Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.CN(C)[CH:16]=[O:17].[BH4-].[Na+]>O1CCCC1.C(O)(=O)C.CO>[Br:13][C:9]1[N:8]=[C:7]([CH2:16][OH:17])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
n-BuLi (2.5M, 20.0 mL, 50.0 mmol) in tetrahydrofuran (40 mL) was cooled to −78° C. 2,6-Dibromopyridine (11.85 g, 50.0 mmol) in 70 mL tetrahydrofuran was added dropwise while keeping the internal temperature of the reaction below −70° C. The resulting dark green solution stirred for 15 min at this temperature upon which N,N-dimethylformamide (6.0 mL, 78 mmol) was added over a period of 30 seconds. The reaction stirred at −78° C. for 15 min and methanol (50 mL) and acetic acid (3.2 mL) were added. Sodium borohydride (1.89 g, 50.0 mmol) was added last. The reaction was allowed to warm to room temperature. The solution was carefully quenched with sat. ammonium chloride and then extracted with ethyl acetate (2 times). The organic layers were combined and washed with brine, dried over sodium sulfate, filtered, and concentrated. Flash chromatography (25% ethyl acetate/hexanes) gave 2.57 g (27% yield) of the alcohol as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])([F:16])[F:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12]Br)[CH:6]=2.C[N+]1([O-])CC[O:29]CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:14]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])([F:16])[F:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]=[O:29])[CH:6]=2
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2cc(CBr)ccc2cc1Br
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)C(F)(F)c1cc2cc(C=O)ccc2cc1Br
Yield: 86.6 %

Procedure:
To a solution of diethyl [3-bromo-7-(bromomethyl)-2-naphthyl](difluoro)methylphosphonate (0.2 g from step 5, example 2) in 5 mL, of dioxane was added N-methylmorpholine N-oxide (0.17 g). The reaction mixture was refluxed for 1 h. The mixture was quenched with a saturated solution of NH4Cl and the mixture was extracted with EtOAc and the extract dried over Na2SO4 and evaporated. The residue was purified by flash chromatography eluting with 10-20% EtOAc/hexanes to afford diethyl (3-bromo-7-formyl-2-naphthyl)(difluoro)methylphosphonate (0.15 grams) which was hydrolyzed with TMSBr (2 mL) in CH2Cl2 (1 mL) at rt. overnight. The mixture was evaporated to dryness and the residue was dissolved in ethanol. It was evaporated to dryness again and the process was repeated 3 times. The reaction residue was dissolved in water and treated with NaOH 1N to afford the titled product as a sodium salt.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1c(F)ccc(F)c1F
Agent: N
Product: Fc1ccc(F)c(-c2nc(-c3cccnc3)no2)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,3,6-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.26-7.35 (m, J=9.4, 9.4, 3.8, 2.0 Hz, 1H), 7.62-7.77 (m, 2H), 8.57 (dt, J=8.0, 1.9 Hz, 1H), 8.76 (dd, J=4.8, 1.6 Hz, 1H), 9.30 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:27]=[CH:26][C:22](C(O)=O)=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:8]([CH3:28])[C:7]=2[CH:29]=1)#[N:2].CNC[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:63][N:64]([CH3:67])[CH:65]=[O:66]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:65]([N:64]([CH3:67])[CH2:63][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:66])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:8]([CH3:28])[C:7]=2[CH:29]=1)#[N:2]
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(C#N)cc12
Reactant: CN(C)C=O
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(C#N)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a mixture of 4-{[(5-cyano-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoic acid (250 mg) synthesized in Example A98(7), ethyl 3-(methylamino)propanoate (127 mg), 1-hydroxybenzotriazole monohydrate (148 mg), triethylamine (269 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (185 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (193 mg, 60%) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([OH:22])[C:19](Cl)=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>O.[Pd]>[O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN1CCc2cc(Cl)c(O)cc2C(c2cccc3ccoc23)C1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2ccc(O)cc2C(c2cccc3c2OCC3)C1
Temperature: 20 °C
Reaction time: 120 h

Procedure:
6.55 g, (0.020 mol) (+)-5-(benzofuran-7-yl)-8-chloro-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 1.0 N sodium hydroxide (100 ml, 0.100 mol) and water (100 ml). 10% palladium-on-carbon (3.0 g) was added, and the resulting suspension was stirred under hydrogen at 20° C. and 100 kPa for 5 days. The reaction mixture was filtered and the filtercake was thoroughly washed with 0.3 N hydrochloric acid (70 ml) and methanol (135 ml). The pH of the combined filtrate and washings was brought to 8.0 and the resulting suspension was filtered. The filtercake was washed with water/methanol (1/1) and dried in vacuo at 40° C. to give 3.45 g (76% of the theoretical yield) of the desired compound as white crystals.) M.p. 227°-30° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6](=O)[CH2:7][C:8]3([O:14]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1.Cl.[O:19]([NH2:21])[CH3:20].N1C=CC=CC=1>CO>[CH3:20][O:19][N:21]=[C:6]1[C:5]2[C:15](=[CH:16][C:2]([OH:1])=[CH:3][CH:4]=2)[O:14][C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7]1
Reactant: O=C1CC2(CCCCC2)Oc2cc(O)ccc21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CC2(CCCCC2)Oc2cc(O)ccc21

Procedure:
The product from Example 16A (479 mg, 2.06 mmol), methoxylamine hydrochloride (275 mg, 3.29 mmol), and pyridine (0.36 mL, 4.45 mmol) were stirred in methanol (5 mL) at room temperature overnight. After this time, the solvent was evaporated in vacuo, and the residue was taken up in ethyl acetate and washed with 1N HCl and brine. The organic solution was dried over Na2SO4 and was evaporated in vacuo. Chromatography on silica gel (4:1 hexane-ethyl acetate, eluant) afforded the title compound as a colorless oil, 524 mg (97%). 1H NMR (300 MHz, DMSO-d6) δ 9.79 (br, 1H), 7.54 (d, J=8.8 Hz, 1H), 6.35 (m, 1H), 6.22 (m, 1H), 3.84 (s, 3H), 2.68 (s, 2H), 1.25-1.79 (m, 10H). MS (DCI+) m/z 262 (M+H).
Reaction SMILES: [Mg].[C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3].S(Cl)(Cl)=O.C[Si]([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])(C)C.[Cl-].[NH4+]>C1COCC1>[F:27][C:26]([F:29])([F:28])[S:23]([O-:25])(=[O:24])=[O:22].[C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S+:23]([C:26]2[CH:11]=[CH:12][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:8][CH:9]=2)[C:10]2[CH:11]=[CH:12][C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][CH:9]=2)=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)Oc1ccc(Cl)cc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc([S+](c2ccc(OC(C)(C)C)cc2)c2ccc(OC(C)(C)C)cc2)cc1
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A Grignard reagent was conventionally prepared using 60.7 g (2.5 mol) of magnesium, 461 g (2.5 mol) of 4-tert-butoxyphenyl chloride, and 700 g of THF. The Grignard reagent solution was cooled in an ice water bath whereupon 59.5 g (0.5 mol) of thionyl chloride diluted with 100 g of THF was added dropwise at less 30° C. Reaction mixture was ripened for about 30 minutes. Thereafter, 277.8 g (1.25 mol) of trimethylsilyltrifluoromethane sulfonate was added dropwise at less 20° C. Reaction mixture was further ripened for 1 hour and thereafter, the reaction solution was allowed to stand overnight at room temperature. After the reaction solution was again cooled in an ice water bath, 1,800 g of 16.7% ammonium chloride aqueous solution (NH4Cl 300 g+H2O 1,500 g) was added thereto at a temperature not in excess of 30° C. After separation, 1,000 g of chloroform was added to the organic layer, which was washed three times using 1,000 g of water. Thereafter, the solvent was distilled off under reduced pressure by means of a rotary evaporator and the resulting oily residue was recrystallized, isolating tris(4-tert-butoxyphenyl)sulfonium trifluoromethanesulfonate of 99% purity in an amount of 141 g (yield 45%).
Reaction SMILES: [N:1]#[C:2][NH2:3].C(OC(=O)[N:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1)(C)(C)C.Br[CH2:28][C:29]([C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)=[O:30]>>[NH2:1][C:2]1[N:3]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][NH:10][CH:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=2)[S:22][C:28]=1[C:29]([C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)=[O:30]
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Reactant: N#CN
Reactant: CC(C)N(CCOc1ccc(N=C=S)cc1)C(=O)OC(C)(C)C
Product: CC(C)NCCOc1ccc(Nc2nc(N)c(C(=O)c3ccc4c(c3)OCCO4)s2)cc1

Procedure:
This compound was prepared from cyanamide, isopropyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-carbamic acid tert-butyl ester of Example 135 and 2-bromo-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)ethanone (Maybridge Chemical) following a procedure similar to Example 130. Mass spectrum (ES) MH+=455.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[NH:12]1[C:20]2[C:15](=[C:16]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH3:37][CH:36]([CH3:38])[C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:15]=3[CH:14]=[CH:13][N:12]4[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]([F:11])([F:10])[F:9])[CH2:23][CH2:24]2)[CH:29]=1)=[O:39]
Reactant: FC(F)(F)c1ccccc1I
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccccc3C(F)(F)F)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2-(trifluoromethyl)benzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 520.1 (M+H)+.
Reaction SMILES: C([C:3]1[CH:7]=[CH:6][O:5][N:4]=1)=O.[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:20]C3OC=NC=3)[CH2:18][C@@H:17]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]([S:33]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:35])=[O:34])[CH2:15][C:14]=2[CH:41]=1)#[N:9].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:20][C:6]3[O:5][N:4]=[CH:3][CH:7]=3)[CH2:18][C@@H:17]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]([S:33]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:35])[CH2:15][C:14]=2[CH:41]=1)#[N:9]
Reactant: O=Cc1ccon1
Reactant: CN(C)CCS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2cnco2)C[C@H]1Cc1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2ccno2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-formylisoxazole (19.4 mg, 0.2 mmol) and Compound B of Example 25 (39.9 mg, 0.1 mmol) in DCM (0.5 mL) at rt was added TFA (45 mg, 0.4 mmol), followed by triethylsilane (35 mg, 0.3 mmol). The resulting mixture was stirred at rt for 1 hour, neutrallized with NaHCO3 solution and extracted with DCM (2×5 mL). The combined extract was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (SiO2; ethyl acetate: methanol ammonia/100:10:0.1) to afford the title compound, 45 mg (87%). MS: m/e (M+H)+=480.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.Cl.[CH3:32][C@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:34]3[CH2:35][CH2:36][CH2:37][C@@H:33]3[CH3:32])[CH:8]=2)[N:3]=1
Reactant: C[C@H]1CCCN1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCCl
Product: C[C@H]1CCCN1Cc1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
100 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 3 ml of 1,2-dichloroethane and 3 ml of tetrahydrofuran. 43 mg of (S)-2-methylpyrrolidine hydrochloride are added, and the mixture is stirred at 40° C. for 6 h. After cooling to 25° C., 113 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.O.[CH3:30][N:31](C=O)C>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.[C-]#N.[C-]#N.[Zn+2]>[CH3:11][C:8]1[N:7]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:3]=[C:2]([C:30]#[N:31])[C:10]=2[N:9]=1
Reactant: CN(C)C=O
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
A mixture of 4-bromo-2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole (prepared following the same procedure as for Example 19, 300 mg, 0.69 mmol), Pd(PPh3)4 (80 mg, 0.069 mmol) and Zn(CN)2 (162 mg, 1.38 mmol) in DMF (30 mL) was stirred at 80° C. under N2 for 18 h. After cooling to rt, the mixture was poured into water and filtered. The filter cake was purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the product (180 mg, 68%), as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 2.44 (s, 3H), 3.07 (t, 4H, J=4.5 Hz), 3.68 (t, 4H, J=4.5 Hz), 6.04 (s, 2H), 6.32 (d, 1H, J=7.2 Hz), 7.31-7.40 (m, 3H), 7.60-7.71 (m, 2H), 7.86 (d, 1H, J=8.4 Hz), 8.01 (d, 1H, J=7.2 Hz), 8.22 (d, 1H, J=8.4 Hz); LC-MS: m/e=383 [M+1]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(#N)C>[CH2:16]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Nc1ccc(S)cc1
Reactant: CCCCCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCSc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
In 100 ml of acetonitrile was dissolved 5.90 g of 4-aminothiophenol. To the solution were added 6.57 ml of triethylamine and 8.44 g of n-heptylbromide, followed by stirring at room temperature for 18 hours. The precipitated crystals were collected by filtration, followed by removing the solvent. To the residue was added water and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution and dried over anhydrous potassium carbonate. After removing the solvent, the residue was purified by silica gel column chromatography using 50 g of silica gel and using chloroform as eluent to obtain 6.06 g of the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][C:7]([CH2:8][O:9][C:10](=[O:40])[CH:11]([N:13]2[CH:16]([S:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH:15]([CH2:37][CH3:38])[C:14]2=[O:39])Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:43]1([P:49]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1.C(Cl)Cl>[N+:1]([C:4]1[CH:42]=[CH:41][C:7]([CH2:8][O:9][C:10](=[O:40])[C:11]([N:13]2[CH:16]([S:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH:15]([CH2:37][CH3:38])[C:14]2=[O:39])=[P:49]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCC1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)C1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)C1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resulting crude 2-[3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazetidin- 1-yl]-2-chloroacetic acid p-nitrobenzyl ester is dissolved in a minimum amount of tetrahydrofuran, 9 g of triphenylphosphine are added and the mixture is stirred overnight at room temperature under nitrogen. The reaction mixture is diluted with 250 ml of methylene chloride, washed with saturated aqueous sodium bicarbonate solution, dried and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (1:1) and yields the title compound with the following physico-chemical properties:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.C(O[Na])(C)=O.[NH2:32][C@H:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:34][SH:35].Cl>C(O)C.O>[CH3:39][O:38][C:36]([CH:33]1[CH2:34][S:35][CH:12]([CH2:11][CH:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:22])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:32]1)=[O:37]
Reactant: CC(C)(C)OC(=O)NC(CC=O)C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CS
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1CSC(CC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)N1
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of 2 (0.7 g, 2.25 mmol), AcOH (0.14 g, 2.25 mmol), AcONa (0.38 g, 4.50 mmol) in ethanol and water (10:1, 11 mL) was added L-Cys-OMe.HCl (0.39 g, 2.25 mmol). After being stirred overnight, the mixture was poured into 100 mL water, extracted with ethyl acetate, and the organic phase was dried and concentrated to give an oily crude product (0.8 g, 82%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ1.43 (s, 9 H), 1.95-2.15 (m, 2 H), 2.29-2.41 (m, 1H), 2.87 (m, 1 H), 3.68 (m, 1 H), 3.77 (s, 3 H), 3.96 (m, 0.6 H), 4.50 (m, 1 H), 4.70 (m, 0.4 H), 5.12-5.23 (m, 2 H), 5.35 (d, 0.4 H), 5.75 (d, 0.6 H), 7.36 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(Br)c1
Product: Cc1ccc([N+](=O)[O-])c(-c2ccccc2)c1
Yield: 94.3 %

Procedure:
The product from Example 219a (0.20 g, 0.93 mmol) was reacted with phenylboronic acid (0.135 g, 1.11 mmol) for 19.5 h at 80° C. as described in Example 218a. The reaction mixture was cooled and filtered through celite, the filtrate concentrated under vacuum to give the crude product which was purified by flash chromatography on silica gel to give the title biphenyl (0.187 g, 94%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:22]1([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:7]=3)=[N:16][CH:17]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Clc1ccc(OC2CCCC2)cn1
Reactant: CC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)NCCc1ccc(Oc2ccc(OC3CCCC3)cn2)cc1

Procedure:
N-[2-(4-Hydroxyphenyl)ethyl]acetamide (668.3 mg, 3.73 mmol), 2-chloro-5-cyclopentyloxypyridine (737 mg, 3.73 mmol) and cesium carbonate (1.458 g, 4.475 mmol) were treated at 230° C. in 24 ml of DMF in a microwave reactor for 2 h. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and water. The organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 8 mg (1%), M+H+: 341.13.