Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[CH2:9][CH2:10][OH:11].[H-].[Na+].[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[CH2:9][CH2:10][O:11][C:26]([N:23]1[CH2:24][CH2:25][N:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:21][CH2:22]1)=[O:27]
Reactant: CN1CCN(C)C(CCO)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C)C(CCOC(=O)N2CCN(c3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.3 %

Procedure:
2-(1,4-Dimethylpiperazin-2-yl)ethanol (703 mg, 4.44 mmol) was dissolved in anhydrous THF (20 mL) and the stirred solution cooled to 0° C. before NaH (60% dispersion in mineral oil; 550 mg, 13.8 mmol) was added. The suspension was left to stir for 10 minutes. 4-Nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 1.89 g, 5.77 mmol) was added to the reaction mixture, which was left to stir at room temperature for 3 hours. After this time the reaction was terminated by cooling the mixture to 0° C. and cautiously quenching with saturated aqueous NaHCO3 solution (50 mL). The THF was removed in vacuo and transferred to a separating funnel where the organic product was extracted with EtOAc (3×75 mL). The combined organic extracts were collected together and washed with saturated aqueous NaHCO3 solution (3×75 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give a crude yellow slurry. The crude residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 15% (over 70 min) to 100% (over 5 min) MeOH in water with 1% formic acid). De-salting (using K2CO3 in DCM), filtration and concentration in vacuo afforded 4-phenylpiperazine-1-carboxylic acid 2-(1,4-dimethylpiperazin-2-yl)ethyl ester (236 mg, 13%) as a dark yellow oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[O:16][CH3:17]>C(O)(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:1](=[O:3])[CH3:2])=[CH:11][C:10]=1[O:16][CH3:17]
Reactant: COc1cc(N)ccc1Br
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cc(NC(C)=O)ccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (13 mL) is added to an ice-cold solution of 4-bromo-3-methoxy-phenylamine (25.0 g) in acetic acid (100 mL). The mixture is stirred for 1 h and then diluted with ice-cold water (500 mL). The precipitate is separated by filtration, washed with water and dried at 60° C. to give the product.
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][CH:9]=2)([O-:4])=[O:3]>C1(C)C=CC=CC=1.C(O)CC>[N+:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH2:1])=[CH:12][CH:11]=[CH:10][CH:9]=2)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: N
Solvent: Cc1ccccc1
Solvent: CCCO
Product: Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 70 °C

Procedure:
Compound 7 was prepared as described elsewhere [Van Galen, P. J. M. et. al. (1991) ibid.]. In brief, ammonia gas was passed, while stirring, through a solution of 3-nitro-4-chloroquinoline 6 (7.0 g, 30 mmol) in toluene (95 ml) and propanol (15 ml) till the product was formed. During the course of the reaction, the temperature was gradually raised till 70° C. After cooling, the solid was separated by filtration and washed successfully with toluene/2-propanol (70:30), ether and cold water until Cl− could no longer be detected. The solid was filtered off and dried at 80° C. Yield: 6.1 g (95%). Mp.: 255-257° C. 1H NMR (DMSO-d6): δ 7.50-7.66 (m, 1H, Ar); 7.81-7.92 (m, 2H, Ar); 8.59 (d, 1H, J=8.0 Hz, Ar); 9.03 (broad s, 2H, NH2); 9.18 (s, 1H, Ar)
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:23][CH2:22][C@H:21](OS(C)(=O)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.[CH3:29][C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1>>[CH3:29][C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH:21]1[CH2:20][CH2:19][CH:18]([C:15]2[CH:14]=[CH:13][C:12]([N:3]3[CH2:4][CH2:5][C:6]4([CH2:7][CH2:8][O:9][CH2:10][CH2:11]4)[C:2]3=[O:1])=[CH:17][CH:16]=2)[CH2:23][CH2:22]1
Reactant: C[C@@H]1CCCN1
Reactant: CS(=O)(=O)O[C@H]1CC[C@@H](c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1
Product: C[C@@H]1CCCN1C1CCC(c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 9 by condensing cis-methanesulfonic acid 4-[4-(1-oxo-8-oxa-2-aza-spiro[4.5]dec-2-yl)-phenyl]-cyclohexyl ester (Intermediate 21) (30 mg, 0.07 mmol, 1 equiv.) and (R)-2-methylpyrrolidine.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:28]=[CH:27][C:7]([C:8]([N:10]2[CH:22]([C:23]([O:25]C)=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]=3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1.I[CH3:30].[H-]>CN(C=O)C.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH:22]([C:23]([OH:25])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH3:30])[C:12]=3[CH2:11]2)=[O:9])=[CH:27][CH:28]=1
Reactant: COC(=O)C1Cc2c([nH]c3ccccc23)CN1C(=O)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccccc31)CC(C(=O)O)N(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (0.96 g, 40.0 mmol) in dry DMF (150 ml) was added portionwise methyl 2-(4-chlorobenzoyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate (7.3 g, 20.0 mmol) at 0° C. to 5° C. After being stirred for 15 min, iodomethane (2.8 g, 20.0 mmol) was added and the reaction mixture was stirred for additional 1 h in an ice bath. The mixture was then stirred at room temperature for 9 h. The excess of hydride was decomposed with methanol and the reaction mixture was then evaporated to dryness in vacuo. The residue was recrystallized from MeOH to give 2-(4-chlorobenzoyl)-9-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]indole-3-carboxylic acid, 5.4 g (74%); mp 262-263° C. 1H NMR (Acetic acid-d4) δ 3.18 (1H, m, CH2), 3.56 (1H, m, CH2), 3.45 and 3.68 (3H, s, NMe), 4.64 and 5.40 (1H, d, J=15.8 Hz, NCH2), 4.70 and 4.93 (1H, d, J=17.1 Hz, NCH2), 5.02 and 6.12 (1H, d, J=5.4 Hz, CH), 7.04-7.07 (1H, m, ArH), 7.15-7.18 (1H, m, ArH), 7.31-7.33 (1H, m, ArH), 7.45-7.47 (1H, m, ArH), 7.50-7.55 (3H, m, 3×ArH), 7.59-7.61 (1H, m, ArH). Anal. Calcd for (C20H17ClN2O3): C, 65.13; H, 4.65; N, 7.60. Found: C, 64.77; H, 4.79; N, 7.68.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][OH:13].CCO>O>[C:1]1([C:7]#[C:8][CH:9]=[N:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC#Cc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: ON=CC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.2 %

Procedure:
A mixture of phenylpropargylaldehyde (859 mg, 6.6 mmol), hydroxylamine hydrochloride (4.59 g, 66 mmol), EtOH (48 mL) and water (12 mL) was stirred at r.t. for 24 h. The reaction mixture was diluted with H2O, extracted with Et2O-EtOAc, washed with brine and evaporated to dryness in vacuo affording 0.96 g of the title compound (syn:anti 1:1) as a pasty brownish solid.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:32]4[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=4[F:40])=[C:23]([O:25]C4CCCCO4)[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:32]4[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=4[F:40])=[C:23]([OH:25])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OC3CCCCO3)c2)ncn1)C1CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(O)c2)ncn1)C1CC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 86.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(6-((6-(2-fluoro-5-methoxyphenyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methoxy)pyrimidin-4-yl)propanoate (163 mg) in methanol (1.5 mL) was added pyridinium p-toluenesulfonate (7.5 mg), and the mixture was stirred at 50° C. for 20 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (119 mg) as a white amorphous solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[NH:8][CH:7]=[CH:6]2)[CH3:2]>[Ni]>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[NH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc2cc[nH]c2cc1[N+](=O)[O-]
Agent: [Ni]
Product: CCc1cc2cc[nH]c2cc1N
Reaction time: 2 h
Yield: 47.4 %

Procedure:
A suspension of 5-ethyl-6-nitro-1H-indole (1.9 g, 10 mmol) and Raney Nickel (1 g) was hydrogenated under H2 (1 atm) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by silica gel column to give 5-ethyl-1H-indol-6-amine (760 mg, 48% over two steps). 1H NMR (CDCl3) δ 7.90 (br s, 1H), 7.41 (s, 1H), 7.00 (s, 1H), 6.78 (s, 2H), 6.39 (s, 1H), 3.39 (br s, 2H), 2.63 (q, J=7.2 Hz, 2H), 1.29 (t, J=6.9 Hz, 3H); MS (ESI) m/e (M+H+) 161.1.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].C[O:12][C:13](=N)N.C[NH+]([CH2:19][C:20](CN(C)C)=[CH:21][NH+](C)C)C.C(OC(C)C)(=O)C.C(=O)(O)[O-].[K+]>O>[CH3:6][O:7][C:8]1[N:9]=[CH:21][C:20]([CH:13]=[O:12])=[CH:19][N:10]=1
Reactant: COC(=N)N
Reactant: CN(C)CC(=C[NH+](C)C)C[NH+](C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: COc1ncc(C=O)cn1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred slurry of O-methylisourea hemisulfate (1.08 g, 4.13 mmol), vinamidinium salt (3.00 g, 8.26 mmol), 1-methylethyl acetate (16.0 mL, 137 mmol) was added a solution of potassium bicarbonate (1.17 g, 11.6 mmol) in water (5.0 mL) over a 10 minutes period. After completion of the addition the resulting reaction mixture was stirred at room temperature for 40 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([F:31])[CH:22]=2)([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C:10]([O:12]C)=[O:11])=[N:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[C:23]([F:31])[CH:22]=2)([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C:10]([OH:12])=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)C[C@](NC(=O)C(C)(C)C)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N[C@@](CC(=O)O)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.7 %

Procedure:
(S)-methyl 3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-pivalamidopropanoate (1.04 g, 2.16 mmol, prepared as described in Procedure 11) was dissolved in THF (30 mL) at room temperature. A4M LiOH solution was added (20 mL) and the reaction mixture stirred at RT for 14 h. The RM was diluted with EtOAc (ca. 100 mL) and the pH adjusted to pH1-2 by addition of 1 M HCl. The organic portion was separated and the aqueous washed with EtOAc (ca.2×20 mL). The combined organic portions were dried over anhydrous Na2SO4, decanted and concentrated yielding (S)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-pivalamidopropanoic acid as a colorless oil (0.856 g, 85% yield) LCMS: 1.90 min [M+1] 467.2 (2 min gradient, MeOH/H2O 0.1% TFA).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:37][CH2:36][O:35][C:34]1=[O:38]>>[O:38]=[C:34]1[N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])[CH2:37][CH2:36][O:35]1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccccc1N1CCOC1=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccccc1N1CCOC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 3-(2-(aminomethyl)phenyl)oxazolidin-2-one, derived from reduction of intermediate 116, 2-(2-oxooxazolidin-3-yl)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.90 (1H, t, J=6.0 Hz), 7.58–7.32 (7H, m), 7.22 (2H, t, J=7.5 Hz), 5.08 (2H, s), 4.48 (2H, t, J=7.8 Hz), 4.44 (2H, d, J=6.0 Hz), 4.06–3.97 (4H, m), 3.88 (2H, m), 1.56 (6H, s); LCMS (M+H)+ m/z 505.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][S:10](Cl)(=[O:12])=[O:11].Cl>C1COCC1>[CH2:1]([NH:8][S:10]([CH3:9])(=[O:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCNS(C)(=O)=O
Reaction time: 0.75 h

Procedure:
A solution of 7.5 ml (50 mmol) of n-heptylamine in 50 ml of THF was cooled in an ice-water bath. Methanesulfonyl chloride (1.93 ml, 25 mmol) was added dropwise, with stirring to the amine solution over a 4 minute period. After stirring for an additional 45 minutes the mixture was poured into dilute HCl, and the product was extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting yellow solid was recrystallized from hexane. Yield: 4.03 gm. 'H-NMR (CDCl3) δ 4.48 (1H, br t); 3.13 (2H, q, J=6H2); 2.96 (3H, s); 1.57 (2H, m); 1.30 (8H, br m); 0.89 (3H, br t).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([O:8]CC)=O)[C:2]#[CH:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[S:20])=[C:14]([CH3:21])[CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:6](=[O:8])[CH2:5][N:4]([CH2:1][C:2]#[CH:3])[C:19]2=[S:20])=[C:14]([CH3:21])[CH:13]=1
Reactant: C#CCNCC(=O)OCC
Reactant: Cc1cc(Cl)ccc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN1CC(=O)N(c2ccc(Cl)cc2C)C1=S
Temperature: 25 °C
Yield: 26.6 %

Procedure:
A mixture of ethyl N-propargylaminoacetate (10.0 g), 4-chloro-2-methylphenylisothiocyanate (12.9 g), triethylamine (7.1 g), and methylene chloride (150 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, washed with 1 N HCl (100 mL), then with water. The organic layer was dried over anhydrous magnesium sulfate, then evaporated to dryness. The residual oil was triturated with hexane. The solid was collected by filtration. Recrystallization from Hexane-EtOAc afford the title compound (5.2 g) as yellow solid, m.p. 99°-102° C. Anal. Calcd. for. C13H11N2O Cl S: C, 56.01; H, 3.98; N, 10.05. Found: C, 55.61; H, 3.83; N, 10.0. Mass spectrum (EI, M.+) m/z 278.
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[O:8]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:27](=[O:28])[NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCN=C=O
Reactant: Oc1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Triethylamine (15 ml, 0.11 mol) was added dropwise under a nitrogen atmosphere to a solution of 4-phenoxyphenol (25.1 g, 0.14 mol) and butyl isocyanate (18 ml, 0.16 mol) in 400 ml of methylene chloride. After the addition, the solution was stirred overnight at room temperature. The solution was extracted with 1 N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 39.59 g of a tan solid. Recrystallization from diisopropyl ether gave the title compound as a white crystalline solid (21.01 g, 55%), mp 75°-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:23]=[CH:24]/[C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)[C:10]([F:13])([F:12])[F:11]>CCOC(C)=O.[Pd].[O-2].[Al+3].[O-2].[O-2].[Al+3]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)[C:10]([F:11])([F:12])[F:13]
Reactant: Cc1cc(C(O)(C(C)c2ccc(/C=C/c3ccc(C(=O)O)cc3)cc2Cl)C(F)(F)F)ccn1
Agent: [Pd]
Agent: [Al+3]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: Cc1cc(C(O)(C(C)c2ccc(CCc3ccc(C(=O)O)cc3)cc2Cl)C(F)(F)F)ccn1
Reaction time: 8 h
Yield: 16.6 %

Procedure:
A mixture of 4-((E)-2-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenyl}-vinyl)-benzoic acid (Example 66, 12 mg) and palladium/aluminum oxide (0.3 mg) in EtOAc (2.5 ml) was stirred overnight under a hydrogen atmosphere. The mixture was filtered and concentrated to give the title compound (2 mg) as light brown oil. MS (m/e)=478.1 [M+H+].
Reaction SMILES: CI.[CH3:3][C:4]1(C)[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.[C:15]([O-])([O-])=[O:16].[K+].[K+]>CC(C)=O>[CH3:15][O:16][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:3])[CH:13]=[CH:12]2
Reactant: O=C([O-])[O-]
Reactant: CC1(C)C=Cc2ccccc2N1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc2ccc(C)nc12

Procedure:
Methyl iodide (10.8 g, 76.3 mmol) was added to a stirred solution of 2-methylquinaldine (1.0 g, 6.3 mmol) and K2CO3 (5.0 g, 36.2 mmol) in 30 ml acetone at RT for 10 h. The reaction mixture was filtered and filtrate removed under a reduced pressure. The residue was purified by flash column chromatography with Hex/EA (3:1) and recrystallized with Hexane/EA to give 8-methoxy-2-methylquinoline as intermediates. LHMDS (2.2 to 2.5 equiv.) was treated with a stirred solution of intermediate (1 equiv.) in THF at 0° C. for 1 h. Corresponding Br(CH2)n−1OH (1.0 to 1.2 equiv.) was added to a reaction mixture and recover to RT for further 12 to 30 h. The solvent was removed under a reduced pressure. The brown oily residue was purified by flash column chromatography with Hex/EA or DCM/EA and recrystallized by Hex/EA to afford series of compounds C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:13][O:14][CH:15]([O:19][CH3:20])N(C)C>CO>[CH3:13][O:14][CH:15]([O:19][CH3:20])[N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:8][CH2:9]1
Reactant: COC(OC)N(C)C
Reactant: c1c[nH]c(CC2CCNCC2)n1
Solvent: CO
Product: COC(OC)N1CCC(Cc2ncc[nH]2)CC1

Procedure:
The free base of 4-(1H-imidazol-2-yl-methyl)piperidine (1.0 g, 0.006M) and dimethylformamide dimethylacetal (15 ml) in methanol (20 ml) were heated at 90° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed at the reduced pressure to give 4-(1H-imidazol-2-yl-methyl)piperidine carboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.16 g, 0.0054M) and diisopropyl ethylamine (0.96 ml) in dry chloroform (20 ml) was added the solution (10 ml CHCl3 and 2 ml MeOH) of the above piperidine carboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C. for 1 hr. and then at room temperature for 3 hrs. After this period, the solvent was removed in vacuo and the residue dissolved in water (20 ml). The aqueous solution, washed with ethylacetate was acidified to pH 3 with dilute aqueous HCl and purified on Sephadex LH 20 columns to give [2 S-(2alpha,5alpha,6beta)]-3,3-dimethyl-6-[[[4-(1H-imidazol-2-yl-methyl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.84 g, 33%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[Na:9].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[CH2:16]([O:15][C:13]([N:2]([CH3:1])[CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na:9]
Reactant: CNCCS(=O)(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: CN(CCS(=O)(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-methylaminoethane-1-sulfonic acid, sodium salt (16.1 g, 100 mmol), in aq. sodium hydroxide (1M, 100 mL, 100 mmol) at 0° C., benzyl chloroformate (16 mL, 112 mmol) was added over a period of 15 minutes. The resulting mixture was stirred at room temperature for 2 hours and extracted with hexane. The aqueous solution was freeze dried to provide 2-[[(benzyloxy)carbonyl](methyl)amino]-ethane-1-sulfonic acid, sodium salt.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]=O)[O:9][CH:10]=1)=[O:5])[CH3:2].[NH2:13]O>CO>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]#[N:13])[O:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)c1coc(C=O)n1
Solvent: CO
Product: CCOC(=O)c1coc(C#N)n1
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a solution of 2-formyl-oxazole-4-carboxylic acid ethyl ester (Panek et al. J. Org. Chem., 6496, (1996)) (171 mg, 1.11 mmol) in MeOH (3 mL) was added NH2OH (50% wt. H2O, 161 μL, 2.4 mmol). The reaction was allowed to stir for 2 h, and then concentrated in vacuo. The crude oxime was treated with acetic anhydride (4 mL) and heated with stirring at 150° C. for 24 h. The acetic anhydride was removed under vacuo, and the crude material was purified by preparative thin layer chromatography (60% ether-hexanes) to afford 56 mg (31%) of the title compound as an off-white solid. 1H-NMR (CDCl3; 400 MHz): δ 8.40 (s, 1H), 4.46 (q, 2H, J=7.1 Hz), 1.43 (t, 3H, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:35])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[N:23][C:22]=3[Cl:34])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>C1COCC1.[Cu](I)I>[Cl:34][C:22]1[N:23]=[CH:24][N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:35])=[O:20]
Reactant: C#C[Si](C)(C)C
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: I[Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (145 mg, 0.232 mmol), copper iodide (2.213 mg, 0.012 mmol) and TEA (162 μL, 1.162 mmol) in THF (8 ml) was added trimethylsilylacetylene (43 μL, 0.302 mmol) and the reaction mixture was degassed for 5 minutes with nitrogen. The resulting mixture was heated with stirring at 60° C. for 4 hours under nitrogen. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(trimethylsilyl)ethynyl]phenyl}oxy)-2-fluorophenyl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (121 mg, 0.189 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (t, 1H), 7.95 (s, 1H), 7.41-7.48 (m, 1H), 7.36 (t, 1H), 7.25 (s, 1H), 7.09 (t, 1H), 6.79 (s, 1H), 5.46 (s, 2H), 4.46 (d, 2H), 3.35 (t, 2H), 0.72 (t, 2H), 0.08-0.31 (m, 9H), −0.12 (s, 9H).