Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]([CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[N:16]=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12])(=O)C.Cl.C(OCC)C>CO>[CH3:22][N:13]1[C:14]2[N:15]=[N:16][N:17]([CH3:21])[C:18]=2[C:19](=[O:20])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:23])[C:11]1=[O:12]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nnn2C)n(C)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2c(nnn2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-3,7-dimethyl-8-azaxanthine (71 mg, 0.22 mmol) in methanol (15 ml) was added an anhydrous solution of hydrogen chloride in ethyl ether (1 M, 1.0 ml, 1.0 mmol). The mixture was stirred at room temperature for 24 hours and then the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-3,7-dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT 12464) (55 mg, 88% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:50]1[CH2:55][CH2:54][CH:53]([OH:56])[CH2:52][CH2:51]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:50]6[CH2:55][CH2:54][CH:53]([OH:56])[CH2:52][CH2:51]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCC(O)CC4)c3)c2)c1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (0.133 g, 0.2 mmol) in DCM (3 mL) was added 4-piperidinol (0.021 g, 0.210 mmol), NaBH(OAc)3 (0.051 g, 0.240 mmol). This mixture was stirred at room temperature for 15 h at which time more 4-piperidinol (0.004 g, 0.04 mmol) was added and stirring continued for 2 h. Then more NaBH(OAc)3 (0.025 g, 0.1 mmol) was added and the mixture was stirred for an additional 2 h. The reaction mixture was filtered, concentrated, and purified using a Gilson HPLC (with 0.1% TFA). The fraction was concentrated and basified with an amine cartridge to afford 0.1067 g of the title compound. LC-MS m/z 748 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.40 (t, J=7.65 Hz, 3 H) 1.49 (t, J=7.15 Hz, 3 H) 1.62-1.83 (m, 1 H) 1.83-2.01 (m, 4 H) 2.05-2.27 (m, 3 H) 3.08 (t, J=12.05 Hz, 1 H) 3.16 (q, J=7.36 Hz, 2 H) 3.32-3.41 (m, 2 H) 3.53 (d, J=12.30 Hz, 1 H) 3.62-3.72 (m, 2 H) 3.76-4.10 (m, 3 H) 4.31-4.51 (m, 5 H) 4.61 (s, 2 H) 4.72 (s, 2 H) 7.18 (dd, J=10.67, 8.41 Hz, 1 H) 7.38-7.46 (m, 1 H) 7.50-7.63 (m, 4 H) 7.65-7.76 (m, 2 H) 8.01-8.09 (m, 2 H) 8.29 (s, 1 H) 8.40 (t, J=1.63 Hz, 1 H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19].CCN(C(C)C)C(C)C.F[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1>CN1C(=O)CCC1>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1)=[O:20]
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1N
Reactant: Fc1cccc(C(F)(F)F)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cccc(C(F)(F)F)n1
Reaction time: 0.33 h

Procedure:
To a microwave vial were charged N-[(1S,2S)-2-Aminocyclopentyl]-2,6-dimethoxybenzamide hydrochloride (Intermediate 5; 80 mg, 0.266 mmol) in dry NMP (1 ml). To this was then added DIPEA (138 μl, 0.798 mmol) and 2-fluoro-6-(trifluoromethyl)pyridine (CAS number 94239-04-0; 53 mg, 0.319 mmol). The reaction was subjected to microwave irradiation at 200° C. for 30 minutes and then at 250° C. for 20 minutes. The reaction mixture was directly purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7].C1(C2C=CC=CC=2)C=CC(S([Cl:19])(=O)=O)=CC=1>>[Cl:19][C:5]1[S:1][C:2]([S:6]([NH2:9])(=[O:8])=[O:7])=[CH:3][CH:4]=1.[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Agent: NS(=O)(=O)c1cccs1
Product: NS(=O)(=O)c1ccc(Cl)s1

Procedure:
5-chlorothiophene-2-sulfonamide was prepared according to the procedure for thiophene-2-sulfonamide YG1-030 except using 4-biphenylsulfonyl chloride, which afforded the title compound 932.5 mg (94.4%) as a white solid, m.p.: 110-112° C.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]1)=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:10]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:9]1[C:11]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]1
Reactant: COC(=O)C1(C(=O)Nc2ccccc2O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1(c2nc3ccccc3o2)CC1
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred suspension of methyl 1-((2-hydroxyphenyl)carbamoyl)cyclopropanecarboxylate (0.147 g, 0.62 mmol) in 2.5 mL THF at room temperature under nitrogen was added triphenylphosphine (0.361 g, 1.375 mmol) followed by DIAD (0.2663 ml, 1.375 mmol). After 2 hours, the reaction mixture was loaded directly onto a Biotage 40S column in THF and was eluted with 9/1 hexanes/EtOAc to provide the desired product as a yellow oil (132 mg, 97%).
Reaction SMILES: N1C(N)=C2C(N=CN2)=NC=1.[NH:11]1[C:20](=[O:21])[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13].O[CH:23]1[C:28]2=[CH:29][C:30]3[CH:31]=[CH:32][C:33]4[C:42]5[C:41]=3[C:40]([CH:39]=[CH:38][C:37]=5[CH:36]=[CH:35][CH:34]=4)=[C:27]2[CH:26](N2C3C(=O)NC(N)=NC=3N=C2)[CH:25](O)[CH:24]1O>>[CH:36]1[C:37]2=[C:42]3[C:41]4[C:40]([CH:39]=[CH:38]2)=[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:28]2=[C:29]([C:17]2[NH:18][C:19]5[C:20](=[O:21])[NH:11][C:12]([NH2:13])=[N:14][C:15]=5[N:16]=2)[C:30]=4[CH:31]=[CH:32][C:33]3=[CH:34][CH:35]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: Nc1nc2ncn(C3c4c(cc5ccc6cccc7ccc4c5c67)C(O)C(O)C3O)c2c(=O)[nH]1
Agent: Nc1ncnc2nc[nH]c12
Product: Nc1nc2nc(-c3c4ccccc4c4ccc5cccc6ccc3c4c65)[nH]c2c(=O)[nH]1

Procedure:
##STR3## wherein R is adenine or guanine. The following compounds are exemplary: 7-(7,8,9-trihydroxy-7,8,9,10tetrahydrobenzo[a]pyren-10-yl)guanine, and
Reaction SMILES: [C:1]([O:13]CC)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[OH-].[K+]>C(O)C>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:13])=[O:12])[CH3:11]
Reactant: CCOC(=O)CCCCCC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCCCCC(=O)O
Temperature: 80 °C
Reaction time: 24 h
Yield: 67.3 %

Procedure:
To a solution of diethyl heptanedioate (65 g, 0.30 mol) in ethanol (400 mL) was added KOH (16.8 g, 0.30 mmol). The mixture was stirred at 80° C. for 24 hours and concentrated under reduced pressure. The resulting mixture was poured into water and the pH value of the solution was adjusted to 1 by concentrated H2SO4. After removal of the solvent, the crude product was purified by flash chromatography SiO2 (EtOH:EtOAc=1:10) to give the desired compound (38 g, yield 67%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[CH:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].CCN=C=NCCCN(C)C.ON1C(=O)CCC1=O.[CH:33]1([C@H:39]([NH:61][C:62]([C:64]2[CH:69]=[N:68][CH:67]=[CH:66][N:65]=2)=[O:63])[C:40]([NH:42][C@@H:43]([C:57]([CH3:60])([CH3:59])[CH3:58])[C:44]([N:46]2[CH2:50][C@@H:49]3[CH2:51][CH2:52][CH2:53][C@@H:48]3[C@H:47]2[C:54](O)=[O:55])=[O:45])=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.N[C@@H](CCC)C(O)C(NC1CC1)=O>CN(C=O)C.C(OCC)(=O)C>[CH:33]1([C@H:39]([NH:61][C:62]([C:64]2[CH:69]=[N:68][CH:67]=[CH:66][N:65]=2)=[O:63])[C:40]([NH:42][C@@H:43]([C:57]([CH3:60])([CH3:59])[CH3:58])[C:44]([N:46]2[CH2:50][C@@H:49]3[CH2:51][CH2:52][CH2:53][C@@H:48]3[C@H:47]2[C:54]([NH:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[CH:3]([OH:10])[C:4]([NH:6][CH:7]2[CH2:8][CH2:9]2)=[O:5])=[O:55])=[O:45])=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)[C@H](NC(=O)[C@@H](NC(=O)c1cnccn1)C1CCCCC1)C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)O
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCC[C@H](NC(=O)[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Reaction time: 24 h

Procedure:
The title compound is prepared from the hydroxy-amino amide product of Step g by condensation with the appropriate acid in the presence of a coupling reagent such as, e.g., EDCI and HOSu. Specifically, in a flask containing 1.2 eq. of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (1.59 g) in 20 mL of DMF, is added 2.5 eq. of diisopropylamine (980 uL), 1.2 eq. N-hydroxybenzotriazole hydrate (411 mg) and 1.3 eq. of EDCI (558 mg). After 15 minutes of stirring at the room temperature, 1.0 eq. of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride (500 mg) is added to the mixture. After another 24 hours, the reaction mixture is diluted into 400 mL of ethyl acetate. The organic phase of the mixture is washed with HCl (1N), water, saturated sodium bicarbonate solution, brine, and then dried over MgSO4. The crude product is purified by chromatography on silica (ethyl acetate 70-100% in Hexanes) to give the tile compound.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][C@H:38]1[CH2:42][O:41][C:40](=[O:43])[N:39]1[C:44]1[CH:49]=[CH:48][N:47]=[C:46]([F:50])[N:45]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.[Cl-].[Na+]>[F:50][C:46]1[N:45]=[C:44]([N:39]2[C@@H:38]([CH2:37][OH:36])[CH2:42][O:41][C:40]2=[O:43])[CH:49]=[CH:48][N:47]=1
Reactant: CC(C)(C)[Si](OC[C@H]1COC(=O)N1c1ccnc(F)n1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1OC[C@H](CO)N1c1ccnc(F)n1
Reaction time: 1 h
Yield: 59.8 %

Procedure:
A solution of tetrabutylammonium fluoride (1.0 M in THF, 0.44 mL, 0.44 mmol, 1.1 equiv) was added to a solution of (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (180 mg, 0.40 mmol) in THF (4 mL) at room temperature. The solution was stirred for 1 hour and then diluted with saturated aqueous sodium chloride (30 mL). The mixture was extracted with ethyl acetate (2×30 mL) and the combined extracts were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (S)-3-(2-fluoropyrimidin-4-yl)-4-(hydroxymethyl)oxazolidin-2-one (0.051 g, white solid) in 60% yield. 1H NMR (400 MHz, CDCl3) δ 8.51 (dd, J=5.8, 2.1 Hz, 1H), 8.19 (dd, J=5.8, 3.8 Hz, 1H), 4.86 (dq, J=8.1, 4.0 Hz, 1H), 4.55 (m, 2H), 4.09 (m, 1H), 3.96 (m, 1H), 2.18 (t, J=5.4 Hz, 1H). MS m/z 214.0 (M+H)+; Rt-0.37 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[C:19]([CH3:20])=[C:18]([NH:21][C:22](=O)[O:23]CC(Cl)(Cl)Cl)[O:17][N:16]=1.CS(C)=O>O>[CH3:14][C:15]1[C:19]([CH3:20])=[C:18]([NH:21][C:22]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[O:23])[O:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: O
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1C
Yield: 41.4 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)piperazine (5.00 g, 26.8 mmol), 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (3.85 g, 13.4 mmol), disopropylethylamine (2.33 ml, 13.4 mmol) and dimethylsulfoxide (50 ml) was stirred at 70° C. for 2 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (1.80 g, 41.4%) as a solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:31][CH2:30][CH2:29][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:11])=[O:7])(C)(C)C.Cl.O1CCOCC1.[CH2:39]([N:46]=C=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([NH:46][C:6]([N:8]1[CH2:31][CH2:30][CH2:29][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:11])=[O:7])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)NCc2ccccc2)cc1

Procedure:
By the same procedure as in Example 21-B), (2S)-1-[N-(t-butoxycarbonyl)-L-prolyl]-2-[1-hydroxy-2-(4-methoxyphenoxy) ethyl]pyrrolidine (722 mg) was treated with 4N hydrochloric acid/1,4-dioxane, followed by reaction with benzylisocyanate (0.21 ml) to give 596 mg of the title compound as crystals. C) (2S)-1-(N-Benzylaminocarbonyl-L-prolyl)-2-(4-methoxyphenoxyacetyl)pyrrolidine
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:13]4=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]4[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(N2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(N4CCCC4)cc3)C2=N1
Temperature: 50 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of 3-(4-(pyrrolidin-1-yl)phenyl)pyridin-2-amine (17.0 mg) in THF (dry) (5 ml) was added to a mixture of NaH (60%, 14.2 mg) and 2-chloroethanesulfonyl chloride (34.7 mg) in THF (dry) (5.00 mL) at room temperature. The mixture was stirred at 50° C. for 1 hr. Water and NH silica gel were added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (14.8 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[Br:6][C:7]1[C:8]([N+]([O-])=O)=[C:9]([CH3:15])[C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1>CO>[Br:6][C:7]1[C:8]([O:2][CH3:1])=[C:9]([CH3:15])[C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1
Reactant: Cc1c([N+](=O)[O-])c(Br)c[n+]([O-])c1C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(Br)c[n+]([O-])c(C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1 M sodium methoxide-methanol solution (30 ml) was added to a methanol (20 ml) solution of the above 5-bromo-2,3-dimethyl-4-nitropyridine 1-oxide (4.80 g) under cooling in an ice bath, and the resulting mixture was stirred at room temperature overnight. Thereafter, the reaction solution was concentrated, and the residue was dissolved in dichloromethane and water for liquid separation. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was then concentrated, so as to obtain a crude product of the title compound (4.91 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])[CH:7]=1.Cl[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[C:5](=[O:17])[N:6]([C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:7]=1
Reactant: CCCCCCNC(=O)n1cc(Cl)c(=O)[nH]c1=O
Reactant: CC(C)COC(=O)Cl
Product: CCCCCCNC(=O)n1cc(Cl)c(=O)n(C(=O)OCC(C)C)c1=O
Yield: 29 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 24, starting from 5-chloro-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide (Example 3) (0.119 g, 0.431 mmol); 2.4 equivalents of isobutyl chloroformate were used herein. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 85:15) to afford the title compound (0.047 g, 29%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.89 (t, J=6.8 Hz, 3H), 1.01 (d, J=6.7 Hz, 6H), 1.28-1.38 (m, 6H), 1.57-1.64 (m, 2H), 2.11 (h, J=6.7 Hz, 1H), 3.39 (td, J=7.1, 5.5, 2H), 4.26 (d, J=6.6, 2H), 8.62 (s, 1H), 8.80 (t, J=4.9 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 14.12, 18.89 (2C), 22.63, 26.58, 27.81, 29.19, 31.48, 41.77, 76.77, 111.14, 135.14, 148.40, 148.58, 149.20, 156.04. MS (ESI) m/z: 391 [M-NH4]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:15][N:14]4[CH2:23][CH2:24][CH:25](Cl)[C:13]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CN1C(=[O:33])CCC1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:15][N:14]4[CH2:23][CH2:24][CH:25]([OH:33])[C:13]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: ClC1CCn2nc(-c3ccccn3)c(-c3ccnc4cc(Br)ccc34)c21
Reactant: CN1CCCC1=O
Product: OC1CCn2nc(-c3ccccn3)c(-c3ccnc4cc(Br)ccc34)c21

Procedure:
A solution of 7-bromo-4-(4-chloro-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (765.0 mg, 1.80 mmol) in 15% (v/v) aqueous N-methyl pyrrolidinone (15 mL) is heated at 120° C. for 18 h. The mixture is concentrated in vacuo and the residue chromatographed on SiO2 (dichloromethane to 20% methanol in dichloromethane) to yield a yellow solid, 408.0 mg (60%).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl>O.O1CCOCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][O:12][C@@H:11]1[C@@H:13]([CH2:14][OH:15])[O:16][C@@H:9]([N:8]2[CH:17]=[C:4]([F:3])[C:5](=[O:19])[NH:6][C:7]2=[O:18])[CH2:10]1
Reactant: ClCc1cccc(Cl)c1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3cccc(Cl)c3)[C@@H](CO)O2)cc1F
Temperature: 45 °C
Reaction time: 72 h
Yield: 13.9 %

Procedure:
A 2.00 g quantity of potassium hydroxide was dissolved in a mixture of 75 ml of water and 40 ml of dioxane. To the solution were added 1.00 g of 2'-deoxy-5-fluorouridine and 2.50 g of 3-chlorobenzyl chloride, and the resulting mixture was stirred at 45° C. for 3 days. After the reaction, the same subsequent procedure as in Examples 4 and 5 was carried out, and the residue was placed on a silica gel column to conduct a gradient elution with chloroform and mixtures of methanol (up to 2%) and chloroform, thereby producing 0.21 g of the title compound in a yield of 14%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH3:24])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:31].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:31])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH3:24])=[CH:17][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: CN1CCCC1c1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Agent: CC=C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: CN1CCCC1c1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
To a mixture of 6-chloro-5-[4-(1-methylpyrrolidin-2-yl)phenyl]-1H-indole-3-carbaldehyde (150 mg, 0.443 mmol) in acetonitrile/t-butanol (9 mL/9 mL) was added 2-methyl-2-butene (7.50 mL, 28.2 mmol). The reaction mixture was cooled to 0° C. followed by the addition of an aqueous solution of sodium chlorite (598 mg, 8.86 mmol) and sodium phosphate (monobasic and monohydrate, 1220 mg, 8.860 mmol) in water (9 mL) dropwise via syringe. The ice bath was removed and the reaction was stirred at room temperature overnight. The reaction was quenched with sodium sulfite (1.12 g, 8.86 mmol) in water (3 mL). The reaction mixture was concentrated under reduced pressure to remove the volatile organics. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to give the title compound (10 mg, 5.0% yield). MS (ES+) 355.0 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 7.97 (s, 1H), 7.59-7.58 (m, 5H), 4.19 (m, 1H), 3.74-3.71 (m, 1H), 3.17-3.14 (m, 1H), 2.70 (s, 3H), 2.55-2.52 (m, 1H), 2.33-2.21 (m, 1H), 2.28-2.21 (m, 3H).
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[CH:11]=[CH:10]1)(OC(C)(C)C)=O.[CH2:32]([C:34]1[CH:38]=[N:37]N[N:35]=1)[CH3:33]>>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]3[N:35]=[C:34]([CH2:32][CH3:33])[CH:38]=[N:37]3)[CH:10]=[CH:11]2)=[C:19]([Cl:23])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CCc1cn[nH]n1
Product: CCc1cnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)n1

Procedure:
The title compound is prepared analogously to di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine (AA3) by replacing di-t-butyliminodicarboxylate with 4-ethyl-2H-[1,2,3]triazole.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[CH3:9][NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:9][N:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([C:3]1[CH:4]=[CH:5][NH:1][CH:2]=1)=[O:8]
Reactant: O=C(O)c1cc[nH]c1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCN(C)C(=O)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
Into a suspension of 3.30 g (30 mmol) of 3-pyrrolecarboxylic acid in 10 ml of dichloromethane, a solution of 5.90 g (45 mmol) of ethyl N-methyl-3-aminopropionate in 50 mt of dichloromethane, a solution of 4.55 g (45 mmol) of triethylamine in 50 ml of dichloromethane, and 8.63 g (45 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were successively added, followed by stirring at room temperature for 3 hours. Dichloromethane was added to the reaction mixture, and the resulting organic layer was washed successively with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure, whereby 5.31 g of the title compound were obtained (yield: 79%).