Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:4]=1[N+:26]([O-:28])=[O:27].[NH3:29]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.O>[Cl:24][C:22]1[CH:23]=[C:18]([C:12]2([C:14]([F:16])([F:15])[F:17])[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH2:29])=[C:4]([N+:26]([O-:28])=[O:27])[CH:5]=3)[CH2:13]2)[CH:19]=[C:20]([Cl:25])[CH:21]=1
Reactant: O=[N+]([O-])c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1CBr
Reactant: N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 3-[4-(bromomethyl)-3-nitrophenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (1.0 g) in tetrahydrofuran (10 mL) was added dropwise to a solution of 28% ammonia (aqueous solution, 5 mL) and tetrabutyl ammonium iodide (0.05 g) in tetrahydrofuran (10 mL) and methanol (20 mL) under ice cooling, and the mixture was then stirred for 10 hours at room temperature. The reaction solution was diluted with water, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to yield 1-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-nitrophenyl}methanamine (0.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[Na].[CH3:10][SH:11].C(=O)([O-])O.[Na+]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([S:11][CH3:10])=[CH:4][N:3]=1
Reactant: CS
Reactant: Nc1cnc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CSc1cnc(N)cn1
Temperature: 60 °C
Reaction time: 15 h
Yield: 83.6 %

Procedure:
A suspension of 2-amino-5-bromopyrazine (100 mg), 95% methanethiol sodium salt (84.8 mg) and tetrakistriphenylphosphine palladium (66.4 mg) in N,N-dimethylformamide (2.9 ml) was stirred at 60° C. for 15 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with toluene, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was separated using silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 67.8 mg (84%) of the desired product as a white powder.
Reaction SMILES: C([O:8][C:9](=[O:38])[CH2:10][N:11]([C:21](=[O:37])[CH2:22][N:23]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])CC1C=CC=CC=1)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)C1C=CC=CC=1.[H][H].[ClH:41].CCOCC>C(O)C.[C].[Pd]>[ClH:41].[CH2:35]([O:34][C:32]([CH2:31][NH:23][CH2:22][C:21]([N:11]([CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)[CH2:10][C:9]([OH:38])=[O:8])=[O:37])=[O:33])[CH3:36]
Reactant: CCOC(=O)CN(CC(=O)N(CC(=O)OCc1ccccc1)C1Cc2ccccc2C1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CNCC(=O)N(CC(=O)O)C1Cc2ccccc2C1

Procedure:
N-(N'-Ethoxycarbonylmethyl-N'-benzylglycyl)-N-(indan-2-yl)glycine benzyl ester (3 g) is dissolved in 100 ml of ethanol, and catalytic reduction is carried out at ordinary temperature and pressure using 5% palladium-carbon as catalyst. After absorption of 2 equivalents of hydrogen, the reaction mixture is filtered to remove the catalyst. The ethanol is distilled off under reduced pressure to give an oily substance. Addition of ethanolic hydrochloric acid with 100 ml of ether to the oily substance gives N-(N'-ethoxycarbonylmethylglycyl)-N-(indan-2-yl)glycine hydrochloride as colorless powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.[C:27]([O:31][C:32]([NH:34][C@H:35]([C:39](O)=[O:40])[CH2:36][CH2:37][OH:38])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[OH:38][CH2:37][CH2:36][C@@H:35]([NH:34][C:32](=[O:33])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])[C:39](=[O:40])[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)O
Product: CC(C)(C)OC(=O)N[C@H](CCO)C(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1

Procedure:
125 mg (326 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20) were transformed in analogy to example 23 using N-(tert-butoxycarbonyl)-L-homoserine to give after working up and purification 32.2 mg (16%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCC.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28](=[O:32])[CH2:29][CH2:30][CH:31]=2)=[CH:23][CH:22]=1>CCOCC>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2([OH:32])[CH2:29][CH2:30][CH:31]=[C:27]2[C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:3][CH:4]=1
Reactant: CSc1ccc(Br)cc1
Reactant: O=C1CCC=C1c1ccc(F)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CSc1ccc(C2(O)CCC=C2c2ccc(F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
To a solution of 3.86 g (19 mmol) of 4-bromothioanisole in 90 mL of Et2O cooled at -78° C., was added 22 mL of 1.7M solution of t-BuLi in pentane (38 mmol) dropwise. The reaction mixture was stirred for 15 min at -78° C. and a solution of 2.23 g of 2-(4-Fluorophenyl)-2-cyclopenten-1-one in 10 mL of Et2O was added. After stirring for 15 min at -78° C., the reaction mixture was warmed to 0° C., and quenched with 50 mL of sat. NH4Cl. The product was extracted with 100 mL EtOAc, dried over Na2SO4, and purified by flash chromatography, eluted with 4:1 hexane/EtOAc to give 3.4 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH:15]3[CH2:16][CH2:17][CH:12]2[CH2:13][CH2:14]3)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CN(C=O)C.C(N(CC)CC)C.[CH3:30][N:31]([CH3:35])[CH2:32][C:33]#[CH:34]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:15]12[N:11]([C:4]3[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:34]#[C:33][CH2:32][N:31]([CH3:35])[CH3:30])[CH:3]=3)[CH:12]([CH2:17][CH2:16]1)[CH2:13][CH2:14]2
Reactant: C#CCN(C)C
Reactant: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1cc(N2C3CCC2CC3)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 79.5 %

Procedure:
To 7-(3-bromo-4-nitro-phenyl)-7-azabicyclo[2.2.1]heptane (500 mg, 1.68 mmol), Pd(PPh3)2Cl2 (59 mg, 0.08 mmol), and CuI (10 mg, 0.05 mmol) were added DMF (5 mL), triethylamine (5 mL), and N,N-dimethylprop-2-yn-1-amine (420 mg, 538 μL, 5.05 mmol) under N2 atmosphere. The reaction was heated under microwave irradiation for 10 min at 100° C. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated NaHCO3 (2×20 mL), water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to a red solid. Purification by silica gel chromatography (0-50% dichloromethane/ethyl acetate) provided 3-[5-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-nitro-phenyl]-N,N-dimethyl-prop-2-yn-1-amine (400 mg, 79% yield). LC/MS m/z 300.5 [M+H]+.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]([OH:21])=[O:20])=O)(C)(C)C.[CH3:22][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO.C(O)(=O)C>[CH3:22][O:21][C:19]([C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=[CH:18][C:9]=1[NH2:8])=[O:20]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccccc2c1C(=O)O
Solvent: CC(=O)O
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1c(N)ccc2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The white solid from Example 128B (7.17 g, 24.61 mmol) was dissolved in benzene (250 ml) and methanol (62 ml). To the stirring solution was added 2 M trimethylsilyldiazomethane (12.3 ml) until the yellow color persisted for ten minutes. The reaction was then stirred at room temperature or 1 hour. To the solution was added acetic acid until the yellow color disappeared. The solvent was then removed. The crude material (7.52 g, 24.61 mmol) was dissolved in acetic acid (100 mL) and Pt2O (3.50 g, 15.4 mmol) was added shaken in a reactor pressurized with 60 psi of H2 at 25° C. for 80 hours, filtered, and concentrated. The concentrate was treated with dichloromethane (70 mL) and TFA (12 mL) and stirred for 3 hours. The organic layer was washed with NaOH (2×250 mL) and brine (200 mL), dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 206+H)+; 1H NMR (300 MHz, DMSO-d6) δ 6.83 (d, 1H), 6.53 (d, 1H), 5.26 (bs, 2H), 3.78 (s, 3H), 2.62 (m, 2H), 2.57 (m, 2H), 1.64 (m, 4H).
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9](Cl)[C:8]=2[N:7]=[C:6]1[CH2:19][OH:20])[CH2:2][CH2:3][CH3:4].[NH3:21]>CO>[NH2:21][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][OH:20])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: N
Reactant: CCCCn1c(CO)nc2c(Cl)nc3ccccc3c21
Solvent: CO
Product: CCCCn1c(CO)nc2c(N)nc3ccccc3c21
Temperature: 160 °C

Procedure:
1-Butyl-4-chloro-1H-imidazo[4,5-c]quinoline-2-methanol (2 g, 6.9 mmole, Example 127) was combined with 12 mL of 12% ammonia in methanol and heated in a Parr bomb at 160° C. for about 20 hours. The resulting solid was collected, rinsed with methanol then purified by silica gel chromatography using ethyl acetate/methanol as the eluent. The resulting solid was slurried with ethyl acetate, collected by filtration and dried to provide the desired product, m.p. 223-225° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17].C(Cl)(Cl)Cl.[CH3:23][O:24][C:25]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C(N(CC)CC)C>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([NH:12][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:25]=3[O:24][CH3:23])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: CC1(C)C(=O)NC(=O)c2c1ccc(N)c2[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3c(c2[N+](=O)[O-])C(=O)NC(=O)C3(C)C)c(OC)c1

Procedure:
2.7 gm of 4,4-dimethyl-7-amino-8-nitro-2H,4H-isoquinoline-1,3-dione were admixed with 50 ml of chloroform and 2.5 ml of triethylamine. Subsequently, 2.2 gm of 2,4-dimethoxybenzoylchloride were added, and the mixture was refluxed for 2 hours. After cooling the solution was evaporated and the precipitate was suction-filtered off and digested with water while heating.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]=[N+:9]=[N-:10].[C:17]([O:23][CH3:24])(=[O:22])[CH2:18][C:19]([CH3:21])=O.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:19]([CH3:21])=[C:18]([C:17]([O:23][CH3:24])=[O:22])[N:10]=[N:9]1
Reactant: [N-]=[N+]=NCc1ccccc1-c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1nnn(Cc2ccccc2-c2ccccc2)c1C
Temperature: 40 °C
Reaction time: 48 h
Yield: 68.8 %

Procedure:
To a solution of 2-biphenylylmethyl azide (Intermediate 2) (1.1 g, 5.2 mmol) and methyl acetoacetate (0.9 g, 7.8 mmol) in DMSO (10 mL) was added potassium carbonate (2.9 g, 20 mmol). The reaction mixture was stirred at 40° C. for 48 hours. After cooling, water was added and the mixture was extracted with ethyl acetate, the organic layer was dried on sodium sulphate and after filtration was evaporated to dryness. The residue was purified by flash column chromatography eluting with DCM and DCM/MeOH: 98/2 to give the title compound as an oil (1.1 g, 68.7%). LC/MS: m/z 308 (M+H)+, Rt: 3.14 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].[H][H].[CH:16](I)([CH3:18])[CH3:17]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:16]([CH3:18])[CH3:17])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)I
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
To a solution of 0.67 g of 2,6-dichloropurine in 5 mL of dry DMF at room temperature was added 0.16 gms (1.1 eq.) of 50% sodium hydride/oil powder.Upon cessation of hydrogen evolution, a large excess (2 mL) of isopropyl iodide was added to the anionic solution. This reaction solution was stirred for three days at ambient temperature. The reaction was quenched with 30 mL of water and extracted with ethyl acetate (3×50 mL). The organic extracts were combined and back washed with 3×50 mL of waterfollowed by 20 mL of brine. The ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated. The compound was subjected to variable gradient flash chromatography on silica gel with hexane/ethyl acetate mixtures and yielded 0.37 gms of desired N-9 product (45%) and 0.08 gms of the N-7 isomer(10%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][CH2:10][C:11]1[NH:12][C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:14]([C:16]([OH:19])([CH3:18])[CH3:17])[N:15]=1)[CH3:8].[C:25]([N:44]1[C:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[C:55]2[CH:62]=[CH:61][C:58]([CH2:59]Br)=[CH:57][CH:56]=2)=[N:47][N:46]=[N:45]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C)C(=O)C.O>[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:59][C:58]2[CH:57]=[CH:56][C:55]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[C:48]3[N:44]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:45]=[N:46][N:47]=3)=[CH:62][CH:61]=2)[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:14]([C:16]([OH:19])([CH3:17])[CH3:18])[N:15]=1)[CH3:8]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
217 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 450 mg of ethyl 2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate [prepared as described in Preparation 44(iii)] in 5 ml of N,N-dimethylacetamide, and the mixture was stirred for 30 minutes. At the end of this time, a solution of 1.47 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 10 ml of N,N-dimethylacetamide was added dropwise to the mixture. The mixture was stirred at room temperature for 2 hours, after which it was mixed with ethyl acetate and water and shaken. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.2 g of the title compound as an amorphous powder.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:6]([CH3:38])[CH2:7][CH2:8][CH:9]([OH:37])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:36])=[CH:20]/[CH:21]=[CH:22]/[C:23]([OH:35])([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([OH:31])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].N1[CH:43]=[CH:42]N=C1.[CH2:44]([Si:46](Cl)([CH2:50][CH3:51])[CH:47]([CH3:49])[CH3:48])[CH3:45]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[CH:6]([CH3:38])[CH2:7][CH2:8][CH:9]([O:37][Si:46]([CH2:42][CH3:43])([CH2:44][CH3:45])[CH:47]([CH3:49])[CH3:48])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:36])=[CH:20]/[CH:21]=[CH:22]/[C:23]([OH:35])([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([O:31][Si:46]([CH2:50][CH3:51])([CH2:44][CH3:45])[CH:47]([CH3:49])[CH3:48])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)C(OC(C)=O)C=CC1C
Reactant: CC[Si](Cl)(CC)C(C)C
Agent: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)C(OC(C)=O)/C=C/C1C
Agent: CCC(O[Si](CC)(CC)C(C)C)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)C(C)C)CCC(C)C(OC(C)=O)/C=C/C1C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(O[Si](CC)(CC)C(C)C)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)C(C)C)CCC(C)C(OC(C)=O)C=CC1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (8E,12E,14E)-7-acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (177 mg, 0.33 mmol) and imidazole (450 mg, 6.61 mmol) in methylene chloride (6 mL) was cooled to 5° C. A solution of diethylisopropylsilyl chloride (272 mg, 1.65 mmol) in methylene chloride (1.5 mL) was added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate, and then the organic layer was washed with water. The resulting organic layer was washed with brine dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 100 μm; ethyl acetate-hexane, 1:19->1:9->1:6->1:4) to obtain the title compound (242.9 mg, 93%) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:13][I:14]>>[I-:14].[CH3:13][N+:8]1([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CI
Reactant: CC1CCCCC1N1CCCC1
Product: CC1CCCCC1[N+]1(C)CCCC1
Product: [I-]
Yield: 94 %

Procedure:
N-(2-methylcyclohexyl)pyrrolidine as synthesized in Example 3 above, was quaternized with methyl iodide using the procedure described in example 4 with the exception of using N-(2-methylcyclohexyl)pyrrolidine in place of N-cyclohexylpyrrolidine. The quaternization procedure afforded the desired N-methyl-N-(2-methylcyclohexyl)pyrrolidinium iodide in 94% yield as an off-white solid. This N-methyl-N-(2-methylcyclohexyl)pyrrolidinium iodide was ion-exchanged with BIO-RAD AGR 1-X* resin as described in example 4 above. The ion-exchange procedure afforded the hydroxide solution of N-methyl-N-(2-methylcyclohexyl)pyrrolidinium cation in 91% yield as determined by titration analysis on a small aliquot.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:18]([O:20][C:21]#[C:22][Mg]Br)[CH3:19].C([O:27]C#C)C.C([Mg]Br)C>CCOCC.C1COCC1>[CH2:18]([O:20][C:21](=[O:27])[CH:22]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)[CH3:2])[CH3:19]
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: C#COCC
Reactant: CCOC#C[Mg]Br
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C=C(C)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 1 h

Procedure:
A solution of 23.2 g. of 4-acetyl-2',4'-difluorobiphenyl in 50 ml. of THF and 50 ml. of ether is added slowly dropwise to a solution of 17.5 g. of ethoxyethinylmagnesium bromide in 200 ml. of ether, prepared by reacting ethoxyacetylene with ethyl magnesium bromide. The mixture is stirred for 1 hour at 20°. The reaction product is hydrolyzed with ice water/ammonium chloride and extracted with ether. The combined ether extracts are dried over MgSO4 and evaporated. Residual 1-ethoxy-3-(2',4'-difluoro-4-biphenylyl)-butyn-3-ol is dissolved in 200 ml. of 95% ethanol and 0.05 g. of solid CO2 is added to the solution and the mixture is left to stand for 12 hours at 20°. The customary work up gives 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid ethyl ester, m.p. 54°-56°.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:8]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[C:7](=[O:21])[C:6]2([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[NH:5]1.[H][H].C[Si](C)(C)[O:31][CH2:32][CH2:33][CH2:34][CH2:35]I>CN(C)C=O>[O:3]=[C:4]1[N:8]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:10]=2)[C:7](=[O:21])[C:6]2([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:5]1[CH2:35][CH2:34][CH2:33][CH2:32][OH:31]
Reactant: N#Cc1ccc(N2C(=O)NC3(CCCCC3)C2=O)cc1C(F)(F)F
Reactant: C[Si](C)(C)OCCCCI
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2C(=O)N(CCCCO)C3(CCCCC3)C2=O)cc1C(F)(F)F
Reaction time: 0.08 h
Yield: 76.6 %

Procedure:
28 mg of 50% sodium hydride and 3 ml of dimethylformamide are introduced, agitation is carried out at ambient temperature for 5 minutes, 170 mg of the product obtained in Stage 3 above is added and the whole is left under agitation for 20 minutes until the release of hydrogen has stopped. 202 mg of O-trimethylsilyl-4-iodo-n-butanol is then added and the reaction medium is left under agitation for 2 hours. After hydrolysis using saturated ammonium chloride, extraction is carried out with ethyl acetate. The organic phases are combined, washed with water, dried, filtered and concentrated. The residue is solubilized in 10 ml of methanol and 0.5 ml of 2N hydrochloric acid is added. After agitation for 5 minutes, the solution is neutralized by the addition of saturated sodium hydrogen carbonate and extraction is carried out with ethyl acetate. The organic phases are combined, dried, filtered and concentrated. After chromatography on silica eluting with methylene chloride-acetone: 9-1, 158 mg of expected product (white solid) is obtained. M.p.=145° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[C:13]4[CH:26]=[CH:25][S:24][C:14]=4[C:15](=[O:23])[NH:16][C:17]=3[CH:18]=[CH:19][C:20]=2[O:21]C)=[CH:7][CH:6]=1)[CH3:4].B(Br)(Br)Br.C(Cl)[Cl:32]>>[ClH:32].[NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3[C:13]4[CH:26]=[CH:25][S:24][C:14]=4[C:15](=[O:23])[NH:16][C:17]=3[CH:18]=[CH:19][C:20]=2[OH:21])=[CH:9][CH:10]=1)[CH3:4]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CN)cc1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: CC(CN)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Temperature: 25 °C
Yield: 42 %

Procedure:
Following General Procedure F, 9-(4-(1-aminopropan-2-yl)phenyl)-8-methoxythieno[2,3-c]quinolin-4(5H)-one (120 mg, 0.33 mmol) in CH2Cl2 at 0° C. was added BBr3 (1.0 M in CH2Cl2, 5 mL, 5 mmol) and the reaction was warmed to room temperature for 4 h. The reaction was quenched by pouring onto water or ice-water and the resulting mixture was concentrated and purified by preparatory HPLC (C18 silica, acetonitrile/water (with 0.05% TFA) gradient). The desired product was dissolved in aqueous HCl, concentrated and dried under high vacuum to afford the desired product as a light yellow solid (48 mg, 42%): 1H NMR (500 MHz, CD3OD) δ 7.57 (dd, J=12.7, 6.7 Hz, 2H), 7.47 (d, J=6.9 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.18 (d, J=8.9 Hz, 1H), 6.15 (d, J=5.4 Hz, 1H), 3.28-3.17 (m, 3H), 1.50 (d, J=6.1 Hz, 3H); ESI MS m/z 351 [C20H18N2O2S+H]+; HPLC >99% (AUC), tR=8.25 min.