Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[CH:8]=[C:9]2[C:12]#[N:13])=[CH:4][CH:3]=1.Cl.[NH+]1C=CC=CC=1>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:8]=[C:9]2[C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(C#N)c3cc(O)ccc3c2)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1cc(-c2ccc(O)cc2)cc2ccc(O)cc12

Procedure:
The title compound was prepared by reacting 7-hydroxy-3-(4-methoxyphenyl)-1-naphthonitrile (0.14 g, 0.51 mmol) with pyridinium HCl (3 g) according to method B to yield 0.10 g (75%) of a white solid: mp 254-257° C.; 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.53 Hz), 7.25 (1H, dd, J=2.15 Hz, J=8.88 Hz), 7.36 (1H, d, J=1.86 Hz), 7.67 (2H, d, J=8.55 Hz), 8.00 (1H, d, J=8.94 Hz), 8.31-8.38 (2H, m), 9.70 (1H, bs), 10.44 (1H, bs); MS (ESI) m/z260 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:23][O:24][C:25](=[O:35])[CH2:26]P(OCC)(OCC)=O.[CH3:36][Si]([N-][Si](C)(C)C)(C)C.[Li+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>>[CH2:23]([O:24][C:25](=[O:35])[CH:26]=[C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)[CH3:36]
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2)c1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: [Li+]
Product: CCOC(=O)C=C(c1cc(OC)cc(OC)c1)c1ccc(OC)c(OC)c1
Yield: 42.9 %

Procedure:
(3,4-Dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (1.50 g, 4.95 mmol), (diethoxyphosphoryl)acetic acid methyl ester (2.29 g, 9.90 mmol), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 9.90 ml, 9.90 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude yellowish oil was purified via preparative HPLC to give 3-(3,4-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylic acid ethyl ester as a light yellow oil (0.79 g, 43%): 1HNMR (CDCl3) δ 6.89-6.72 (m, 2H, Ar), 6.48-6.45 (m, 4H, Ar), 6.28 (s, 1H, double bond proton), 4.09 (q, J=7 Hz, 2H, CH2CH3), 3.92 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.75 (s, 6H, 2OCH3), 1.16 (t, J=7 Hz, 3H, CH2CH3). The product was carried over to the next step.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][NH:12][C:13](=[O:24])[C@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].[CH:25]1[CH2:29][CH:28]=[CH:27][CH:26]=1>ClCCl.ClCCl.CS(C)=O.C(N(CC)CC)C>[C:19]([O:18][C:17](=[O:23])[NH:16][C@H:14]([CH3:15])[C:13]([N:12]1[O:11][CH:27]2[CH2:28][CH:29]1[CH:25]=[CH:26]2)=[O:24])([CH3:20])([CH3:22])[CH3:21]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NO
Reactant: C1=CCC=C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1OC2C=CC1C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
At about −78° C. and under an atmosphere of nitrogen, oxalyl dichloride (30.43 g, 239.74 mmol, 4.00 equiv.) was added dropwise, over a period of 20 minutes, to stirred solution of dimethylsulfoxide (28.1 g, 359.66 mmol, 6.00 equiv.) in dichloromethane (200 mL). To this mixture was added dropwise, over a period of about 10 minutes, a solution of (R)-tert-butyl 1-(hydroxyamino)-1-oxopropan-2-ylcarbamate (12.24 g, 59.94 mmol, 1.00 equiv.) and cyclopenta-1,3-diene (4.15 g, 62.78 mmol, 1.05 equiv.) in a mixture of dichloromethane/dimethylsulfoxide (5:1) (60 mL). The resulting mixture was stirred for at about −78° C. for about 30 minutes, and then triethylamine (66.8 mL) was added. The resulting mixture was washed with 1M hydrochloric acid (2×200 mL), and extracted with dichloromethane (3×100 mL). After the organic layers were combined, the organic phase was washed with 10% sodium bicarbonate (2×200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:10)) to give the desired product as a white solid (8.6 g; yield=53%). 1H NMR (300 MHz, CDCl3) δ: 6.54 (s, 1H), 6.39 (m, 1H), 5.22-5.34 (m, 3H), 4.51 (m, 1H), 2.02 (d, J=8.4 Hz, 1H), 1.86 (d, J=8.7 Hz, 1H), 1.43 (s, 9H), 1.09 (m, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([CH:10]=1)[C:8]#[N:9].[OH:16][C:17]1[CH:25]=[CH:24][C:23]2[N:22]3[CH2:26][CH2:27][CH:28]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:21]3=[CH:20][C:19]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CS>CN(C=O)C.C(O)(C(F)(F)F)=O.O>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[CH:5][C:6]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:2][O:16][C:17]1[CH:25]=[CH:24][C:23]2[N:22]3[CH2:26][CH2:27][CH:28]([CH2:29][C:30]([OH:32])=[O:31])[C:21]3=[CH:20][C:19]=2[CH:18]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: N#Cc1cc(CCl)ccc1C1CCCC1
Agent: N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)ccc1C1CCCC1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
5-(Chloromethyl)-2-cyclopentylbenzonitrile (38.2 mg, 0.174 mmol), tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (50 mg, 0.174 mmol), and K2CO3 (36.1 mg, 0.261 mmol) were dissolved in DMF and heated to 60° C. for 16 h. The reaction mixture was filtered through Celite® and purified by HPLC. The intermediate was isolated and dissolved in TFA (0.2M) and added D/L-cysteine. After 15 min, the mixture was poured into water and extracted with DCM. The organic extract was concentrated to give the title compound. LCMS m/z=415.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.55-1.67 (m, 2H), 1.70-1.78 (m, 2H), 1.80-1.88 (m, 2H), 2.11-2.20 (m, 2H), 2.26-2.36 (m, 1H), 2.66 (dd, J=16.5, 8.6 Hz, 1H), 2.86-2.97 (m, 2H), 3.42 (quintet, J=8.6 Hz, 1H), 3.75 (quintet, J=7.3 Hz, 1H), 3.97-4.05 (m, 1H), 4.10-4.17 (m, 1H), 5.06 (s, 2H), 6.12 (s, 1H), 6.85 (dd, J=8.0, 2.0 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.69 (s, 1H).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][CH:5]([CH3:42])[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:34](=[O:35])[CH2:33][O:32][C:31]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:30]2)=[CH:24][CH:23]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[CH2:11]1)=[O:8].Cl>C1COCC1.O>[CH3:4][CH:5]([CH3:42])[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:34](=[O:35])[CH2:33][O:32][C:31]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[N:30]2)=[CH:24][CH:23]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:11]1)=[O:8]
Reactant: COC(=O)CCC1CCCC(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(C(=O)NC1CCCC(CCC(=O)O)C1)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
94 mg (2.25 mmol) of lithium hydroxide monohydrate were added to a solution of 600 mg (1.12 mmol) of methyl 3-{3-[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoyl)amino]cyclohexyl}propanoate (Example 142A) in 15 ml of THF and 15 ml of water, and the mixture was stirred at room temperature overnight. The reaction mixture was then adjusted to pH 2 with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. This gave 573 mg (1.10 mmol, 98% of theory) of the title compound as a mixture of isomers.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([C:36]([NH:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:37])[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][CH:22]=2)=[O:19])[CH:15]=[CH:16][CH:17]=1.C(O)(C(F)(F)F)=O.[OH-].[Li+]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH:27]([C:36]([NH:38][CH2:39][C:40]([OH:42])=[O:41])=[O:37])[CH2:28][C:29]([OH:31])=[O:30])=[CH:25][CH:26]=2)=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CNC(=O)C(CC(=O)OC(C)(C)C)c1ccc(NC(=O)c2cccc(NC=NN)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NN=CNc1cccc(C(=O)Nc2ccc(C(CC(=O)O)C(=O)NCC(=O)O)cc2)c1
Temperature: 25 °C
Yield: 104 %

Procedure:
The compound of Example 72 (500 mg) was added to methylene chloride (5 mL) followed by the addition of TFA (2 mL). The reaction was monitored by HPLC. After the reaction was complete the product was freeze dried. The product was added to water/aceonitrile 1:1 (50 mL), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction was stirred at 25° C., and monitored by HPLC. After complete hydrolysis the product was extracted with ethyl acetate and dried over Na2SO4 to give a yellow oil (450 mg). NMR and MS were consistent with the proposed structure.
Reaction SMILES: CO[N:3](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:4]1[NH:5][C:6](=[O:30])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:15]([O:16]C4CCCCO4)[C@@:14]3([C:28]#[CH:29])[F:27])[C:11]=2[N:12]=1>CC(O)=O.C1COCC1.O>[C:28]([C@@:14]1([F:27])[C@H:15]([OH:16])[C@@H:23]([CH2:25][OH:26])[O:24][C@H:13]1[N:10]1[CH:9]=[N:8][C:7]2[C:6](=[O:30])[NH:5][C:4]([NH2:3])=[N:12][C:11]1=2)#[CH:29]
Reactant: C#C[C@@]1(F)[C@H](OC2CCCCO2)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
20 was synthesized from 19 (0.09 mmol), as described for 9k. The crude material was then stirred at room temperature in AcOH/THF/H2O (4/2/1) solution overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (DCM/MeOH) to yield the title compound. White lyophilized powder. Molecular Formula C26H37FN5O9PS2 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.16 (s, 20H), 3.06-3.09 (m, 4H), 3.90-3.91 (d, J=5.40 Hz, 1H), 3.99-4.10 (q, J=6.70 Hz and J=7.00 Hz, 4H), 4.32-4.38 (m, 2H), 4.63 (m, 1H), 6.10-6.14 (d, J=16.93 Hz, 1H), 6.69 (s, 2H), 7.79 (s, 1H), 10.96 (s, 1H) 31P NMR (DMSO-d6, 162 MHz) δ (ppm) −1.91 (s, 1P) 19F NMR (DMSO-d6, 376 MHz) δ (ppm) −156.82 (s, 1F) Scan ES+ 678 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(O)(=O)C>C(O)(C)C>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[CH:8]=[C:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1

Procedure:
Following a procedure similar to that of Example 1C but using 64.9 g. of 2-(2-oxocyclohexyl)acetophenone and 37 g. of 4-methoxyaniline in 180 ml. glacial acetic acid there was obtained 80.9 g. of 1-(4-methoxyphenol)-2-phenol-4,5,6,7-tetrahydroindole; m.p. 132°-133°C. (isopropyl alcohol).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:23]([C:24]2[N:28]([CH3:29])[N:27]=[C:26]([C:30]([CH3:32])=[O:31])[CH:25]=2)=[C:22]([Cl:33])[CH:21]=[CH:20][C:9]=1[C:10]([O:12]C1N(CC)N=CC=1)=O.O>O1CCOCC1>[Cl:7][C:8]1[C:23]([C:24]2[N:28]([CH3:29])[N:27]=[C:26]([C:30]([CH3:32])=[O:31])[CH:25]=2)=[C:22]([Cl:33])[CH:21]=[CH:20][C:9]=1[C:10]([C:25]1[CH:26]=[N:27][N:28]([CH2:24][CH3:23])[C:1]=1[OH:4])=[O:12]
Reactant: CCn1nccc1OC(=O)c1ccc(Cl)c(-c2cc(C(C)=O)nn2C)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1ncc(C(=O)c2ccc(Cl)c(-c3cc(C(C)=O)nn3C)c2Cl)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 135.1 %

Procedure:
0.076 g (0.6 mmol) of potassium carbonate was added to 0.16 g (0.4 mmol) of (1-ethylpyrazol-5-yl) 2,4-dichloro-3-(1-methyl-3-methylcarbonyl-1H-pyrazol-5-yl)benzoate in 3 ml of dioxane and the mixture was heated under reflux for 3 hours and then stirred at room temperature for 12 hours. 50 ml of water were added, the solution was washed with methylene chloride and methyl t-butyl ether, nitrogen was passed through and the pH was adjusted to 1 using 10% strength hydrochloric acid. The precipitate that had formed was filtered off with suction, washed with water and taken up in ethyl acetate. After drying, this organic phase was concentrated. 0.11 g (69% of theory) of 4-[2,4-dichloro-3-(1-methyl-3-methylcarbonyl-1H-pyrazol-5-yl)benzoyl]-1-ethyl-5-hydroxy-1H-pyrazole was obtained.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]=O.O>C1CCCCC1>[CH:1]1([N:7]2[CH2:8][CH2:9][CH2:10][NH:11][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCNC1CCCCC1
Reactant: C=O
Solvent: C1CCCCC1
Solvent: O
Product: C1CCC(N2CCCNC2)CC1
Yield: 73.8 %

Procedure:
312 g of N-cyclohexyl-1,3-propanediamine are slowly added dropwise at 60° C. to a suspension of 66 g of paraformaldehyde in 200 ml of cyclohexane. The water of reaction is then removed by boiling under reflux on a water separator. Insoluble constituents are removed by filtration and the filtrate is subjected to fractional distillation. 248 g of N-cyclohexyl-hexahydropyrimidine boiling at from 87° to 91° C. at 0.3 mbar are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]([C:11](O)=[O:12])[CH:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1.C(Cl)Cl.S(Cl)(Cl)=O.[N:30]1[CH:35]=CC=CC=1.CN(C)[CH:38]=[O:39]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]([C:11]([N:30]([O:39][CH3:38])[CH3:35])=[O:12])[CH:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1
Reactant: CN(C)C=O
Reactant: c1ccncc1
Reactant: COc1ccc(C2Sc3cc(OC)ccc3C2C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2Sc3cc(OC)ccc3C2C(=O)N(C)OC)cc1
Temperature: 5 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
To a mixture of 2,3-dihydro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxylic acid (349.4 mg, 1.105 mmol) and methylene chloride (4 ml) is added thionyl chloride (195.7 mg, 1.645 mmol) and a catalytic amount of N, N-dimethylformamide. The contents are heated to reflux for 1 hour, then cooled and concentrated to a residue. This is then subjected to three cycles of dissolution in toluene and reconcentration, and the resulting residue taken up in methylene chloride (4 ml). To this solution is added N, O-dimethylhydroxylamine hydrochloride (118.9 mg, 1.22 mmol) and the resulting suspension cooled to 5° C. Pyridine (215 mg, 2.71 mmol) is then added via syringe. The reaction is allowed to warm to room temperature and is stirred for 16 hours. The contents are then partitioned between methylene chloride and water, and the layers separated. The organic layer is washed sequentially with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and water, then dried over magnesium sulfate, filtered and concentrated to an oil. The oil is then chromatographed on silica gel (6:4 hexanes:ethylacetate) to afford 262.5 mg (66.1%) of title compound. IR (KBr) 2960, 2905, 1660, 1511, 1479, 1246, 1178, 1059 cm-1 ; 1H NMR (CDCl3): δ7.46 (d, 2 H, J=8.1 Hz), 6.85 (m, 3 H), 6.74 (s, 1 H), 6.57 (d, 1 H, J=8.1 Hz), 5.54 (d, 1 H, J=10.5 Hz), 4.82 (d, 1 H, J=10.5), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.42 (s, 3 H), 3.23 (s, 3 H); 13C NMR (CDCl3): d 172.0, 160.2, 159.5, 143.1, 131.1, 130.2, 129.2, 124.9, 114.1, 110.9, 107.6, 61.7, 57.8, 57.3, 55.5, 55.3, 32.6. Anal. Calcd. for C19H21NO4S: C, 63.49; H, 5.89, N, 3.90; S, 8.92. Found: C, 63.48; H, 5.90; N, 3.81; S, 8.64.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:10])[CH2:4][C:5]1[O:6][CH:7]=[CH:8][CH:9]=1.[CH2:11]=O.C#C.O1[CH2:20][CH2:19]OCC1>>[CH3:1][N:2]([C:11]#[C:19][CH3:20])[CH:3]([CH3:10])[CH2:4][C:5]1[O:6][CH:7]=[CH:8][CH:9]=1
Reactant: C1COCCO1
Reactant: CNC(C)Cc1ccco1
Reactant: C=O
Agent: C#C
Product: CC#CN(C)C(C)Cc1ccco1
Reaction time: 30 h

Procedure:
13.9 g. (0.1 mole) of N-methyl-N-[1-methyl-2-(2-furyl)-ethyl] amine are dissolved in 80 ml. of dioxane, whereupon 6 g. of paraformaldehyde and 1 g. of cuprous chloride are added and gaseous acetylene is introduced into the solution at 80° C. under stirring for 30 hours. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in benzene, the benzene solution is washed with water, dried over potassium carbonate and evaporated. The residue is distilled off in vacuo. Thus 6.8 g. of N-methyl-N-[1-methyl-2-(2-furyl)-ethyl]-propynyl amine are obtained. Bp.: 114°-116° C./20 Hgmm; nD20 =1.4910.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6](C(OCC)=O)[CH:7]2[C:12]([OH:14])=[O:13].[CH3:20]CO.[OH-].[Na+].S(Cl)(Cl)=O>O1CCOCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[C:12]([O:14][CH3:20])=[O:13]
Reactant: CCO
Reactant: CCOC(=O)N1CCc2c(Br)cccc2C1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1NCCc2c(Br)cccc21
Reaction time: 18 h
Yield: 80 %

Procedure:
5-Bromo-2-(ethoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1 g, 3.05 mmol) (Ortwine, et al., J. Med. Chem, 1992, 35, 1345), in two batches, was heated in a microwave to 150° C. in 1,4-dioxane (4 mL)/EtOH (2 mL)/2N NaOH (5 mL) for a total of 3 h. The combined reaction mixtures were concentrated, dissolved in MeOH (30 mL) and thionyl chloride (0.222 mL, 3.05 mmol) was slowly added. After 18 h, the solvent was removed and the residue was partitioned with EtOAc (50 mL)/saturated NaHCO3(30 mL), the phases separated and aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine (25 mL) and dried (MgSO4) to afford 0.56 g (80%) of Intermediate 4A as a yellow oil. MS (ESI) m/z: 270-272 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:13])[NH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1>Cl.O1CCOCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)[C:8]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:13]
Reactant: CC(C)NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccc(N2CCNCC2)c(F)c1
Reaction time: 0.5 h

Procedure:
tert-butyl 4-(2-fluoro-4-(isopropylcarbamoyl)phenyl)piperazine-1-carboxylate 303 (1.10 g, 3.01 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen and dried in vacuum to afford the title compound as a white solid. ESI-MS: m/z 302 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[C:13]([O:16][C:17](=O)C)(=O)[CH3:14].C(OCC)(OCC)OCC>>[CH2:1]([O:3][C:4](=[O:12])/[C:5](=[CH:17]/[O:16][CH2:13][CH3:14])/[C:6](=[O:11])[C:7]([F:10])([F:8])[F:9])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: CCO/C=C(/C(=O)OCC)C(=O)C(F)(F)F
Yield: 96.4 %

Procedure:
4,4,4-Trifluoro-3-oxo-butyric acid ethyl ester (16 g, 86.4 mmol) was dissolved in acetic anhydride (33.6 g, 329.6 mmol) and triethyl orthoformate (38.4 g, 260 mmol) was added to the mixture. The resultant mixture was refluxed for 18 hours. The mixture was concentrated under reduced pressure to obtain 20 g of 2-[1-Ethoxy-meth-(E)-ylidene]-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester as crude. This was taken in EtOH (50 mL) and added to a suspension of cyclopropyl hydrazine hydrochloride (9.95 g, 91.7 mmol) and DIPEA (28.3 ml, 166.7 mmol) in EtOH (150 mL) at −20° C. The resultant mixture was slowly warmed to room temperature and stirred for 16 hours. The mixture was concentrated under reduced pressure and residue formed was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with 2N HCl (25 mL), water (25 mL), brine (25 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc:Hexane 5:95) to afford the title compound as off white sticky solid in 7% yield, 1.4 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:16]CO.[O:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O>[CH:12]([C:11]1[CH:14]=[CH:15][C:8]([C:5]2[N:6]=[CH:7][C:2]([C:23]3[O:22][C:21]([CH:20]=[O:19])=[CH:16][CH:24]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)=[O:13]
Reactant: O=Cc1ccc(-c2ccc(Br)cn2)cc1
Reactant: C1COCCO1
Reactant: CCO
Solvent: O
Product: O=Cc1ccc(-c2ccc(-c3ccc(C=O)o3)cn2)cc1
Temperature: 100 °C
Yield: 79 %

Procedure:
To a stirred solution of 6 (10 mmol) in 40 mL dry 1,4-dioxane was added palladium tetrakis-triphenylphosphine (400 mg), then 5-(diethoxymethyl-furan-2-yl)-trimethylstannane (10 mmol) was added and the reaction mixture was refluxed at 100° C. for 24 h. The solvent was then evaporated to dryness to give a dark brown residue that was suspended in water and extracted with CH2Cl2. The organic layer was passed over hyflo, dried (Na2SO4) and evaporated to dryness under reduced pressure, followed by acid hydrolysis with 2M HCl to furnish 7. Yield 79%; mp 204-206° C. (EtOH). 1H NMR (DMSO-d6); δ 7.55 (d, J=3.6 Hz, 1H), 7.73 (d, J=3.6 Hz, 1H), 8.06 (d, J=8.4 Hz, 2H), 8.27 (d, J=8.4 Hz, 1H), 8.37-8.41 (m, 3H), 9.24 (d, J=2.1 Hz, 1H), 9.67 (s, 1H), 10.09 (s, 1H). 13C NMR (DMSO-d6); δ 192.8, 178.1, 155.2, 154.7, 152.3, 146.3, 142.9, 136.5, 133.3, 130.0, 127.2, 125.1, 124.3, 121.4, 110.6. Anal. Calc. for C17H11NO3: C %, 73.63; H %, 3.99. Found C %, 73.75; H %, 3.81.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:13]([CH2:25][CH2:26][OH:27])=[N:12][C:11]=2[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:33]([N:35]=C=O)=[O:34].C(=O)([O-])O.[Na+].C(N(CC)CC)C>O1CCCC1.CO>[C:33]([O:27][CH2:26][CH2:25][C:13]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:28]([CH3:30])[CH3:29])[N:12]=1)(=[O:34])[NH2:35]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)c1nc(CCO)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)c1nc(CCOC(N)=O)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -20 °C
Yield: 98 %

Procedure:
In 5 ml of tetrahydrofuran was dissolved 467 mg (1 mmol) of 5-(3,5-dichlorophenylthio)-2-(2-hydroxyethyl)-4-isopropyl-1-p-nitrobenzyl-1H-imidazole (126a), and there was added 0.23 g (1.2 mmol)of trichloroacetylisocyanate under stirring on a cooling bath at -20° C. Then, the bath was taken off, and the mixture was reacted for 2 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and extracted with methylene chloride. The extract was washed with water, dried, and the solvent was distilled off, and the trichloroacetylcarbamoyloxy compound which was able to use for the next reaction, was obtained in the residue. The intermediate was dissolved in 10 ml of aqueous methanol (10%), followed by addition of 0.2 ml of triethylamine under stirring at room temperature, and the mixture was stirred with heating at 50° C. for 3 hours and worked up. When the crystals were precipitated, the mixture was filtered directly. When the crystals were not precipitated, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extracted with methylene chloride. The extract was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate) to give 2-(2-carbamoyloxyethyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(p-nitrobenzyl)-1H-imidazole (128a)as oil (yield 98%)