Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][CH:19](SC)SC)[CH:15]=[N:14]1.BrN1C(=O)CCC1=O.O.[NH2:33]/[C:34](/[C:39]#[N:40])=[C:35](\[NH2:38])/[C:36]#[N:37]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][CH:19]=[N:33][C:34]([C:39]#[N:40])=[C:35]([NH2:38])[C:36]#[N:37])[CH:15]=[N:14]1
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CSC(Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)SC
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: N#CC(N)=C(C#N)N=CCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-4-[2,2-di(methylthio)ethyl]-2H-1,2,3-triazole was treated with N-bromosuccinimide in aqueous acetonitrile., After 10 minutes the mixture was added to water and extracted with diethyl ether. The extract was worked up to give crude 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-acetaldehyde. This was then treated with diaminomaleonitrile in a similar manner to Example 1, to give 2-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-[2-(2-amino-1,2-dicyanoethenylimino)ethyl]-2H-1,2,3-triazole, which was cyclised in a similar manner to Example 1a, to give 2-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-[(4,5-dicyano-1H-imidazol-2-yl)methyl]-2H-1,2,3-triazole (Compound 30).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]3)=[C:14]([F:28])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[C:29]([O-])(O)=O.[Na+].ClC(OCC)=O>CC(C)=O.O>[C:1]([NH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][CH3:29])=[O:25])[CH2:22][CH2:23]3)=[C:14]([F:28])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: COC(=O)N1CCN(c2ccc(N3CC(CNC(C)=O)OC3=O)cc2F)CC1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)N1CCN(c2ccc(N3CC(CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
The same procedure as followed in Example 1, steps a-k, were followed. Then a solution of 100 mg (0.30 mmol) of N-((3-(4-(3-fluoro-4-(1-piperazinyl))phenyl)-2-oxo-5-oxazolidinyl)methyl)-acetamide (23) (the product from step k above) and 50 mg (0.59 mmol) of solid NaHCO3 in 2 mL acetone and 1 mL water at 0° C. was treated with 35 mg (31 μL, 0.33 mmol) of ethyl chloroformate. The solution was stirred at 0° C. for 2 hours, followed by warming to ambient temperature for 18 hours. The solution was diluted with 30 mL water and was extracted with 40 mL ethyl acetate. The organic layer was washed with 30 mL water and 30 mL saturated NaHCO3 solution. Drying (Na2SO4) and concentration in vacuo afforded a white solid. This material was subjected to radial chromatography on a 2 mm plate, eluting with 2% (v/v) methanol in chloroform. These procedures afforded 70 mg (58%) of 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorophenyl)-1-piperazinecarboxylic acid, ethyl ester (24) as a white solid, mp=224°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Mg].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:16](=[O:17])[O:15][CH2:14]2.[Cl-].[NH4+]>CCOCC.O1CCCC1>[OH:15][CH2:14][C:13]1[CH:12]=[C:11]([Br:10])[CH:20]=[CH:19][C:18]=1[C:16]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: Clc1ccc(Br)cc1
Reactant: O=C1OCc2cc(Br)ccc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)c1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
A Grignard-solution prepared from 220 grams (1.15 mol) of p-chlorobromobenzene and 29 grams of magnesium turnings (1.2 mol) in 1500 milliliters of dry ether was added dropwise in the course of one hour to a suspension of 213 grams of 5-bromphthalide (1 mol) in 1500 milliliters of dry tetrahydrofuran. The temperature was not allowed to rise over 10 degrees Centigrade. After the addition was completed the reaction mixture was stirred for three hours at room temperature. The mixture was then poured into 2 liters of icewater and 100 milliliters of saturated aqueous ammonium chloride were added. The etherphase was separated and the water-tetrahydrofuranphase extracted once with 500 milliliters of ether. The etherphase was washed with water, dried over anhydrous magnesiumsulphate, filtered and evaporated in vacuum to yield 320 grams of 2-hydroxymethyl-4-bromo-4'-chloro-benzophenone in the form of a yellow oil which was not purified further but used directly in the next step. The 320 grams of oil were dissolved in 200 milliliters of dry tetrahydrofuran and added dropwise to a great excess of N,N-dimethylaminopropyl magnesium chloride in tetrahydrofuran under gentle reflux. After completed addition the mixture was refluxed over night. The reaction mixture was then poured into 5 liters of icewater and 200 milliliters of saturated aqueous ammonium chloride solution added. The mixture was extracted with a total of 2500 milliliters of ether. The etherphase was then extracted with 20% aqueous acetic acid to acid reaction, whereupon the acetic acid solution was made alkaline with 10 N sodiumhydroxide solution. After cooling, the oil, which separated out, was extracted twice with 500 milliliters of ether. The combined ether extracts were dried over anhydrous potassium carbonate, treated with active carbon and evaporated in vacuum. The remaining oil consists of somewhat impure (4-bromo-2-(hydroxymethyl)phenyl)-(4-chlorophenyl)-(3-dimethylaminopropyl)methanol which was used in the next step without further purification. Yield: 219 grams.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].CO[C:8](=[O:33])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:19][C:18]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)=[CH:11][C:10]=1[CH3:32]>CO>[Cl:30][C:28]1[CH:29]=[C:24]([C:18]2([C:20]([F:23])([F:21])[F:22])[O:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:2][OH:3])=[O:33])=[C:10]([CH3:32])[CH:11]=3)[CH2:19]2)[CH:25]=[C:26]([Cl:31])[CH:27]=1
Reactant: NO
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NO
Temperature: 40 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
In a solution of 0.30 g of hydroxylamine hydrochloride in 10 ml of methanol, a solution of 0.65 g of potassium hydroxide in 5 ml of methanol was added, then a solution of 1.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoic acid methyl ester synthesized similarly to Steps 1 to 4 of Synthetic Example 28 in 10 ml of methanol was added, and stirred at 40° C. for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, 10 ml of acetic acid aqueous solution (1:1) was added in the residue, and extracted with ethyl acetate (20 ml×2), the organic phase was dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled under reduced pressure. Toluene was added in the residue and the remaining acetic acid was distilled off azeotropically to to obtain 1.01 g of crude 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzhydroxamic acid as white crystal.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[N:6][C:7]=1[O:8][CH3:9].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][NH:23]2)=[CH:19][C:18]=1B1OCC(C)(C)CO1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][NH:23]2)=[CH:19][C:18]=1[C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: COc1nc(N2CCC(O)C2)ccc1Br
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(N4CCC(O)C4)nc3OC)cc12
Temperature: 80 °C
Yield: 35.3 %

Procedure:
A vial was charged with 1-(5-bromo-6-methoxypyridin-2-yl)pyrrolidin-3-ol (100.0 mg, 0.37 mmol), methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (176.4 mg, 0.55 mmol), Pd(dppf)C12 (26.8 mg, 0.04 mmol), potassium carbonate (152 mg, 1.10 mmol, 2M/L aqueous) and toluene/ethanol (1.5 mL/0.5 mL). The mixture was purged with nitrogen for 5 minutes and then sealed. The reaction was heated to 80° C. overnight. The mixture was cooled to room temperature and filtered. The filtrate was diluted with water (5 mL) and extracted with ethyl acetate (5 mL×3). The organic layer was dried (sodium sulfate) and concentrated. The resulting residue was purified through prep. TLC (petroleum ether: ethyl acetate, 2:1) to give the title compound (52.5 mg, 35.7%) as an off-white solid. 1H NMR (400 MHz, CDCl3) ppm: 8.62 (br. s), 8.05 (s, 1H), 7.89 (d, 1H), 7.50 (s, 1H), 7.35 (d, 1H), 6.00 (d, 1H), 4.61 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.73-3.57 (m, 4H), 2.24-2.05 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18]
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: Cc1ccc(F)c(N)c1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1ccc(F)c(NC(=O)c2ccccc2CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-fluoro-5-methylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-fluoro-5-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (77%) as a colorless solid: mp 214-216° C.; 1H NMR (300 MHz, CDCl3) δ 8.25-8.06 (m, 2H), 7.65-7.57 (m, 1H), 7.47-7.33 (m, 2H), 7.33-7.26 (m, 1H), 7.22-7.12 (m, 2H), 7.07-6.86 (m, 4H), 6.46 (s, 1H), 6.40 (s, 1H), 5.27 (s, 2H), 4.95 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.52 (t, J=8.7 Hz, 2H), 2.96 (t, J=8.5 Hz, 2H), 2.36 (s, 3H); MS (ES+) m/z 543.1 (M+23).
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH-].[K+].[CH2:25](I)[CH3:26]>CS(C)=O>[CH2:25]([O:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:26]
Reactant: CCI
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 0 °C
Yield: 80 %

Procedure:
A mixture of racemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl)propionate of the formula (10) (70 g) obtained according to the procedure described in step (iii) above. potassium hydroxide (26 g), dimethylsulphoxide (280 ml) and molecular sieves (36 g) was stirred at room temperature for 15 minutes. Ethyliodide (110 g) was added slowly at room temperature over 15 minutes. The reaction was stirred at the same temperature for a period of 15–20 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with water and the solvent was removed under reduced pressure to afford title compound of the formula (12a) (61–63 g, 80–82%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:9](=[O:17])[CH:8]=[CH:7][C:6]2=[O:18].Br[CH:22]1[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]1Br.BrC1C2=CC=CC=C2C1I.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]([F:19])([F:20])[C:3]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]2[C:9](=[O:17])[C:8]3[C:7](=[CH:23][C:24]4[C:25]([CH:22]=3)=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:6](=[O:18])[C:5]=2[CH:4]=1
Reactant: O=C1C=CC(=O)c2cc(C(F)(F)F)c(C(F)(F)F)cc21
Reactant: BrC1c2ccccc2C1Br
Agent: BrC1c2ccccc2C1I
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1c2cc(C(F)(F)F)c(C(F)(F)F)cc2C(=O)c2cc3ccccc3cc21

Procedure:
25 mmol of 6,7-bis-trifluoromethyl-1,4-naphthquinone, approx. 37 mmol of 1,2-dibromobenzocyclobutene [see J. Am. Chem. Soc. 79, pages 1701 et seq. (1957)] containing a little 1-bromo-2-iodobenzocyclobutene and 100 ml of xylene are kept under reflux for 16 hours in a water separator. The reaction mixture is cooled and the precipitate is filtered off and washed with xylene. The crystalline 2,3-di-(trifluoromethyl)-naphthacene-5,12-dione is obtained in a yield of 5.82 g (71%), melting point>280° C.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.[Cu]I>[CH3:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Reactant: CS(N)(=O)=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(N2CCCC2)c2ccc(NS(C)(=O)=O)cc2n1
Temperature: 110 °C
Yield: 19 %

Procedure:
In a dried reaction flask flushed with argon a suspension of 169 mg (0.5 mmol) 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline and 57 mg (0.6 mmol) of methanesulfonamide, 325 mg (1 mmol) of cesium carbonate, 1.9 mg (0.01 mmol) copper (I) iodide in 1,4-dioxane was treated at RT with 5.7 mg (0.05 mmol) of trans-diaminocyclohexane and the mixture was heated at 110° C. (oil bath temperature) for 48 h under an argon atmosphere (for the gerneal method: Buchwald: J. Am. Chem. Soc., p7727, 2001). The reaction mixture was then cooled to RT, diluted with methylene chloride and filtered. The filtrate was concentrated in a vacuo, the residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (9:1:0.5) as eluent. Combination of the purified fractions and concentration in vacuo gave 29 mg (25.5%) of the desired N-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-methanesulfonamide which was re-crystallized from methylene chloride: light brown solid. ISP mass spectrum, m/e: 306.3 (M+1 calculated for C15H19IN3O2S: 306).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C.C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCCCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(N)ccc1N1CCCCC1

Procedure:
1-(2-Methoxy-4-nitro-phenyl)-piperidine (Stage 85.2; 4.0 g, 17 mmol) in ethanol/THF 5:1 (90 ml) is hydrogenated in the presence of Pd/C 10 % (“Engelhard 4505”; 0.4 g). Then the catalyst is filtered off and the filtrate is concentrated yielding the title compound: 1H-NMR (DMSO-d6): 6.58 (d, 1H), 6.19 (d, 1H), 6.04 (dd, 1H), 4.66 (s, H2N), 3.65 (s, H3CO), 2.70 (m, 4H), 1.56 (m, 4H), 1.43 (m, 2H).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[S:6][C:7]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccc(COCc2ccccc2)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(COCc3ccccc3)s2)c1Br
Yield: 31.2 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamide was prepared as described in Example 2 from 2-chlorosulfonyl-5-(benzyloxymethyl)thiophene (520 mg, 1.72 mmol) and 5-amino-4-bromo-3-methyl isoxazole (319 mg, 1.8 mmol). Purification by column chromatography using 10% MeOH/CHCl3) gave 238 mg of pure N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamide as brown semisolid (31% yield, m.p. 92° C.).
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[NH:12][C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[N:12]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:25]=3[CH3:34])[C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Br)c2nc(C3CC3)[nH]c2c1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cn2c(C3CC3)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a 250 mL round bottomed flask containing DMF (50 mL) was added 4-bromo-2-cyclopropyl-6-nitro-1H-benzo[d]imidazole (4.3 g, 15.24 mmol), 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (3.6 mL, 21.34 mmol) and potassium carbonate (6.32 g, 45.7 mmol). The resultant suspension was heated to 50° C. and after stirring for 30 minutes the mixture was allowed to cool to rt and diluted with 100 mL H2O. The mixture was stirred overnight and the next day a brown filterable solid was isolated by filtration providing crude 4-bromo-2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (5.97 g, 13.14 mmol, 86% yield). MS (ES+) m/e: 453.0, 454.0 [M+H]+
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:24][CH2:25][CH2:26]Cl)[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[I-].[Na+].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>CN(C=O)C.O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:24][CH2:25][CH2:26][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(CCCCl)C(C(=O)OC)C(C)C)cc1
Reactant: CCNCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(CCCN(CC)CC)C(C(=O)OC)C(C)C)cc1
Temperature: 80 °C
Yield: 90.2 %

Procedure:
To a solution of 0.45 g (1.08 mmol) of methyl 2-[{[4-(2-butynyloxy)-phenyl]-sulfonyl}(3-chloropropyl)amino]-3-methylbutanoate in 5.0 mL of DMF was added 0.163 g (1.08 mmol) of sodium iodide and 0.34 mL (3.24 mmol) of diethylamine. The reaction was heated to 80° C. for 3 h and then cooled to room temperature. The mixture was then diluted with water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.441 g of methyl 2-{{[4-(2-butynyloxy)-phenyl]sulfonyl}[3-(diethylamino)propyl]amino}-3-methylbutanoate as a brown oil. Electrospray Mass Spec 453.5 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([CH3:11])[CH:3]=1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][C:4]1[CH:3]=[C:2]([O:1][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([CH3:8])=[CH:6][C:5]=1[CH2:9][OH:10]
Reactant: Cc1cc(CO)c(C)cc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OCc2ccccc2)c(C)cc1CO
Yield: 99 %

Procedure:
A mixture of 18.0 g (118 mmol) of 4-hydroxy-2,5-dimethyl-benzenemethanol (Example H), 14.9 g (118 mmol) of benzyl chloride and 18.0 g (1.1×118 mmol) of anhydrous potassium carbonate in 300 mL of acetonitrile is stirred at reflux for 18 hours overnight. The reaction flask and inorganic residue are washed with fresh acetonitrile and the solvent is removed on a rotary evaporator. A diethyl ether solution of the residue is washed with 2×50 mL of 2N potassium hydroxide solution, brine, dried (magnesium sulfate) and evaporated leaving 28.3 g of a pale yellow viscous residue. Distillation through a short path apparatus affords the title compound; mp 58°-59° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:19]=[C:18](C(O)=O)[C:17]2[C:12](=[C:13]([CH3:23])[CH:14]=[CH:15][CH:16]=2)[N:11]=1)([OH:3])=[O:2].O.[OH-].[Na+]>N1C2C(=CC=CC=2)C=CC=1>[CH3:23][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]=[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1]([OH:3])=[O:2])[CH:19]=[CH:18]2
Reactant: Cc1cccc2c(C(=O)O)cc(-c3ccccc3C(=O)O)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: Cc1cccc2ccc(-c3ccccc3C(=O)O)nc12
Temperature: 170 °C
Yield: 58.4 %

Procedure:
In 5 ml of quinoline was dissolved 0.1 g of the 2-(2-carboxyphenyl)-8-methyl-4-quinolinecarboxylic acid obtained in Example 11 and the solution was heated at 170° C. for 1.5 hours. Then the reaction mixture was poured into water, made alkaline by adding sodium hydroxide and washed with toluene. The aqueous layer was neutralized with 3M hydrochloric acid until a precipitate was formed. After extracting with dichloromethane, 0.05 g of 2-(8-methylquinolin-2-yl)benzoic acid were obtained. NMR (270 MHz, CD3OD): δ 7.5-8.3 (m,9H); 2.63 (s,3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:32])[CH:5]([CH:21]([OH:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:8][Si](C)(C)C)[CH:7]=1.N1C=CC=CC=1.N1C=CC=CC=1.F.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:1][S:2][C:3]1[C:4](=[O:32])[CH:5]([CH:21]([OH:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:6]([OH:8])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=1
Reactant: CCCCCCCCC1(O[Si](C)(C)C)C=C(SC)C(=O)C1C(O)CCCCCC(=O)OC
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCC1(O)C=C(SC)C(=O)C1C(O)CCCCCC(=O)OC
Reaction time: 18 h
Yield: 41 %

Procedure:
To a solution of 63 mg of 2-methylthio-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-octyl-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 71 dissolved in 6 ml of acetonitrile was added 130 μl of pyridine. A hydrogen fluoride-pyridine solution (260 μl) was added, and the mixture was stirred for 18 hours. The reaction mixture was poured onto saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtration and concentration, the concentrate was subjected to silica gel column chromatography to give 22 mg (yield 41%) of 2-methylthio-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-hydroxy-4-octyl-2-cyclopentenone.