Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([NH:28][C:24]3[CH:23]=[C:22]([CH2:21][CH2:20][C:19]([OH:29])=[O:18])[CH:27]=[CH:26][CH:25]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)o1
Reactant: CCOC(=O)CCc1cccc(N)c1
Solvent: CCOC(C)=O
Product: O=C(O)CCc1cccc(NC(=O)c2ccc(-c3ccc(F)cc3)o2)c1

Procedure:
Carboxylic acid (76) (53 mg, 0.26 mmol) was coupled to aniline (124) (50 mg, 0.26 mmol) using Method C. During this reaction, hydrolysis occurred. The acid was re-dissolved in EtOAc (2 ml) and the organic layer was washed with 1M HCl (2×1 ml), dried (Na2SO4), filtered and the solvent removed in vacuo. The solid was recrystallised from a hot 10% EtOH in H2O mixture to give the title compound.
Reaction SMILES: [N+](=[CH:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[N-].[CH2:38]([SH:40])[CH3:39]>>[CH2:38]([S:40][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12][CH:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:39]
Reactant: [N-]=[N+]=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: CCS
Product: CCSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of benzhydryl 3-diazomethyl-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate (9.0 × 10-4 mole), prepared by the process described in Example 2, and ethanethiol (5 ml.) is stirred at room temperature for 15 minutes. The excess ethanethiol is removed in vacuo and the residue chromatographed over silica gel with chloroform:acetone (10:1) to give benzhydryl 3-ethylthiomethyl-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH:16]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:6]=2[N:7]=1>C(O)(=O)C.[Fe]>[CH3:1][N:2]([CH2:15][CH:16]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC(CN(C)c2nc3cc([N+](=O)[O-])ccc3o2)C1
Agent: [Fe]
Solvent: CC(=O)O
Product: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
Dissolve rac-methyl-(1-methyl-pyrrolidin-3-ylmethyl)-(5-nitro-benzooxazol-2-yl)-amine (1.48 g, 5.09 mmol) in acetic acid (90 mL) and add Fe (1.42 g, 25.4 mmol) to the solution. Stir the mixture at 40° C. for 3 h. Filter the reaction mixture through Celite® and wash with H2O/MeOH. Concentrate the reaction mixture in vacuo. Subject the residue to silica gel flash column chromatography (120 g column, 10% 2N NH3 in MeOH/CH2Cl2) to yield the desired product (0.913 g, 69%). mass spectrum (m/e): 261.2 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17](OC)=[O:18])[CH:11]=[CH:10]2.[Li]>O1CCCC1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH2:17][OH:18])[CH:11]=[CH:10]2
Reactant: COC(=O)c1ccc2cc(Cc3ncc[nH]3)ccc2c1
Agent: [Li]
Solvent: C1CCOC1
Product: OCc1ccc2cc(Cc3ncc[nH]3)ccc2c1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
0.2 g (0.75 mmol) of methyl 6-(1-imidazolylmethyl)-2-naphthoate in 5 ml of absolute tetrahydrofuran are added dropwise to 28.5 mg (0.75 mmol) of lithium alanate in 1 ml of absolute tetrahydrofuran. The mixture is allowed to stand at room temperature overnight. Excess lithium alanate is destroyed by addition of 2N HCl. After neutralization with sodium bicarbonate, the mixture is extracted with ethyl acetate, and the ethyl acetate phase is dried and evaporated in vacuo. 0.13 g (73%) of 6-(1-imidazolylmethyl)-2-naphthylmethanol is obtained. Melting point 122°-125° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[C:4]([O:12][CH2:13][O:14][CH3:15])[C:3]=1[C:16](=[O:18])[CH3:17].C([O-])([O-])=O.[K+].[K+].[N+:25]([C:28]1[CH:33]=[CH:32][C:31](F)=[CH:30][CH:29]=1)([O-:27])=[O:26]>CS(C)=O.O.C(OCC)(=O)C>[CH3:15][O:14][CH2:13][O:12][C:4]1[CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=[C:2]([O:1][C:31]2[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)[C:3]=1[C:16](=[O:18])[CH3:17]
Reactant: COCOc1cc(O)c(C(C)=O)c(OCOC)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COCOc1cc(OCOC)c(C(C)=O)c(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
To a stirred suspension of 1-[2-hydroxy-4,6-bis(methoxymethoxy)phenyl]ethanone (78 g, 298 mmol) and K2CO3 (45.3 g, 328 mmol) in DMSO (500 mL) and water (40 ml) was added 4-nitro-1-fluorobenzene (46.3 g, 328 mmol, 1.1 eq). After stirring for 15 min. at room temperature, the resulting suspension was heated for 6 hours at 55° C. After cooling, the dark solution was diluted with ethyl acetate (2000 mL) and thoroughly washed with 10% citric acid solution, then with brine and dried over Na2SO4. The solvent was removed and the residue was columned over silica gel eluting with cyclohexane/ethyl acetate 3/1, to provide the title compound (56 g, 52% yield).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C[Al](C)C.[CH3:10][S:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:19]([O:21]CC)=O)=[N:16][CH:17]=1.C(=O)([O-])O.[Na+].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH3:2][O:3][N:4]([CH3:5])[C:19](=[O:21])[CH:18]([C:15]1[CH:14]=[CH:13][C:12]([S:11][CH3:10])=[CH:17][N:16]=1)[CH2:24][CH:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: CNOC
Reactant: CCOC(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Agent: C[Al](C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CON(C)C(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.5 %

Procedure:
A solution of N-methoxymethanamine hydrochloride (1.48 g) in toluene (15 mL) was cooled to 0° C., and trimethylaluminum (1.4M hexane solution, 10.9 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 hr, and a solution of ethyl 2-[5-(methylsulfanyl)pyridin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoate (1.57 g) in toluene (15 mL) was added dropwise. The reaction mixture was stirred at room temperature for 6 hr, saturated aqueous sodium hydrogen carbonate and saturated aqueous Rochelle salt solution were added and the mixture was stirred for 1 hr. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (404 mg, yield 25%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1)=[O:4].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][OH:20])[CH:15]=[N:16][C:17]=1Cl>>[CH3:1][NH:2][C:3]([CH:5]1[CH2:10][N:9]([C:17]2[C:12]([Cl:11])=[CH:13][C:14]([CH2:19][OH:20])=[CH:15][N:16]=2)[CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: CNC(=O)C1CNCCN1
Product: CNC(=O)C1CN(c2ncc(CO)cc2Cl)CCN1

Procedure:
piperazine-2-carboxylic acid methylamide from step (c) above (570 mg, 4.0 mmol) and (5,6-dichloro-pyridin-3-yl)-methanol (710 mg, 4.0 mmol, TCI-US) reacted under the conditions of Example 3a to give the title compound as a light-yellow gum. MS ESI, pos. ion) m/e: 285 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[N:10][N:11]([CH3:12])[C:7]=2[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].ClN1C(=O)CCC1=O>C(COC)OC.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>[CH3:12][N:11]1[C:7]2[CH:6]=[C:5]([CH:3]=[O:2])[CH:14]=[CH:13][C:8]=2[N:9]=[N:10]1
Reactant: COC(=O)c1ccc2nnn(C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cn1nnc2ccc(C=O)cc21

Procedure:
3-Methyl-3H-benzotriazole-5-carboxylic acid methyl ester was taken on separately to the corresponding aldehydes by reduction with lithium aluminum hydride (1 equivalent) in anhydrous dimethoxyethane. The resulting alcohols were oxidized using 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (1 equivalent), tetrabutylammonium chloride (1 equivalent), and N-chlorosuccinimide (1.3 equivalent) in methylene chloride and pH 8.6 sodium bicarbonate/potassium carbonate buffer to give 3-methyl-3H-benzotriazole-5-carbaldehyde.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][O:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:13][O:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: O=C(CC1CCC(c2ccc(Br)cc2)CO1)OCc1ccccc1
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: C1COCCO1
Product: Nc1ccc(-c2ccc(C3CCC(CC(=O)OCc4ccccc4)OC3)cc2)cc1
Temperature: 120 °C
Yield: 80.8 %

Procedure:
To a solution of benzyl 2-(5-(4-bromophenyl)tetrahydro-2H-pyran-2-yl)acetate (300 mg, 0.771 mmol) in dioxane (6 ml) at room temperature was added 4-aminophenylboronic acid (211 mg, 1.541 mmol), Pd(Ph3P)4 (178 mg, 0.154 mmol) and 2M Na2CO3 (1.541 ml, 3.08 mmol) and the mixture was degassed and heated at 120° C. in microwave for 30 min. The reaction was quenched by sat. aq. NH4Cl and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10 to 50% EtOAc (2% TEA)/Heptane) to give the title compound 250 mg (yield 81%). MS (ESI) m/z 402.3 (M+1). Retention time 1.48 min (condition A).
Reaction SMILES: N#N.C[Si](C)(C)[O:5][C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]=1.[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CC(=O)OCC>C(#N)C>[F:22][CH:11]1[C:6](=[O:5])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (5.30 g, 19.53 mmol) in dry acetonitrile (25 mL) was added Selectfluor® (8.01 g, 21.48 mmol) at rt. The reaction mixture was stirred at rt for 2 h then poured into EA and successively washed with aq. 1% NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (hexanes-EA, 4:1) to afford the title compound as a pale yellow solid. LC-MS-conditions 08: tR=0.55 min.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([CH:13]3[CH2:17][CH2:16][CH2:15][N:14]3C(OCC3C=CC=CC=3)=O)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[NH:14]1[CH2:15][CH2:16][CH2:17][CH:13]1[C:10]1[O:11][C:12]2[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=1
Reactant: NC(=O)c1cccc2nc(C3CCCN3C(=O)OCc3ccccc3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCCN3)oc12
Yield: 13.7 %

Procedure:
A mixture of benzyl 2-(7-carbamoylbenzo[d]oxazol-2-yl)pyrrolidine-1-carboxylate (68 mg, 0.19 mmol), 10% Pd/C (20 mg) in methanol (30 ml) was stirred at room temperature over 1 atm hydrogen for 2 hr. Then the mixture solution was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by pre-HPLC to give 6 mg of 2-(pyrrolidin-2-yl)benzo[d]oxazole-7-carboxamide. Yield 13%. LC-MS (ESI) m/z: 232 (M+1)+. 1H-NMR (400 MHz, CDCl3): δ 1.24 (brs, 1H), 1.97 (m, 2H), 2.21 (m, 1H), 2.35 (m, 1H), 3.12 (m, 1H), 3.22 (m, 1H), 4.58 (m, 1H), 5.99 (brs, 1H), 7.03 (brs, 1H), 7.43-7.47 (t, J=8 Hz, 1H), 7.85-7.87 (d, J=8 Hz 1H), 8.08-8.09 (d, J=7.6 Hz, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8](=[O:36])[C@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])=[CH:24][CH:23]=1)[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[Cl:19].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:36])[C@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])=[CH:24][CH:23]=1)[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([N:18]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:13]=1[Cl:19]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(N)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
MeSO2Cl (24 μL) was added to a solution of N-(4-amino-2-chlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (56.0 mg) in anhydrous CH2Cl2 (1 mL) containing DIEA (66.6 μL). The resulting mixture was stirred at room temperature under N2 for 3 h and diluted with CH2Cl2, washed with 1N HCl, water, dried (MgSO4) and evaporated. The residue was purified through a silica gel column using CH2Cl2 as an eluent to give N-[2-chloro-4-(N,N-dimethanesulfonylamino)benzoyl]-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (59.4 mg). ESMS: m/z 595 (MH+).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15](O)=O)[CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:30]=1[NH2:31].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>N1C=CC=CC=1>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[NH:31][C:30]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[N:24]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1
Reactant: Nc1ccncc1N
Reactant: O=C(O)C1CCN(C(=O)c2ccc(-c3ccccc3)cc2)CC1
Agent: O=P(Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCC(c2nc3cnccc3[nH]2)CC1
Temperature: 120 °C
Yield: 27.8 %

Procedure:
To a mixture of 1-(biphenyl-4-ylcarbonyl)piperidine-4-carboxylic acid (0.10 g, 0.32 mmol) and 3,4-diaminopyridine (35 mg, 0.32 mmol) in pyridine (1 mL) is added triphenyl phosphate (0.10 mL, 0.38 mmol). The mixture is heated under microwave irradiation at 120° C. for 50 mins. Purification by preparative HPLC gives 34 mg of biphenyl-4-yl[4-(1H-imidazo[4,5-c]pyridin-2-yl)piperidin-1-yl]methanone.
Reaction SMILES: Cl.O[NH3+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1.[CH2:13]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25]Br)=[CH:20][CH:19]=1)[CH2:14][CH2:15][CH2:16][CH3:17]>C(N)C.CO.O.Cl[Cu]>[CH2:13]([C:18]1[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)=[CH:22][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: C#Cc1ccc(F)cc1
Reactant: CCCCCc1ccc(C#CBr)cc1
Agent: Cl[Cu]
Agent: CCN
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCCc1ccc(C#CC#Cc2ccc(F)cc2)cc1

Procedure:
A solution of 0.2 g of CuCl and 0.5 g of hydroxylammonium hydrochloride in 16 ml of 50% aqueous ethylamine is added to a solution of 0.1 m of 4-fluorophenylacetylene in 100 ml of methanol. 0.1 m of p-n-pentylphenylbromoethyne dissolved in methanol is added dropwise under a nitrogen atmosphere and with stirring, the mixture is stirred for one hour, diluted with water and extracted with ether, and the extracts are washed until neutral. Customary work-up gives 1-p-n-pentylphenyl-4-p-fluorophenylbutadiyne.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](I)[CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[S:11]([CH3:14])(=[O:12])=[O:13])[CH2:3][CH2:2]1
Reactant: CC(C)CCI
Reactant: CS(=O)(=O)Nc1cnccc1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCN(c1cnccc1C1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.8 %

Procedure:
A suspension of Example 17F (814 mg, 3.83 mmol) and cesium carbonate (1.87 g, 5.75 mmol) in N,N-dimethylformamide was treated with isoamyl iodide (555 μL, 835 mg, 4.22 mmol) followed by stirring at room temperature for 48 hours. The mixture was diluted with ethyl acetate and extracted with water (3×) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded an amber oil, which was chromatographed over a 50 g silica gel cartridge, eluting with 15-70% ethyl acetate in dichloromethane. These procedures afforded the product (474 mg, 44%) as an off-white solid.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([SH:22])[C:14]=1[C:15]([OH:17])=[O:16].Cl>[OH-].[Na+]>[C:6]1([CH:2]([S:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:13]([OH:12])[C:14]=2[C:15]([OH:17])=[O:16])[C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1c(O)cccc1S
Reactant: O=C(O)C(Br)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c(O)cccc1SC(C(=O)O)c1ccccc1

Procedure:
α-Bromophenylacetic acid (0.26 g, 1.2 mmol) was added to a solution of 2-hydroxy-6-mercaptobenzoic acid (0.20 g, 1.2 mmol) in 1N aqueous sodium hydroxide (25 ml). The reaction mixture was stirred at reflux temperature for 1 hour under a nitrogen atmosphere. The cooled reaction mixture was acidified with 2N hydrochloric acid. The solid that precipitated out was collected by filtration, washed with water, and dried in vacuo over calcium sulfate; yield 0.20 g (38%). NMR (CDCl3, 60 MHz): δ4.86 (s, SCHCO2H) p.p.m.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:19][C:6]1=2.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2([C:44]#[N:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:33][CH:32]=1>O.C(#N)C.C(OCC)(=O)C>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:38]2([C:44]#[N:45])[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][CH:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[N:15][C:10]=4[CH2:9][O:8][C:7]4[CH:16]=[CH:17][C:18]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:19][C:6]3=4)[CH2:40][CH2:39]2)=[CH:35][CH:36]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: N#CC1(Nc2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(C#N)(Nc3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 50 °C
Reaction time: 8 h
Yield: 7.6 %

Procedure:
The title compound was prepared by dissolving 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (106.7 mg, 0.285 mmol) in water (4 ml) and acetonitrile (1 ml). To this was added potassium carbonate (82.7 mg, 0.599 mmol) and 4-(4-Chloro-phenylamino)-piperidine-4-carbonitrile (84.0 mg, 0.356 mmol). The reaction was heated to 50° C. and stirred overnight. The next day the reaction was allowed to cool to room temperature and diluted with ethyl acetate and water. The organic layer was washed twice with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC to give the title compound (11.5 mg, 8% yield, 88% pure by LC/MS).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH3:6][C:7]1[CH:12]=[C:11]([C:13](=O)[CH3:14])[CH:10]=[CH:9][N:8]=1>CO>[CH3:6][C:7]1[CH:12]=[C:11]([C:13](=[N:2][OH:3])[CH3:14])[CH:10]=[CH:9][N:8]=1
Reactant: CC(=O)c1ccnc(C)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=NO)c1ccnc(C)c1

Procedure:
To 4.03 g. (58.4 mmoles) of hydroxylamine hydrochloride in 27 ml. of a 2 N sodium hydroxide solution was added 3.95 g. (29.2 mmoles) of 2-methyl-4-acetylpyridine and the resulting mixture heated on a steam bath, methanol being added to keep the mixture homogeneous. The mixture was heated for an additional 5 minutes and was then cooled. The resulting precipitate was filtered, washed with water and dried 3.95 g. (90%), m.p. 151°-152° C.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=O)[N:12]=1)=[O:6])[CH3:3].[CH2:18]([O:20][C:21](=[O:29])[CH2:22][C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1)[CH3:19].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:17][C:2]([CH3:1])([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([NH:28][C:25]2[S:26][CH:27]=[C:23]([CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:29])[N:24]=2)=[O:16])[N:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1csc(NC(=O)Cc2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-[[1,1-Dimethylethoxy]carbonylamino]-4-thiazoleacetic acid (1.7 g) (Chem. Pharm. Bull. 1993, 41, 758), 2-amino-4-thiazoleacetic acid ethyl ester (1.35 g), 4-[dimethylamino]pyridine (0.8 g) and bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (3.3 g) in dry dichloromethane (50 ml) was treated with diisopropylethylamine (2.4 ml). The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with aqueous sodium bicarbonate and diluted with ethyl acetate. The organic solution was washed with brine and 2M HCl. The solution was dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.8 g.