Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:33].O>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH3:33])[C:25]([F:27])([F:28])[F:26])=[CH:4][CH:3]=1
Reactant: CI
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OC)C(F)(F)F)c23)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 1-[9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (100 mg, 0.224 mmol) in N,N-dimethylformamide (2.0 mL) was added sodium hydride (60% dispersion in mineral oil, 14 mg, 0.35 mmol) at 0° C. After the mixture was stirred at 0° C. for 0.5 hr, iodomethane (0.0697 mL, 1.12 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (79.1 mg, 0.172 mmol, 77%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]5[C:27](F)=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:21][CH2:20]4)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[F-].[K+].[CH3:35][O-:36].[Na+]>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]5[C:27]([O:36][CH3:35])=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:21][CH2:20]4)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(N1CCC(Cc2cccnc2F)CC1)[C@@]12C[C@@H](c3ccccc31)c1ccc(Cl)cc12
Reactant: C[O-]
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1CC1CCN(C(=O)[C@@]23C[C@@H](c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of 1-((9S,10S)-2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)-4-(2-fluoro-3-pyridylmethyl)piperidine, (2.60 g, 5.8 mmol), prepared as described in Example 55a, in methanol (25 mL) was added potassium fluoride (4.15 g, 71.4 mmol) which caused a slight exotherm (~ 35° C.). Sodium methoxide solution in methanol (4.4 mL of a 25 wt% solution) was added which caused another exotherm (18 50° C.) and thinned the suspension. This suspension was heated to reflux for 6 h. Additional potassium fluoride (4.15 g, 71.4 mmol) was added and the suspension was refluxed for 18 h. Additional sodium methoxide solution (1.0 mL) was added and the suspension was refluxed for 5 h. The mixture was cooled to room temperature, partitioned between basic brine and dichloromethane. The organic extract was separated and the aqueous was extracted with dichloromethane (2×). The dichloromethane extracts were combined, dried oversodium sulfate, filtered and concentrated on a rotary evaporator. The crude foam was purified by flash chromatography on silica (eluant: 15% acetone/hexanes) to give the title compound as a white solid (1.82 g, 3.95 mmol, 68%).
Reaction SMILES: O.NN.[C:4]([C:6]1[C:7]([N:17]2C(=O)C3=CC=CC=C3C2=O)=[N:8][CH:9]=[C:10]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:11]=1)#[N:5]>CO>[NH2:17][C:7]1[C:6]([C:4]#[N:5])=[N:11][C:10]([CH:12]([O:15][CH3:16])[O:13][CH3:14])=[CH:9][N:8]=1
Reactant: COC(OC)c1cnc(N2C(=O)c3ccccc3C2=O)c(C#N)n1
Agent: NN
Solvent: CO
Solvent: O
Product: COC(OC)c1cnc(N)c(C#N)n1
Yield: 75.1 %

Procedure:
0.2 g of hydrazine hydrate were added dropwise to a suspension of 2 g of 3-cyano-5-dimethoxymethyl-2-phthalimidopyrazine in 40 ml of absolute methanol at 40° C. Immediately after the addition, the solution became clear, and crystals were precipitated after a few minutes. Chromatography over silica gel gave 0.9 g (75%) of 2-amino-3-cyano-5-dimethoxymethylpyrazine. 1H-NMR (270 MHz, DMSO-d6): δ3.3 (s, 6H), 5.0 (s, 1H), 8.35 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[NH:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[NH:7][C:6]=2[N:19]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CCOC(C)=O>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:42])=[O:43])[C:37]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[O:11])[NH:9][CH:8]([C:12]6[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=6)[NH:7][C:6]=5[N:19]=4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1
Reactant: O=C1NC(c2cccc(F)c2)Nc2nc(Cl)ccc21
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)NC(c3cccc(F)c3)NC4=O)cc12
Temperature: 100 °C
Yield: 48.8 %

Procedure:
To a solution of 7-chloro-2-(3-fluorophenyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (66 mg, 0.237 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.199 mmol) and K3PO4.3H2O (106 mg, 0.398 mmol) in 1 mL of dioxane and 0.1 mL of water were added X-phos (10 mg) and Pd2(dba)3 (10 mg) under nitrogen. The mixture was heated at 100° C. for 6 h, concentrated in vacuo and the residue was suspended in water. The mixture was extracted with EtOAc and the organic phase was washed with brine, then dried over sodium sulfate. 2-(4-fluorophenyl)-5-(2-(3-fluorophenyl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, yield: 49%) was obtained by the prep-TLC (PE:EtOAc=1:2). 1H-NMR (CD3OD, 400 MHz) δ 8.06 (d, J=7.6 Hz, 1H), 7.91˜7.95 (m, 2H), 7.81 (s, 1H), 7.77 (s, 1H), 7.37˜7.40 (m, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.21˜7.27 (m, 3H), 7.02˜7.08 (m, 2H), 5.96 (s, 1H), 3.27 (d, J=6.0 Hz, 3H), 2.90 (s, 3H), 2.80 (s, 3H). MS (M+H)+: 618.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[CH:11]([O:14][C:15](=[O:17])[CH3:16])[CH2:12]C.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:26][C:23]2[CH:24]=[CH:25][C:20]([NH2:19])=[CH:21][CH:22]=2)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:12])[CH3:27]
Reactant: O=C([O-])[O-]
Reactant: CCC(OC(C)=O)C(=O)Nc1ccc(I)cc1Cl
Reactant: Nc1ccc(S)cc1
Agent: Cl[Cu]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC(C)(C)C(=O)Nc1ccc(Sc2ccc(N)cc2)cc1Cl
Temperature: 135 °C
Reaction time: 3 h

Procedure:
Copper (I) chloride (0.90 g) was added to a mixture of N-[2-chloro-4-iodophenyl]-2-acetoxy-3-methylpropanamide (Method 23) (8.3 g), 4-aminothiophenol (1.07 ml) and potassium carbonate (9.1 g) in DMF (100 ml). The mixture was heated at 135° C. with stirring under argon for 3 hours, cooled and then filtered through diatomaceous earth. The filter was washed with ethyl acetate (3×20 ml) and the filtrates were combined and washed with water (50 ml), brine and dried. The volatile material was removed by evaporation. The crude product was purified by flash chromatography eluting with 20-40% ethyl acetate/hexane to give the title compound (4.99 g) as a solid. Mp 130-132° C.; NMR (CDCl3): 1.7 (s, 6H), 2.1 (s, 3H), 3.8 (s, 2H), 6.6 (d, 2H), 7.1 (m, 2H), 7.2 (m, 2H), 8.2 (d, 1H), 8.4 (s, 1H); MS (ESP−): 377.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:14]O)=[NH:4].N[N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22].[ClH:23]>C(O)(C)C>[ClH:23].[ClH:23].[OH:1][NH:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:14][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22])=[NH:4]
Reactant: Nc1nccn1N
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Agent: Cl
Solvent: CC(C)O
Product: N=C(NO)c1cccc2c1CCC2=Nn1ccnc1N

Procedure:
A mixture of 0.837 g (4.079 mmol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.40 g (4.077 mmol) of 1,2-diamino-imidazole, 23 ml of isopropanol and 1.33 ml of concentrated hydrochloric acid is heated under reflux for 22 hours. Filtration of the hot reaction mixture, washing of the crystallizate with isopropanol and diethyl ether and drying under a high vacuum yield the title compound, m.p. 258°-260° C. (decomp.), 1H-NMR (DMSO/D2O): δ=8.29 (d, 1H); 7.80 (d, 1H); 7.65 (t, 1H); 7.55 (d, 1H); 7.13 (d, 1H); 3.22-3.32 (m 4H).
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6](C(O)=O)/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]O)=[O:23])[CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>COCCOC.C(Cl)Cl.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[C:22]([O:24][C@@H:6]1[N:3]2[C@H:2]([O:11]/[C:7]/1=[CH:8]\[CH2:9][OH:10])[CH2:1][C:4]2=[O:5])=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21)c1cccc(Cl)c1
Reaction time: 15 h
Yield: 11.4 %

Procedure:
Clavulanic acid (containing ca 0.5 meq. ethyl acetate; 410 mg., 1.7 mmole) was dissolved in dry 1,2-dimethoxyethane/methylene chloride (1:1, 10 ml.). The solution was stirred and ice-cooled with exclusion of moisture while m-chloroperbenzoic acid (380 mg.) and dicyclohexylcarbodiimide (400 mg.) were added. The mixture was stirred with exclusion of moisture for 3 hours at 0° and then for 15 hours at room temperature. The mixture was diluted with ethyl acetate (50 ml.) and was filtered. The filtrate was washed with saturated sodium bicarbonate solution and then with saturated brine. The solution was dried (magnesium sulphate and the solvent was evaporated under reduced pressure to yield a yellow gum. The gum was chromatographed on silica gel (25 g.) using ethyl acetate/petroleum ether (b.p. 60°-80°) to give the title compound as a colourless gum (60 mg., 11% yield). [α]D21 +88.8° (c=1.0 CHCl3). νmax (CHCl3): 3320 (hydroxyl OH), 1805 (β-lactam C=O), 1730 (ester C=O), 1700 (olefinic C=C)cm-1. δ (CDCl3): 2.28 (br.s, 1H, OH), 3.11 (d, J 16 Hz, 1H, C(6)H), 3.48 (dd, J 16, J' 2 Hz, 1H, C(6)H), 4.26 (d, J 7 Hz, 2H, CH2O), 5.03 (t, J 7 Hz, 1H, olefinic H), 5.77 (d, J 2 Hz, 1H, C(5)H), 6.70 (s, 1H, C(2)H), 7.25-7.60 (m, 2H, Ar-H), 7.80-8.00 (m, 2H, Ar-H).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOC(C)=O.O>[Cl:24][C:2]1[O:1][C:5]([C:6]2[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: N#Cc1ccc(-c2cnco2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of 4-Oxazol-5-yl-benzonitrile (3 g, 17.65 mmol) in anhydrous THF (80 mL) at −78° C. under an argon atmosphere was slowly added a solution of LiHMDS (21.2 mL, 1 M in THF, 21.2 mmol). After 1 h at −78° C., solid hexachloroethane (6.275 g, 26.48 mmol) was added. The mixture was then stirred at −78° C. for 1 h and allowed to slowly warm to room temperature and stir for 3 h. The reaction was diluted with AcOEt/H2O (50 mL/15 mL). The organic layer was washed with brine, dried with MgSO4 and filtered. After removal of solvent the solid obtained was recrystallize from Hexane to give the title compound as a white solid (2.95 g, 82%). m.p.=144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:38]([S:40][CH2:41][C:42]#[CH:43])[CH3:39].CCO>ClCCl.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.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:43]=[C:42]([CH2:41][S:40][CH2:38][CH3:39])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCSCC
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCSCc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and CuI (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), and propargyl ethyl sulfide (0.066 mL). The reaction is stirred at room temperature for 4 days. The reaction mixture is diluted with dichloromethane and partitioned against dilute aqueous sodium bicarbonate. The aqueous phase is extracted with two portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel eluting with 1% to 2% methanol in ethyl acetate. Product containing fractions are combined and condensed to afford a mixture of cyclized and uncyclized materials. To a flask is added the mixture, EtOH (2 mL), and Et3N (0.1 mL). The suspension is heated at 75° C. overnight tightly capped. The reaction mixture is cooled to room temperature, concentrated under reduced pressure, adsorbed onto silica, and flash column chromatographed eluting with 2% to 4% methanol in ethyl acetate. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid. The solid is crystallized from acetonitrile to give 0.12 g of the title compound as light tan product.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]=O)[CH:3]=1.[C:16](OCC)(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1CCCCC1>C(O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][N:13]=3)[CH:14]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])[CH:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(Nc2ncccc2C=O)no1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cccnc2n(-c2cc(C)on2)c1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
3.3 g (16 mmol) of (2-(5-methyl-3-isoxazolyl)amino)nicotinaldehyde was dissolved in ethanol (60 mL), and 3.9 g (24 mmol) of diethyl malonate and 0.56 g (6.5 mmol) of piperidine were added thereto. The resulting mixture was stirred overnight at 90° C. The reaction mixture was cooled, and then the solvent was distilled off. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:4 to 7:3), and thus 2.7 g of the title compound was obtained as pale yellow crystals (yield: 55%).
Reaction SMILES: [F:1]/[C:2](=[CH:8]\[CH3:9])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10]N1C(=O)CCC1=O.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:9]/[CH:8]=[C:2](\[F:1])/[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C/C=C(\F)C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C(F)=C/CBr
Yield: 59.1 %

Procedure:
After 9.0 g of (Z)-ethyl 2-fluorocrotonate was dissolved in 60 ml of carbon tetrachloride, 13.5 g of N-bromosuccinimide and 10 mg of benzoyl peroxide were added thereto. The mixture was heated to reflux for 6 hours. This reaction solution was filtered and the filtrate was concentrated to give a residue. The residue was subjected to silica gel column chromatography (eluent; n-hexane:ethyl acetate=20:1), thereby obtaining 8.5 g of the desired compound.
Reaction SMILES: [BrH:1].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11](O)[C:12]([OH:14])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3]1>C1(C)C=CC=CC=1.ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([Br:1])[C:12]([OH:14])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C(O)c1ccc2c(c1)OCO2
Reactant: Br
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(O)C(Br)c1ccc2c(c1)OCO2
Reaction time: 4 h

Procedure:
62% Aqueous hydrobromic acid (220 ml) was added slowly to a stirred suspension of 2-(1,3-benzodioxol-5-yl)-2-hydroxyacetic acid (see J Org Chem, 50(23), 4523-6, 1985; 82.4 g) in a mixture of toluene (500 ml) and dichloromethane (1 liter). The mixture was stirred vigorously for 4 h. The aqueous layer was separated and removed and the organics were dried (MgSO4) and concentrated to give a brown oil. The oil crystallised over a 24 h period to give 105.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.Cl.[CH:16]1([CH2:20][NH2:21])[CH2:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C.O>ClCCl>[CH:16]1([CH2:20][NH:21][C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:13])[CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Reactant: NCC1CCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(NCC1CCC1)c1cnc(Cl)nc1C(F)(F)F
Temperature: -30 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
A mixture of 2-chloro-4-trifluoromethyl-pyrimidine-5-carbonyl chloride (613 mg) (Maybridge) and C-cyclobutylmethylamine hydrochloride (304 mg) in dry dichloromethane (10 ml) was cooled to −30° C. and N,N-diisopropylethylamine (958 ul) was added dropwise. The mixture was stirred at room temp for 1 hour. Water (10 ml) was added, the layers separated and the organic layer was washed sequentially with 10 ml portions of water, dilute hydrochloric acid, water, dilute sodium bicarbonate solution and water, dried (MgSO4) and evaporated. Purification by chromatography on silica gel (dichloromethane/ether 25:1) gave the title compound (449 mg).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:19]
Reactant: [H][H]
Reactant: O=C(NOCCc1ccccn1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NOCCc1ccccn1)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 49.8 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-N-[2-(pyridin-2-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 126 (0.26 g, 0.65 mml) in methanol (20 mL) was added 5% Pd/C (0.25 g). The mixture was hydrogenated at 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2S,5R)-6-hydroxy-7-oxo-N-[2-(pyridin-2-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 127 (0.10 g, 50%) as a white foam.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([Si](C)(C)C)[N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1COCC1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)c1cn(-c2cccc([N+](=O)[O-])c2)nn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-n2ccnn2)c1

Procedure:
1-(3-Nitro-phenyl)-4-trimethylsilanyl-1H-[1,2,3]triazole (16.7 g, 64 mmol) tetrabutylammonium fluoride in THF (1M, 100 ml, 100 mmol) were stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (hexane/ethyl acetate 1:1) and the desired product was obtained as a brown solid (9.96 g, 82%), mp 80-83° C.
Reaction SMILES: B(F)(F)F.[F:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].O>C(OCC)C>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=1[OH:12])=[O:20]
Reactant: Oc1cccc(F)c1
Reactant: O=C(Cl)CCCCCCl
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: O=C(CCCCCCl)c1ccc(F)cc1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
Reaction under N2 atmosphere. BF3 in diethylether (215 ml) was cooled to 0° C. 3-Fluoro-phenol (0.25 mol) was added. 6-Chloro-hexanoyl chloride (0.51 mol) added and the resulting reaction mixture was stirred for 15 min at 0° C., then allowed to warm to room temperature. The reaction mixture was then stirred overnight at 130° C. The mixture was cooled room temperature. Water was added while cooling. This mixture was extracted twice with diisopropyl ether. The separated organic layer was dried, filtered and the solvent evaporated. The residue was by column chromatography over silica gel (eluent: CH2Cl2/hexane 50/50), then by HPLC (eluent: CH2Cl2/hexane 50/50). The fractions were collected and the solvent was evaporated, yielding 52.2 g of 6-chloro-1-(4-fluoro-2-hydroxyphenyl)-1-hexanone (interm 17).
Reaction SMILES: Br[C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH2:19])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1.[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>C(O)CC>[C:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:21]=[CH:22][C:23]([CH2:26][NH:27][C:2]2[N:3]([C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH2:19])[C:17]=3[N:18]=2)[C@@H:4]2[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]2)=[CH:24][CH:25]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: Nc1ncnc2c1nc(Br)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: Nc1ncnc2c1nc(NCc1ccc(-c3ccccc3)cc1)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
A mixture of 8-bromo-2′-deoxyadenosine (0.07 g), biphenyl-4-ylmethylamine (0.12 g) and N,N-diisopropyl-ethylamine (0.15 mL) in 1-propanol (2.1 mL) was stirred under reflux for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on amino-propylated silica gel (eluent: dichloromethane/methanol=12/1) to give the title compound (0.05 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc(Br)cc2)cc1
Temperature: 25 °C

Procedure:
4-Bromophenol (25.00 g, 145 mmol), para-methoxybenzyl chloride (24.89 g, 159 mmol), potassium iodide (2.17 g, 14.45 mmol), and potassium carbonate (39.9 g, 289 mmol) in acetone (600 mL) was heated to reflux for 18 h. The crude reaction mixture was then cooled to room temperature and filtered through a sintered glass funnel. The filtrate was concentrated in vacuo, and the white solid was recrystallized from ethanol yielding the product as a white solid (33.44 g, 79%). 1HNMR (300 MHz, CDCl3) δ 3.80 (s, 3H), 4.95 (s, 2H), 6.85 (d, 2H), 6.92 (d, 2H), 7.32-7.40 (m, 4H). Part II: