Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH:8]1[C:20]2[CH:19]([CH2:21][O:22][C:23]([NH:25][C@@H:26]([CH2:30][NH2:31])[C:27]([OH:29])=[O:28])=[O:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1>C1COCC1.[OH-].[Na+]>[CH:17]1[C:18]2[CH:19]([CH2:21][O:22][C:23]([NH:25][C@@H:26]([CH2:30][NH:31][C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:6])[C:27]([OH:29])=[O:28])=[O:24])[C:20]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)C1CCC1
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CNC(=O)C1CCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclobutanecarbonyl chloride (72.7 mg, 0.613 mmol) and NaOH (0.735 mL, 0.735 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-aminopropanoic acid (200 mg, 0.613 mmol) in THF (1.5 mL) and NaOH (1N, 0.8 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (156 mg, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21](F)=[C:20]([F:25])[CH:19]=3)[CH2:16][O:15][C:14]2=[O:26])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:27]C1C=C(C=C(F)C=1)C=O>>[F:27][C:22]1[CH:23]=[C:18]([C@H:17]2[CH2:16][O:15][C:14](=[O:26])[N:13]2[C:11]([O:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:19]=[C:20]([F:25])[CH:21]=1
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1cc(F)cc(F)c1
Product: O=C1OC[C@H](c2cc(F)cc(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure for the synthesis of 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester, 3,5-diflourobenzaldehyde yielded the desired product. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, 2H, J=9.3 Hz), 7.33–6.81 (m, 5H), 5.41 (dd, 1H, J=4.1, 8.7 Hz), 4.81 (t, 1H, J=9.3 Hz), 4.33 (dd, 1H, J=4.1, 9.3 Hz); Anal. Calc. for C16H10F2N2O6+0.2EtOAc: C, 52.84; H, 3.06; N, 7.34. Found: C, 53.26; H, 2.83; N, 7.73.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=3)=[O:12])[C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:37][Mg+].[Br-]>C1COCC1.CCOCC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:17]=3)([OH:12])[CH3:37])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2c1OCCO2
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2c1OCCO2
Yield: 98 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-5-yl)-(1-trityl-1H-imidazol-4-yl)-methanone (Intermediate B1) (0.91 g, 1.93 mmol) in THF (80 mL) at −10° C. was treated with MeMgBr (2.6 mL, 7.68 mmol of a 3M solution in Et2O) for 45 m. The mixture was quenched with a sat. solution of NH4Cl and water. The layers were separated and the organic layer dried over MgSO4. The suspension was filtered and evaporated to dryness. The material was purified by chromatography on SiO2 with 50% EtOAc in CHCl3 to give 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-1-(1-trityl-1H-imidazol-4-yl)-ethanol as a foam 0.95 g (98%).
Reaction SMILES: [P:1]([Cl:15])(Cl)([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2].Cl.[CH2:17]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[CH3:18].CCN(CC)CC>C(Cl)Cl>[Cl:15][P:1]([NH:22][C@H:21]([C:20]([O:19][CH2:17][CH3:18])=[O:24])[CH3:23])([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)NP(=O)(Cl)Oc1cccc2ccccc12

Procedure:
Following the procedure described for Example 1, step 2, treatment of a solution in DCM (0.144 M) of 1-naphthyl dichlorophosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colorless oil as a 1:1.1* mixture of diastereoisomers. 31P NMR (300 MHz, CDCl3) δ: 9.47 and 9.14*.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Br)[CH:6]=[CH:5]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH:6]=[CH:5]2
Reactant: BrCc1ccc2cc(Br)ccc2n1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2nc(CN3CCCC3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.60 g (15.28 mmol) 6-bromo-2-bromomethyl-quinoline are added to a solution of 1.40 mL (16.8 mmol) pyrrolidine and 6.34 g (45.9 mmol) K2CO3 in 50 mL acetonitrile. The reaction is stirred overnight at RT and then the inorganic salts are filtered off. The organic phase is washed with water and the aqueous phase is extracted with EtOAc. The combined organic extracts are dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [CH2:1]([S:3]([CH2:5][S:6][CH2:7][CH3:8])=[O:4])[CH3:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25]>O1CCCC1>[CH2:7]([S:6][CH:5]([S:3]([CH2:1][CH3:2])=[O:4])[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])[CH3:8]
Reactant: CCSCS(=O)CC
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSC(CCCN1C(=O)c2ccccc2C1=O)S(=O)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 mmole of [((ethylsulfinyl)methyl)-thio]ethane in 20 ml of tetrahydrofuran is treated with 10 mmole of sodium hydride at 25° C for 2 hours after which 10 mmole of N-(3-bromopropyl)phthalimide in 5 ml of tetrahydrofuran is added. The reaction mixture is stirred overnight at 25° C then quenched with brine and extracted with chloroform. The organic phase is washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromotography on silica gel to give N-(4-ethylthio-4-ethylsulfinylbutyl)phthalimide. To a solution of 22 mmole of N-(4-ethylthio-4-ethylsulfinylbutyl)phthalimide in 20 ml of tetrahydrofuran is added under nitrogen at 0° C a solution of lithium diisopropylamide in 23 mmole of tetrahydrofuran. The reaction mixture is stirred for 30 minutes at 25° C then is saturated with difluorochloromethane. Stirring is continued for 2 hours at 40° C. After quenching with brine, the reaction mixture is extracted with ether. The organic phase is decanted, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give N-(4-ethylthio-4-ethylsulfinyl-4-difluoro-methylbutyl)phthalimide. To a solution of 30 mole of N-(4-ethylthio-4-ethylsulfinyl-4-difluoromethylbutyl)-phthalimide in 33 ml of acetonitrile is added at 0° C 1.1 ml of a 70% aqueous solution of perchloric acid. After stirring for 2 hours at 0° C the reaction mixture is poured into 60 ml of water then extracted with chloromethane. The organic phase is washed with brine, dried, filtered and the filtrate concentrated under reduced pressure to afford difluoromethyl 3-phthalimidopropyl ketone.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)=[CH:12][C:11]=1[CH3:21]>>[CH:18]1([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9](=[O:22])[CH2:6][C:2]#[N:1])=[C:11]([CH3:21])[CH:12]=2)[CH2:19][CH2:20]1
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)c1ccc(OCC2CC2)cc1C
Product: Cc1cc(OCC2CC2)ccc1C(=O)CC#N
Yield: 69 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis from 4-cyclopropylmethoxy-2-methyl-benzoic acid methyl ester (route Albis). 0.54 g of the title product was extracted from water and dried (yield 69%) and used directly for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1B(O)O.C([O:15][C@@H:16]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[CH2:27][S:26][C@H:17]1[O:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=1)(=O)C>>[O:18]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH:24]=1)[C@@H:17]1[S:26][CH2:27][C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:16]1[OH:15]
Reactant: Cc1ccc(F)c(B(O)O)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: Cc1ccc(F)c(-c2cncc(O[C@@H]3SC[C@@H](O)[C@H](O)[C@H]3O)c2)c1

Procedure:
By following a procedure analogous to Example 122 starting from 2-fluoro-5-methylphenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(2-fluoro-5-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=48%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([Cl:36])[C:15]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=3)=[CH:16][CH:17]=2)[CH2:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([Cl:36])[C:15]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:32])([F:34])[F:33])[CH:24]=3)=[CH:16][CH:17]=2)[CH2:12]1
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(CCO[Si](C)(C)C(C)(C)C)CC3)cc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(CCO)CC3)cc1C(F)(F)F
Yield: 56.3 %

Procedure:
N-(2-(2-Tert-butyldimethylsilyloxyethyl)-8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.09 g) in tetrahydrofuran (10 ml) was treated with tetrabutylammonium fluoride in tetrahydrofuran (1M, 0.16 ml) at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, the organic phase dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ammonia/methanol/dichloromethane mixtures as eluant) to give the title compound (0.04 g)
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:9]1[CH:10]=[CH:11][C:12]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: Fc1cccc(C(F)(F)F)c1
Reactant: C[C@@H]1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1
Temperature: 110 °C
Yield: 33.6 %

Procedure:
(R)-2-methyl-piperazine (3.88 g, 38.70 mmol), 2-bromo, 5-fluoro benzotrifluoride (8.55 g, 35.18 mmol), tris(dibenzylidineacetone)dipalladium (0) (32.0 mg g, 0.35 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (657.0 mg, 1.06 mmol) and sodium tert-butoxide (5.07 g, 52.77 mmol) were charged to a reaction flask. Toluene (40 mL) was introduced under nitrogen atmosphere and the reaction mixture was heated up at 110° C. for 5.0 hours. Reaction was complete as determined by TLC. The reaction mixture was diluted with dichloromethane, washed with water, saturated brine then dried over MgSO4 and concentrated. The crude product was purified via flash column chromatography to yield (R)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-3-methylpiperazine as a light brown oil (3.1 g, 33.6% yield).
Reaction SMILES: [CH3:1][C:2]1[C:18](=O)[CH2:17][CH2:16][C@@:15]2([CH3:20])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:14]2[CH2:13][CH2:12][C@@:11]2([CH3:21])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:22].[ClH:23].Cl.[NH2:25][CH2:26][CH2:27][O:28][NH2:29]>O1CCOCC1.O.[Cl-].[Na+].O>[ClH:23].[NH2:25][CH2:26][CH2:27][O:28]/[N:29]=[C:18]1/[C:2]([CH3:1])=[C:3]2[C@:15]([CH3:20])([CH2:16][CH2:17]/1)[C@@H:14]1[C@H:6]([C@H:7]3[C@@:11]([CH2:12][CH2:13]1)([CH3:21])[C@@H:10]([OH:22])[CH2:9][CH2:8]3)[CH2:5][CH2:4]2
Reactant: CC1=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Reactant: NCCON
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC/C1=N\OCCN
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
To a stirred solution of 4-methyltestosterone (203 mg) in dioxane (3.7 ml), a solution of 2-aminoethoxyamine dihydrochloride (259 mg) in water (2 ml) was rapidly added dropwise. After 24 h dioxane (20 ml) and brine (10 ml) were added and the mixture was stirred for 10 min. The phases were separated and the aqueous phase was extracted with dioxane (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to dryness. The residue was triturated with Et2O for 5 h and the precipitate was filtered. The crude product was dissolved in water and freeze-dried to give the title compound (I-aa) as a white solid (197 mg, 74%).
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[CH3:12][O:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH3:12][O:13][CH2:14][CH2:15][C:16]([C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1)=[O:17]
Reactant: COCCC(=O)Cl
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COCCC(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reaction time: 2.5 h

Procedure:
To a solution of 2-trichloroacetyl pyrrole (1.0 equivalent, 4.67 g, 22 mmol) in methylene chloride (5 mL) was added 3-methoxypropionyl chloride (1.0 equivalent, 22 mmol) then aluminium trichloride (1.0 equivalent, 2.93 g, 22 mmol) was added in small portions. After 2.5 hours, the crude mixture was chromatographed on silica gel (MeOH 2% in DCM) to afford 3.0 g of the Friedel-Craft product. 1H NMR consistent with structure.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.[C:12](#[N:15])[CH:13]=C.C(N1CCOCC1)C>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:13][C:12]#[N:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: C=CC#N
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCN1CCOCC1
Solvent: Cc1ccc(C)cc1
Product: N#CC=Cc1ccc(C=O)cc1

Procedure:
The amounts of palladium acetate shown in Table 2 below, 6.74 g (40 millimols) of 4-formylbenzoyl chloride, 2.63 ml (40 millimols) of acrylonitrile and 5.12 ml (40 millimols) of N-ethylmorpholine, in 80 ml of p-xylene, are stirred for 5 hours at 120° C. The yields of 4-formylcinnamonitrile are shown in Table 2.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH:26]=[CH:25]1>O>[C:24]([O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:7])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Reactant: O=C1C=CC(=O)O1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(OC(=O)/C=C\C(=O)O)cc(C(C)(C)C)c1O

Procedure:
3,5-di tert.butyl-4-hydroxyphenyl hydrogen maleate was prepared by stirring a mixture of 15.5 grams of 2,6-di tert.butyl hydroquinone, 10 grams of trifluoroacetic acid and 8.6 grams maleic anhydride for 12 hours at 35° C. to 40° C. Addition of 100 milliliters of water resulted in the precipitation of a light brown paste which crystallized when mixed with petroleum ether. The solid was filtered off and washed twice with petroleum ether yielding 10.5 grams of product melting at 120° C. to 125° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH:10]=[CH:11][CH3:12].[OH-:14].[Na+].O>CN1CCCC1=O>[CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH:10]=[CH:11][CH3:12]
Reactant: [OH-]
Reactant: CC=CC=CCCCCCCCBr
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC=CC=CCCCCCCCO
Temperature: 95 °C
Yield: 65.5 %

Procedure:
8,10-dodecadienyl bromide (1.0 g, 4.08 mmol), prepared as described above, was dissolved in N-methylpyrrolidinone (0.96 mL) under Ar-atmosphere, and 50% NaOH (0.22 mL, 4.18 mmol) was added via syringe. The reaction mixture was heated to 95° C. for 4 hrs. A colourless precipitate was observed. After cooling to room temperature, water (10 mL) was added and the resulting mixture was extracted with heptane (3×6 mL). The resulting organic phase was washed with water (10 mL) and dried (Na2SO4). Evaporation of the solvent from the organic phase gave the 8,10-dodecadienol product as a yellow liquid (487 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12](=O)[CH2:13][C:14]([O:16]C)=O.[CH3:19][NH:20][NH2:21]>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]1[NH:21][N:20]([CH3:19])[C:14](=[O:16])[CH:13]=1
Reactant: COC(=O)CC(=O)Cc1ccc(OC)c(Cl)c1Cl
Reactant: CNN
Product: COc1ccc(Cc2cc(=O)n(C)[nH]2)c(Cl)c1Cl

Procedure:
46.2 g (0.16 mol) of methyl 4-(2,3-dichloro-4-methoxyphenyl)-3-oxobutyrate and 8.1 g (0.18 mol) of methylhydrazine were reacted by the method of Example 1. Yield: 30.8 g;
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:25]2=[O:49])=[CH:21][CH:20]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:49])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCC3Cc4ccccc4N3)cc2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
A mixture of 3.55 g of 5-[4-(1-t-butoxycarbonylindolin-2-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 4) and 30 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was poured into water and the aqueous mixture was neutralized by the addition of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.41 g of the title compound. This product was dissolved in ethanol and precipitated by adding water, to give a powder melting at 55.8-58.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][OH:21])[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(N1CCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
The amide derivative 1 (5.0 g, 16.3 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0° C. To this solution was added triethylamine (5.0 mL) followed by dropwise addition of methanesulfonyl chloride (2.05 g, 17.9 mmol). The reaction was stirred at 0 C. for 1 h, and then at room temperature overnight. The reaction mixture was washed successively with water, 1 N HCl, water, sat. sodium bicarbonate solution, and water (100 mL each). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (2:1) to give 2 (4.45 g, 71%) as a tan gum; C18H24ClNO4S, LRMS (m/z)=386 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N+:16]([O-:18])=[O:17])(=[O:26])=[O:27])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccnc2c(N)cccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cccc12
Yield: 93.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-amino-quinoline-4-carboxylic acid methyl ester (Intermediate 475) (370 mg, 1.38 mmol), 2-nitrobenzenesulfonyl chloride (530 mg, 2.3 mmol), DMAP (cat.), pyridine (0.44 ml, 5.4 mmol) and DCM (15 ml) gave the title compound (500 mg, 70%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C[O-].[Na+].[C:14](OCC)(=[O:16])C>[Cu]Br.O>[CH3:14][O:16][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2sccc2c1
Reactant: CCOC(C)=O
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
To a solution of 4-bromobenzenethiol (24.7 g) in acetone (100 ml) was added potassium carbonate (18.5 g), then 2-bromo-1,1-diethoxyethane (19.5 ml) was added dropwise thereto, the solution was stirred overnight at room temperature, then acetone was added thereto. The solution was filtered, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system). To a solution of the resulting 1-bromo-4-(2,2-diethoxyethylsulfanyl)benzene (32.5 g) in chlorobenzene (350 ml) was added polyphosphoric acid (60 ml), and then the solution was stirred for 2 hours at 140° C. The reaction mixture was poured into an ice, extracted with ethyl acetate, then sequentially washed with aqueous ammonia, water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, the resulting residue was purified by silica gel column chromatography (hexane) to provide 5-bromobenzo[b]thiophene (13.7 g). By referring to the synthetic method of Tetrahedron Lett., 1993, 34, 1007, to 5-bromobenzo[b]thiophene (13.7 g) was added sodium methoxide (28% solution in methanol) (200 ml). Copper(I) bromide (13.5 g) and ethyl acetate (40 ml) were sequentially added thereto followed by stirring for 4.5 hours at 80° C. Ethyl acetate and water were sequentially added thereto, the solution was stirred, then filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (9.2 g).