Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:3]1=[O:17].[CH:19]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:28]2[N:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=2)=[O:27])[CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O1CCOCC1>[CH:19]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:28]2[N:29]=[N:30][C:31]([N:14]3[CH2:13][CH2:12][CH:11]([N:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[C:2]([F:1])([F:18])[C:3]4=[O:17])[CH2:16][CH2:15]3)=[CH:32][CH:33]=2)=[O:27])[CH2:21][CH2:20]1
Reactant: O=C1N(C2CCNCC2)c2ccccc2C1(F)F
Reactant: O=C(NCCCC1CC1)c1ccc(Cl)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1COCCO1
Product: O=C(NCCCC1CC1)c1ccc(N2CCC(N3C(=O)C(F)(F)c4ccccc43)CC2)nn1
Yield: 60 %

Procedure:
A mixture of 3,3-difluoro-1-piperidin-4-yl-1,3-dihydroindol-2-one (0.180 g, 0.71 mmol), 6-chloropyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide (0.160 g, 0.66 mmol), K2CO3 (0.150 g, 1.08 mmol) and n-Bu4NI (10 mg) in dioxane (10 mL) was heated to reflux overnight, then concentrated. The residue was purified by flash chromatography to yield the title compound as a white powder in 60% yield (0.183 g). m.p. 51-53° C. 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J=9.3 Hz, 1H), 7.86 (s, br, 1H), 7.50 (d, J=6.6 Hz, 1H), 7.12-6.91 (m, 3H), 4.66 (d, J=12.9 Hz, 2H), 4.35 (s, br, 1H), 3.46-3.42 (m, 2H), 3.09 (t, J=12.9 Hz, 2H), 2.52-2.35 (m, 2H), 1.90 (d, J=11.4 Hz, 2H), 1.69-1.65 (m, 2H), 1.28-1.23 (m, 2H), 0.72-0.55 (m, 1H), 0.48-0.25 (m, 2H), 0.08-−0.07 (m, 2H.); 13C NMR (75 MHz, CDCl3) δ 165.1, 163.1, 159.7, 144.9, 142.4, 133.4, 127.0, 125.1, 123.7, 120.3, 112.3, 110.7, 106.9, 50.9, 44.6, 39.1, 35.1, 29.5, 28.3, 27.5, 26.1, 10.4, 4.4. MS (ES+) m/z 456.3 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C@H:14]([C:15](OC)=[O:16])[C@H:13]([C:19](O)=[O:20])[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]1=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[Ca+2].[Cl-].Cl>C(O)C>[CH2:22]([N:12]1[C@H:13]2[CH2:19][O:20][C:15](=[O:16])[C@H:14]2[N:10]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:11]1=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
To a mixture of sodium borohydride (0.55 g) and 99.5% ethanol (20 ml) were added dropwise a solution of (4R,5S)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 149°-150° C., [α]365b =-27.7 ° at c=1 in DMF, 2.00 g) in 99.5% ethanol (30 ml) at 0°-5° C. and a solution of anhydrous calcium chloride (0.80 g) in 99.5% ethanol (8 ml) at the same temperature. The obtained mixture was allowed to warm up to room temperature and to react at the same temperature for 18 hours under stirring. Then, 1N hydrochloric acid was added dropwise to the reaction mixture. The solvent was removed from the mixture at 50°-55° C. under reduced pressure. The residue was shaken with chloroform (50 ml) and water (50 ml). Chloroform layer was washed successively with 5% aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was treated with ether (10 ml), filtered and dried to give (3aS,6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (1.43 g). M.P., 116°-117° C. [α]D25 =+60.9° (c=1, CHCl3).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[SH:6].Cl[C:8]1[S:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O>[N+:16]([C:9]1[CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[S:12][C:8]=1[S:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([O-:18])=[O:17]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2nccs2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
To a solution of thiazole-2-thiol (0.05 g, 0.5 mmol) in toluene (10ML), was added 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.102 g, 0.5 mmol) and K2CO3 (0.69 g, 5 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water (10 mL) and was extracted with ethyl acetate. The organic extract was dried (Na2SO4), concentrated under vacuum and the residue purified by silica gel chromatography using a mixture of 70:30 ethyl acetate and hexane as eluent to afford the title product as a solid (60 mg, 43% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.51 (2H, s), 8.26 (2H, dd), 8.23 (2H, dd), 2.54 (3H, s). MS m/z: 287.9 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21](=[O:22])[C:20]3[C@@H:19]4[C:23]([CH3:25])([CH3:24])[C@@:16]([CH3:26])([CH2:17][CH2:18]4)[C:15]=3[NH:14]2)=[CH:9][CH:8]=1.O.Cl>C(S)C>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21](=[O:22])[C:20]3[C@@H:19]4[C:23]([CH3:25])([CH3:24])[C@@:16]([CH3:26])([CH2:17][CH2:18]4)[C:15]=3[NH:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCS
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(O)cc3)c(=O)c12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
A solution of aluminum chloride (2.40 g, 18.0 mmol) in ethanethiol (20 mL) was cooled to 0° C. and (4S,7R)-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 40; 2.00 g, 6.7 mmol) was added. The flask was capped and the reaction mixture was stirred at 0° C. for about 20 min and then at room temperature for 2 h. The solution was added to water (100 mL) with vigorous stirring and the resulting mixture was acidified to pH 1-2 with 1 M HCl. The resulting solid was filtered off, washed with water and then hexanes, air-dried and then dried under vacuum to give (4S,7R)-2-(4-hydroxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.63 g, 85%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]([N:11]2[C:15]3=[CH:16][S:17][CH:18]=[C:14]3[N:13]=[C:12]2[S:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)=[O:10])=[CH:5][CH:4]=1.[OH:30]P([O-])(O)=O.[K+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[C:15]3=[CH:16][S:17][CH:18]=[C:14]3[N:13]=[C:12]2[S:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)=[O:30])=[O:10])=[CH:28][CH:29]=1
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(COC(=O)n2c(SCc3ccc(C)cn3)nc3cscc32)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(COC(=O)n2c(S(=O)Cc3ccc(C)cn3)nc3cscc32)cc1
Temperature: 25 °C

Procedure:
850 mg (2 mmol) of the title compound from Example 21 were dissolved in 50 ml of CH2Cl2, and 50 ml of aqueous Na2HPO4 /KH2PO4 buffer solution (pH 7.5; 7.4 ml of KH2PO4 solution (45.35 g/l)+42.5 ml of Na2HPO4 solution (59.5 g/l) were added. While stirring vigorously at room temperature, 500 mg (2.5 mmol) of m-chloroperbenzoic acid dissolved in CH2Cl2 were added dropwise. The organic phase was dried over MgSO4 and concentrated, and the residue was chromatographed on silica gel using ethyl acetate. The title compound crystallized from isopropanol. Melting point 119°-120° C.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH2:20][CH3:21])=[CH:11][C:10]=2[F:26])[CH2:6][CH2:5][O:4]1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([N:29]([CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH2:20][CH3:21])=[CH:11][C:10]=2[F:26])[CH2:6][CH2:5][O:4]1)[CH2:30][CH3:31])[CH3:28]
Reactant: CCNCC
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCl)C3)c(F)c21
Product: CCN(CC)CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)CCO1

Procedure:
By the use of 7-(2-chloromethylmorpholino)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and diethylamine, the reaction is similarly carried out as Example 4 to give 7-[2-(diethylaminomethyl)morpholino]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: Br[C:2]([F:14])([F:13])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]>COCC>[F:6][C:5]([F:8])([F:7])[C:4]([F:10])([F:9])[C:3]([F:12])([F:11])[C:2]([F:14])([F:13])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Agent: CCOC
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A copolymer of poly-d-L-lactide is dissolved in methylethyl ether (b.p. 10.8° C.) at a polymer concentration of 10 mg/mL. To the mixture is added 1-bromoperfluorobutane to yield a perfluorohexane concentration of 2 mg/mL. The mixture is maintained in an ice water bath and agitated vigorously by sonication, as in Example 6. Water is then added to yield approximately 10 parts water for every one part ether. The mixture is then shaken in a Wig-L-Bug, producing a 1-bromoperfluorobutane-in-ether-in-water emulsion, equivalent to an oil-in-oil-in-water emulsion. The temperature is gradually increased and the pressure reduced resulting in evaporation of the ether phase. The poly-d-L-lactide copolymer precipitate out on the surface of the 1-bromoperfluorobutane, resulting in a suspension of 1-bromoperfluorobutane microspheres coated by a polymeric shell of poly-d-L-lactide.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.N1([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)CCCC1>>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC[C@H]1CCCN1
Reactant: COC(=O)c1ccc(CN2CCCC2)cc1
Product: COC[C@H]1CCCN1Cc1ccc(C(=O)OC)cc1

Procedure:
The title compound was synthesized from (R)-2-(methoxymethyl)pyrrolidine (0.175 g, 1.52 mmol) according to a procedure similar to that used for compound 56. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 4.16 (d, J=13.6 Hz, 1H), 3.91 (s, 3H), 3.42 (m, 2H), 3.33 (m, 4H), 2.92 (m, 1H), 2.73 (m, 1H), 2.19 (m, 1H), 1.93 (m, 1H), 1.70 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 166.7, 144.7, 129.1, 128.4, 128.3, 76.0, 62.8, 58.9, 58.7, 54.2, 51.6, 28.0, 22.4. ESI-LRMS: [M+H]+=264 m/z.
Reaction SMILES: [Cl:1][C:2]1[C:27]([O:28]C)=[CH:26][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:11][C:10]=3[CH2:23][CH2:24][CH3:25])=[N:7][O:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.CCCCCCC.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:27]([OH:28])=[CH:26][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)=[CH:11][C:10]=3[CH2:23][CH2:24][CH3:25])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(OC)cc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(O)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step 5 (0.82 g, 1.9 mmol) in dichloromethane (15 mL) cooled at 0° C. was added a solution of boron tribromide in heptane (1.0 M, 3.8 mL, 3.8 mmol). The reaction was stirred at 25° C. for 30 min and then poured into aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combine organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel to give the title product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]2[CH3:45])[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]2[CH3:45])[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Product: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(C#Cc4ccccc4)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) (231 mg, 0.75 mmol) and 3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H9) (157 mg, 0.5 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (140 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[N:15][CH:16]=1.[H-].[Na+].Cl[CH2:26][CH2:27][O:28][Si](C)(C)C.Cl>CN(C=O)C>[OH:28][CH2:27][CH2:26][N:17]([C:13]1[CH:14]=[N:15][CH:16]=[C:11]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=1)[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19]
Reactant: C[Si](C)(C)OCCCl
Reactant: CCS(=O)(=O)Nc1cncc(-c2cc3ccccc3n2C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(CCO)c1cncc(-c2cc3ccccc3n2C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A flask is charged with ethanesulfonic acid [5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide (example 226, 200 mg, 0.634 mmol) and DMF (3 mL). The reaction is cooled to 0° C. and sodium hydride (38.0 mg, 0.951 mmol) is added. The reaction is stirred at room temperature for 10 min, then 2-chloro-ethoxytrimethylsilane (0.154 mL, 0.951 mmol) is added. The reaction is stirred at 100° C. for 16 h then cooled to room temperature. Aqueous 1M HCl (1 mL) is added and stirring is continued for 30 min. The mixture is purified using an Xbridge C18 eluting with a 10 to 100% acetonitrile-water gradient to afford ethanesulfonic acid (2-hydroxy-ethyl)-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. MS (ESI) m/z 360.1 (M+H)+. 1H NMR (400 MHz, MeOD) δ ppm 1.42 (t, J=7.3 Hz, 3H), 3.29 (t, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.84 (s, 3H), 3.96 (t, J=5.6 Hz, 2H), 6.75 (s, 1H), 7.14 (td, J=7.5, 0.9 Hz, 1H), 7.28 (td, J=7.7, 1.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 8.18 (t, J=2.1 Hz, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.75 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 360.1383 [(M+H)+ Calcd for C18H12N3O3S 360.1376].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([Cl:22])=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Product: O=C(Cl)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid (1.05 g, 4 mmol) in anhydrous dichloromethane (10 mL), thionyl chloride (0.573 g, 4.81 mmol) was added drop wise at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give benzyl-3-(chlorocarbonyl)piperidine-1-carboxylate.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:13]=[C:12]([C:14]#[C:15][CH3:16])[CH:11]=[C:10]2[CH:17]=[O:18])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(NC(C)C)(C)C>N1C=CC=CC=1>[C:19]([O:8][CH2:7][C@H:5]1[O:6][C@@H:1]([N:9]2[CH:13]=[C:12]([C:14]#[C:15][CH3:16])[CH:11]=[C:10]2[CH:17]=[O:18])[CH2:2][C@@H:3]1[OH:4])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC#Cc1cc(C=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)c1
Solvent: CC(C)NC(C)C
Solvent: c1ccncc1
Product: CC#Cc1cc(C=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c1
Temperature: 25 °C
Reaction time: 29 h
Yield: 80.4 %

Procedure:
To a solution of 1-(2-deoxy-β-D-ribofuranosyl)-4-(1-propynyl)pyrrole-2-carbaldehyde (249 mg, 1.00 mmol) (I. Hirao, et al., Nature Methods, 3: 729-735 (2006)) dissolved in anhydrous pyridine (10 ml) were added trityl chloride (1.18 g, 4.21 mmol) and N,N-diisopropylamine (1.11 ml, 6.40 mmol), and the reaction mixture was stirred at room temperature for 29 hours, and then at 50° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, and the organic layers were washed twice with a saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The resulting crude product was purified by column chromatography on silica gel (eluent:dichloromethane:ethyl acetate=100:0→400:3, then dichloromethane:methanol=100:2) to give the title product (395 mg, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21].[Br:22][CH2:23][CH2:24][CH2:25]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21]
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OC)CC2
Reactant: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1c(OCCCBr)ccc2c1OC(C)(CCC(=O)OC)CC2
Yield: 79 %

Procedure:
To a solution of 1.7 g (5.51 mmole) of the title compound from Example 10, 1.1 ml (11 mmoles) of 1,3-dibromopropane and 1.9 g (11 mmole) of tetrabutylammonium hydrogen sulfate in 12ml of methylene chloride was added 5.5 ml of 2M sodium hydroxide solution. The reaction mixture was heated to reflux for 15 minutes and cooled. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. Chromatography of the residue on silica gel using 10% ethyl acetate/hexane as eluent gave 1.8 g of the title compound as an oil. Structure assignment was confirmed by nmr and infrared spectra.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[S:13]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][C:16]=2[N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:19]2[CH2:20][CH2:21][C:22]3[S:13][CH:14]=[N:15][C:16]=3[CH2:17][CH2:18]2)[N:7]=1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Reactant: c1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ncsc3CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1c 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1a) was treated with the 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine in N,N-dimethylformamide in the presence of potassium carbonate at room temperature to yield the 2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-yl)-3H-pyrimidin-4-one as yellow amorphous solid; MS: (M−H]−=306.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[F:10][C:9]1[CH:8]=[CH:7][C:4](/[CH:5]=[CH:14]/[N+:11]([O-:13])=[O:12])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])/C=C/c1ccc(F)c(F)c1
Yield: 76.8 %

Procedure:
Using analogous reaction conditions and workup as described in example 1, 3,4-difluorobenzaldehyde (5 g, 35.1864 mmol) in ethanol (175 mL) was reacted math nitro methane (1.9 mL, 35.1864 mmol) and 10N NaOH (1.47 g, 36.9457 mmol) to afford 5 g of the product (76.80% yield). 1H NMR (CDCl3, 300 MHz): δ 7.92 (d, 1H), 7.58-7.0 (m, 4H).
Reaction SMILES: CC(C)=O.C1(C([NH:24][CH:25]2[C:38](=[O:39])[N:27]3[CH:28]([C:33]4[NH:37][N:36]=[N:35][N:34]=4)[C:29]([CH3:32])([CH3:31])[S:30][C@H:26]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[NH2:24][CH:25]1[C:38](=[O:39])[N:27]2[CH:28]([C:33]3[NH:34][N:35]=[N:36][N:37]=3)[C:29]([CH3:31])([CH3:32])[S:30][C@H:26]12
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.17 h

Procedure:
To a slurry of dry acetone (5 ml.) and 6-triphenylmethylamino-2,2-dimethyl-3-(5-tetrazolyl)penam (483 mg., 1.0 mmole) at room temperature is added p-toluenesulfonic acid monohydrate (209 mg., 1.1 mmole). The resulting solution is stirred for 10 minutes and then ether (30 ml.) is added over a 5 minute period. The mixture is stirred for 10 minutes after which the solvent is decanted from the solid which separates. The solid is dissolved in tetrahydrofuran (30 ml.) and placed on a column (300 × 6 mm.) packed with 10 g. of Florisil (synthetic magnesium silicate). The column is washed with tetrahydrofuran until a total of 125 ml. is collected. The eluate is concentrated to dryness under reduced pressure at 40° C. to give 210 mg. of solid. The solid is slurried in ether (30 ml.), filtered, washed with ether and air-dried. Yield = 121 mg. (50%). The NMR spectrum (in DMSO-d6) shows absorption bands at 1.08 ppm, (2s, 3H each, C-2 methyls), 4.60 + 5.52 (2d, J=4.0 Hz, 2H, H5 + H6), 5.10 (s, 1H H3) and 5.88 (s, 3H, NH3)ppm. (s, 3H), 1.59ppm (s,3H), 4.60 ppm (d,1H), 5.52 ppm (d,1H), 5.10ppm (s, 1H), and 5.88 ppm (s,3H).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH:12]([CH3:13])[C:11](=[O:14])[N:10]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([C@@:8]1([CH2:23][CH2:24][OH:25])[CH:12]([CH3:13])[C:11](=[O:14])[N:10]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The aforementioned crude (3S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran (10 mL). Then, acetic acid (0.572 mL, 10.0 mmol) and a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (10.0 mL, 10.0 mmol) were sequentially added in a nitrogen atmosphere. After stirring at room temperature for 12 hours, the reaction solution was poured into a mixture of ethyl acetate (100 mL) and brine (50 mL), followed by extraction with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL), and then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:2) to give 1.56 g (90%, two steps) of the diastereomer mixture title compound as a colorless oil.