Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].[Cl:32][C:33]1[N:34]=[CH:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:43]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1>[Cl:32][C:33]1[N:34]=[CH:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:43][N:14]1[C:13]2[CH:18]=[C:19]([F:20])[C:10]([S:7]([NH:6][C:21]3[S:25][N:24]=[CH:23][N:22]=3)(=[O:9])=[O:8])=[CH:11][C:12]=2[O:16][C:15]1=[O:17]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)[nH]c3cc2F)c(OC)c1
Reactant: OCc1cccc2cc(Cl)ncc12
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1oc2cc(S(=O)(=O)Nc3ncns3)c(F)cc2n1Cc1cccc2cc(Cl)ncc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (11-3) and (3-chloroisoquinolin-8-yl)methanol in THF (697 μl) at 0° C. was treated with ps-triphenylphosphine (73.1 mg, 0.279 mmol) (152 mg resin-bound PPh3, 1.84 mmol PPh3/g of resin), then (E)-di-tert-butyl diazene-1,2-dicarboxylate (64.2 mg, 0.279 mmol). Reaction mixtured was monitored at 0° C. After stirring at 0° C. for 2 h, the reaction was filtered and concentrated in vacuo. Residue was dissolved in 1 mL of DCM and treated with 0.25 mL of TFA. After stirring at RT for 30 minutes, the solvent and TFA were removed in vacuo. Purified by reverse phase chromatography (10-95% MeCN in water w/0.1% TFA, C18 column) to yield 25-2. 1H NMR δ (ppm)(CH3OH-d4): 9.48 (1H, s), 8.20 (1H, s), 7.96 (1H, s), 7.90 (1H, d, J=8.36 Hz), 7.81 (1H, d, J=5.48 Hz), 7.75 (1H, t, J=7.75 Hz), 7.57 (1H, d, J=7.08 Hz), 7.12 (1H, d, J=9.32 Hz), 5.69 (2H, s). HRMS [M+H]C19H11ClFN5O4S2 calc'd 491.9998. Found 492.0001.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([CH:13]=[O:14])[CH:9]=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].C[Mg+].[Br-].[CH3:18]C(O)=O>C1COCC1>[F:1][C:2]1[C:11]([F:12])=[C:10]([CH:13]([OH:14])[CH3:18])[CH:9]=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)O
Reactant: CC(=O)Nc1ccc(C=O)c(F)c1F
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(C)O)c(F)c1F
Temperature: 15 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 7.7 g of 2',3'-difluoro-4'-formylacetanilide in 190 mL of THF under an N2 atmosphere is added 29 mL of a 2.85M solution of MeMgBr at a temperature of 10°-20° C. The thick suspension is stirred 20 minutes at 20°-25° C., cooled to 15° C. and 5 mL of AcOH cautiously added. The mixture is then poured onto 500 mL of ice/H2O and the product extracted into 500 mL of CH2CL2. This extract is washed with H2O, saturated NaHCO3 and H2O (100 mL each) and stripped to give 8.1 g of yellow gummy 2',3'-difluoro-4'-(1-hydroxyethyl)-acetanilide. 8.1 g of the crude 2',3'-difluoro-4'-(1-hydroxyethyl)-acetanilide is stirred in acetone (175 mL) while 54 mL of Kilianis' reagent (Fieser and Fieser, "Reagents for Organic Synthesis", Vol. I p144) is added dropwise during 30 min. at a temperature of 20°-25° C. After stirring 30 min. longer, the reaction mixture is poured onto 200 mL of ice/H2O containing 5 g of Na2S2O5. The green suspension is extracted three times with CH2Cl2 (total volume 1 L) and the organic extract is washed with H2O, saturated NaHCO3, H2O (100 mL each) and stripped in vacuo. There is obtained 5.8 g of off-white solid which is slurried with 75 mL of Et2O to afford 5.23 g (65% yield) of 4'-acetyl-2',3'-difluoroacetanilide, m.p. 149°-152° C., (Mass spectrum shows an ion of 214).
Reaction SMILES: [OH:1][C:2]1([CH:13]([N+:17]([O-:19])=[O:18])[CH:14]([CH3:16])[CH3:15])[CH2:5][N:4]([C:6]([O:8]C(C)(C)C)=O)[CH2:3]1.Cl.[F:21][C:22]1[C:23]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=2[F:40])=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])C(O)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1.CN(C=O)C.C(OCC)(=O)C.CO>[F:21][C:22]1[C:23]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=2[F:40])=[C:24]([C:6]([N:4]2[CH2:3][C:2]([CH:13]([N+:17]([O-:19])=[O:18])[CH:14]([CH3:15])[CH3:16])([OH:1])[CH2:5]2)=[O:8])[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC(C)C([N+](=O)[O-])C1(O)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)C([N+](=O)[O-])C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
1,1-Dimethylethyl 3-hydroxy-3-(2-methyl-1-nitropropyl)azetidine-1-carboxylate (105 mg, 0.38 mmol) was taken into methanol (1 mL) followed by addition of 4 N anhydrous hydrogen chloride in dioxane (1 mL) and the acidic solution was allowed to stand for 15 minutes at room temperature then concentrated and dried in vacuo to an amorphous residue. 3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (150 mg, 0.38 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, was taken into DMF (0.7 mL) followed by addition of PyBOP (198 mg, 0.38 mmol) and the solution was allowed to stir for 10 minutes at room temperature. The above amine hydrochloride salt and DIPEA (190 μL, 1.1 mmol) in DMF solution (0.7 mL) was added and the mixture was allowed to stir for one hour at room temperature. The mixture was partitioned with ethyl acetate and 0.5 N aqueous hydrochloric acid and the organic phase washed three times with water then brine and dried over anhydrous magnesium sulfate. Filtration and concentration afforded a residue that was further purified by silica gel flash chromatography using 1.5:1 hexanes:ethyl acetate as eluent to give 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-methyl-1-nitropropyl)azetidin-3-ol (189 mg, 90% yield) as an amorphous solid. 1H-NMR (400 MHz, CDCl3): 8.41 (br s, 1H), 7.41 (dd, 1H), 7.34 (d, 1H), 7.09 (br m, 1H), 6.81 (q, 1H), 6.65-6.60 (m, 1H), 4.49 (d, 1H), 4.15-4.09 (m, 4H), 3.66 (s, 1H), 2.56-2.46 (m, 1H) 1.03 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15](C(O)=O)[CH2:14]1)=[O:11])[CH:7]=[CH:6][S:5]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([NH:12][C:10]([C:9]2[N:8]3[C:4]([S:5][CH:6]=[CH:7]3)=[N:3][C:2]=2[CH3:1])=[O:11])[CH2:14]1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCN(C(=O)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a cold (˜0° C.) solution of (R)-3-[(6-methyl-imidazo[2,1-b]thiazole-5-carbonyl)-amino]-piperidine-1-carboxylic acid tent-butyl ester (1.47 g) in dry DCM (30 mL) was added slowly TFA (4.63 mL). The reaction mixture was stirred at RT for 20 h, 5 eq more of TFA (4.63 mL) was added and the stirring was continued for 2 h. The reaction was concentrated in vacuo to yield the title compound as a bis-trifluoroacetate salt which was used for the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=3[F:29])=[CH:6][C:7]3[C:11]([CH:12]=2)=[N:10][N:9]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=3)[CH2:3][CH2:2]1.CO.CN(C)N>CCOC(C)=O.C(Cl)Cl>[CH:1]1([C:4]2[C:5]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=3[F:29])=[CH:6][C:7]3[C:11]([CH:12]=2)=[N:10][N:9]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=3)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cn(C4CCCCO4)nc3cc2C2CC2)c(F)c1
Agent: CN(C)N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc(Oc2cc3cn(C4CCCCO4)nc3cc2C2CC2)c(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a 25 mL glass vial is added 6-cyclopropyl-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (395 mg, 994 μmol) and MeOH (20 mL, 494 mmol). To the suspension is added N,N-dimethylhydrazine (756 μL, 9.94 mmol) and FeCl3 (163 mg, 994 μmol). The vial is capped, and heated to 60° C. and stirred for 2 hours and then stirred at 50° C. overnight. The mixture is filtered over a Buchner funnel and the solid washed with MeOH (100 mL). The filtrate is collected and concentrated to give a brown/orange solid. The residue is purified on a silica gel column eluting with DCM (A) and a 10% MeOH in a DCM solution (B), gradient from 100% (A) to 85%(A): 15%(B) over 50 min to give a yellow solid as the title compound (358 mg, 98% yield). MS (m/z): 368 (M+H).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH3:10])[CH2:2][CH3:3].[OH-].[Na+].[H][H]>[Ni].C(O)C>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:18][CH:19]=1)[CH3:10])[CH2:21][CH3:22]
Reactant: [H][H]
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(C#N)cc1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CN)cc1
Yield: 98 %

Procedure:
14.6 g of 4-[(4-dipropylaminobutyl)methylamino]methylbenzonitrile (2b), 292 ml of ethanol, and 102 ml of a 1N sodium hydroxide aqueous solution were charged in a 1-liter recovery flask. 1.46 g (10 wt %) of Raney nickel prepared using the method described in Example 1 was slowly added to the solution. After replacing the atmosphere in the flask with nitrogen and then with hydrogen, the mixture was stirred at room temperature for 17 hours using a hydrogen balloon. After confirming the disappearance of the raw material, the catalyst was removed by celite filtration, and the product was washed with 70% ethanol solution. The obtained filtrate was concentrated under reduced pressure. After the addition of 100 ml of distilled water to the residue, the product was extracted twice with 200 ml of hexane. The organic layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated, thereby obtaining 14.5 g of 4-[(4-dipropylaminobutyl)methylamino]methylbenzylamine (13) as a yellow oily substance (yield: 98%, GC: 93%). [HPLC: 90% (HPLC measurement conditions A)]
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10](=O)[NH:9][CH:8]=[N:7][C:6]=2[Se:5][C:4]=1[CH3:13])[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:10]1[C:11]2[C:3]([CH2:1][CH3:2])=[C:4]([CH3:13])[Se:5][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1c(C)[se]c2nc[nH]c(=O)c12
Product: CCc1c(C)[se]c2ncnc(Cl)c12
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A mixture of 5-ethyl-6-methylselenopheno[2,3-d]pyrimidin-4(3H)-one (300 mg) and phosphorous oxychloride (5 mL) was refluxed for 1 h. The reaction mixture was attained to rt and poured into ice cold water and stirred for 10 min. The precipitated solid was filtered, washed with water and dried to give the product as a brown color solid (260 mg, 81%), mp 58-60° C. 1H NMR (400 MHz, CDCl3): δ 8.68 (1H, s), 3.06 (2H, q, J=7.5 Hz), 2.62 (3H, s), 1.23 (3H, t, J=7.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.S(=O)(=O)(O)O.[C:26]1(=[O:44])[N:30]([C:31]2[CH:32]=[C:33]([CH:37]=[C:38]([N+:40]([O-:42])=[O:41])[CH:39]=2)[C:34]([OH:36])=[O:35])[C:29](=[O:43])[CH2:28][CH2:27]1.[OH-].[Na+]>>[C:29]1(=[O:43])[N:30]([C:31]2[CH:32]=[C:33]([CH:37]=[C:38]([N+:40]([O-:42])=[O:41])[CH:39]=2)[C:34]([OH:36])=[O:35])[C:26](=[O:44])[CH2:27][CH2:28]1.[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=1)[NH:1][C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)O1
Agent: O=C(O)c1cc(N2C(=O)CCC2=O)cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)CCC(=O)Nc1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
3-Succinimido-5-nitrobenzoic Acid [D; Y is CH2CH2, Z is OH] was prepared by heating 3-amino-5-nitrobenzoic acid with succinic anhydride in the presence of sulfuric acid. It had the m.p. 285°-290° C. when recrystallized from aqueous dimethylformamide. b. 3'-Carboxy-5'-nitrosuccinanilic Acid [F; Y is CH2CH2, Z is OH]was prepared by treating 3-succinimido-5-nitrobenzoic acid with warm dilute aqueous sodium hydroxide, and had the m.p. 220°-221° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[BH4-].[Na+].CO.O>C(O)(C)(C)C>[Br:1][C:2]1[CH:12]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(C)(C)O
Product: OCc1cncc(Br)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1.1 1.3 g of ethyl 5-bromonicotinate are initially introduced in 40 ml of tert-butanol, and 427 mg of sodium borohydride are added. The entire mixture is heated under reflux (100° C.) and under N2 for one hour. 6 ml of methanol are then added. The mixture is stirred overnight. 10 ml of water is added to the reaction solution. The mixture is then extracted with dichloromethane, dried using sodium sulfate and evaporated in a rotary evaporator, giving 300 mg of (5-bromopyridin-3-yl)methanol.
Reaction SMILES: C([S:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)=[O:24])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[SH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=1)=[O:24]
Reactant: Cc1ccc(OCCCCCCCCCCCOC(=O)CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(OCCCCCCCCCCCOC(=O)CCS)cc1

Procedure:
The compound 17 (1.11 g) was weighed and poured into a 100-ml round-bottomed flask, and 10 ml of trifluoroacetic acid was added and stirred, to obtain an orange-colored homogenous solution. After 0.9 ml of triethylsilane was added to generate a white-colored precipitate, the supernatant solution (transparent) was distilled away under reduced pressure. The solid obtained was purified by chromatography, and 0.6 g of the compound e, which was a white solid, was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH:11]([OH:14])[CH2:12]Cl)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:1][C:2]1[N:3]([CH2:10][CH:11]2[CH2:12][O:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1cn(CC(O)CCl)c(Cl)n1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])c1cn(CC2CO2)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
2-Chloro-1-(3-chloro-2-hydroxypropyl)-4-nitroimidazole prepared in Example 1 (2.04 g, 8.5 mmol) was dissolved in methylene chloride (20 ml), and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (2.04 ml, 13.67 mmol) was added to the solution. The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with 3N hydrochloric acid (20 ml) and a saturated saline solution (20 ml) in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=20/1) to afford 2-chloro-4-nitro-1-(oxiran-2-ylmethyl)imidazole (190 mg, yield 11%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH3:16])=[CH:8][CH2:9][OH:10].C(P(CCCC)CCCC)CCC.[CH2:30]([O:32][C:33](=[O:46])[CH:34]([O:43][CH2:44][CH3:45])[CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:46])[CH:34]([O:43][CH2:44][CH3:45])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:10][CH2:9][CH:8]=[C:7]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[CH3:16])[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[CH:38][CH:37]=1)[CH3:31]
Reactant: Cc1ccsc1C(=CCO)c1sccc1C
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Product: CCOC(=O)C(Cc1ccc(OCC=C(c2sccc2C)c2sccc2C)cc1)OCC
Yield: 36.2 %

Procedure:
Reaction of 3,3-bis-(3-methylthiophen-2-yl)-prop-2-en-1-ol (1.0 mg, 3.99 mmol), tributylphosphine (0.91 g, 4.5 mmol), 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (1.07 g, 4.5 mmol) and azodicarboxylic dipiperidide (1.14 g, 4.5 mmol) in an identical manner to example 3 gave the title compound (680 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([C:24]([F:27])([F:26])[F:25])[CH2:13][C:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=3)=[N:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C([O-])=O.[O:35]=[S:36]1(=[O:41])[CH2:39][CH:38]([NH2:40])[CH2:37]1.ON1C2C=CC=NC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([C:24]([F:25])([F:26])[F:27])[CH2:13][C:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:40][CH:38]4[CH2:39][S:36](=[O:41])(=[O:35])[CH2:37]4)=[O:20])=[C:16]([CH3:23])[CH:15]=3)=[N:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NC[C@@](c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: NC1CS(=O)(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C2=NC[C@@](c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CS(=O)(=O)C1
Reaction time: 0.08 h
Yield: 35.4 %

Procedure:
To a stirred solution of 4-[(3R)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol-5-yl]-2-methyl-benzoic acid (68 mg) in dichloromethane (2.5 mL) was added triethylamine (0.05 mL) at ambient temperature. The solution was then stirred for 5 min under argon and trifluoroacetate salt of 1,1-Dioxo-llambda*6*-thietan-3-ylamine (46 mg) was added. To this solution, 1-hydroxyazabenzotriazole (25 mg) then 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg) were added. The solution was stirred at ambient temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with water. The combined organic phases were dried over anhydrous sodium sulfate, the suspension was filtered and the solution was evaporated to give a crude residue which was purified by chromatography on silica gel (eluent: heptane/ethyl acetate, from 1:0 to 6:4) to give 4-[(3R)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol-5-yl]-N-(1,1-dioxothietan-3-yl)-2-methyl-benzamide (30 mg) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([SH:8])=[N:6][N:7]=1.[CH3:9][N:10]=[C:11]=[O:12]>O1CCOCC1.C(N(CC)CC)C>[CH3:9][NH:10][C:11]([N:2]([CH3:1])[C:3]1[S:4][C:5]([SH:8])=[N:6][N:7]=1)=[O:12]
Reactant: CN=C=O
Reactant: CNc1nnc(S)s1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)N(C)c1nnc(S)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a stirred slurry of 126 g of 2-methylamino-5-mercapto-1,3,4-thiadiazole in 525 ml of dioxane containing a few drops of triethylamine is added 49 g of methyl isocyanate. After stirring two hours at room temperature, the solid is collected by filtration and washed with hexane giving 165 g, melting at 162°-3°. This product is heated on the steam bath 11/2 -2 hours with 250 ml of triethylamine, during which time the initial solid is converted to a heavy amber oil. The supernatent liquid is decanted and the oil is dissolved in water and neutralized with dilute hydrochloric acid to pH 2-3. The precipitated solid is collected and washed with water and air dried, giving 132 g of N,N'-dimethyl-N'-(5-mercapto-1,3,4-thiadiazol-2-yl)urea, m.p. 230° (dec.).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:8][N:7]=1)=[O:5])C.O.[OH-].[Li+]>C1COCC1.O>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]=1[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[N:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid ethyl ester (481 mg, 1.42 mmol) in THF (12 mL) was added a solution of lithium hydroxide monohydrate (418 mg, 9.8 mmol) in water (6 mL) and the resulting mixture stirred at room temperature overnight. The mixture was acidified with HCl (1 N, 10 mL) and evaporation afforded the title compound (335 mg, 70%) which was obtained as a light yellow solid. MS: m/e=309.0 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[Br:20]Br>C(Cl)Cl>[Br:20][C:11]1[CH:12]=[CH:13][C:5]([O:4][CH2:3][C:2]([F:14])([F:15])[F:1])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: BrBr
Reactant: O=C(O)c1ccccc1OCC(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)c1cc(Br)ccc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)benzoic acid (22 g) in methylene chloride (100 ml), was added AlCl3 (13.3 g) at 0° C.followed by bromine (16.0 g, 0.1 mol). The reaction mixture was stirred at 0° C. for 1 hour and then at reflux for 2 hours. The solids were filtered and water (50 ml) and ethyl acetate (50 ml) were added to the filtrate. The aqueous layer was separated and extracted with ethyl acetate (2×60 ml) and the combined organic layers were washed with water (2×60 ml). The organic layer was concentrated under vacuum to dryness and hexane (100 ml) was added and the resulting suspension was stirred at 20 to 25° C. for 1 hour. The mixture was filtered and the cake was rinsed with heptanes (2×20 ml). The damp solids were dried in vacuum at 45° C. for 5–6 hours to give a white solid (28.3 g, yield 94.6%), m.p. 126–128° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6]Cl.C1(C)C=CC=CC=1.[C:16]1([CH2:34][OH:35])[S:17][CH:18]=[C:19]2[C:25]=1[C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[S:22][C:21]1[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=1>[OH-].[Na+].[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[C:16]1([CH2:34][O:35][CH2:6][CH2:5][CH2:4][N:3]([CH3:8])[CH3:2])[S:17][CH:18]=[C:19]2[C:25]=1[C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[S:22][C:21]1[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=1
Reactant: OCc1scc2c1-c1ccccc1Sc1ccccc1-2
Reactant: CN(C)CCCCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCCOCc1scc2c1-c1ccccc1Sc1ccccc1-2
Temperature: 25 °C

Procedure:
To a solution of 3-dimethylaminopropylchloride-hydrochloride (6.7 mmoles) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.88 mmole) and toluene solution of the alcohol 15 (0.67 mmole) were added. The reaction mixture was heated under vigorous stirring and refluxing for 5 hours. Then it was cooled to room temperature, diluted with water and extracted by dichloromethane. After purification by column chromatograpy an oily product was isolated.