Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[N:10]=[N:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:26][CH2:25][C:20]4(OCCO4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:7]1)C.[NH2:28][CH2:29][C@@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[OH:31]>>[OH:31][C@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[CH2:29][NH:28][CH:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:8]3[N:9]=[N:10][N:6]([CH2:5][C:4]([OH:3])=[O:27])[N:7]=3)=[CH:16][CH:15]=2)[CH2:26][CH2:25]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)Cn1nnc(-c2ccc(N3CCC4(CC3)OCCO4)cc2)n1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(-c4nnn(CC(=O)O)n4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from ethyl{5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2H-tetraazol-2-yl}acetate (which was obtained in Example 48) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedures of Example 98 and Example 99 as a white solid; mp >240° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.45-1.65 (m, 2H), 1.90-2.10 (m, 2H), 2.50-3.10 (m, 5H), 2.95 (s, 3H), 3.65-3.85 (m, 2H), 4.89 (brd, J=8.3 Hz, 1H), 5.08 (d, J=15.9 Hz, 1H), 5.15 (d, J=15.9 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.95 (d, J=8.7 Hz, 2H), 7.09 (dd, J=8.3, 2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.87 (d, J=8.7 Hz, 2H); MS (ES) m/z: 532.1 (MH+); HRMS Calcd. for C21H30N7O4S(MH+): 532.1973. Found: 532.1965.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.[CH2:18]([N:21]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2)[C:19]#[CH:20].O>O1CCCC1.C(N(CC)CC)C.[Cu]I.[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>[O:11]=[C:5]1[NH:6][C:7]2[C:3](/[C:4]/1=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[C:2]([C:20]#[C:19][CH2:18][N:21]1[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=3)[CH:10]=[CH:9][CH:8]=2
Reactant: C#CCn1c(=O)c2ccccc2c2ccccc21
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C1Nc2cccc(C#CCn3c(=O)c4ccccc4c4ccccc43)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (from Example 71, infra) (50 mg, 0.15 mmol), and 5-(2-propynyl)-6(5H)-phenanthridinone (45 mg, 0.19 mmol) (prepared according to Walser et al., J. Med. Chem. 34(3), 1209-1221 (1991)) in 1 mL tetrahydrofuran and 1 mL triethylamine was degassed by bubbling argon through the solution for 10 minutes. At this time, copper (I) iodide (11 mg, 0.06 mmol) and tetrakis(triphenylphosphine) palladium(0) (3 mg, 0.03 mmol) were added, and the reaction was stirred at room temperature for 72 hours. Water (10 mL) was then added and the precipitate was filtered off and dried. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with ethyl acetate/hexane, to yield a yellow powder which was recrystallized from ethyl acetate/hexane, to give (Z)-5-[3-[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-4-yl]-2-propynyl]-6(5H)-phenanthridinone. (Yield 25 mg, 38%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].O>O1CCCC1>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][Br:15]
Reactant: O=C(Cl)CCCCBr
Reactant: NCCCCCO
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCCCBr)NCCCCCO
Reaction time: 18 h
Yield: 78.8 %

Procedure:
Part A. A solution of 5-aminopentanol (30.0 g, 291 mmol) and triethylamine (50.0 mL, 359 mmol) in tetrahydrofuran (500 mL) was cooled to 0° C., and a solution of 5-bromovaleryl chloride (30.0 mL, 226 mmol) in tetrahydrofuran (200 mL) was added dropwise. After slow warming and stirring for 18 hours, the mixture was poured into water (1 L), and the phases were separated. The aqueous layer was extracted with methylene chloride (2×600 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The oily product was purified by elution through a silica gel plug with ethyl acetate, and evaporation afforded the product, N-(5-hydroxypentyl)-5-bromopentanamide (47.3 g, 178 mmol, 79%).
Reaction SMILES: [F:1][C:2]1[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:23][C@H:24]([CH3:46])[CH2:25][O:26]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)(=[O:14])=[O:15])[CH:9]=[C:8]([O:23][C@H:24]([CH3:46])[CH2:25][OH:26])[N:7]=1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)N2CCN(C)CC2)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)N2CCN(C)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-{2-[(2,3-difluorobenzyl)thio]-6-[(1R)-1-methyl-2-(trityloxy)ethoxy]pyrimidin-4-yl}-4-methylpiperazine-1-sulfonamide (the product from step ii) (100 mg) in DCM (3 ml) was added TFA (3 ml) dropwise. The reaction was then allowed to stir at room temperature for the following 3 h until complete. The reaction was then reduced in vacuo and the resulting residue was purified by preparative HPLC to yield the title compound as a white solid. Yield: 45 mg
Reaction SMILES: [ClH:1].[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[N+:40]([C:43]1[CH:52]=[CH:51][C:46]2[N:47]=[C:48]([NH2:50])[S:49][C:45]=2[CH:44]=1)([O-:42])=[O:41]>CN(C)C=O>[ClH:1].[NH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:50][C:48]2[S:49][C:45]3[CH:44]=[C:43]([N+:40]([O-:42])=[O:41])[CH:52]=[CH:51][C:46]=3[N:47]=2)=[O:12])=[CH:13][CH:14]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N=C(N)Nc1ccc(C(=O)Nc2nc3ccc([N+](=O)[O-])cc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred, cold (-5° C.) solution of 1.07 g. of 4-guanidinobenzoic acid hydrochloride and 740 mg. of 1-hydroxybenzotriazole in 8 ml. of dimethylformamide was added 1.12 g. of dicyclohexylcarbodiimide in one portion. After two hours at 0° C., 950 mg. of 6-nitro-2-aminobenzothiazole was added and the reaction mixture was stirred at room temperature for two hours. The mixture was filtered and the filtrate applied to 35 g. of ionexchange resin GC 50 (H+ form). The column was washed with 200 ml. of water and sufficient methane until the washliquid became colorless. Following a second water/methanol wash the product was eluted from the column using a 0.05 M hydrochloric acid in methanol solution. The fractions containing the product are combined, concentrated to dryness and recrystallized from methanol, 60 mg., m.p. 311-329° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:28][CH:27]=2)[CH:19]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:30][CH:31]=2)[CH:19]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(OCCCc4ccccn4)cc3C)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCCc2ccccn2)ccc1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 75 h
Yield: 47.7 %

Procedure:
A solution of methyl 3-(4-{[2′-methyl-4′-(3-(pyridin-2-yl)propoxy)biphenyl-3-yl]methoxy}phenyl)propanoate (0.401 g, 0.809 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 2 M aqueous sodium hydroxide solution (1.5 mL) and the mixture was stirred at room temperature for 75 hrs. Water was added to the reaction mixture, and the mixture was neutralized with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (0.186 g, yield 48%) as colorless prism crystals.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OOC(C)(C)C)(C)(C)C.[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1>>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][CH:36]2[CH2:35][CH2:34][CH2:33][CH:32]=[CH:31]2)[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=CCCCC1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: CC(C)(C)OOC(C)(C)C
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1C=CCCC1
Yield: 81 %

Procedure:
A solution of 33.6 grams (122 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 23.0 grams (157 mmol) of di-tert-butyl peroxide, and 70 ml of cyclohexene is heated in a Fischer-Porter pressure bottle at 138° C. for 6.5 hours. The reaction mixture is purified by flash chromatography on silica gel (200:1 heptane:ethyl acetate) to afford 35.1 grams (81% yield) of the title compound as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@H:16]([CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:83])[C@@H:67]([NH:75]C(OC(C)(C)C)=O)[CH2:68][S:69][S:70][C:71]([CH3:74])([CH3:73])[CH3:72])[C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:60])([OH:59])=[O:58])([OH:40])=[O:39])=[O:18])=O)(C)(C)C>ClCCl>[NH2:15][C@H:16]([CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:83])[C@@H:67]([NH2:75])[CH2:68][S:69][S:70][C:71]([CH3:72])([CH3:73])[CH3:74])[C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:60])([OH:59])=[O:58])([OH:40])=[O:39])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)SSC[C@H](N)C(=O)NCCCC[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-6-((R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoate (Compound 55) (12 mg, 10.38 μmol) in dichloromethane (0.4 mL) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-6-((R)-2-amino-3-(tert-butyldisulfanyl)propanamido)hexanoate (Lys(Cys(StBu))-pdCpA) (Compound 48) (9.3 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:15])[CH:3]=1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:17]([CH3:16])[N:18]=[CH:19]3)=[CH:6][C:5]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:15])[CH:3]=1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: COC(=O)CCc1cc(Br)c(N)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(N)cc1C
Temperature: 90 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
A solution of Intermediate 9 (460 mg) in 1,4-dioxane (5 ml, KANTO) was added with 1-methyl-1H-indazol-5-ylboronic acid (rgt1, 350 mg), cesium carbonate (410 mg, KANTO), and PdCl2dppf·CH2Cl2 (115 mg, Ald), and stirred at 90° C. for 18 hours. The reaction mixture was cooled to room temperature, and then added with water (30 ml) and ethyl acetate (30 ml×2) to perform extraction. The reaction mixture was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, the organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1), and the solvent was evaporated under reduced pressure by using a rotary evaporator to obtain the title compound (400 mg).
Reaction SMILES: CN1CCN(C)C1=O.[C:9]([NH:12][NH2:13])([NH2:11])=[NH:10].Cl.[N:15]1([CH2:22][C:23]2[S:27][C:26]([C:28](Cl)=O)=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O>CCCCCC>[NH2:10][C:9]1[NH:12][N:13]=[C:28]([C:26]2[S:27][C:23]([CH2:22][N:15]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:24][CH:25]=2)[N:11]=1
Reactant: N=C(N)NN
Reactant: O=C(Cl)c1ccc(CN2CCCCCC2)s1
Agent: Cl
Solvent: CCCCCC
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: Nc1nc(-c2ccc(CN3CCCCCC3)s2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 ml of 1,3-dimethyl-2-imidazolidinone and 18.0 g (163.2 mM) of aminoguanidine hydrochloride were added to 24.0 g (81.6 mM) of 5-(hexahydro-1H-azepin-1-yl)methyl-2-thiophenecarbonyl chloride, and the mixture was stirred at room temperature for 1 hour. Then, 16.3 g (60% oil, 408 mM) was added and the mixture was stirred overnight at 130° C. The reaction solution was cooled to room temperature, 50 ml of water and 500 ml of n-hexane were added to effect separation of layers. To the resulting lower layer was added 1,000 ml of saturated brine, and then the mixture was extracted seven times with 500 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under a reduced pressure, and 1,000 ml of acetonitrile was added. With ice-cooling, 150 ml of 4 N hydrochloric acid/ethyl acetate was added, and the thus precipitated crystals were collected by filtration. The resulting crystals were added to 200 ml of 1 N sodium hydroxide, extracted three times with 200 ml of ethyl acetate, dried over anhydrous sodium sulfate and then concentrated to 1/10 volume under a reduced pressure. The thus precipitated crystals were collected by filtration to give 10.4 g (51% in yield) of the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]2)=[C:6](Cl)[N:5]=1.[CH:21]([OH:24])([CH3:23])[CH3:22]>>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]2)=[C:6]([O:24][CH:21]([CH3:23])[CH3:22])[N:5]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Temperature: 75 °C

Procedure:
A flask was charged with sodium hydride (60% oil dispersion, 240 mg, ~6 mmol) which was washed with hexanes before the addition of isopropanol (20 mL) and (±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.318 g, 1.19 mmol) from Example 4. This solution was heated at 75° C. for 2 hours before being allowed to cool to room temperature and neutralized by addition of 1.0 N HC1. The solution was concentrated and the residue was placed on a silica gel column which was eluted with 10% methanol-chloroform. Crystallization from ethanol:water 1:1 yielded off-white crystals (265 mg, 77%), m.p. 188-191° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[NH2:10][C:11]1[CH2:12][C:13]([C:29](OCC)=[O:30])=[CH:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[CH:18][C:16]=2[N:17]=1>C1(C)C=CC=CC=1.ClCCCl>[NH2:10][C:11]1[CH2:12][C:13]([C:29]([N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])=[O:30])=[CH:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:28])([F:27])[C:23]([F:24])([F:25])[F:26])=[CH:18][C:16]=2[N:17]=1
Reactant: COCCNCCOC
Reactant: CCOC(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: COCCN(CCOC)C(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Temperature: 75 °C

Procedure:
Trimethylaluminuni (0.34 mL of a 2.0 M solution in toluene) was added to bis(2-methoxyethyl)amine (92 mg, 0.69 mmol) in DCE (3 mL). After 10 minutes solid (1E,4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate (80 mg, 0.23 mmol) was added and the vessel was sealed and heated to 75° C. for 16-20 hours. Upon cooling the reaction was quenched with saturated Rochelle's salt (2 mL) and after 20 minutes the mixture was partitioned between CH2Cl2 (50 mL) and brine (50 mL). The phases were separated and the aqueous was extracted with CH2Cl2 (2×20 mL). The combined organics were dried and concentrated. The crude material was purified via preparative TLC (2, 0.5 mm plates, eluting with 5-10% MeOH/CH2Cl2 with 4-6 drops of NH4OH). 1H NMR (CDCl3) δ 2.81 (s, 2H), 3.36 (s, 6H), 3.55-3.74 (m, 8H), 6.98 (s, 1H), 7.20 (d, 1H), 7.40 (d, 1H), 7.39 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:31][O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][NH:35]1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH3:31][O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a cooled (0-5° ) solution of N-benzyloxycarbonyl-L-valine (450.0 g) in dry N,N-dimethylformamide (3.0 liter) was added 1-hydroxybenzotriazole hydrate (483.3 g): and the reaction mixture was stirred for 20 min, followed by the addition of a slurry of L-proline methyl ester hydrochloride (296.4 g) and triethylamine (186.6 g) in N,N-dimethylformamide (1.5 liter). After the resulting mixture was cooled to 0°, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (377.6 g, 1.97 mol) in N,N-dimethylformamide (500 ml) was added. The reaction mixture was stirred at 0°-5° for 3 hr and then allowed to warm gradually to room temperature. Stirring was continued for 65 hr, and the mixture was filtered and evaporated. The residue was partitioned between ether and lN HCl, and the precipitate which formed was removed by filtration. The etheral layer was then separated: washed with water, saturated aqueous NaHCO3 and brine; dried (MgSO4); and evaporated. The crude ester was purified by flash chromatography using a gradient elution of methylene chloride, then methanol:methylene chloride (1:99), (2.5:79.5), and, finally, (5:95). The impure material from the first column was rechromatographed using a gradient elution of methylene chloride:hexanes (1:3), methylene chloride, and, finally, methanol:methylene chloride (2:98). The combined chromatographies afforded the ester (596.9 g, 92%) as a colorless oil; TLC, Rf =0.45-0.60, methanol:methylene chloride (5:95); MS, m/e=363(M+1, base), 319, 255, 130, 91.
Reaction SMILES: [CH3:1][C:2](=[N:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:3].[H][H]>[Pd].C(O)(=O)C.CO>[CH:2]([NH:4][NH:5][C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])([CH3:3])[CH3:1]
Reactant: CC(C)=NNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NNC(=O)OC(C)(C)C

Procedure:
tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 was reduced with palladium catalyst on carbon with hydrogen gas in acetic acid and methanol to give tert-butyl 2-isopropylhydrazinecarboxylate 3 (CAS Reg. No. 16689-35-3).
Reaction SMILES: Cl.[NH2:2][O:3][CH:4]([CH3:8])[C:5]([OH:7])=[O:6].[CH:9]1[C:18]2[N:19]3[C:23]([C:24](=O)[C:16]4[C:17]=2[C:12]([CH:13]=[CH:14][N:15]=4)=[CH:11][CH:10]=1)=[CH:22][CH:21]=[CH:20]3>O.C(O)C.N1C=CC=CC=1>[C:5]([CH:4]([O:3][N:2]=[C:24]1[C:16]2[C:17]3[C:12]([CH:13]=[CH:14][N:15]=2)=[CH:11][CH:10]=[CH:9][C:18]=3[N:19]2[C:23]1=[CH:22][CH:21]=[CH:20]2)[CH3:8])([OH:7])=[O:6]
Reactant: CC(ON)C(=O)O
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: CC(ON=c1c2nccc3cccc(c32)n2cccc12)C(=O)O
Yield: 76.4 %

Procedure:
A solution of 2-aminooxypropionic acid hydrochloride (15.0 g.) in water (37.5 cc.) is added to a stirred boiling solution of 7H-indolizino[5,6,7-ij]isoquinolin- 7-one (15.0 g.) in ethanol (375 cc.) and pyridine (8.14 g.). Boiling is maintained for 2 hours 30 minutes. After cooling, the orange crystals are filtered off, washed with 90% ethanol, then with absolute ethanol and finally with diethyl ether. After drying, 7-(1-carboxyethoxyimino)-7H-indolizino[5,6,7-ij]isoquinoline (16.0 g.), melting at 225° C. with decomposition, is obtained.
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)(=[O:3])[CH3:2].[Br:26]Br>C(OCC)(=O)C.Br>[Br:26][CH2:2][C:1]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: BrBr
Agent: Br
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)CBr)c3c2)c1=O
Temperature: 25 °C

Procedure:
To a solution of 3-(3-acetyl-1,2-benzisothiazol-5-yl)-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.800 g, 0.00217 mol) in ethyl acetate at room temperature is added hydrobromic acid (48%, 3 drops) followed by bromine in ethyl acetate (0.522 M, 4.35 ml, 0.00277 mol). The resultant mixture is stirred two hours at reflux, cooled to room temperature, diluted with ethyl acetate, washed sequentially with sodium thiosulfate, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a white solid. The solid is recrystallized from hexanes:ethyl acetate to give the title compound as a white, crystalline solid (mp 191-193° C.) which is identified by NMR spectral analysis.