Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18](=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:25]=[C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: N=C(NO)c1cccnc1
Solvent: Cc1ccccc1
Product: COc1ccc(C=Cc2nc(-c3cccnc3)no2)cc1OC
Reaction time: 1.25 h

Procedure:
To a solution of 4.35 g (20.95 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 35 mL of toluene, 3.703 g (22.8 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thickened mixture, 15 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxy-nicotinimidamide (compound of Example 53; 6 g, 43.7 mmol) in 5 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled completely to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][C:26]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:27]=1[CH:28]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:28][C:27]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:26]=2[CH3:25])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(C)c(C=O)c1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Cc1ccc(C)c(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2,5-dimethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 450.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:29]1[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 89.1 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate (27 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 34 mg of the titled compound (yield, 83%). 1H NMR (300 MHz, CDCl3): δ 3.28-3.31 (m, 4H), 3.75-3.78 (m, 4H), 4.15 (s, 4H), 6.90-6.97 (m, 3H), 7.24-7.42 (m, 5H), 7.80 (dd, J=9.0 and 6.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][S:14]([NH:17][C:18](=[O:21])[O:19][CH3:20])(=[O:16])=[O:15].[CH3:22][CH:23]([CH2:26]O)[CH2:24]O.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>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[S:14](=[O:15])(=[O:16])[N:17]([C:18]([O:19][CH3:20])=[O:21])[CH2:24][CH:23]([CH3:26])[CH2:22]1
Reactant: CC(CO)CO
Reactant: COC(=O)NS(=O)(=O)Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)N1CC(C)CN(c2c(Cl)cc(C(F)(F)F)cc2Cl)S1(=O)=O
Temperature: -20 °C
Reaction time: 5 h
Yield: 56.7 %

Procedure:
Methyl N-(2,6-dichloro-4-(trifluoromethyl)phenyl)sulfamoylcarbamate (6.00 g, 16.34 mmol), 2-methylpropane-1,3-diol (2.21 g, 24.51 mmol) and triphenylphosphine (10.71 g, 40.85 mmol) were dissolved in anhydrous THF (100 mL) in a reactor, and then cooled down −20° C. after removal of air in the reactor by purging nitrogen gas. DIAD (8.2 g, 40.8 mmol) was dropwisely added to the reaction mixture and agitated for 5 hr at room temperature. The resultant was concentrated under reduced pressure and purified by column chromatography (dichloromethane:hexane:ethyl acetate=5:4:1), finally yielding the title compound (3.9 g, 70%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.66 (s, 2H), 4.45-4.39 (m, 1H), 3.88 (s, 3H), 3.84-3.75 (m, 2H), 3.54-3.37 (m, 1H), 2.72-2.69 (m, 1H), 1.02 (d, 3H, J=6.7 Hz).
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([CH2:9][C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1)=O.Cl>CO.O1CCCC1.C(=O)(O)[O-].[Na+]>[NH2:3][C:4]1[S:5][C:6]([CH2:9][C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cnc(NC=O)s3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cnc(N)s3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (4.67 g) and conc. hydrochloric acid (4.67 g) in methanol (93 ml) and tetrahydrofuran (46 ml) was stirred at 30° C. for 4 hours. After the organic solvent was removed by evaporation, to the residue was added water (70 ml), followed by adjusting to pH 6 to 7 with 10% aqueous solution of sodium hydroxide. After the insoluble substance was removed by filtration, the filtrate was adjusted to pH 3.0 with 10% hydrochloric acid under cooling, followed by stirring at the same temperature for 20 minutes. The precipitated substance was collected by filtration, washed with water and dried to give a residue, which was dissolved in an aqueous solution of sodium bicarbonate and then chromatographed on alumina (12 ml) using 5% aqueous sodium acetate as an eluent. The fractions containing the desired compound were collected and acidified to pH 3.1 with 10% hydrochloric acid, and the precipitated substance was collected by filtration and then dried to give 7-[2-(2-aminothiazol-5-yl)acetamido]-3-vinyl- 3-cephem-4-carboxylic acid (1.52 g), mp>290° C.
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].[C:5]([N:12]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl-].[NH4+]>C1COCC1>[C:5]([N:12]1[CH2:16][CH2:15][C:14]([OH:17])([C:1]#[CH:2])[CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: C#C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC1(O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
Ethynyl magnesium chloride (0.5 M in THF, 210 mL, 105 mmol) was diluted with THF (100 mL) and cooled in an ice-water bath. A solution of N-Boc-3-pyrrolidinone (9.21 g, 50 mmol) (Example 97A above) in THF (100 mL) was added dropwise with cooling. The mixture was stirred for 2 h and aqueous ammonium chloride solution (100 mL, 15% WN) was then added. The mixture was then extracted with ether (2×400 mL). The ether layers were washed with saturated aqueous sodium chloride solution (200 mL), combined, dried (MgSO4), filtered and concentrated. The residue was chromatographed (Biotage Flash 40S, EtOAc—hexanes as solvent) to give rac-N-Boc-3-hydroxy-3-ethynyl-pyrrolidine as a pale yellow oil that crystallized on standing. (Yield 10.13 g, 96.4%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:5][NH:4][C:3]1=[S:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(O)(=O)C>C(O)C>[Cl:18][CH2:17][CH2:16][CH2:15][S:13][C:3]1[N:2]([CH3:1])[C:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:5][N:4]=1
Reactant: Cn1c(C2CCOCC2)n[nH]c1=S
Reactant: ClCCCBr
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(SCCCCl)nnc1C1CCOCC1
Temperature: 90 °C

Procedure:
To 4-methyl-5-(tetrahydro-2H-pyran-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.4 g, prepared in analogy to the method described in Preparation 2) in ethanol (6 ml) sodium ethanolate (0.83 ml) was carefully added with stirring followed by 1-bromo-3-chloropropane (0.30 ml). The mixture was heated at 90° C. for 1 h. Acetic acid was added at room temperature until pH=4. After elimination of the solvent under reduced pressure the residue was partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to give the title compound as white solid (0.173 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:43]12[CH2:50][CH2:49][CH:46]([CH2:47][CH2:48]1)[C@@H:45](O)[CH2:44]2>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([O:11][C@@H:45]2[CH:46]3[CH2:49][CH2:50][N:43]([CH2:48][CH2:47]3)[CH2:44]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1ccc(Cl)cc1)N1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccc(Cl)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
2-(4-Chlorophenyl)-2-(piperidin-1-yl)acetic acid (190 mg, 0.75 mmol), DCC (309 mg, 1.50 mmol), and HOBT (229 mg, 1.50 mmol) were dissolved in dry THF (8 ml). (R)-quinuclidin-3-ol (286 mg, 2.25 mmol) was added and the reaction was stirred at room temperature for 16 hours. THF was evaporated and the residue was dissolved in EtOAc and washed with 1M NaHCO3, water and brine. The organic layer was separated, dried over Na2SO4, filtered and evaporated. The crude compound was purified by flash chromatography (DCM/MeOH/NH4OH=9 5/5/0.1) to obtain (R)-quinuclidin-3-yl 2-(4-chlorophenyl)-2-(piperidin-1-yl)acetate (167 mg, 61.5% yield) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([S:27]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]4[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]4)=[CH:7][CH:8]=3)[CH:3]=[N:2]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3[nH]ncc3c2)C1
Product: CC(C)(C)OC(=O)N1CC(c2ccc3c(cnn3S(=O)(=O)c3ccccc3)c2)C1

Procedure:
This compound was prepared from tert-butyl 3-(1H-indazol-5-yl)azetidine-1-carboxylate and benzenesulfonylchloride by the method outlined under 44.c).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][C:4]=1[F:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C1CCN2C(=NCCC2)CC1>>[F:12][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][NH:11][S:14]([CH3:13])(=[O:16])=[O:15])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1ccc(CN)c(F)c1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NCCc1ccc(CNS(C)(=O)=O)c(F)c1
Yield: 37 %

Procedure:
2-[4-(Aminomethyl)-3-fluorophenyl]ethylamine (0.3 g, 1.25 mmol) was combined with methanesulfonyl chloride (0.2 mL, 2.75 mmol), and DBU (1 mL, 3.12 mmol) in a manner analogous to the procedure described in example 2 to provide the final title compound, [(2-fluoro-4-{2-[(methylsulfonyl)amino]ethyl}phenyl)methyl](methylsulfonyl)amine, (0.15 g, 37%) as a white crystalline solid. Electron spray M.S. 323 (M*−H). Analysis for C11H17FN2O4S2:
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:2]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][C@@H:7]([C:3]4[CH:2]=[C:1]([CH3:26])[CH:6]=[CH:5][CH:4]=4)[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1cccc([C@@H](C)OC(=O)Nc2c(C)noc2-c2ccc(Br)cc2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4cccc(C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-m-tolyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[Na].[CH3:20][SH:21]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH3:20][S:21][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CS
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na]
Solvent: C1CCOC1
Product: CSC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl 4-(methylsulfonyl)oxypiperidine-1-carboxylate (12.5 g), methylmercaptan sodium salt (3.31 g), tetra-n-butylammonium iodide (1.66 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 72 hrs. The insoluble material was filtered through celite and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and tert-butyl 4-(methylthio)piperidine-1-carboxylate was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio) (6.89 g, yield 67%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:21]=[CH:20][C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][CH:13]=[N:12]3)[N:9]=1.CC(C)([O-])C.[Li+:27]>O1CCCC1>[N:9]1[C:10]2[C:19](=[CH:18][CH:17]=[C:16]3[C:11]=2[N:12]=[CH:13][CH:14]=[CH:15]3)[CH:20]=[CH:21][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O-:1].[Li+:27]
Reactant: Oc1ccccc1-c1ccc2ccc3cccnc3c2n1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: [O-]c1ccccc1-c1ccc2ccc3cccnc3c2n1

Procedure:
2-(2-Hydroxyphenyl)-1,10-phenanthroline (4) (20 g, 73.45 mMole) was dissolved in tetrahydrofuran and with good stirring treated with lithium t-butoxide (5.65 g, 88.14 mMole). The precipitated product was stirred at room temperature in the reaction mixture for 1 hour to complete the reaction. The lithium 2-(1,10-phenanthrolin-2-yl)-phenolate was filtered off, washed well with diethyl ether and air-dried. Yield 21 g.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[C:26]([O:29][C:30]1[CH:40]=[CH:39][CH:38]=[CH:37][C:31]=1[CH:32]=[CH:33][C:34](O)=[O:35])(=[O:28])[CH3:27].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:26]([O:29][C:30]1[CH:40]=[CH:39][CH:38]=[CH:37][C:31]=1[CH:32]=[CH:33][C:34]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([CH3:2])[CH:4]=1)=[O:35])(=[O:28])[CH3:27]
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Reactant: CC(=O)Oc1ccccc1C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccccc1OC(C)=O
Yield: 83.1 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (3.0 g), triethylamine (1.7 mL), 2-acetoxycinnamic acid (2.5 g), WSC.HCl (2.4 g), and methylene chloride (80 mL), to give the captioned compound (3.9 g, 83%) as an oily product.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.COP([CH2:19][C:20]1[N:21]([CH3:36])[C:22]2[C:27]([N:28]=1)=[C:26]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[N:25]=[C:24]([Cl:35])[N:23]=2)(=O)OC.[C:37]([O:41][C:42]([N:44]1[CH2:47][C:46](=O)[CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:47][C:46](=[CH:19][C:20]2[N:21]([CH3:36])[C:22]3[C:27]([N:28]=2)=[C:26]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[N:25]=[C:24]([Cl:35])[N:23]=3)[CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: COP(=O)(Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)OC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cn1c(C=C2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
To a solution of diisopropylamine (1.4 mL, 9.8 mmol) in THF (3 mL) at −78° C. was added n-BuLi (3.9 mL, 9.8 mmol, 2.5 M in hexanes) and the resulting mixture allowed to stir for 20 min. The resulting solution was added to a pale green solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)phosphonic acid dimethyl ester (3.36 g, 8.9 mmol) in THF (80 mL) at −78° C. The resulting mixture was warmed to r.t. before a solution of 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (1.76 g, 10.2 mmol) in THF (10 mL) was added. The resulting pink mixture was stirred for 16 h then quenched with H2O. The mixture was concentrated in vacuo and the residue was partitioned between DCM and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-70%) affording the title compound as a green powder (3.46 g, 92%). 1H NMR (CDCl3, 400 MHz): δ 6.33-6.32 (1 H, m), 4.91-4.90 (2 H, m), 4.71-4.70 (2 H, m), 4.28 (4 H, brd s), 3.81 (4 H, t, J=4.74 Hz), 3.71 (3 H, s), 1.48 (9 H, s).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:14][N:15]3[CH2:31][CH2:30][C:18]4([N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:21][NH:20][C:19]4=[O:29])[CH2:17][CH2:16]3)[C:10]2=[O:13])=[CH:5][CH:4]=1.[BH4-].[Na+].[BH4-]>CO.O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([CH2:14][N:15]3[CH2:31][CH2:30][C:18]4([N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:21][NH:20][C:19]4=[O:29])[CH2:17][CH2:16]3)[C@@H:10]2[OH:13])=[CH:5][CH:4]=1
Reactant: O=C1c2cc(Cl)ccc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1NCN(c2ccccc2)C12CCN(C[C@@H]1CCc3ccc(Cl)cc3[C@H]1O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
A slurry of 8-[(7-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)methyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, hydrochloride (1:1) (9.0 g, see example 189) in 200 ml of methanol is treated with a solution of 3.7 g of sodium borohydride in 25 ml of water. The soldium borohydride solution is added dropwise with ice cooling. The resulting mixture is stirred for 16 hours under nitrogen at room temperature. The reaction mixture is diluted with water and extracted with methylene chloride. Concentration of the dried methylene chloride solution affords a crude semi-solid. Trituration with absolute ehtanol gives 6.4g of the title compound, melting point 248°-249° C.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[S:20][CH:21]=[N:22][N:23]=1>CO.O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[S:20][CH:21]=[N:22][N:23]=1
Reactant: Nc1nncs1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Solvent: O
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@H](CO)C(O)N(c3nncs3)C2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde, (uridinedialdehyde), (2.42 g) was dissolved in a mixture of methanol (50 ml) and water (50 ml). To the solution was added 2-amino-1,3,4-thiadiazole (1.00 g). The mixture was stirred at ambient temperature for four hours and evaporated in vacuo. The residue was triturated with acetone to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(1,3,4-thiadiazol-2-yl)morpholin-2-yl]-uracil (3.0 g).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[S:8])=[CH:5][C:4]=1[CH3:12].C(O)(=O)C.Br.C([O-])([O-])=O.[Na+].[Na+]>O>[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[S:8])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(C(O)=S)cc1C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(O)=S)ccc1O
Temperature: 25 °C

Procedure:
4-Methoxy-3-methylthiobenzoic acid (0.5 g, 2.5 mmol) is suspended in 7 ml of a mixture of glacial acetic acid and 48% strength HBr (1+1). The reaction mixture is stirred under reflux for 6 h. The reaction mixture is cooled to RT and added to 20 ml of H2O. The aqueous solution is adjusted to pH=2 using 10% strength Na2CO3 solution and extracted 4× using 20 ml of diethyl ether each time. The organic extracts are combined, washed 2× with saturated NaCl solution, dried over Na2SO4 and concentrated: dirty-brown oil, which crystallizes on allowing to stand at RT. The crystallizate is dried, washed with H2O with stirring, filtered off and dried. Yield: 240 mg (52%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][Cl:16])[C:9]2=[O:17])=[N:5][N:4]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1C=CC=CC=1>[F:19][C:2]([F:1])([F:18])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][CH2:11][N:10]([CH2:15][Cl:16])[C:9]2=[O:17])=[N:5][N:4]=1
Reactant: O=C1N(CCl)CCC(O)N1c1nnc(C(F)(F)F)s1
Reactant: CCCCCC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC(=O)OC1CCN(CCl)C(=O)N1c1nnc(C(F)(F)F)s1

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Hexanoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl- 1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-hexanoyloxy-2(1H)-pyrimidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.S(=O)(=O)(O)O.[CH3:19]O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:19])=[O:12])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
5-Chloroindole-2-carboxylic acid (0.95 g, 4.65 mmol) was dissolved in methanol (35 ml) and treated with sulphuric acid (0.5 ml). The mixture was refluxed for 5 h and cooled and the solvent was removed. The residue was recrystallized twice from methanol to give the product.