate via ortho-metalation followed by treatment with iodine. Basic hydrolysis provided 3-chloro-4-fluoro-2-iodophenol, which was coupled to (2-hydroxyphenyl)boronic acid under Suzuki conditions to give 6-chloro-5-fluorobiphenyl-2,2′-diol. Copper-mediated cyclization provided 4-fluorodibenzo[b,d]furan-1-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][C:11]([Br:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:22]([O:26][C:27]([N:29]1[CH2:33][C@H:32]([CH3:34])OS1(=O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[N:15]([C@H:32]([CH3:34])[CH2:33][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[C:9]2=[N:10][C:11]([Br:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(Br)nc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2ccc(Br)nc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to Example 1, intermediate a) from 6-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, potassium tert-butoxide and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.