Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[Cl:30][C:31]1[N:36]=[C:35]([C:37]([OH:39])=O)[CH:34]=[CH:33][CH:32]=1>>[Cl:30][C:31]1[N:36]=[C:35]([C:37]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:39])[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)c1cccc(Cl)n1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 6-chloro-2-pyridinecarboxylic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(6-chloro-2-pyridylcarbonyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 503 (M-H)-.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN1CCOCC1.ClC1C=C(Cl)C(Cl)=CC=1[O:38][C:39](=O)[C@H:40]([CH:52]([CH3:54])[CH3:53])[NH:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].Cl>CS(C)=O>[NH:41]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:40]([C:39]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:38])[CH:52]([CH3:54])[CH3:53]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Tyrosylisoleucine (29.4 parts) is suspended in 300 parts by volume of dimethyl sulfoxide and 10.1 parts of N-methylmorpholine added. Carbobenzoxyvaline-2,4,5-trichlorophenyl ester is added and the mixture stirred 48 hours at room temperature. The clear solution is poured into 6000 parts by volume of 0.1 N hydrochloric acid and the mixture is stirred until the initially oily product solidifies. The crude product, after washing with water and drying, is boiled with 1 l. of ether. The desired tri-peptide, Z-Val-Tyr-Ile, is obtained as a white powder.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12](SC)[N:13]=[N:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1.[CH3:26][OH:27]>C(OCC)C>[CH3:26][O:27][C:12]1[N:13]=[N:14][C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: CO
Reactant: COc1ccc(-c2nnc(SC)nc2-c2ccc(OC)cc2)cc1
Agent: [Na]
Solvent: CCOCC
Product: COc1ccc(-c2nnc(OC)nc2-c2ccc(OC)cc2)cc1

Procedure:
Sodium, 3.0 g. (0.13 mole), was added piecewise under a nitrogen atmosphere to 100 ml. of dry methanol, followed by the addition of a slurry of 31.6 g. (0.1 mole) of 5,6-bis(4-methoxyphenyl)-3-methylthio-1,2,4-triazine in methanol. The reaction mixture was heated at reflux overnight. The reaction mixture was cooled and filtered. The filter cake and the filtrate were extracted with diethyl ether. The diethyl ether was concentrated, giving a solid, m.p. >220° C. The solid was taken up in diethyl ether and the insoluble material was removed by filtration. The filtrate was dried over anhydrous sodium sulfate and concentrated to give a solid residue which was recrystallized from petroleum ether to give 3-methoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, m.p. about 105°-108° C.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[Br:14][C:15]1[N:16]=[CH:17][N:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[O:12][CH3:13])[CH:19]=1
Reactant: COC(=O)c1ccc(F)c(OC)c1
Reactant: Brc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)ccc1-n1cnc(Br)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
A mixture of methyl 4-fluoro-3-methoxybenzoate (2.13 g), 4-bromo-1H-imidazole (3.74 g) and potassium carbonate (4.80 g) in DMF (20 mL) was stirred at 100° C. overnight, and allowed to cool to room temperature, and ethyl acetate and water were added. The aqueous layer was separated, and acidified with 6N hydrochloric acid (pH=3-4), and the resultant precipitate was collected by filtration to give the title compound (1.92 g).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[C:17]2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=2[O:15][N:14]=1>C(Cl)Cl>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[OH:6])[C:17]=2[CH:18]=1)([O-:24])=[O:23]
Reactant: COc1ccccc1-c1noc2ccc([N+](=O)[O-])cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2onc(-c3ccccc3O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 molar solution of boron tribromide in methylene chloride (15 mL, 15 mmol) is added to a solution of 3-(o-methoxyphenyl)-5-nitro-1,2-benzisoxazole (1.96 g, 7.25 mmol) in methylene chloride at 0° C. The reaction mixture is warmed to and stirred at room temperature for 2 hours and diluted with an ice/water mixture. The phases are separated and the aqueous phase is extracted with methylene chloride. The organic phase and methylene chloride extracts are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a solid, mp 172°-176° C.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[O:18][CH2:19][C@@H:20]1[O:24][C:23](=[O:25])[N:22]([C@H:26]([CH3:29])[CH2:27][OH:28])[CH2:21]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.O[C:52]1[CH:84]=[CH:83][C:55]([CH2:56][CH:57]2[S:61][C:60](=[O:62])[N:59]([C:63]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:58]2=[O:82])=[CH:54][CH:53]=1>C1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[O:18][CH2:19][C@@H:20]1[O:24][C:23](=[O:25])[N:22]([C@H:26]([CH3:29])[CH2:27][O:28][C:52]2[CH:84]=[CH:83][C:55]([CH2:56][CH:57]3[S:61][C:60](=[O:62])[N:59]([C:63]([C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=4)([C:70]4[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=4)[C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)[C:58]3=[O:82])=[CH:54][CH:53]=2)[CH2:21]1
Reactant: C[C@H](CO)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Yield: 34.1 %

Procedure:
A procedure similar to that described in Preparation 6 was repeated, except that 526 mg of tributylphosphine, 25 ml of anhydrous benzene, 900 mg of 2(R)-[5(R)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propanol (prepared as described in Preparation 44), 656 mg of azodicarbonyldipiperidine and 1.21 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione were used, to give 0.65 g of the title compound, melting at 74° C. to 81° C. and having [α]D =-29.0° (methanol, c=1.000).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>[Pd]>[CH2:26]([O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:44]([C:41]2[CH:40]=[CH:39][C:38]([O:37][CH3:36])=[CH:43][CH:42]=2)(=[O:46])=[O:45])[CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:21][CH:20]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(OC)cc2)cc1
Yield: 2.6 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (0.68 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-methoxybenzenesulfonyl chloride (575 mg) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-methoxybenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (3 19 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([F:24])([F:23])C([O-])=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH:19]([F:24])[F:23])=[CH:7][N:6]=1)=[O:4]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(=O)c1cnc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC(F)F)cn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 3.5 %

Procedure:
To 5-hydroxypyrazine-2-carboxylic acid methyl ester (2.0 g, 13 mmol) in a glass tube reaction vessel in DMF (26 mL) was added potassium carbonate (5.3 g, 39 mmol) and sodium 2-chloro-2,2-difluoroacetate (4.0 g, 26 mmol). The reaction vessel was capped and warmed to 100° C. The reaction was stirred for 30 minutes and cooled to room temperature. The reaction was filtered washing with EtOAc. The filtrate was concentrated in vacuo. The residue was taken up into EtOAc and washed with brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc/hex) to give methyl-5-(difluoromethoxy)pyrazine-2-carboxylate (0.09 g, 0.46 mmol) (0.40 g, 20%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:29]=[CH:28][C:27]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC(=O)c1ccc(-c2ccc3c(c2)C(C)(C)CC3=O)cc1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 4-acetylphenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 279.2; HRMS: calcd for C19H18O2+H+, 279.13796; found (ESI, [M+H]+), 279.1395.
Reaction SMILES: [OH:1][C:2]([CH3:25])([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH:5]1[O:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:7][CH2:6]1.[CH3:26]O>>[CH3:26][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:8]1[CH2:7][CH2:6][CH:5]([CH2:4][CH2:3][C:2]([OH:1])([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9]1
Reactant: CCCCCC(C)(O)CCC1CCC(CCCCCCCC(=O)O)O1
Reactant: CO
Product: CCCCCC(C)(O)CCC1CCC(CCCCCCCC(=O)OC)O1
Temperature: 0 °C
Yield: 98 %

Procedure:
XI (1.78 g, 0.00500 mole), methanol (25 ml), and ethyl ether-borontrifluoride complex (0.1 ml) were stirred and heated under reflux for 1 hour. After cooling, the reaction mixture was poured into ice-water (200 ml) and extracted with ether (50 + 50 + 25 ml). The combined ethereal extracts were washed with cold 2% aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). The ethereal solution was dried over sodium sulfate and evaporated to dryness from a water bath (60° C, 10 mm Hg). The residual yellowish oil (1.95 g) was distilled under reduced pressure to give 1.82 g (98%) of XII as a colourless oil, b0.03 160°-170° C, nD25 1.4625.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.[CH2:15]([N:17](CC)CC)[CH3:16].C(N)C>C(O)C>[CH:12]([C:4]1[N:3]=[C:2]([NH:17][CH2:15][CH3:16])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=1)([CH3:14])[CH3:13]
Reactant: CCN(CC)CC
Reactant: CC(C)c1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: CCN
Solvent: CCO
Product: CCNc1nc(C(C)C)nc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
4.72 g (0.02 mol) of 4,6-dichloro-2-isopropyl-5-nitro-pyrimidine are dissolved in 100 ml of abs. ethanol. At -30° C, 2 g (0.02 mol) of triethylamine and 0.9 g (0.02 mol) of ethylamine are added and the mixture is then stirred for 4 hours at -20° C and for 6 hours at 0° C. Subsequently the reaction mixture is concentrated to dryness and the product is taken up in water and extracted with ether, to yield 4.5 g of 2-isopropyl-4-ethylamino-5-nitro-6-chloro-pyrimidine; m.p. 50° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[O:5][C:6]1[N:11]=[C:10]([NH2:12])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:7]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[O:5][C:6]1[N:11]=[C:10]([NH:12][C:32](=[O:34])[CH3:33])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:7]=1
Reactant: Nc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)Nc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
To a round bottom flask fitted with a magnetic stirrer bar and rubber septum was added 2-(3,4-difluorophenoxy)-4-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Example 32) (20 mg, 0.04 mmol), 500 μL acetic anhydride and 10 mg of 4-(N,N-dimethylamino)pyridine (DMAP). The mixture was heated at reflux for 10 minutes and then worked up by removing the solvent/reagent under high vacuum. Flash chromatography on silica gel (70/30 hexanes/ethyl acetate) afforded the desired product. 1H-NMR 500 MHz (CDCl3): δ 2.41 (s, 3H), 7.06-7.67(m, 10H), 8.03 (bs, 1H).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]2[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1ccc(C#N)c(Cl)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(C#N)c(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.8 %

Procedure:
A suspension of 2-chloro-6-methylnicotinonitrile (2.0 g, 13.1 mmol) and 3-chlorophenylboronic acid (3.0 g, 19.7 mmol) in a mixture of toluene (20 mL), dioxane (20 mL), and 2N Na2CO3 (20 mL) was treated with tetrakis(triphenylphosphine)-palladium (0) (0.76 g, 0.65 mmol), heated to reflux, stirred for 16 hours, cooled to room temperature, and extracted with dichloromethane. The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3:1 hexanes/ethyl acetate to provide 3.2 g (100%) of the desired product. MS (DCI/NH3) m/z 229 (M+H)+; 1H NMR (CDCl3) δ 7.96 (d, 1H), 7.89 (m, 1H), 7.82 (m, 1H), 7.68-7.49 (m, 3H), 2.70 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.C1OC2(CCC(C3C4C(=CC=C(F)C=4)NC=3)=CC2)OC1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH:12]=1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: Fc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Product: O=C1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Yield: 88 %

Procedure:
This compound was prepared in the manner described above for intermediate 3c by replacing 4-(5-fluoro-1H-3-indolyl)-cyclohexanone ethylene ketal with 4-(5-fluoro-1H-3-indolyl)-cyclohex-3-enone-ethylene ketal (1.37 g) to afford 1.01 g (88%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]=2[C:6](=[O:16])[C:5]2[C:17](=[O:24])[C:18]3[C:23]([C:4]1=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:2].[BH4-].[Na+]>>[CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]=2[C:6](=[O:16])[C:5]2[CH:17]([OH:24])[C:18]3[C:23]([C:4]1=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:2]
Reactant: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(=O)c1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Product: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ethanolic solution of 5-ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (500 mg, 1,58 mmol) was added sodium borohydride (62 mg, 1.64 mmol) in portions followed by stirring at room temperature for 1 hour. After removing ethanol, the reaction mixture was diluted with water and extracted with chloroform twice. The combined organic layers were washed with saturated sodium chloride solution and dried with sodium sulfate followed by evaporating to remove chloroform. The title compound was obtained by crystallizing the residue from acetone-diethyl ether mixture. 1H-NMR (CDCl3) δ 1.35 (6H, d, CH(CH3)2), 1.72 (3H, t, NCH2CH3), 3.11 (1H, septet, CH), 4.79 (2H, q, NCH2), 5.86 (1H, s, H-11), 7.52-7.63 (3H, m, Ar—H), 7.85 (1H, dd, H-9)
Reaction SMILES: [C:1]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17](O)=[C:16]([Cl:21])[CH:15]=1.ClC1C=C(N)C=CC=1OCC1C=CC=CN=1>>[Cl:21][C:16]1[CH:15]=[C:14]([NH2:13])[CH:19]=[CH:18][C:17]=1[O:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: OCc1nccc2ccccc12
Reactant: Nc1ccc(O)c(Cl)c1
Agent: Nc1ccc(OCc2ccccn2)c(Cl)c1
Product: Nc1ccc(OCc2nccc3ccccc23)c(Cl)c1

Procedure:
Compound 11A was prepared from 4-amino-2-chloro-phenol 1-isoquinolinyl methanol by a route analogous to that used for the preparation of 1C.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].[C:6]1([CH3:12])[CH:11]=CC=C[CH:7]=1>>[C:6]([C:3]1[CH:2]=[C:1]([OH:5])[CH:3]=[CH:2][C:1]=1[OH:5])([CH3:7])([CH3:11])[CH3:12]
Reactant: Cc1ccccc1
Reactant: C=CC(=O)O
Product: CC(C)(C)c1cc(O)ccc1O
Yield: 5 %

Procedure:
Then, after adding a mixture of 17.2 g of acrylic acid and 150 g of toluene to the reaction mixture obtained above together with 1.0 g of t-butylhydroquinone, the reaction was further carried out under refluxing with stirring for 4 hours. After cooling to room temperature, the reaction mixture obtained was reprecipitated from 2 liters of methanol and the solid thus precipitated was collected by filtration and dried under reduced pressure to obtain 135 g of Macromonomer MM-1 having a weight average molecular weight of 6.8×103. ##STR51##
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C@@H:10]([CH:13]=[CH2:14])[CH2:11][OH:12].[H-].[Na+].[CH3:17]I>CN(C=O)C>[CH3:17][O:12][CH2:11][C@@H:10]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH:13]=[CH2:14]
Reactant: CI
Reactant: C=C[C@@H](CO)N1Cc2ccccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[C@@H](COC)N1Cc2ccccc2C1

Procedure:
To a solution of (S)-2-(Isoindolin-2-yl) but-3-en-1-ol (FIG. 2, No. 3)(2.0 g, 9.2 mmol) in 40 mL DMF was successively added NaH (442 mg, 18.4 mmol) at 0° C., stirred for ten minutes followed by addition of MeI (1.73 mL, 27.6 mmol) and then the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched by addition of ice cold water, extracted with diethyl ether, washed with brine and dried over anhydrous MgSO4. The organic layer was then concentrated in vacuo and purified by silica gel column chromatography using ethyl acetate/hexane (1:9) as eluent to furnish 1.83 g (86%) yield of (S)-2-(1-Methoxybut-3-en-2-yl) isoindoline (FIG. 2, No. 4) as a crystalline white solid. [Rf=0.56, ethyl acetate/hexane (3:7)]; [α]D25 −75.1 (c 1.0, CH2Cl2); IR (CH2Cl2) v: 1773, 1708, 1468, and 1384 cm−1; 1H NMR (400 MHz, CDCl3) δ:3.3 (s, 3H), 3.6 (m, 1H), 4.06 (m, 1H), 5.0 (m, 1H), 5.22-5.31 (m, 2H), 6.12 (ddd, J=7.32 Hz, 1H), 7.68 (dd, J=2.76, 5.48 Hz, 2H), 7.80 (dd, J=2.76, 5.48 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 52.8, 58.7, 71.3, 119.0, 123.2, 131.9, 132.1, 133.9, 168.0; HRMS (ESI-TOF) m/z calcd for C13H13NO3Na [M+Na+] 254.080. Found 254.079.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])[CH3:32]>O1CCCC1>[C:31]([O:34][CH2:35][C:36]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1)=[O:37])(=[O:33])[CH3:32]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(N)c3)cs2)c1
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(NC(=O)COC(C)=O)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution (4 mL) of the crude compound (310 mg, 0.88 mmol) obtained in Example 26a in tetrahydrofuran were added triethylamine (0.16 mL, 1.1 mmol) and acetoxyacetylchloride (145 mg, 1.1 mmol), and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=7/3) to give the title compound (270 mg, 72% in 2 steps) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][C:32]([OH:34])=[O:33])[CH:29]=2)[CH:24]=[CH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][C:32]([OH:34])=[O:33])[CH:29]=2)[CH:24]=[CH:23]1.[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][C:32]([OH:34])=[O:33])[CH:29]=2)[CH:24]=[CH:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: BrCc1ccccc1-c1ccccc1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccccc3-c3ccccc3)c2c1

Procedure:
The titled compound (41 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2-phenylbenzyl bromide according to the method of the process (7) of Example 4.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[CH2:7][N:6]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:4].[Li+].[OH-]>CO>[C:29]([O:28][C:26]([N:6]1[CH2:7][CH:8]([N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]([O:13][CH2:14][C:15]([Cl:16])([Cl:17])[Cl:18])=[O:12])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)C1CC(N(Cc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N(Cc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)CC1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of 4-[(benzyl)-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester in MeOH, cooled to 0 degree is added LiOH, and the mixture is stirred overnight. After removal of the solvent, the residue is acidified with HCl. The aqueous layer is extracted with EA, and the organic solution is dried, concentrated and purified to afford 4-[(benzyl)-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (20).