Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]1[C@@H:11]([NH:12]C([C@@H](O)CCN)=O)[C@H:10]([OH:20])[C@@H:9]([O:21][C@@H:22]2[O:26][C@H:25]([CH2:27][OH:28])[C@H:24]([OH:29])[C@H:23]2[OH:30])[C@H:8]([O:31][C@H:32]2[O:37][C@H:36]([CH2:38][NH2:39])[C@@H:35]([OH:40])[C@H:34]([OH:41])[C@H:33]2[NH2:42])[C@H:7]1[NH2:43]>[OH-].[Ba+2].[OH-]>[CH2:6]1[C@H:7]([NH2:43])[C@@H:8]([O:31][C@H:32]2[O:37][C@H:36]([CH2:38][NH2:39])[C@@H:35]([OH:40])[C@H:34]([OH:41])[C@H:33]2[NH2:42])[C@H:9]([O:21][C@@H:22]2[O:26][C@H:25]([CH2:27][OH:28])[C@H:24]([OH:29])[C@H:23]2[OH:30])[C@@H:10]([OH:20])[C@@H:11]1[NH2:12]
Reactant: NCC[C@H](O)C(=O)N[C@@H]1C[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2N)[C@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H]2O)[C@H]1O
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Agent: [OH-]
Product: NC[C@H]1O[C@H](O[C@H]2[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H]3O)[C@@H](O)[C@H](N)C[C@@H]2N)[C@H](N)[C@@H](O)[C@@H]1O

Procedure:
In 250 parts by volume of an 0.5N aqueous solution of barium hydroxide is dissolved 5.0 parts of butirosin A. The solution is refluxed for 2 hours and then cooled. The solution is neutralized with 1N sulfuric acid. The resulting precipitate of barium sulfate is removed off by centrifuge. The supernatant fluid is run onto a column of 300 parts by volume of cation exchange resin [Amberlite CG-50 (NH4+ -form) (Rohm and Haas Co.)]. The column is washed with water and eluted with 0.2N aqueous ammonia. Fractions containing xylostasin which is detected by thin layer chromatography are pooled and concentrated under reduced pressure to dryness and lyophilized, whereby 3.8 parts of xylostasin as white powders are obtained.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:20]=[C:19]1[CH:40]([CH3:42])[CH3:41])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[CH:40]([CH3:42])[CH3:41])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-4-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 37, 0.361 g, 0.58 mmol) following the procedure described for Intermediate 18. The desired product was obtained as a tan foam (0.257 g, 87%).
Reaction SMILES: [C:1]([N:5]1[CH:17]=[C:16]2[C:7]([C:8](=[O:18])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C)[CH2:21][CH2:22]N(C)C.C([Li])CCC.C(I)C>C(OCC)(=O)C.C1COCC1>[C:1]([N:5]1[C:17]([CH2:21][CH3:22])=[C:16]2[C:7]([C:8](=[O:18])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1cc2c(n1)c(=O)[nH]c1ccccc12
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1c2c(nn1C(C)(C)C)c(=O)[nH]c1ccccc12
Temperature: 0 °C
Yield: 91.3 %

Procedure:
To a round-bottomed flask containing 2-tert-butyl-2,5-dihydropyrazolo[3,4-c]quinolin-4-one (20.0 g, 82.99 mmol) was added THF (500 mL) followed by N,N,N′,N′-tetramethylethylenediamine (48.13 g, 414.94 mmol). The reaction was stirred under a nitrogen atmosphere in an ice bath. To this suspension n-butyl lithium (2.5 M in hexanes, 130.0 mL, 324.91 mmol) was added dropwise. The reaction mixture was stirred in the ice bath for 2 minutes and then ethyl iodide (258.38 g, 1.66 mol) was added to the reaction. The reaction was stirred in the ice bath for 10 minutes and then the ice bath was removed. The reaction was stirred at ambient temperature overnight. Methanol (60 mL) was carefully added to quench the reaction and the solvent was evaporated to afford a dark oil. The oil was taken up in ethyl acetate (800 mL) and the organic layer was washed with water (3×600 mL). The organic layer was separated, dried (MgSO4), filtered, and evaporated to afford 2-tert-butyl-1-ethyl-2,5-dihydro-pyrazolo[3,4-c]quinolin-4-one (20.4 g) as a brown solid. A portion of this solid (15.2 g) was transferred to a round-bottomed flask and concentrated hydrochloric acid (410 mL) was added. The reaction was heated to 120° C. for 1 hour and then stirred at ambient temperature overnight. The solids in the reaction mixture were separated by filtration and washed with water. The solids were transferred to a round-bottomed flask and stirred in diethyl ether (100 mL) for 15 minutes. The product was isolated by filtration to afford 1-ethyl-2,5-dihydro-pyrazolo[3,4-c]quinolin-4-one as the hydrochloride salt. The product was stirred in 2N sodium hydroxide (60 mL) for 1.5 hours, filtered, washed with diethyl ether (600 mL), and dried under reduced pressure to afford 1-ethyl-2,5-dihydro-pyrazolo[3,4-c]quinolin-4-one as a tan brown solid (4.23 g).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[S:18][CH2:19][C@@H:20]2[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][C@:21]2([C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)[N:22]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[N:34]1[CH:35]=[CH:36][N:37]=[CH:38][C:33]=1[C@:21]12[CH2:23][NH:24][CH2:25][C@H:20]1[CH2:19][S:18][C:17]([NH:16][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N:22]2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cnccn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1=N[C@@]2(c3cnccn3)CNC[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 100.1 %

Procedure:
Trifluoroacetic acid (1.5 mL) is added to a stirred solution of tert-butyl(4aR,7aR)-2-benzamido-7a-pyrazin-2-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (299 mg, 0.680 mmol) in dichloromethane (6 mL) at room temperature. The reaction is stirred at room temperature for 80 minutes and the solvent is evaporated under reduced pressure. The resulting residue is dissolved in methanol (20 mL) and this solution is loaded onto an ion exchange column and eluted with methanol then with 7 M ammonia/methanol solution. The basic fraction is collected and concentrated under reduced pressure to give the title compound (231 mg, quantitative). ES/MS (m/e): 340 (M+1).
Reaction SMILES: [CH3:1][O:2][S:3]([CH2:6]P(OCC)(OCC)=O)(=[O:5])=[O:4].[Li][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)CCC.O>C1COCC1.CCCCCC>[CH3:1][O:2][S:3]([CH:6]=[CH:16][CH2:17][CH2:18][CH3:19])(=[O:4])=[O:5]
Reactant: [Li]CCCC
Reactant: CCOP(=O)(CS(=O)(=O)OC)OCC
Solvent: C1CCOC1
Solvent: CCCC=O
Solvent: O
Product: CCCC=CS(=O)(=O)OC
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
(Diethoxy-phosphoryl)-methanesulfonic acid methyl ester (150 mg, 0.61 mmol) is dissolved in THF (5.0 mL) and it is cooled down to −78° C. 1.6M nBuLi (0.46 mL, 0.73 mmol) in hexane is added into it dropwise. The mixture is stirred for 30 min at that temperature and Butyraldehyde (0.066 mL, 0.73 mmol) is added. Then mixture is gradually warmed up to room temperature in 3 hrs and the reaction is further stirred for 2 hr at room temperature. Then 30 mL of water is added and the mixture is extracted with EtOAc (3×50 mL). The organic layers are combined, dried and concentrated to give 100 mg (100%) of Pent-1-ene-1-sulfonic acid methyl ester.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][C@@H:41]([OH:43])[CH3:42]>>[OH:43][C@@H:41]([CH3:42])[CH2:40][NH:39][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])=[CH:38][CH:37]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 54.5 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 32 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]+.
Reaction SMILES: Cl[CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][SH:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].[H-].[Na+]>O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH:2]([S:26][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=2)[CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(CS)cc1
Reactant: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CSC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.35 g of 1-[2-chloro-4-(4-chlorophenyl)butyl]imidazole and 1.60 g of 4-nitrobenzyl mercaptan in 40 ml tetrahydrofuran was treated with 380 mg of 50% sodium hydride dispersion in mineral oil. After stirring at room temperature for 1 hour and under reflux for 12 hours the solvent was evaporated under vacuum and 50 ml of ether added. The resulting mixture was washed twice with water and the ethereal solution dried (MgSO4) and evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in methylene chloride to give 1-[4-(4-chlorophenyl)-2-(4-nitrobenzylthio)-n-butyl]imidazole.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[CH:30]=[CH:31][O:32]CC)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:31](=[O:32])[CH3:30])[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(=O)c1ccc2c(c1)OCCc1sc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 100 °C
Yield: 63 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.220 g, 0.000543 mol), tributyl-ethoxyvinyl-tin (0.202 mL, 0.000597 mol), and bis(triphenylphosphine)palladium(II) chloride (0.0190 g, 0.0271 mmol) was degassed with N2. The reaction was heated to 100° C. overnight. The crude was hydrolyzed with 10% HCl and extracted 3 times with ethyl acetate. The organic layers were combined, dried with MgSO4 and concentrated. The crude was loaded as a solid onto silica and purified by flash chromatography (45-100% ethyl acetate in hexanes) to give 1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethanone as a white solid (126 mg). MS (ESI+) 369.2
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22]>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:27]3[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=3)[C:21]#[N:22])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:19]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: N#Cc1cccc(B(O)O)c1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(-c3cccc(C#N)c3)c2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-cyano-phenylboronic acid to give 3-[3-(5-methyl-1H-pyrazol-3-ylamino)-7-methoxy-isoquinolin-1-yl]-benzonitrile LC-MS m/e 356(MH+).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])[CH:10]=[CH:9][C:8]=2[NH:24][C:25]([C:27]2[N:28](COCC[Si](C)(C)C)[CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCO>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)(=[O:17])=[O:16])[CH:10]=[CH:9][C:8]=2[NH:24][C:25]([C:27]2[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(CCS(=O)(=O)N3CCOCC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.8 %

Procedure:
A solution of 221 mg (0.367 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[2-(morpholine-4-sulfonyl)-ethyl]-phenyl}-amide (as prepared in the previous step) in CH2Cl2 (20 mL) was treated with EtOH (3 drops) and TFA (1.8 mL) and stirred at RT for 2 h. Solvents were evaporated in vacuo, and the resulting residue was chromatographed on a 25-g Varian MegaBond Elut SPE column with 50-70% EtOAc-hexane to afford 6.6 mg (4%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.15 (d, 1H, J=8.0 Hz), 7.96 (s, 1H), 7.20 (dd, 1H, J=8.0, 2.0 Hz), 7.12 (s, 1H, J=2.0 Hz), 5.83-5.78 (m, 1H), 3.72-3.66 (m, 4H), 3.48-3.46 (m, 1H), 3.26-3.20 (m, 4H), 3.14-3.11 (m, 1H), 3.10-3.03 (m, 2H), 2.32-2.23 (m, 4H), 1.90-1.73 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H27N5O4S, 470.2 (M+H). found 469.9.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C(O[C@@H:13]1[O:30][C@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C.[Sn](Cl)(Cl)(Cl)Cl.C(#N)C>ClCCCl>[C:16]([O:15][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:30][C@H:13]1[N:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3])(=[O:18])[CH3:17]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Solvent: ClCCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Cytosine is silylated by the general method of Wittenberg. It is reacted with 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose in 1,2 dichloroethane followed by tin tetrachloride in 1,2-dichloroethane (or acetonitrile) according to the method of Vorbruggen and Niedballa to provide the 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)cytosine 33.1b (Xi=β-cytidin-1-yl). Following methanolysis with sodium methoxide in methanol the 1-(β-D-glucopyranosyl)cytosine is obtained. Following protection of the heterocyclic amine this is converted into the morpholino subunit 32.2b (Xi=β-N4-benzoylcytidin-1-yl) by the general procedure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[CH3:43][O:44][C:45]([C:47]1[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=1)=[O:46].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCCl.C(OCC)(=O)C.O1CCCC1>[CH2:24]([N:12]([C@H:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:51]([C:50]2[CH:54]=[CH:55][C:47]([C:45]([O:44][CH3:43])=[O:46])=[CH:48][CH:49]=2)=[O:52])=[CH:3][CH:4]=1)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1ccc(C(=O)Nc2ccc(C[C@@H](CO)N(Cc3ccccc3)C[C@H](O)COc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a solution of (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl)amino)-1-propanol (300 mg) in 1,2-dichloroethane (3.0 ml) was added N,O-bis(trimethylsilyl)acetamide (182 μl) and the solution was stirred at room temperature for 1 hour. To the solution were added successively 4-(methoxycarbonyl)benzoic acid (160 mg), 1-hydroxybenzotriazole hydrate (120 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (170 mg) at room temperature. After stirring at the same temperature for 3 hours, N,O-bis(trimethylsilyl)acetamide (182 μl) was added and the mixture was stirred overnight. The mixture was diluted with ethyl acetate (30 ml) and washed with a saturated aqueous sodium bicarbonate solution (30 ml×1), water (30 ml×2) and brine (30 ml×1) successively, dried over magnesium sulfate, and evaporated to give a yellow solid. The solid was dissolved in tetrahydrofuran (3.0 ml). To the solution was added a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.48 ml) at room temperature and the solution was stirred for 10 minutes. The solution was diluted with ethyl acetate (20 ml) and washed with water (20 ml×2) and brine (20 ml×1) successively, dried over magnesium sulfate, and evaporated to give a yellow solid. The crude product was purified by a recycling preparative high pressure liquid chromatography equipped with a gel permeation chromatography column (eluent: chloroform) and silica gel chromatography (eluent: hexane/ethyl acetate=1/1) to give methyl 4-[[[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]amino]carbonyl]benzoate (132 mg) as a pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[C:12]([CH3:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:15])[C:4]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.[NH3:25]>>[C:18]1([C:17]2[N:25]=[CH:1][C:3]3[C:4](=[C:5]([CH3:15])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH3:14])[CH:13]=3)[N:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1c(C)cc(C=O)c(NC(=O)c2ccccc2)c1C
Reactant: N
Product: CCOC(=O)c1c(C)cc2cnc(-c3ccccc3)nc2c1C

Procedure:
Ethyl 4-formyl-2,6-dimethyl-3-benzoylaminobenzoate was used instead of the compound of formula (II) used in Example 1 and reacted with ammonia in the same way as in Example 1. The reaction product was chromatographed on a silica gel column in the same way as in Example 1. The solvent was evaporated, and the residue was recrystallized from diethyl ether/n-hexane to give 2-phenyl-7-ethoxycarbonyl-6,8-dimethylquinazoline having a melting point of 85° to 86° C. in a yield of 35% by weight.
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[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:6]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(F)cc3)c3ccc(F)cc23)CC1

Procedure:
(30 mg, 57%), from 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4b) and 4-fluorophenylsulfonyl chloride (52.9 mg, 0.27 mmol); HRMS-FAB+ for C20H19N2O2SF2 calculated MH+ : 389.11353; found: 389.11544.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:16][CH:17]1[CH2:22][O:21][CH2:20][C:19]([CH3:24])([CH3:23])[O:18]1)(=O)=O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:16][CH:17]2[CH2:22][O:21][CH2:20][C:19]([CH3:24])([CH3:23])[O:18]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)COCC(COS(C)(=O)=O)O1
Reactant: Nc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)COCC(CNc2cccc(Br)n2)O1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 38.6 %

Procedure:
6-Bromopyridin-2-amine (722 mg, 4.17 mmol) was dissolved in 8 mL of anhydrous DMF and cooled to 0° C. NaH (60% in mineral oil, 195 mg, 4.87 mmol) was added. After 10 min the solution was warmed to ambient temperature and stirred for 45 min until bubbling ceased. The solution was cooled to 0° C. again and (6,6-dimethyl-1,4-dioxan-2-yl)methyl methanesulfonate (520 mg, 2.32 mmol) in 2 mL of DMF was added. After the addition was completed the solution was warmed to ambient temperature and stirred overnight. It was diluted with EtOAc and washed four times with water. The aqueous layers were combined and extracted once with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on prep HPLC and the collected fractions were combined, concentrated, basified with Na2CO3 and extracted with EtOAc three times. The organic layers were combined, dried over Na2SO4 and concentrated to give the product as a light yellow oil (270 mg, 39%). LC-MS (m/z): 301.0/303.0 (M+H), retention time=0.86 min.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:51])[N:32]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[C:44]([CH3:50])[N:43]=1)[CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)([CH3:29])([CH3:28])[CH3:27].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:26]([O:30][C:31](=[O:51])[N:32]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]([OH:49])[C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[C:44]([CH3:50])[N:43]=1)[CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cncnc21
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(C)n2)cn1
Agent: CC(C)[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncncc34)c(C)n2)cn1
Temperature: -25 °C
Yield: 59.7 %

Procedure:
To 5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (38, 0.37 g, 0.92 mmol) in a round bottom flask, 1.1 mL of tetrahydrofuran was added and the mixture cooled to −25° C. Isopropylmagnesium chloride (0.49 mL, 2.0 M in tetrahydrofuran, 0.97 mmol) was added and the reaction stirred, coming to 0° C. The reaction was cooled to −25° C. and (5-formyl-6-methyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (74, 0.300 g, 0.839 mmol) in 2.5 mL of tetrahydrofuran was added. The reaction was stirred, coming to 0° C., then poured into aqueous saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate, filtered and the filtrate adsorbed onto silica. This was purified by silica gel column chromatography eluting with 10-80% ethyl acetate in hexanes. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (75, 317 mg). MS (ESI) [M+H+]+=634.09.