Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[NH:17][C:16]=2[CH2:25][CH3:26])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:51][O:52][C:53]([CH:55]1[CH2:58][CH:57](OS(C)(=O)=O)[CH2:56]1)=[O:54]>CN(C)C=O>[CH3:51][O:52][C:53]([C@H:55]1[CH2:58][C@H:57]([N:17]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH2:24])[C:23]=3[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)=[C:16]2[CH2:25][CH3:26])[CH2:56]1)=[O:54]
Reactant: COC(=O)C1CC(OS(C)(=O)=O)C1
Reactant: CCc1[nH]c2ncnc(N)c2c1-c1cccc(OCc2ccccc2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@H](C(=O)OC)C1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.26 g (2.74 mmol) 5-(3-benzyloxy-phenyl)-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, 1.53 g (10.9 mmol) of powdered potassium carbonate and 2.92 g (10.9 mmol) 18-crown-6 ether in 12 ml dry N,N-dimethylformamide is stirred for 15 min at 80° C. 1.7 g (8.2 mmol) of 3-Methanesulfonyloxy-cyclobutanecarboxylic acid methyl ester, dissolved in 9 ml dry N,N-dimethylformamide, is added dropwise in 15 min. After stirring for 42 h at 80° C., work-up is effected by filtering the reaction mixture on hyflo and evaporating the solvent. The residue is partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo. The crude product is purified and separated by flash chromatography (hexane-ethyl acetate 1:2). The ratio cis to trans isomer is about 70:30 (by HPLC, Grad25).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:31][C:32]([C:34]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:35]=1[CH2:36][CH2:37][C@H:38]2[NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[NH:33]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:33]=[C:32]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH2:36][CH2:37][C@H:38]4[NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[N:31]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)no2)cc1C#N
Temperature: 95 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Prepared using General Procedure 4. To a solution of 3-cyano-4-isopropoxybenzoic acid (7.74 g, 37.7 mmol) in DMF (50 mL) was added HOBt (6.02 g, 44.6 mmol) and EDC (8.53 g, 44.6 mmol) at room temperature. The reaction was stirred for 2 h until complete formation of the HOBt-acid complex. (R)-tert-butyl 4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-10 (10.0 g, 34.3 mmol) was added and the reaction mixture stirred at room temperature for 2 h until the formation of INT-11, (R)-tert-butyl 4-(N-(3-cyano-4-isopropoxybenzolyloxy)carbamimidoyl)-2,3-dihydro-1H-inden-1-ylcarbamate. The mixture was partitioned between EA and NaHCO3 and the organic layer was collected and dried over MgSO4. INT-11 (16.3 g, 34.0 mmol) was re-dissolved in DMF (50 mL) and the mixture was heated to 95° C. for 12 hrs. The reaction was diluted with NaHCO3 (200 mL) and extracted with EA (3×50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to produce 12.8 g (81%) of (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-12 as a light brown solid and used without further purification in the next step. LCMS-ESI (m/z) calculated for C26H28N4O4: 460.5. found 483.2 [M+Na]+, tR=4.25 min. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=2.1, 1H), 8.34 (dd, J=8.9, 2.2, 1H), 8.09 (d, J=7.6, 1H), 7.51 (d, J=7.5, 1H), 7.39 (t, J=7.6, 1H), 7.12 (d, J=9.0, 1H), 5.28 (d, J=8.2, 1H), 4.80 (hept, J=6.0, 1H), 3.47 (ddd, J=17.4, 8.9, 3.5, 1H), 3.27-3.03 (m, 1H), 2.68 (d, J=8.7, 1H), 1.87 (td, J=16.7, 8.5, 1H), 1.53-1.43 (m, 15H). 13C NMR (101 MHz, CDCl3) δ 173.00, 168.82, 162.70, 155.68, 145.31, 142.96, 134.05, 133.83, 128.25, 127.21, 126.79, 123.09, 116.78, 115.24, 113.52, 103.87, 79.52, 72.70, 55.72, 33.86, 31.47, 28.39, 21.70. Chiral HPLC: (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylcarbamate was eluted using 20% i-PrOH in hexanes: >99.9% ee, tR=13.33 min. The (S)-enantiomer INT-13 was prepared in an analogous fashion using (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate using General Procedures 3 and 4 (tR for (S)-enantiomer=16.31 min).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C@H:16]([OH:17])[CH2:15][C@@H:14]([CH2:18][OH:19])[O:13]3)[C:6]=2[N:7]=1.N1C=CN=C1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27].CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C@H:16]([OH:17])[CH2:15][C@@H:14]([CH2:18][O:19][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31])[O:13]3)[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)C[C@H]2O)c(=O)[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Yield: 62.7 %

Procedure:
To a solution of 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 38b, 3.8 g, 12.7 mmol) in DMF (30 mL) was added imidazole (2.6 g, 38 mmol) and tert-butylchlorodimethylsilane (4.2 g, 28 mmol) with stirring. After being stirred at room temperature for 2 hours, the resulting solution was diluted by EtOAc (200 mL), washed with water, brine, dried over Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:5 EtOAc in petroleum ether) to afford 3.3 g of 5-amino-3-[(2R,3R,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-hydroxy-tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 38d).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:12])[N:4]=1.COC1C(OC)=NS(=O)N=1.NCCS.CN.[CH3:29][N:30]([CH2:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38]O)[N:37]=1)[CH3:31]>>[CH3:29][N:30]([CH2:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:12])[N:6]=2)[N:37]=1)[CH3:31]
Reactant: CNC1=NS(=O)N=C1NCCS
Reactant: CN(C)Cc1nc(CO)cs1
Agent: CN
Agent: COC1=NS(=O)N=C1OC
Agent: NCCS
Product: CNC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
Reaction of 3-methylamino-4-(2-mercaptoethylamino)-1,2,5-thiadiazole 1-oxide [prepared by reacting 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide with 2-aminoethanethiol and methylamine according to the procedure described in Example 25, Step A] with about one equivalent of 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Example 34, Step D], produces the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1.Cl[C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:15][C:14]1[C:9]([C:4]2([C:6]#[N:7])[CH2:5][C:2](=[CH2:1])[CH2:3]2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Fc1cccnc1Cl
Reactant: C=C1CC(C#N)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C1CC(C#N)(c2ncccc2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89767.9 %

Procedure:
To a solution of 3-methylenecyclobutanecarbonitrile (150 g, 1.61 mol, 1 equiv) and 2-chloro-3-fluoropyridine (212 g, 1.61 mmol, 1 equiv) in toluene (1 L) was added NaHMDS (2 M in THF, 885 mL, 1.1 equiv) dropwise at 0-10° C. Upon completion of addition, the reaction mixture was warmed to rt, stirred overnight, and quenched with NH4Cl(sat) solution. The organic layer was washed with water (2×500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated to give the crude title compound (272 g, 90%) which was used in next step without further purification. LRMS (M+H+) m/z 189.1.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])[CH:16]=2)[CH:10]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.[CH:42]([OH:44])=[O:43].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:42]([OH:44])=[O:43].[CH:42]([OH:44])=[O:43].[Cl:26][C:22]1[CH:21]=[C:20]([N:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[CH:10]=3)=[CH:16][C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])=[N:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: CN1CCN(CCOc2cccc(-c3cc(C(=O)N4CNC(=O)C4)nn3-c3cccc(Cl)c3)c2)CC1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 121A and 1-methylpiperazine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 46 mg (38% of theory) of the title compound are obtained.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][O:4][C:5]([C:7]1[S:11][C:10]2[S:12][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:14][C:9]=2[CH:8]=1)=[O:6]>CC(C)=O>[CH3:3][O:4][C:5]([C:7]1[S:11][C:10]2[S:12][C:13]([S:15]([NH2:2])(=[O:17])=[O:16])=[CH:14][C:9]=2[CH:8]=1)=[O:6]
Reactant: [NH4+]
Reactant: COC(=O)c1cc2cc(S(=O)(=O)Cl)sc2s1
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)c1cc2cc(S(N)(=O)=O)sc2s1
Reaction time: 0.5 h

Procedure:
To stirred ammonium hydroxide (150 ml) was added dropwise 5-methoxycarbonylthieno[2,3-b]thiophene-2-sulfonyl chloride (11.58 g. 39.02 mmoles) dissolved in acetone (140 ml). After the addition was complete, the solution was stirred for 30 minutes. The reaction was worked up by evaporating the ammonia and acetone in vacuo. The crystals were collected and dried (9.66 g.) (89%). Recrystallization from nitromethane gave 7.02 g. mp 219°-220° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:30][NH:31][CH3:32].CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[Cl:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[N:4][C:5]([N:31]([CH3:32])[CH3:30])=[CH:6][CH:7]=1
Reactant: CNC
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(C)c1ccc(Cl)c(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C
Yield: 13.9 %

Procedure:
To a microwave vial was added 2 ml of a solution of 3,6-dichloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (306 mg, 0.71 mmol) in DMSO (6 ml). Dimethylamine (2M in THF, 0.123 ml, 0.25 mmol) and DIPEA (0.129 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was further purified by Mass Directed Automated Preparative HPLC (Method E) and product-containing fractions were dried under a stream of nitrogen to afford the title compound (15 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>C1COCC1.C(N(CC)C(C)C)(C)C>[F:15][C:16]([F:26])([F:27])[C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1)=[O:20]
Reactant: COC(=O)c1cc(N)cc2[nH]cnc12
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]cnc12
Temperature: 0 °C

Procedure:
To a solution of methyl 6-amino-1H-benzimidazole-4-carboxylate (266 mg) in dehydrated THF (12 mL), N,N-diisopropylethylamine (284 μL) was added, and the solution was stirred under ice-cooling. To this solution, 2-(trifluoromethyl)benzoyl chloride (284 μL) in dehydrated THF (5 mL) was added slowly dropwise, and stirred at the same temperature for 3 hours. After ice water was added, THF was removed under reduced pressure, and aqueous saturated sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on NH silica gel column chromatography (ethyl acetate→ethyl acetate/MeOH) to obtain the titled compound (309 mg) as pale yellow powder.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]#[N:38])[CH2:33][CH2:32]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:14]([N:31]1[CH2:36][CH2:35][CH:34]([C:37]#[N:38])[CH2:33][CH2:32]1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: N#CC1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A round-bottomed flask was charged with Boc-D-tert-leucine (2.5 g, 10.8 mmol), HOBT (4.2 g, 24.9 mmol), EDC (4.77 g, 24.9 mmol) and piperidine-4-carbonitrile (2.98 g, 27.0 mmol). Then added DMF (50 mL) followed by N,N-diisopropylethylamine (10.7 ml, 61.6 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with 10% citric acid and extracted with EtOAc (2×). The combined organic layers were washed twice with 10% citric acid, twice with sat'd LiCl and once with brine then dried over MgSO4, filtered and concentrated to give 3.4 g (97%) of [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester as a beige foamy solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1(C)C=CC=CC=1>[F:10][C:5]1[CH:4]=[CH:3][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cc(-c2ccccc2)ccc1F

Procedure:
5-Bromo-2-fluorobenzonitrile (53) (500 mg, 2.54 mmol) was coupled to phenylboronic acid (335 mg, 2.75 mmol) with Cs2CO3 (1.63 g, 5.00 mmol) in toluene (4 mL) in a microwave at 140° C. for 30 minutes. Water was added and the organics extracted several times with EtOAc, dried (MgSO4), filtered and the solvent concentrated in vacuo. The crude product was purified by Flash Master Jones Chromatography using a 25 g silica cartridge and eluting with 10% EtOAc in heptane to yield the title compound. Yield: 375 mg, 76%; LC-MS tr 1.63 min; HPLC Purity: 97%; MS (ES+) m/z not detectable (M+H)
Reaction SMILES: Br.[NH:2]([C:4]1[NH:5][CH2:6][CH2:7][N:8]=1)[NH2:3].Br.[OH:10][C@H:11]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@:17]3([OH:35])[CH2:18][CH2:19][C@@H:20]2/[CH:21]=[C:22](\[CH3:25])/[CH:23]=O)[CH2:12]1>O.O1CCOCC1>[NH:8]1[CH2:7][CH2:6][N:5]=[C:4]1[NH:2]/[N:3]=[CH:23]/[C:22](/[CH3:25])=[CH:21]/[C@H:20]1[CH2:19][CH2:18][C@:17]2([OH:35])[C@H:16]3[C@H:29]([CH2:28][CH2:27][C@:26]12[CH3:34])[C@:30]1([CH3:33])[C@@H:13]([CH2:12][C@@H:11]([OH:10])[CH2:32][CH2:31]1)[CH2:14][CH2:15]3
Reactant: C/C(C=O)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NNC1=NCCN1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: CC(/C=N/NC1=NCCN1)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 72 h

Procedure:
A solution of 0.55 g of 2-hydrazino-2-imidazoline hydrobromide in 10 ml of water and 30 ml of dioxane was made acid to pH 3 with 0.1N HBr. A solution of 1.00 g of (E)-3β,14β-dihydroxy-21-methyl-5β-pregn-20-ene-21-carboxaldehyde (Prepn, 1) in 10 ml of dioxane was added at room temperature. After 3 days, the solution was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 90/10/1 as the eluant: the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with ethyl acetate and ethanol to give 0.85 g of the title compound (I-ab) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]=[C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([NH:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:29]([N:31](CC)CC)[CH3:30].[ClH:36].C(=N)(OCC)C.Cl>CO.C(OCC)(=O)C>[ClH:36].[ClH:36].[C:29]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][N:16]2[CH2:17][CH2:18][N:13]([S:10]([C:7]3[CH2:8][O:9][C:4]4[CH:3]=[C:2]([Br:1])[CH:28]=[CH:27][C:5]=4[CH:6]=3)(=[O:11])=[O:12])[CH2:14][C:15]2=[O:26])[CH2:21][CH2:22]1)(=[NH:31])[CH3:30]
Reactant: CCN(CC)CC
Reactant: O=C1CN(S(=O)(=O)C2=Cc3ccc(Br)cc3OC2)CCN1NC1CCNCC1
Agent: CCOC(C)=N
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=N)N1CCC(NN2CCN(S(=O)(=O)C3=Cc4ccc(Br)cc4OC3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 188.2 %

Procedure:
A solution of 4-(7-bromo-2H-benzopyran-3-sulfonyl)-1-(4-piperidinylamino)-2-piperazinone (104 mg) and triethylamine (272 mg) in methanol (10 ml) was combined with ethyl acetoimidate hydrochloride (272 mg) and stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was dissolved in dichloromethane, washed with a 1N aqueous solution of sodium hydroxide and brine, dried and concentrated. The residue obtained was suspended in ethyl acetate, combined with a 4N solution of hydrochloric acid in ethyl acetate to precipitate a hydrochloride, which was collected by filtration and dried to obtain the title compound (243 mg) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:23][CH:24](C)[CH2:25][CH2:26][OH:27]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(N)CCO
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 7-bromo-4-chloro-3-nitroquinoline (10.00 g, 34.78 mmol) in dichloromethane (140 mL) was added triethylamine (10.2 mL, 73.1 mmol). The solution was cooled to 0° C., and 3-amino-1-butanol (2.80 mL, 36.5 mmol) was added. The solution was stirred overnight at ambient temperature and then filtered to collect a precipitate. The precipitate was washed with dichloromethane and water. The filtrate was washed with saturated aqueous sodium bicarbonate and then added to the precipitate. The mixture was concentrated under reduced pressure. Methanol and toluene were added several times and removed under reduced pressure. The resulting solid was dried under high vacuum to provide 11.34 g of 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: [CH2:1]=[C:2]([OH:10])[CH:3]([OH:9])[CH:4]([OH:8])[C:5]([OH:7])=[CH2:6].CC([O-:15])(C)C.[K+].C1COCC1.CO.C(=O)=O>C1COCC1>[CH2:6]([OH:15])[C@H:5]([C@H:4]([C@@H:3]([C@@H:2]1[O:10][CH2:1]1)[OH:9])[OH:8])[OH:7]
Reactant: C=C(O)C(O)C(O)C(=C)O
Reactant: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H]1CO1
Reaction time: 30 h
Yield: 17 %

Procedure:
To a solution of 1,2:5,6-dianhydro-D-mannitol (0.50 g) in dry THF (3.4 mL) was added t-BuOK/THF solution (0.17 mL, 1.0 mol·L−1) under a nitrogen atmosphere. After 30 hours, the reaction mixture was poured into a large amount of methanol and neutralized with aqueous dry ice. The solvent was evaporated, and the residue was purified using a permeable membrane in water to give the polymer 0.085 g (17.0% yield); a specific rotation+19.6f (c 1.0, H2O, 23 fC). The Mw,SEC and Mw/Mn were 1,600 and 5.07, respectively, and the Mw,SLS was 13.1×105 in aqueous sodium nitrate solution (0.2 mol·L−1). The inertial and hydrodynamic radii of the polymer were 131 nm (SLS) and 132 nm (DLS), respectively, at 40° C. in aqueous sodium nitrate solution (0.2 mol·L−1). The 1H NMR and 13C NMR spectra of the polymer are shown in FIG. 3 and FIG. 4, respectively.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH2:9])[CH3:2].[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22]3[C:23]4[S:30][C:29]([C:31]5[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=5)=[CH:28][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH:9][CH2:35][C:34]1[CH:33]=[CH:32][C:31]([C:29]2[S:30][C:23]3[C:22]([NH:21][C:17]4[CH:16]=[C:15]5[C:20](=[CH:19][CH:18]=4)[NH:12][CH:13]=[CH:14]5)=[N:27][CH:26]=[N:25][C:24]=3[CH:28]=2)=[CH:38][CH:37]=1)[CH3:2]
Reactant: CCOC(=O)CNC(=O)CN
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: CCOC(=O)CNC(=O)CNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from (2-amino-acetylamino)-acetic acid ethyl ester and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 98-115° C.; LC-MS: 515 (MH+); HPLC RT: 3.88 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.CO>O>[CH3:20][O:19][C:3]([O:2][CH3:1])([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][N:13]([S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:12]=1)=[O:7])[CH3:4]
Reactant: COC(C)(OC)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(C)(OC)OC(=O)N[C@@H](Cc1cn(S(=O)(=O)c2ccc(C)cc2)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-[(1,1-Dimethoxyethoxy)carbonyl]-L-histidine (12.7 g, 50 mmol) was dissolved in a solution of sodium carbonate (10.6 g, 100 mmol) in 150 ml water and cooled to 10°. p-Toluenesulfonylchloride (12.8 g, 67 mmol) was added in very small portions over a period of 30 minutes while maintaining vigorous stirring and controlling the temperature between 10°-15°. After the addition was complete, the reaction mixture was warmed to room temperature and stirring continued for an additional 4 hours. The reaction mixture was extracted twice with ethyl ether (75 ml) and the organic portions were discarded. The aqueous layer was acidified with 1N hydrochloric acid, extracted twice with ethyl acetate (150 ml) and the combined organic extracts were dried and concentrated to give an oily residue. Crystallization from ethyl acetate afforded 9.42 grams of the title A compound. m.p.=120°, [α]D =15.3° (c=1.66, CH3OH).