Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([F:31])=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1.Br[CH2:33][CH2:34][CH2:35]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.ClCCl>[N:1]1([C@H:2]2[C@@H:10]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][C:6]([F:31])=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]4[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=4)(=[O:24])=[O:23])[CH:8]=3)[CH2:3]2)[CH2:35][CH2:34][CH2:33]1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2cc3c(cc2F)CC(N)C3Cc2ccccc2)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Cn1cnc(S(=O)(=O)NCCOc2cc3c(cc2F)C[C@@H](N2CCC2)[C@H]3Cc2ccccc2)c1
Reaction time: 0.33 h

Procedure:
To N-(2-(2-amino-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (17.9 mg, 0.040 mmol) was added 1,3-dibromopropane (4.90 μL, 0.048 mmol) and potassium carbonate (6.12 mg, 0.044 mmol) in water (1 mL)+1 drop acetonitrile were added. Microwave at 120° C. for 20 min. Evaporated acetonitrile, re-dissolved in dichloromethane and extracted with water and brine, dried over sodium bi-carbonate, filtered and evaporated to obtain the crude product, that was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 10% methanol in dichloromethane to afford cis-N-(2-{[2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide as a clear glass. m=4.0 mg (20%)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][CH:10]=[C:9]([CH2:13][CH2:14][NH2:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>C1COCC1>[CH3:2][O:3][C:4]1[C:12]2[O:11][CH:10]=[C:9]([CH2:13][CH2:14][NH:15][C:24](=[O:25])[O:26][CH2:27][CH3:28])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cl
Reactant: COc1cccc2c(CCN)coc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)NCCc1coc2c(OC)cccc12
Reaction time: 18 h
Yield: 82 %

Procedure:
To the suspension of 2-(7-methoxy-1-benzofuran-3-yl)ethanamine hydrochloride (from step 2) (0.432 g, 1.9 mmol) in dry THF, triethylamine (0.769 g, 7.6 mmol) was added followed by ethyl chloroformate (0.265 g, 2.4 mmol) and stirred for 18 hrs. Water was added to it and extracted with ethyl acetate. Organic layer was concentrated and purified on Silica gel column to yield Ethyl 2-(7-methoxy-1-benzofuran-3-yl)ethylcarbamate (82%).
Reaction SMILES: [O:1]=[C:2]1[CH2:15][C@@H:14]([CH3:16])[C@H:13](/[CH:17]=[CH:18]/[C@@H:19]([O:27]C2CCCCO2)[C:20]([CH3:26])([CH3:25])[CH2:21][C:22]#[C:23][CH3:24])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.C1COCC1>[OH:27][C@@H:19]([C:20]([CH3:25])([CH3:26])[CH2:21][C:22]#[C:23][CH3:24])/[CH:18]=[CH:17]/[C@@H:13]1[C@@H:3]([CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2](=[O:1])[CH2:15][C@H:14]1[CH3:16]
Reactant: CC#CCC(C)(C)[C@@H](/C=C/[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC#CCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
300 mg. of (5Z,13E)-(11R,15R)-9-oxo-15-(tetrahydropyran-2-yloxy)-11,16,16-trimethyl-5,13-prostadien-18-ynoic acid is agitated for 16 hours at room temperature with 10 ml. of a mixture of glacial acetic acid/water/THF (65/35/10); the reaction mixture is evaporated under vacuum and the residue purified by chromatography on silica gel. With methylene chloride/2% methanol, 180 mg. of the title compound is obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:3]=1N.[NH3:11].O.C(OCC)(=O)C.[N:19]1[CH:24]=CC=CC=1>C1C=CC=CC=1>[NH2:11][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:3]=1[C:24]#[N:19]
Reactant: N
Reactant: c1ccncc1
Reactant: CCc1ccc(N)c(Br)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCc1ccc(C#N)c(N)c1
Temperature: 160 °C
Reaction time: 16 h

Procedure:
A mixture of 2-bromo-4-ethylaniline (29.2 g) and cuprous cyanide (14.4 g) in dry pyridine (25.4 g) was stirred for 16 hours at 160° C. After cooling to 60° C., the resultant mixture was poured into a mixture (250 ml) of conc. aqueous ammonia and water (1:1) with stirring. To the resultant mixture was added ethyl acetate (300 ml) with stirring. Insoluble materials were filtered off. The organic layer was washed three times with water and with aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oily residue, to which was added benzene and concentrated under reduced pressure. These operations were repeated twice to remove pyridine. The resultant oily residue was subjected to a column chromatography using silica gel (developing solvent: a mixture of benzene and hexane (3:1)) to give 2-amino-4-ethylbenzonitrile (16.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11](OC)[O:12]C)=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncccc1C(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ncccc1C=O

Procedure:
To a solution of 3-(dimethoxymethyl)-2-pyridinecarboxylic acid methyl ester (1.02 g) in dioxane (20 mL) was added water (20 mL), followed by p-toluenesulfonic acid (0.3 g). This solution was heated at 55°-60° C. for 24 hours. The reaction mixture was cooled, diluted with water (50 mL), treated with aqueous saturated sodium bicarbonate until the pH was 7.5-8.0, and extracted with methylene chloride (3×). The combined organic extracts were washed with dilute brine (3×), dried (K2CO3) and evaporated to afford a light yellow solid which yielded 540 mg (62.5%) of an almost pure product.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16]([C@@H:18]3[CH2:22][C@@H:21]([O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([O:34][CH3:35])=[CH:26][N:25]=4)[CH2:20][NH:19]3)=[O:17])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:69]([O:73][C:74]([NH:76][CH:77]([C@H:81]([CH3:89])[CH2:82][CH:83]([CH3:88])[CH2:84][CH2:85][CH:86]=[CH2:87])[C:78](O)=[O:79])=[O:75])([CH3:72])([CH3:71])[CH3:70]>ClCCl>[CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16]([C@@H:18]3[CH2:22][C@@H:21]([O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([O:34][CH3:35])=[CH:26][N:25]=4)[CH2:20][N:19]3[C:78](=[O:79])[CH:77]([NH:76][C:74](=[O:75])[O:73][C:69]([CH3:72])([CH3:71])[CH3:70])[C@H:81]([CH3:89])[CH2:82][CH:83]([CH3:88])[CH2:84][CH2:85][CH:86]=[CH2:87])=[O:17])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2ncc(OC)c3ccccc23)CN1)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OC)c3ccccc23)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)—N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxamide (595 mg, 1.9 mmol) in dichloromethane (15 mL) was added HATU (755 mg, 1.9 mmol) followed by DIPEA (1.7 mL, 9.9 mmole) at room temperature. The reaction mass was stirred at the same temperature for 10 min. (3R)-2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoic acid (1.0 g, 1.9 mmole) was added to the reaction mass and the solution was stirred at room temperature for 30 min. The reaction mass was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get the crude compound. The crude compound was purified by silica gel chromatography (70% ethyl acetate in pet ether) to get desired product tert-butyl ((3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate as a pale yellow solid. MS: MS m/z 782.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[C:11]([CH3:13])[CH:10]=[N+:9]2[O-])=[CH:4][CH:3]=1.[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:18][C:10]1[C:11]([CH3:13])=[N:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1)(=[O:17])[CH3:16]
Reactant: Cc1c[n+]([O-])n(-c2ccc(F)cc2)n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1nn(-c2ccc(F)cc2)nc1C

Procedure:
2-(4-Fluorophenyl)-4-methyl-2H-1,2,3-triazole 1-oxide (i.e. the product of Step A, 6.6 g, 34 mmol) was added to acetic anhydride (47 mL, 500 mmol), and the reaction mixture was stirred at reflux for 28 h. The reaction was concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed successively with water and saturated aqueous sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to afford the title compound (7.8 g) as a beige solid. The title compound was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5](=[O:16])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Br[C:21](Br)([CH2:24][CH3:25])[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].[K+].[Br-:34]>CC(C)=O>[Br:34][CH2:23][CH2:22][CH2:21][CH2:24][CH2:25][O:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5](=[O:16])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(C=CC(=O)c2cccc(O)c2)cc1
Reactant: CCC(Br)(Br)CC
Reactant: [Br-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C=CC(=O)c2cccc(OCCCCCBr)c2)cc1

Procedure:
This compound (40) was prepared from 3′-hydroxy-4-methoxy-chalcone, 8 (2 g, 7.87 mmol), dibromo pentane (5.4 mL, 39.4 mmol) and potassium carbonate (2.2 g, 15.8 mmol) in dry acetone (100 mL) using the identical procedure as described for 39. Yield 2.7 g (85%); mp 83-84° C.; MS (FAB) 403/405 (M++1); IR (KBr) 1650; 1H NMR (200 MHz, CDCl3) δ 7.78 (d, J=15.6 Hz, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.58 (d, J=7.4 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.39 (d, J=15.6 Hz, 1H), 7.10 (dd, J=8.0 Hz, 2.3 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 4.04 (t, J=6.2 Hz, 2H), 3.85 (s, 3H), 3.44 (t, J=6.7 Hz, 2H), 1.99-1.81 (m, 4H), 1.71-1.60 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2].[BrH:14].BrBr>C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])=[O:3]
Reactant: CC(=O)Nc1ccccc1C(C)=O
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
31 g (0.175 mol) of N-(2-Acetylphenyl)-acetamide (prepared by acylation of 2-aminoacetophenone with acetyl chloride as described by Fuerstner, Alois; Jumbam, Denis N.; Tetrahedron; 48; 29; 5991-6010, (1992)) was dissolved in 200 ml of glacial acetic acid. 127 ml of 33% strength HBr in glacial acetic acid was added and then, at room temperature, 8.75 ml (0.175 mol) of bromine was slowly run in. The mixture was stirred at room temperature overnight. The mixture was stirred into 1.5 l of ice-water, and the precipitated product was filtered off with suction, thoroughly washed with ice-water and dried in vacuo. The crude product contained, according to HPLC and NMR, some precursor and dibrominated product, but was pure enough (about 85% strength) for further reaction.
Reaction SMILES: [NH2:1][CH:2]([CH3:21])[CH2:3][N:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)(=O)C>[C:22]([NH:1][CH:2]([CH3:21])[CH2:3][N:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Solvent: CC(=O)O
Product: CC(=O)NC(C)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Temperature: 0 °C
Yield: 83 %

Procedure:
A mixture of 5 g of 2-(2-aminopropyl)-4-phenyl-1(2H)-isoquinolone, 10 ml of acetic anhydride and 10 ml of glacial acetic acid was warmed on a water bath for 3 hours and the resulting reaction mixture was poured into ice-water. The precipitated crystals were extracted with dichloromethane, and the extract was thoroughly washed successively with a 5% aqueous solution of sodium hydroxide and water, and then dried over anhydrous sodium sulfate. The crystals obtained by distilling off the solvent was recrystallized from ethanol to obtain 4.8 g (83% yield) of 2-(2-acetamidopropyl-4-phenyl-1(2H)-isoquinolone having a melting point of 177° C. as colorless needles.
Reaction SMILES: B.C1COCC1.C1(C)C=CC=CC=1.[Br:14][C:15]1[C:16]([O:29][CH3:30])=[C:17]([C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=1>CO>[Br:14][C:15]1[C:16]([O:29][CH3:30])=[C:17]([C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=1
Reactant: CCCCCCC(=O)c1cccc(Br)c1OC
Agent: B
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCC[C@H](O)c1cccc(Br)c1OC
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Under room temperature, a 1M borane THF solution (48 mL) was added to an R-CBS 1M toluene solution (120 mL). 1-(3-Bromo-2-methyloxyphenyl)heptane-1-one (7, 13 g) was added, and the mixture was stirred for 1 hour. Methanol was added, a solvent was distilled off, and the residue was purified by chromatography to obtain (S)-1-(3-bromo-2-methyloxyphenyl)heptane-1-ol (8, 12.86 g, yield 75%).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: Clc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc(Cl)cc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.6 g--see Preparation 8), 4-chlorophenethyl bromide (0.46 g), anhydrous potassium carbonate (0.6 g) and acetonitrile (20 ml) was heated under reflux for 1.25 hours. The mixture was partitioned between 10% aqueous potassium carbonate (10 ml) and dichloromethane (30 ml), the layers were separated, and the aqueous layer was extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to Rive a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.43 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:14][C:13]([O:15][C@@H:16]4[CH:23]5[CH2:24][N:19]6[CH2:20][CH:21]([CH2:25][CH:17]4[CH2:18]6)[CH2:22]5)=[N:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:34])C=1>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:14][C:13]([O:15][C@@H:16]4[CH:17]5[CH2:18][N+:19]6([O-:34])[CH2:20][CH:21]([CH2:22][CH:23]4[CH2:24]6)[CH2:25]5)=[N:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cc2cc(-c3cnc(OC4C5CC6CC4CN(C6)C5)s3)ccc2[nH]1
Solvent: CO
Product: [O-][N+]12CC3CC(C1)C(Oc1ncc(-c4ccc5[nH]ccc5c4)s1)C(C3)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the product of Example 28A (105 mg, 0.30 mmol) in methanol (4 mL) was treated with 3-chloroperbenzoic acid (mCPBA; 70-75%; 71.0 mg, 0.30 mmol; Aldrich) and stirred at ambient temperature for 4 hours. The resulting material was purified by preparative HPLC [Waters® XTerra RP18 column, 5μ, 30×100 mm, flow rate 40 mL/minutes, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide] to afford the title compound: 1H NMR (300 MHz, methanol-D4) δ ppm 1.70-2.02 (m, 2H), 2.10-2.29 (m, 1H), 2.29-2.47 (m, 1H), 2.58-2.78 (m, 2H), 3.57-3.67 (m, 5H), 5.32 (t, J=3.3 Hz, 1H), 6.46 (d, J=3.0 Hz, 1H), 7.26 (d, J=3.3 Hz, 1H), 7.27-7.31 (m, 2H), 7.36-7.42 (m, 1H), 7.66 (d, J=1.3 Hz, 1H), MS (DCI/NH3) m/z=368 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=[C:11]([Cl:23])[C:10]=1[CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C1COCC1>[CH2:16]([O:15][C:13]1[N:12]=[C:11]([Cl:23])[C:10]([CH2:24][CH3:25])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]=1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCc1c(OCc2ccccc2)cc(OCc2ccccc2)nc1Cl
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1c(Cl)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
To a solution of the intermediate obtained in Step 2 (7.7 g, 21.8 mmol) in THF (80 mL), at −78° C. was added n-BuLi (21.8 mL, 54.4 mmol) dropwise, and stirred for additional 15 min. at −78° C. after the addition. Benzyl chloroformate (4.7 mL, 32.6 mmol) was then added and the resulting mixture was stirred for 10 min before the cooling bath was removed. The mixture was allowed to warm to room temperature while stirring. The reaction was quenched with a solution of NH4Cl (5 mL), diluted with ethyl ether (150 mL), washed with water (2×30 mL) and brine (30 mL). After drying with Na2SO4, the solvent was removed and the residue was chromatographed (silica gel, ethylacetate in hexanes, 0-5%) to provide product as white crystalline material (6.9 g, yield: 65%).
Reaction SMILES: C(OC([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH3:49][NH:50][O:51][CH3:52]>C(OCC)(=O)C.CN(C)C=O>[CH3:52][O:51][N:50]([CH3:49])[C:12]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:16][CH2:15]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of N-tert-butoxycarbonyl isonipecotic acid (1.50 g, 6.54 mmol, 1 eq), 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (1.88 g, 9.81 mmol, 1.5 eq), 1-hydroxybenzotriazole (1.33 g, 9.81 mmol, 1.5 eq), and N,N-dimethylformamide (26 ml) was treated with N,N-diisopropylethylamine (4.60 ml, 26.2 mmol, 4 eq). The resultant yellow solution was stirred at room temperature for 5 minutes, and then N,O-dimethylhydroxylamine hydrochloride (766 mg, 7.85 mmol, 1.2 eq) was added, and stirring continued for 92 hours. The reaction mixture was diluted with 100 ml of ethyl acetate and washed sequentially with 1 N aq. NaOH, 1 N aq. HCl and brine. The organic phase was dried over Na2SO4 and concentrated to give an oil which was used with no further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:19][S:20]([O:18][CH2:17][CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:10]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCCO)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A mixture of 3-(3-tert-butoxycarbonylaminophenyl)propanol (3.24 g, 12.9 mmol), methanesulfonylchloride (1.63 g, 14.2 mmol), triethylamine (1.44 g, 14.2 mmol) and ethyl acetate (50 ml) was stirred at room temperature for 1 hour. Then the reaction mixture was diluted with ethyl acetate and successively washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (50 g) with hexane-ethyl acetate (3:1) to give 3-(3-tert-butoxycarbonylaminophenyl)propyl methanesulfonate as a colorless oil (3.50 g, 82%).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]([OH:39])[C:10]1([OH:43])[CH2:40][CH2:41][CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:46](OC)([CH3:48])[CH3:47].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CC(C)=O>[CH2:1]([O:8][CH:9]1[C:10]2([CH2:40][CH2:41][CH3:42])[CH:11]([O:39][C:46]([CH3:48])([CH3:47])[O:43]2)[CH:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:14]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC1(O)C(O)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCC12OC(C)(C)OC1C(OCc1ccccc1)C(OCc1ccccc1)C(OCc1ccccc1)C2OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.6 %

Procedure:
21 (0.22 g, 0.37 mmol) was dissolved in 20 mL dry acetone. 5 mL (40.8 mmol) 2.2-dimethoxypropane and 48 mg (0.25 mmol) p-toluene sulfonic acid were added an the solution was stirred for three days at room temperature. Then the reaction was stopped by adding 150 μL (1.08 mmole) triethylamine. All volatile components were removed under reduced pressure and the residue was dissolved in t-butylmethyl ether and washed with 0.5 M phosphate buffer pH=7 and brine. The organic phase was dried over Na2SO4, filtered and dried under reduced pressure. The residue was purified by preparative HPLC (RP18, 94% MeOH, 40 mL/min, tRet=35.10 min) to give 22 (160 mg, 0.25 mmol, 69.3% yield) as a slightly yellow oil.