Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](OCC)(=[O:14])[CH:12]=[CH2:13]>>[NH:1]1[C:2]2=[N:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]2[CH2:13][CH2:12][C:11]1=[O:14]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: C=CC(=O)OCC
Product: O=C1CCn2c(nc3ccccc32)N1
Temperature: 130 °C
Reaction time: 6 h
Yield: 54.7 %

Procedure:
5.32 g (40 mmol) 2-aminobenzimidazole and 4.00 (40 mmol) ethyl acrylate were dissolved in 25 ml Proglyde DMM. The reaction mixture was heated to 130° C. and the reaction was allowed to continue for 6 hours at 130° C. The reaction mixture was allowed to cool down to room temperature. Upon standing over night, 3,4-dihydro-pyrimidino[1,2-a]benzimidazol-2(1H)-one crystallized from the medium and was isolated by filtration. 3,4-dihydro-pyrimidino[1,2-a]benzimidazol-2(1H)-one was recrystallized from 1-methoxy-2-propanol. 4.1 g (54.7%) 3,4-dihydro-pyrimidino[1,2-a]benzimidazol-2(1H)-one was isolated (m.p. >260° C.).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.C(OCC)(=O)C.O1CCCC1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(=O)CCN
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)CCNC(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To a solution of 4-aminobutan-2-one hydrochloride (2.95 g, 24 mmol) in N,N-dimethylacetamide (50 mL) was slowly added (4-fluorophenyl)acetylchloride (4.90 g, 29 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Triethylamine (4.80 g, 48 mmol) was added to the mixture, and the mixture was stirred at room temperature for 17 hr. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (2.10 g, 39%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(Cn1ccc2ncnc(Cl)c21)OCC
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (1 g) was dissolved in N,N-dimethylformamide (13 mL), cesium carbonate (6.37 g) and 2-bromo-1,1-diethoxyethane (2.94 mL) were sequentially added and the mixture was stirred at 80° C. for 4.5 hrs. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100) to give the title compound (1.26 g) as a yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH:12]([OH:19])[CH2:13][CH2:14][CH:15]([OH:18])[CH2:16][CH3:17])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH2:13][CH:12]([O:19][S:2]([CH3:1])(=[O:4])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CCC(O)CCC(O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CCC(OS(C)(=O)=O)c1ccccc1)OS(C)(=O)=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Stir methanesulfonyl chloride (2.94 g, 25.7 mmol) in dichloromethane (40 mL) in a flask that has been purged with nitrogen. Cool the mixture to −20° C. and add 1-phenyl-hexane-1,4-diol (2.0 g, 10.3 mmol) dissolved in dichloromethane (5 mL), and triethylamine (3.13 g, 30.9 mmol). After 2 h of stirring at −20° C., quench with saturated aqueous NH4Cl solution and concentrate to a quarter of the volume. Dilute with EtOAc, and wash with saturated NaHCO3 solution, water, and brine. Dry the organic portion over Na2SO4, filter, and concentrate to obtain 3.0 g (83%) of the title compound. Use with no further purification. 1H NMR (400 MHz, CD3OD): δ 7.37-7.24 (m, 5H), 4.69-4.59 (m, 1H), 4.21-4.14 (m, 1H), 3.01 (s, 3H), 2.73 (s, 3H), 1.91-1.55 (m, 6H), 0.96-0.88 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.O.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]([CH3:35])=[CH:31][C:32](Cl)=[O:33]>CO>[CH3:29][C:30]([CH3:35])=[CH:31][C:32]([N:19]1[CH2:18][CH2:17][N:16]([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH2:21][CH2:20]1)=[O:33]
Reactant: CC(C)=CC(=O)Cl
Reactant: Oc1cccc(CC(c2ccccc2)N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)=CC(=O)N1CCN(C(Cc2cccc(O)c2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
In methanol (300 ml) is dissolved dl-N-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine (3.5 g) and thereto are added water (6 ml) and potassium carbonate (3.3 g). To the mixture is further added dropwise with stirring 3,3-dimethylacryloyl chloride (1.9 g) over a period of about 1 hour. The mixture is stirred at room temperature for 2 hours, and then the solvent is distilled off under reduced pressure. To the residue is added a 10% sodium carbonate aqueous solution and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate, and the solvent is distilled off to give the desired compound (3.6 g), which is recrystallized from methanol to give coloress crystals, melting point: 186°-187° C.
Reaction SMILES: C1(=O)N([CH:6]([N:12]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]2=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])C(=O)C=C1.[C:21]([NH:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][SH:27])(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([NH:24][CH:25]([C:28]([OH:30])=[O:29])[CH2:26][S:27][C:6]([S:27][CH2:26][CH:25]([C:28]([OH:30])=[O:29])[NH:24][C:21](=[O:23])[CH3:22])([N:12]1[C:13](=[O:18])[CH2:14][CH2:15][C:16]1=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:23])[CH3:22]
Reactant: CCCCCC(N1C(=O)C=CC1=O)N1C(=O)C=CC1=O
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Solvent: c1ccncc1
Product: CCCCCC(SCC(NC(C)=O)C(=O)O)(SCC(NC(C)=O)C(=O)O)N1C(=O)CCC1=O
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Bis-maleimidohexane (0.05 g, 1.81×10−4 mol) and N-acetylcysteine (0.059 g, 3.62×10−4 mol) were dissolved in pyridine (1 ml). The reaction was stirred at 40° C. for 24 h. The solvent was removed in vacuo and the residue was dissolved in ethanol (5 ml) and the solvent removed in vacuo. This procedure was repeated 3 times more. The residue of the title compound weighed 0.1 g.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1.[CH2:48]([O:56][C:57]1[CH:64]=[CH:63][C:60]([CH:61]=O)=[CH:59][CH:58]=1)[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C1COCC1.CCCCCC>[CH3:8][O:9][CH:10]=[CH:61][C:60]1[CH:63]=[CH:64][C:57]([O:56][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:58][CH:59]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C=COC)cc1
Reaction time: 0.08 h

Procedure:
Potassium t-butoxide (1.9 g) is added to a slurry of methoxymethyl triphenylphosphonium chloride (6.17 g) and 18-Crown-6 (100 mg) in dry THF (40 ml). The mixture is stirred for 5 min, cooled to 15°, and a solution of 4-octyloxybenzaldehyde (3.52 g) in THF (5 ml) is added dropwise. The reaction mixture is stirred at room temperature for 20 min, diluted with 250 ml hexane, and the resulting mixture filtered through a pad of diatomaceous earth. Evaporation of the filtrate leaves crude 1-(2-methoxyethenyl)-4-(octyloxy)benzene as a mixture of cis and trans isomers, containing about 15 mol % triphenylphosphine oxide. The crude material may be used as is, or may be chromatographed with 1:1 hexanedichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6].FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(=O)C2CCNCC2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) (˜0.1128 mol) was cooled to 0° C., treated with trifluoroacetic acid (85 mL), and stirred at ambient temperature for 1 hour. Following concentration in vacuo, the material was dissolved in water (300 mL), washed with hexane (2×110 mL) and then treated with solid sodium hydroxide (18 g). The resulting aqueous solution was then extracted with methylene chloride (3×170 mL). The combined organic extracts were washed with brine (220 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in ethanol (110 mL), cooled to 0° C., treated with anhydrous hydrogen chloride gas until acidic, diluted with ether (110 mL) and stirred for 1 hour. The resulting solid was collected by filtration, then washed with a mixture of ethanol and ether (1:1, 110 mL) to afford 4-(2,3-dimethoxybenzoyl)piperidine (16) hydrochloride salt as a white solid (19.18 g, 53%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[O:26][CH3:27])[N:6]=1>CO>[CH3:1][O:2][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[O:26][CH3:27])[N:6]=1
Reactant: COc1cc(OC(F)(F)F)ccc1-c1nc(Cl)c([N+](=O)[O-])cc1C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC(F)(F)F)ccc1-c1nc(OC)c([N+](=O)[O-])cc1C
Temperature: 25 °C

Procedure:
A solution of sodium methoxide in MeOH (14 ml, 25%, 60.7 mmol) is added to a solution of 2-chloro-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine (20 g, 55.14 mmol) in MeOH (170 ml) at room temperature. The mixture is refluxed for 8 hours. Additional sodium methoxide in MeOH (14 ml, 25%, 60.7 mmol) is added and refluxed for 15 hours. After cooling to room temperature, the mixture is concentrated under reduced pressure. Water (300 ml) is added to the concentrated mixture and the mixture is extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure and the residue is purified by flash column chromatography (hexane/EtOAc 20:1) to give 2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine as white solid. Rf (hexane/EtOAc=9:1)=0.32.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:29]1[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]([C:22]([S:25]([CH3:28])(=[O:27])=[O:26])([CH3:24])[CH3:23])[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:7]=1.CC(C[Al]CC(C)C)C>C(Cl)Cl>[CH3:28][S:25]([C:22]([C:14]1[CH:15]=[C:16]2[C:21](=[C:12]([C:8]3[CH:7]=[C:6]([CH2:5][CH:4]([C:29]4[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=4)[CH:3]=[O:2])[CH:11]=[CH:10][CH:9]=3)[CH:13]=1)[N:20]=[CH:19][CH:18]=[CH:17]2)([CH3:24])[CH3:23])(=[O:26])=[O:27]
Reactant: COC(=O)C(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(SC)cc1
Agent: CC(C)C[Al]CC(C)C
Solvent: ClCCl
Product: CSc1ccc(C(C=O)Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionic acid methyl ester from Step 1 (1.48 g, 7.5 mmol) in CH2Cl2 (80 mL) at −78° C. was added dibal-H (1.6 mL, 7.8 mmol). The resulting reaction mixture was stirred 1 h at −78° C., then quenched with sodium potassium tartrate solution and stirred at 21° C. for 3 h. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated to provided the 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionaldehyde compound as a white foam.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:8](Cl)([Cl:17])(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[P:8]([Cl:17])(=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Product: O=P(Cl)(Oc1ccccc1)Oc1ccccc1

Procedure:
To the reaction mixture of (1), there is added 188 g. phenol and the temperature is raised to 150°C. for 2 hours. The reaction mixture is alllowed to cool and stripped of phenyl phosphorodichloridate. Distillation of the residue affords principally diphenyl phosphorochloridate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.CC(O)=O>CCO.[Fe]>[NH2:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(Cl)ncc1N
Temperature: 80 °C

Procedure:
2-Chloro-4-methyl-5-nitropyridine (1 g, 5.8 mmol) was dissolved in EtOH (60 mL). AcOH (4 mL) and Fe (5 eq.) were added and the mixture was refluxed at 80° C. overnight. The mixture was filtered through celite and reduced under vacuum to afford the crude 5-amino-2-chloro-4-methylpyridine which was used in the next step with no further purification. The amine was dissolved in conc. HCl (6 mL), transferred to a 3-neck round bottom flask, and cooled to −5° C. A solution of NaNO2/H2O (440 mgs/5 mL) was slowly added and the mixture was allowed to stir for 10 mins. To a second, separate 3-neck round bottom flask was added H2O (12 mL) and cooled to −5° C. Thionyl chloride (4.5 eq.) was then added dropwise. After complete addition the mixture was allowed to warm to room temp. whereupon CuCl (0.05 eq.) was added and the mixture was then cooled back down to −5° C. The first reaction mixture, containing the amine precursor, was slowly added to the second reaction mixture. A froth formed and was filtered off to afford 6-chloro-4-methylpyridine-3-sulfonyl chloride which was used in the next step with no further purification. The title compound was synthesized from 2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-(pyrid-4-yl)ethyl acetamide and 6-chloro-4-methylpyridine-3-sulfonyl chloride using Method G.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].CS(O[C@H:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]1)(=O)=O>CN(C=O)C>[NH2:19][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:12]([C@@H:35]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34]3)[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:18]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc([N+](=O)[O-])cc3)c12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2nc(-c3ccc([N+](=O)[O-])cc3)c3c(N)ncnc32)C1
Reaction time: 2 h
Yield: 45.8 %

Procedure:
A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (0.62 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 2 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford (R)-tert-butyl 3-(4-amino-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.38 g, 46% yield). ESI-MS m/z [M+H]+ found 426.5, calculated 426.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:9]([N:20]=[N+]=[N-])[C@H:8]([O:23][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:7]=1)=[O:5])[CH3:2].O.C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38].C(P(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:9]([NH:20][C:37](=[O:39])[CH3:38])[C@H:8]([O:23][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N=[N+]=[N-])[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
A solution of 1.59 g (3R,4R,5S)-4-azido-5-tert.-butoxycarbonylamino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester (4 mmol) and 0.36 ml water (20 mmol) in 5 ml tetrahydrofuran was cooled to 0° C. 1.12 ml triethylamine (8 mmol) and 0.38 ml acetic anhydride were added and stirring at 0° C. was continued for 15 min. 1.14 ml tri-n-butyl phosphine (4.4 mmol) were added over 5 min. and the yellowish solution was stirred for 30 min. at 0° C. and then for 1 h at room temperature. After the addition of 5.58 ml triethylamine (40 mmol) 1.89 ml acetic anhydride (20 mmol) were added slowly under ice cooling and stirring at room temperature was continued for 1 h. The reaction mixture was diluted with 30 ml ethyl acetate and washed sequentially with 25 ml 2N HCl, 10 ml 10% Na2CO3 and 20 ml 10% brine. The aqueous layers were extracted sequentially with 20 ml ethyl acetate. The combined organic layers were dried (Na2SO4) and the solvent was removed by rotary evaporation (30° C./210 mbar) affording 2.89 g crude, which was purified by chromatography on SiO2 (100 g) with hexane ethyl acetate 1.4:1 (100 ml fractions). Rotary evaporation (30° C./≧10 mbar) gave 1.39 g (84%) of the title product as a colorless, crystalline residue, m.p. 153.5-154.5° C. [α]D=−89.7° (CHCl3; c=1)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([F:17])[CH:16]=1.[F-].[K+].C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[F:10][C:11]1[CH:12]=[C:13]([C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=2)[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1cc(Br)nc(C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1cc(-c2cc(F)cc(F)c2)nc(C)n1
Temperature: 85 °C
Reaction time: 18 h
Yield: 20.7 %

Procedure:
To a suspension of 8.0 g, (43 mmol) of 4-Bromo-2,6-dimethyl-pyrimidine [CAS 354574-56-4], 8.1 g (51 mmol, 1.2 equiv.) of 3,5-Difluorophenylboronic acid, an 1.917 g (33.0 mmol, 3.3 equiv.) of KF in 80 ml of DME were added 20 ml of 2M sodium carbonate solution and the mixture was purged with Argon for 10 min. Then 2.24 g (8.6 mmol, 0.2 equiv.) of Triphenylphosphine and 0.96 g (4.3 mmol, 0.1 equiv.) of Palladium acetate were added and the mixture was stirred under Argon atmosphere for 18 h at 85° C. The reaction was allowed to cool to r.t., and worked up with ethyl acetate/water. The crude material was purified by flash chromatography on silicagel (heptane/ethyl acetate 1:1) to yield the title compound (1.96 g, 21%) as a red solid, MS (ISP): m/e=221.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[Mg].[CH3:19]I>CCOCC>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH2:8][C:7]([OH:10])([CH3:19])[C:6]=2[CH:11]=1
Reactant: CI
Reactant: O=C1COc2cc(N3CCCCC3)c(Cl)cc21
Agent: [Mg]
Solvent: CCOCC
Product: CC1(O)COc2cc(N3CCCCC3)c(Cl)cc21

Procedure:
A solution of 5.03 g (20.0 mmole) of crude 5-chloro-6-(piperidin-1-yl)-benzofuran-3(2H)-one in 30 ml of absolute ether is added dropwise at room temperature to a freshly prepared Grignard solution of 750 mg (30.8 mmole) of magnesium filings and 4.0 g (28.2 mmole) of methyl iodide in 30 ml of absolute ether. The whole is subsequently boiled under reflux for 45 minutes and poured onto ice/ammonium chloride. The ether phase is separated off and the aqueous phase is extracted twice more with ether. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Chromatography over silica gel with chloroform/ethyl acetate (10:1) yields 5-chloro-3-hydroxy-3-methyl-6-(piperidin-1-yl)-2,3-dihydrobenzofuran in the form of an oil having an Rf of 0.24 [silica gel, chloroform/ethyl acetate (10:1)].
Reaction SMILES: FC1C=CC2OC(CCC)CC(=O)C=2C=1.C([O:23][N:24]1[CH2:28][CH2:27][C:26]2([C:33]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=3[O:31][CH:30]([CH:39]([CH3:41])[CH3:40])[CH2:29]2)[C:25]1=[O:42])C1C=CC=CC=1.FC1C=CC2OC(CCC3C=CC=CC=3)CC(=O)C=2C=1>>[OH:23][N:24]1[CH2:28][CH2:27][C:26]2([C:33]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=3[O:31][CH:30]([CH:39]([CH3:40])[CH3:41])[CH2:29]2)[C:25]1=[O:42]
Reactant: CC(C)C1CC2(CCN(OCc3ccccc3)C2=O)c2cc(F)ccc2O1
Agent: CCCC1CC(=O)c2cc(F)ccc2O1
Agent: O=C1CC(CCc2ccccc2)Oc2ccc(F)cc21
Product: CC(C)C1CC2(CCN(O)C2=O)c2cc(F)ccc2O1

Procedure:
Prepared from 2,3-dihydro-6-fluoro-2-propyl-4H-1-benzopyran-4-one via the intermediacy of the less polar diasteromer of 1'-benzyloxy-2,3-dihydro-6-fluoro-2-(2-propyl)-spiro-(4H-1-benzopyran-4,3 '-pyrrolidine)-2'one (Rf=0.3, 1:1 diethyl ether/hexanes) using the same procedure as that used for preparation of Example 7 from 2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-one.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5](=[C:7]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[C:8]1=O)[O-])C.[NH:15]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[NH2:16].Cl>C(O)C.O>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[N:15]1[C:8]2[C@@H:9]3[CH2:10][C@@H:11]3[CH2:12][C:7]=2[C:5]([C:4]([OH:3])=[O:14])=[N:16]1
Reactant: NNc1cnccn1
Reactant: CCOC(=O)C([O-])=C1C[C@H]2C[C@H]2C1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a stirred suspension of 2-ethoxy-2-oxo-1-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolate (300 mg, 1.28 mmol) in ethanol (5 mL) was added 2-hydrazinylpyrazine (141 mg, 1.28 mmol) followed by 6 N HCl (0.5 mL, 3.0 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with H2O and extracted with DCM. The combined organic phases were washed with H2O, dried over MgSO4, and concentrated. Purification by silica gel flash chromatography gave the title compound (150 mg). LCMS m/z=271.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.7 and 3.4 Hz, 1H), 1.22-1.28 (m, 1H), 1.39 (t, J=7.1 Hz, 3H), 2.26-2.30 (m, 1H), 2.77-2.82 (m, 1H), 2.87 (d, J=16.6 Hz, 1H), 2.98 (dd, J=16.6 and 6.3 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 8.40 (dd, J=2.6 and 1.5 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 9.39 (d, J=1.3 Hz, 1H).