Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH:28]([C:32]([OH:34])=O)[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:36]([NH2:38])[CH3:37].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][C:14]([F:18])([F:17])[CH2:15][CH2:16]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH:28]([C:32]([NH:38][CH2:36][CH3:37])=[O:34])[CH2:27]3)(=[O:24])=[O:25])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOC(C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)C1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)CCO1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)morpholine-2-carboxylic acid (500 mg, 1 mmol) (see following steps B and C for preparation) was dissolved in DMF (10 mL). Ethylamine hydrochloride (122 mg, 1.5 mmol) and N,N-diisopropylethylamine (1 mL, 5 mmol) were added and the reaction mixture was cooled down to 0° C. HATU (456 mg, 1.2 mmol) was added portionwise and the reaction was stirred overnight at room temperature. The reaction was concentrated, extracted with EtOAc and washed with sodium bicarbonate, water then brine and dried over anhydrous sodium sulfate. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 200 mg (40%) as white solid racemic mixture of the title compound. The two enantiomers were separated on a chiral OD 5 microns column using 20% ethanol/hexane. Example 112 (isomer-1): 1H NMR (400 MHz, METHANOL-D4) δ 1.04 (t, J=7.23 Hz, 3 H), 1.46-1.56 (m, 2 H), 1.57 (s, 9 H), 1.61-1.70 (m, 3 H), 1.70-1.81 (m, 1 H), 1.98-2.08 (m, 2 H), 2.12-2.23 (m, 1 H), 2.39 (m, 1 H), 2.74 (q, J=7.23 Hz, 2 H), 3.17 (dd, J=7.23, 3.91 Hz, 2 H), 3.68 (m, 1 H), 3.87-3.94 (m, 1 H), 4.01 (dd, J=10.45, 2.83 Hz, 2 H), 4.40 (d, J=7.62 Hz, 2 H), 7.64 (dd, J=8.59, 1.56 Hz, 1 H), 7.77 (d, J=8.59 Hz, 1 H), 8.03 (d, J=1.76 Hz, 1 H); MS (APPI) (M+H)+=527.3; Anal. Calc. for C21H29F2N3O3S+4.9C2HO2F3+5.0H2O+2.7 CH3CN: C, 39.47; H, 4.14; N, 6.31. Found: C, 39.48; H, 4.14; N, 6.30.
Reaction SMILES: [O-:1]CC.[Na+].[Na].Br[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[N:11]=1.Cl>CC(C)=O.C(O)C>[O:1]=[C:7]1[NH:11][C:10]2[C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=[CH:15][C:9]=2[S:8]1
Reactant: CC[O-]
Reactant: Brc1nc2c(Oc3ccccc3)cccc2s1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Solvent: CCO
Product: O=c1[nH]c2c(Oc3ccccc3)cccc2s1
Reaction time: 0.75 h

Procedure:
To a sodium ethoxide solution prepared with sodium metal (460 mg) and anhydrous ethanol (50 ml) was added 2-bromo-4-phenoxybenzothiazole (3.0 g). The mixture was refluxed with stirring 45 minutes. The solvent was removed under reduced pressure to give a residue, to which was added 10% hydrochloric acid (30 ml) and acetone (50 ml). The resultant mixture was refluxed with stirring for 2 hours. The solvent was removed under reduced pressure to give a residue, which was recrystallized from a mixture of ethanol and n-hexane to give crystalline 2-oxo-4-phenoxybenzothiazoline (2.0 g).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:19]=1[NH2:20].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[C:36]([CH3:42])=[N:35][CH:34]=[C:33]2[CH2:43][C:44](O)=O>CO.O>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[C:36]([CH3:42])=[N:35][CH:34]=[C:33]2[CH2:43][C:44]1[NH:13][C:14]2[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:19]=2[N:20]=1
Reactant: COc1cc2c(CC(=O)O)cnc(C)c2cc1OC
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc2c(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)cnc(C)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.201 g, 1.30 mmol) is added to 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (0.223 g, 1.05 mmol)) and (6,7-dimethoxy-1-methyl-isoquinolin-4-yl)-acetic acid (0.25 g, 0.96 mmol) in methanol (5 ml) and water (1 ml) and the mixture is stirred at ambient temperature for 16 hours. The methanol is evaporated and the resultant solid collected by filtration, taken into methanol (5 ml) and 5M aqueous sodium hydroxide (0.5 ml) is added. The reaction is heated to reflux for 1 hour, cooled to ambient temperature and evaporated. The residue is dissolved in water and extracted with dichloromethane, the combined organic extracts are dried over sodium sulfate and evaporated to afford 8-(6,7-dimethoxy-1-methyl-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione, M+ 437.
Reaction SMILES: C([O:3][C:4](=O)[C@@H:5]([NH2:18])[C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[OH:7])C.[BH4-].[K+].Cl.O>CO>[NH2:18][C@H:5]([CH2:4][OH:3])[C@@H:6]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=1)[OH:7]
Reactant: CCOC(=O)[C@@H](N)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Temperature: 25 °C

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound VIc) (10 g, 0.0348 moles) in methanol (about 100 mL) is reacted in a reaction vessel with potassium borohydride (about 2.8 g, 0.0522 moles) over about 6 hours while maintaining the temperature below about 60° C. The reaction is cooled to ambient room temperature and about 1N HCl and water (about 75 mL) are added. Thereafter, the solution is heated to evaporate the methanol. Next, sodium hydroxide is added (about 25%), the resulting solids are filtered and washed with water, then dried to yield (1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propanediol (Compound V wherein R1 is methylsulfonyl).
Reaction SMILES: [H-].[Na+].[C:3]1(=[N:15][OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[CH2:21][CH2:22]Cl)([CH3:19])[CH3:18].C(O)(=O)/C=C/C([O-])=O>>[CH:17]([N:20]([CH2:21][CH2:22][O:16][N:15]=[C:3]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH:24]([CH3:26])[CH3:25])([CH3:19])[CH3:18]
Reactant: ON=C1CCCCCCCCCCC1
Reactant: CC(C)N(CCCl)C(C)C
Agent: O=C([O-])/C=C/C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)N(CCON=C1CCCCCCCCCCC1)C(C)C

Procedure:
Starting from 2.4 g. (0.1 moles) of sodium hydride, 19.73 g. (0.1 moles) of cyclododecanone oxime and 17.95 g. (0.11 moles) of 1-diisopropylamino-2-chloroethane the title compound is prepared as in Example 1. Yield: 22.1 g. (68.20%); b.p.: 164°-166° C./0.6 torr. Hydrogen fumarate, m.p.: 120°-121° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1([C@H:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C@H:31]([NH:33][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:23])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: C[C@@H](N)c1ccccc1
Product: C[C@@H](NC(=O)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1)c1ccccc1

Procedure:
The product from Example 33B and (R)-1-phenylethanamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 437 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][NH:16][C:17](=O)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:36][C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CNC(=O)Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cnc(Cc3ccccc3)s2)CC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
A mixture of 1-t-butyloxycarbonyl-4-(2-phenylacetamido)acetylpiperidine (595 mg, 1.653 mmol) from Step E and Lawesson's reagent (607 mg, 1.66 mmol) in 5 mL of toluene was heated to 120° C. for 3.5 h. After cooling, 3:1 mixture of ethyl acetate and methylene chloride and saturated sodium bicarbonate solution were added and the mixture was stirred for 0.5 h. The organic phase was separated and washed with brine. Solvent removal gave a crude product which was purified on silica gel using 2:3 mixture of ethyl acetate-hexane as solvent to give 330 mg of the desired product.
Reaction SMILES: [C:1]([O:7][C@H:8]([CH3:13])[C:9]([O:11]C)=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:14][CH2:15]C([O-])=O.[Na+].C(N(CC)CC)C.C([Mg]Cl)(C)(C)C.Cl>C(#N)C.C(OCC)(=O)C.O.C1COCC1>[Cl:14][CH2:15][C:9](=[O:11])[C@H:8]([O:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])[CH3:13]
Reactant: COC(=O)[C@@H](C)OC(=O)C(C)(C)C
Reactant: O=C([O-])CCl
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](OC(=O)C(C)(C)C)C(=O)CCl
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A mixture of 32.8 g (147 mmol) of methyl (R)-2-pivaloyloxypropionate, 30.5 g (261.8 mmol) of sodium chloroacetate, 26.4 g (261.55 mmol) of triethylamine, and 400 mL of THF was cooled in ice, and 299 g (523.5 mmol) of a 1.75 M solution of tert-butylmagnesium chloride was added dropwise thereto over a period of 3 hours. After the completion of the dropwise addition, the reaction was performed at 25° C. for another 2 hours, and the reaction solution was cooled in ice. A solution of 45 ml of concentrated hydrochloric acid/200 ml of water was added thereto, and subsequently 250 mL of ethyl acetate was added. Furthermore, concentrated hydrochloric acid was added for adjusting the pH to 6.0. Stirring was performed at 25° C. for 1 hour. The resulting ethyl acetate layer was separated, and 150 mL of ethyl acetate was added to the resulting aqueous layer to perform extraction again. The resulting ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 42.6 g of a crude product as an oil. A quantitative analysis was performed by HPLC. Thereby, 29.4 g of the title compound was obtained (yield: 82%, 98.7% e.e.) (HPLC, column: YMC-A302 manufactured by YMC Co. Ltd.; mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=6/4, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 5 minutes) 1H-NMR (400 MHz, CDCl3) δ: 1.25 (s, 9H), 1.46 (d, 1H, J=6.6 Hz), 4.30 (s, 2H), 5.27 (q, 1H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:10]1[C:11]2[C@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH3:29]
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: CCOC(=O)CI
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 100 °C
Yield: 59.4 %

Procedure:
A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 355 mg, 1.16 mmol) and ethyl iodoacetate (700 μL, 5.91 mmol) in dimethylformamide (5 mL) was heated at 100° C. for 2 h. The solvent was evaporated, dichloromethane (50 mL) was added and the solution was washed with 1:1 water/aqueous sodium thiosulfate (25 mL). The aqueous layer was back-extracted with dichloromethane (2×25 mL) and the combined organic layers were washed with brine (25 mL). The solution was dried (magnesium sulfate), filtered, evaporated, purified using an ISCO 12 g column, eluting with 40-100% ethyl acetate/petroleum ether, and dried under high vacuum at 75° C. to give [(4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-3-oxo-2,3,4,5,6,7-hexahydro-4,7-methano-indazol-1-yl]-acetic acid ethyl ester (269 mg, 59%) as an off-white solid. ES(+)-MS (M+H) 391.
Reaction SMILES: CCCCCC.[CH2:7]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([O:27][CH3:28])[CH:21]=[CH:20]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:29][S:30]SC.[Cl-].[NH4+]>C1COCC1>[CH2:7]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([O:27][CH3:28])[C:21]([S:30][CH3:29])=[CH:20]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CSSC
Reactant: CCCCCCCCCCc1ccc2cc(OC)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCc1ccc2cc(OC)c(SC)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.3 %

Procedure:
A hexane solution of 1.57 Mn—BuLi (28 ml, 44 mmol) was added to a THF (100 ml) solution of 6-n-decyl-2-methoxynaphthalene (compound (3)-64) (12 g, 40 mmol) at −78° C., and the solution was stirred at room temperature for 1 hour. Dimethyl disulfide (4.4 ml, 48 mmol) was added to the solution at −78° C., and the solution was stirred at room temperature for 18 hours. The reaction solution was added to a saturated ammonium chloride aqueous solution (50 ml), and extracted with ether (30 ml×3). The extracted solutions obtained by repeating the extraction 3 times were collected, washed with a saturated saline water (30 ml×3), and dried with MgSO4. The dried product was condensed with an evaporator to obtain 6-n-decyl-3-methylthio-2-methoxynaphthalene (compound (4)-64) (15.2 g, quantitative) as a yellow oil. The compound can be used in the subsequent reaction without performing further refining.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[C:6]1([C:12]2[NH:13][C:14]3[C:19]([C:20]=2[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>S(=O)(=O)(O)O>[C:6]1([C:12]2[NH:13][C:14]3[C:19]([C:20]=2[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][C:17]([N+:1]([O-:4])=[O:2])=[CH:16][CH:15]=3)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)CCCc1c(-c2ccccc2)[nH]c2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCc1c(-c2ccccc2)[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 5 °C
Yield: 30 %

Procedure:
A solution of 1.19 g (4.10−3 mol) of sodium nitrate in 50 ml of concentrated sulfuric acid is added at 0-5° C., with stirring, to a solution of 3.67 g (13.15.10−2 mol) of 2-pheny-1H-indole-3-butanoic acid in 200 ml of concentrated sulfuric acid. Stirring is maintained at 5° C. for 20 min and the reaction medium is then poured into a mixture of water and ice. The yellow precipitate formed is filtered off and washed on the filter with water and with a small amount of petroleum ether. The product is then dried under reduced pressure and purified by chromatography on silica gel using a hexane/ethyl acetate mixture (1/1) as the eluent to give 1.3 g of the expected product in the form of a yellow solid with a yield of 30%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5]O.N1C=CC=CC=1.P(Br)(Br)[Br:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][Br:20]
Reactant: COc1ccc(CO)c(OC)c1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(CBr)c(OC)c1
Temperature: 4 °C
Reaction time: 0.75 h

Procedure:
2 g (11.77 mmol) of 2,4-dimethoxybenzyl alcohol (Aldrich, Steinheim, FRG) are dissolved in 30 ml of abs. toluene, and this solution is treated with 0.3 ml of pyridine. The clear solution is cooled down to approximately 4° C. and 1.12 ml (0.992 equivalents) of PBr3 in 6 ml of abs. toluene are added dropwise to it over the space of 30 min. After a further 45 min, the reaction solution is poured onto ice-water and the whole is extracted with ether. The organic phase is washed, in succession, with water, sat. sodium bicarbonate solution and saline (all being cold). The combined aqueous phases are reextracted with ether. The combined organic phases are dried over Na2SO4 and the ether is removed on a RE at about 30° C. The toluene solution which remains, and which contains the title compound, is immediately subjected to further use. TLC (hexane:ethyl acetate, 1:1): decomposition.
Reaction SMILES: [Si]([O:8][CH:9]([C:19]1[CH:20]=[CH:21][C:22]([C:25](=O)[CH2:26][CH2:27][C:28](=O)[CH:29]([C:36]2[CH:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][N:37]=2)[CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[N:23][CH:24]=1)[CH2:10][O:11][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.C([O-])(=O)C.[NH4+:50].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH:31]1([CH2:30][CH:29]([C:28]2[NH:50][C:25]([C:22]3[N:23]=[CH:24][C:19]([CH:9]([OH:8])[CH2:10][OH:11])=[CH:20][CH:21]=3)=[CH:26][CH:27]=2)[C:36]2[CH:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][N:37]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)CCC(=O)c2ccc(C(CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)cn2)nc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1ccc(C(CC2CCCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 53.4 %

Procedure:
To a solution of 1-[5-(1,2-bis{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyridin-2-yl]-6-cyclopentyl-5-[5-(methylsulfanyl)pyridin-2-yl]hexane-1,4-dione (682 mg) in acetic acid (7 mL) was added ammonium acetate (1.26 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. To a solution of the obtained residue in tetrahydrofuran (4 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 8.16 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (230 mg, yield 53%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (99:1, volume ratio). MS: 424 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]([C:8]1[C:25]2=[C:26]3[C:15]([C:16]4[C:27]5[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=5)[CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1)=O.O.NN.[OH-].[K+].Cl>C(O)COCCO.O>[C:8]1([CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])[C:25]2=[C:26]3[C:15]([C:16]4[C:27]5[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=5)[CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1
Reactant: COC(=O)CCC(=O)c1ccc2cccc3c4cccc5cccc(c1c23)c54
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)CCCc1ccc2cccc3c4cccc5cccc(c1c23)c54
Temperature: 140 °C
Yield: 68.8 %

Procedure:
To a suspension of 3-perylenoyl propanoic acid methyl ester (360.2 mg, 0.983 mmol) in 2.0 mL diethylene glycol, 98% hydrazine hydrate (150.6 μL, 2.949 mmol) and powdered potassium hydroxide (275.3 mg, 4.916 mmol) were added. The reaction mixture was heated to 140° C. for 2 hrs, then to 190° C. and kept over night, cooled to room temperature, diluted with 20 mL water, acidified with 0.5 mL concentrated hydrochloric acid, the precipitate formed was filtered, washed with water to pH 7.0, dried on air or washed with acetone, then with a mixture chloroform-methanol (8:2 by vol.). The filtrate was concentrated in vacuo. The crude product was applied onto a silica gel column and eluted with chloroform to 20% methanol in chloroform to give perylenebutanoic acid (228.9 mg, 68.8%). Rf 0.66 (system 3). 1H-NMR (CDCl3/DMSO-d6, 20:1) (δ, ppm): 1.92 (quin., 2H, 3-CH2), 2.38 (t, 2H, J 7.00 Hz, 2-CH2), 3.03 (t, 2H, J 7.00 Hz, 4-CH2), 7.41 (d, 1H, J 7.82 Hz, Ar), 7.43-7.64 (m, 3H, Ar), 7.76 (d, 1H, J 3.42 Hz, Ar), 7.80 (d, 1H, J 3.41 Hz, Ar), 8.00 (d, 1H, J 8.49 Hz, Ar), 8.21-8.60 (m, 4H, Ar).
Reaction SMILES: [CH2:1]([O:17]CCCOS(C)(=O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCCCCCCCCCCCCCOCCCOS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C=CCCCCCCCCCCCCCCO
Temperature: 97.5 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
Substitution of (32) with Bz-c-CDV. 1.7 g (4.6 mmol) of Bz-c-CDV was dissolved in 10 mL of NMP and 1.2 mL (7 mmol) of DIPEA was added to it followed by 9 g (23.9 mmol) of 32. The reaction was heated at 95-100° C. for 24 h at which time the TLC showed the product together with some Bz-c-CDV. At this stage the reaction was allowed to proceed for an additional 4 h, but as the TLC did not show much progress, the reaction mixture was cooled to room temperature and the solvent was evaporated under high vacuum. The residue was purified by combiflash using chloroform/MeOH as eluent to furnish 1.33 g of target product 26 as yellow oil in 45% yield.
Reaction SMILES: NC1CC2[C:5](=CC=CC=2)[N:4](CC2CO2)[C:3]1=O.[Cl:17][C:18]1[S:44][C:21]2[NH:22][C:23]([C:25]([NH:27][CH:28]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:38][CH:39]([OH:42])[CH2:40]O)[C:29]3=[O:43])=[O:26])=[CH:24][C:20]=2[CH:19]=1>>[Cl:17][C:18]1[S:44][C:21]2[NH:22][C:23]([C:25]([NH:27][CH:28]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:38][CH:39]([OH:42])[CH2:40][N:4]([CH3:5])[CH3:3])[C:29]3=[O:43])=[O:26])=[CH:24][C:20]=2[CH:19]=1
Reactant: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reactant: NC1Cc2ccccc2N(CC2CO2)C1=O
Product: CN(C)CC(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21

Procedure:
The title compound was prepared by a two-step coupling-epoxide opening sequence. Standard amide bond formation analogous to Method 3 except using 3-amino-1-(oxiran-2-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (Method 19) as amine and 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Method 9) as the acid component formed the title compound as a white solid which was used without further purification. The crude amide product (150 mg) was dissolved in EtOH (5 mL) followed by addition of dimethylamine in EtOH (5.0-6.0 M in EtOH, 0.5 mL) and the reaction was stirred overnight under argon. The reaction was diluted with EtOAc (40 mL) and sat. aqueous NaHCO3 (20 mL) and the separated organic layer was dried (MgSO4), filtered and evaporated to dryness. Purification by column chromatography (MeOH:DCM 2:9) afforded the title compound (41 mg) as a yellow solid.