Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[N:17][C:18]=4[NH2:20])[N:13]([CH3:21])[N:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:24]([F:34])=[C:25]([CH2:30][C:31](O)=[O:32])[CH:26]=[CH:27][C:28]=1[F:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:22][C:23]1[C:24]([F:34])=[C:25]([CH2:30][C:31]([N:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]4[C:19]5[C:14](=[N:15][CH:16]=[N:17][C:18]=5[NH2:20])[N:13]([CH3:21])[N:12]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:32])[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: O=C(O)Cc1ccc(F)c(Cl)c1F
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2ccc(F)c(Cl)c2F)c2c(N)ncnc21
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to a solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine HCl (70 mg, 0.231 mmol), (3-chloro-2,4-difluorophenyl)acetic acid (47.8 mg 0.231 mmol), and HATU (88 mg, 0.231 mmol) in DMF (2 mL) was added Hunig's base (0.162 mL, 0.925 mmol). The mixture was stirred overnight. The reaction was poured into water (100 mL), and an off-white solid was formed. The solid was filtered, washed with water (10 mL), and dried to afford the title compound as an off-white solid. LC-MS (ES) m/z=455.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.24-3.31 (m, 2H), 3.94 (s, 3H), 4.03 (s, 2H), 4.32 (t, J=8.46 Hz, 2H), 7.30-7.36 (m, 1H), 7.39-7.46 (m, 2H), 7.54 (s, 1H), 8.14 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:23]=[CH:22][N:21]([C:24]2([CH2:28][C:29]#[N:30])[CH2:27][NH:26][CH2:25]2)[N:20]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:23]=[CH:22][N:21]([C:24]2([CH2:28][C:29]#[N:30])[CH2:27][N:26]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:25]2)[N:20]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3cccc(Cl)c3)n12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CN(S(C)(=O)=O)C5)n4)n3Cc3cccc(Cl)c3)n12
Reaction time: 0.17 h

Procedure:
To (3-{3-[6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl]-1H-pyrazol-1-yl}azetidin-3-yl)acetonitrile (6.0 mg, 0.013 mmol, from Example 106, Step 1) was added methanesulfonyl chloride (1.2 μL, 0.016 mmol, Aldrich) in DCM (0.46 mL), followed by triethylamine (3.7 μL, 0.026 mmol). After 10 minutes, the product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (4.6 mg, 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[CH2:13]1[S:18](=[O:20])(=[O:19])[O:17][CH2:16][CH2:15][CH2:14]1>CC(C)=O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N+:3]=1[CH2:16][CH2:15][CH2:14][CH2:13][S:18]([O-:20])(=[O:19])=[O:17]
Reactant: O=S1(=O)CCCCO1
Reactant: Cc1ccc2nc(C)ccc2c1
Solvent: CC(C)=O
Product: Cc1ccc2c(ccc(C)[n+]2CCCCS(=O)(=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
After 72.3 g (0.46 mol) of 2,6-dimethylquinoline and 188 g (1.4 mol) of butane sultone were heated at 145° C. with stirring for 4 hours, the mixture was allowed to cool to room temperature, and 500 ml of acetone was added thereto. While cooling, crystallization was conducted for 30 minutes. The resulting crystal was recovered by filtration, washed with acetone and dried to obtain 127.3 g (yield: 94%) of 4-[2,6-dimethyl-1-quinolinio]butane sulfonate.
Reaction SMILES: IC.[C:3]([O-:6])([O-])=O.[K+].[K+].[CH2:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:13]=1O)[CH:10]=[CH2:11]>CC(C)=O.O>[CH2:9]([C:12]1[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[C:17]=1[O:6][CH3:3])[CH:10]=[CH2:11]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc(F)cc(F)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: C=CCc1cc(F)cc(F)c1OC
Yield: 61.7 %

Procedure:
A solution of iodomethane (1.8 mL, 29.4 mmol), K2CO3 (2.4 grams, 17.6 mmol) and 2-Allyl-4,6-difluorophenol (1.0 grams, 5.9 mmol) in 20 mL acetone was refluxed overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. Flash chromatography (Hexane) afforded 0.67 g (63%) of the title compound. 1H NMR (400 MHz, CDCl3). S 3.36 (d, 21), 3.82 (s, 3H), 4.97-5.12 (m, 2H), 5.85-6.0 (m, 1H), 6.4-6.5 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1.C(O)C>C1(O)C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:19]3[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Solvent: CCO
Solvent: Oc1ccccc1
Product: NC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccccc23)CC1

Procedure:
In a manner analogous to that of Example 6, 4-chloro-2-(4-chlorophenyl)quinoline was reacted with isonipecotamide in phenol at 170° C., yielding the named compound, mp. 245°-247° dec., from ethanol.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.Cl[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:4]1[S:3][C:2]([S:1][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[O:18])=[N:6][C:5]=1[CH3:7]
Reactant: COc1ccc(COC(=O)CCCCl)cc1
Reactant: COC(=O)Cc1sc(S)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1sc(SCCCC(=O)OCc2ccc(OC)cc2)nc1C
Temperature: 25 °C

Procedure:
10.2 g of methyl 2-mercapto-4-methyl-1,3-thiazol-5-yl-acetate are dissolved in 200 ml of acetone, and the solution is vigorously stirred with 12.1 g of 4-methoxybenzyl 4-chlorobutyrate in the presence of 13.0 g of powdered, dry potassium carbonate (potash) while maintaining the ambient temperature. After filtration, acetone is removed in vacuo, and the residue is purified by column chromatography (SiO2, ethyl acetate/cyclohexane 1:1). ##STR8##
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[O:19][CH2:20][O:21][CH3:22])C.O>C1COCC1>[CH3:22][O:21][CH2:20][O:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)CCc1ccncc1OCOC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cnccc1CCCO
Yield: 99.7 %

Procedure:
Lithium aluminum hydride (6.0 g, 0.16 mmol) is suspended in THF (500 ml), and thereto is added with stirring 3-(3-methoxymethoxypyridin-4-yl)propionic acid ethyl ester (21 g, 89 mmol) obtained in Reference Example 25 at 50° C. over a period of time for 30 minutes. The mixture is heated under reflux for 30 minutes, and thereto are added successively water (6 ml), a 15% sodium hydroxide (6 ml) and water (18 ml) in order to quench the reaction. The reaction solution is filtered to remove the insoluble materials, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound (17.5 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:22]1[CH:27]=[C:26]([CH:28]=O)[N:25]=[CH:24][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:28][C:26]4[CH:27]=[CH:22][CH:23]=[CH:24][N:25]=4)[CH2:18][CH2:17]3)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Brc1ccc2c(c1)Sc1ccccc1N2C1CCNCC1
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)Sc1ccccc1N2C1CCN(Cc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e (10.5 mg; 0.029 mmol) and 2-pyridyl carboxaldehyde (9.3 mg; 0.087 mmol) in dichloroethane (120 μL) was added acetic acid (5 μL) and a solution of sodium triacetoxyborohydride (12 mg, 0.057 mmol) in DMF (100 μL). The mixture was stirred at rt for 18 h, quenched with water (50 μL), and lyophilized. The thus obtained crude 3-bromo-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine, 1f was used as such for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[C:25]([N+:27]([O-])=O)[CH:26]=2)[O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.CO>C(OCC)(=O)C>[NH2:27][C:25]1[CH:24]=[C:9]([CH:8]=[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:31][CH:30]=2)[CH:26]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:22])([CH3:23])[C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)(C)c1ccc(Oc2cc(Oc3ccc(F)cc3)cc([N+](=O)[O-])c2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)c1ccc(Oc2cc(N)cc(Oc3ccc(F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Under an argon atmosphere, to a 500-mL pear-shaped evaporating flask was added the compound prepared in Example 5 (53.6 g) to which a mixed solution of methanol (50 mL) and ethyl acetate (175 mL) was added. The mixture was heated until dissolution, and the flask was purged with argon prior to addition of 5% palladium carbon (10.8 g). The flask was degassed and charged with hydrogen gas. The flask was vigorously stirred at room temperature for 3 hours. The reaction system was purged with argon, filtered with celite and washed with ethyl acetate. The obtained filtrate was subjected to distillation under reduced pressure to give the titled compound (43.9 g) having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N:6][C:7]=1[CH3:8].IC.[C:15]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[N:11]=[CH:10][N:9]([CH3:15])[C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2[nH]cnc2c(F)c1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cc1nc2c(ncn2C)c(F)c1Br
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-7-fluoro-5-methyl-3H-imidazo[4,5-b]pyridine (1.00 equivalent) in DMF is added iodomethane (1.20 equivalents) and K2CO3 (1.50 equivalents) at room temperature. The resulting mixture is stirred at 75° C. for 1 hour. The reaction mixture is diluted with EtOAc and washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:5]=2[N:6]=1.[Cl:16][C:17]1[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:11][C:9]1[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:5]2[NH:6][C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:18]4[C:17]([Cl:16])=[CH:22][C:21]([Cl:23])=[CH:20][N:19]=4)[CH2:25][CH2:26]3)=[N:3][C:4]=2[CH:10]=1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Reactant: FC(F)(F)c1cc2nc(Cl)[nH]c2cc1Cl
Product: FC(F)(F)c1cc2[nH]c(N3CCN(c4ncc(Cl)cc4Cl)CC3)nc2cc1Cl

Procedure:
2,5-Dichloro-6-(trifluoromethyl)benzoimidazole (255 mg, 1.0 mmol, Example 84c) reacted with 1-(3,5-dichloropyridin-2-yl)piperazine (232 mg, 1.0 mmol, Example 9a) under the conditions of Example 3c to give the title compound as a white solid. M.p. 93.5-196.4° C. MS (ESI, pos. ion) m/z: 452.0, 454.1 (M+1).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([CH2:63][CH2:64][CH2:65][C@H:66]([NH:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67](OCC#N)=[O:68])=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([CH2:63][CH2:64][CH2:65][C@@H:66]([NH:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:68])=[N+:61]=[N-:62]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN=[N+]=[N-])C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCN=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (77 mg, 0.121 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 5-azido-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk70) (144 mg, 0.484 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (18 mL), and the mixture was stirred at room temperature for 0.5 hour. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk71) (24.5 mg, 23%).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:10]Br>>[Br:10][CH:8]([CH3:9])[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: BrBr
Product: COC(=O)CC(=O)C(C)Br

Procedure:
reacting methyl 3-oxovalerate (commercially available) with bromine to give methyl 4-bromo-3-oxovalerate, or reacting ethyl 3-oxovalerate (commercially available) with bromine to give ethyl 4-bromo-3-oxovalerate,
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:16][O:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=4)[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1>>[Br:2][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[N:20]=[C:19]([CH2:18][O:17][CH2:16][C:12]3([C:9]4[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=4)[CH2:15][CH2:14][CH2:13]3)[O:23][N:22]=2)=[CH:25][CH:26]=1
Reactant: OCc1ccc(-c2noc(COCC3(c4ccc(Cl)cc4)CCC3)n2)cc1
Reactant: BrP(Br)Br
Product: Clc1ccc(C2(COCc3nc(-c4ccc(CBr)cc4)no3)CCC2)cc1
Reaction time: 16 h
Yield: 94.5 %

Procedure:
Phosphorous tribromide (30 μL, 323 μmol) was added to a stirred solution of crude (4-(5-(((1-(4-chlorophenyl)cyclobutyl)methoxy)methyl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (83 mg, 215 μmol) at 0° C. The ice bath was removed and stirring was continued for 16 h. The reaction mixture was diluted with dichloromethane and water. The dichloromethane extract was washed with satd. Aqueous NaHCO3 solution, brine, dried (Na2SO4), filtered, and evaporated under reduced pressure to obtain crude 3-(4-(bromomethyl)phenyl)-5-(((1-(4-chlorophenyl)cyclobutyl)methoxy)methyl)-1,2,4-oxadiazole (91 mg, 95% crude yield). LC/MS: m/e 448.92 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.O1CCCC1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C(O)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:18][CH:15]1[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: O=Cc1ccccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Brc1ccccc1CNC1CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
1 ml of 2-bromobenzaldehyde are dissolved in 20 ml of 1,2-dichloroethane and ml of tetrahydrofuran. 799 μl of cyclopropylamine and 643 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 5.3 g of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Br)=[CH:4][CH:3]=1.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16]>>[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:24]#[C:23][C:20]3[CH:21]=[CH:22][C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=3)=[CH:4][CH:3]=2)=[CH:21][CH:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: Brc1ccc(Br)c2ccccc12
Product: CCCCc1ccc(C#Cc2ccc(C#Cc3ccc(CCCC)cc3)c3ccccc23)cc1

Procedure:
The title compound is prepared analogously to Example 3 from 1,4-dibromonaphthalene and two equivalents of 4-n-butylphenylacetylene.
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:42][C@@H:43]1[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])[C@H:45]([CH:61]2[CH2:65][CH2:64][N:63]([C:66]([O:68][CH2:69][C:70]3[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=3)=[O:67])[CH2:62]2)[CH2:44]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:42][C@@H:43]3[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[C@H:45]([CH:61]4[CH2:65][CH2:64][N:63]([C:66]([O:68][CH2:69][C:70]5[CH:71]=[CH:72][C:73]([N+:76]([O-:78])=[O:77])=[CH:74][CH:75]=5)=[O:67])[CH2:62]4)[CH2:44]3)[CH2:19][C@H:20]12)[CH3:39]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)C[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 76.7 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (255 mg, 0.45 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidine (240 mg, 0.45 mmol, compound of Reference Example 5) to obtain p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidin-4ylthio]-1-carbapen-2-em-3-carboxylate (297 mg, yield: 78.6%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:26].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:26]
Reactant: CCNCC
Reactant: O=C1c2c(ccc(F)c2Cl)-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Yield: 83.6 %

Procedure:
0.88 g (2.5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one was stirred at room temperature overnight with 0.5 g (6.8 mmol) of diethylamine and 10 ml of N,N-dimethylformamide. After evaporating the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with water. By drying the organic phase over magnesium sulfate and evaporating the solvent there was obtained 0.9 g (95%) of (S)-8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CO.O>[C:13]([O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:17])=[O:4])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)CCCCC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
Lithium hydroxide (0.53 g, 22 mmol) was added to a solution of hexanedioic acid tert-butyl ester methyl ester (4.8 g, 22 mmol) in 3:1 methanol-water (80 mL), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was evaporated under vacuum. The residue was partitioned between water (60 mL) and methylene chloride (75 mL), and the aqueous phase was washed with methylene chloride (3×75 mL) and evaporated, providing 4.0 g of hexanedioic acid mono-tert-butyl ester, lithium salt; 1H NMR (D2O) δ 1.45 (s, 9H), 1.54-1.58 (m, 4H), 2.15-2.20 (m, 2H), 2.25-2.34 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]([F:28])([F:27])[C:4]([F:26])([F:25])[C:5]([F:24])([F:23])[C:6]([F:22])([F:21])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].[F:29][C:30]1[C:35]([N+:36]([O-:38])=[O:37])=[C:34]([F:39])[C:33]([F:40])=[C:32](F)[C:31]=1[F:42].C(N(CC)CC)C.Cl>CN1C(=O)CCC1.O>[N+:18]([C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([F:21])([F:22])[C:5]([F:23])([F:24])[C:4]([F:25])([F:26])[C:3]([F:27])([F:28])[CH2:2][O:1][C:32]1[C:31]([F:42])=[C:30]([F:29])[C:35]([N+:36]([O-:38])=[O:37])=[C:34]([F:39])[C:33]=1[F:40])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2c(F)c(F)c([N+](=O)[O-])c(F)c2F)c([N+](=O)[O-])c1
Yield: 93.1 %

Procedure:
1-(6-hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)-2,4-dinitrobenzene (3.7 g) was treated with pentafluoronitrobenzene (2.21 g) and triethylamine (0.96 g) in NMP (5 mL) for 18 hrs at room temperature. The mixture was diluted with water, acidified with hydrochloric acid, and extracted with ethyl ether. The extracts were washed with water, dried (MgS04), concentrated and purified by chromatography to give 4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]-2,3,5,6-tetrafluoronitrobenzene (5.0 g) as an oil.