Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].N([O-])=O.[Na+].[BrH:15]>O1CCOCC1.O.[Cu]Br>[Br:15][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5]
Reactant: Br
Reactant: N#Cc1c(N)cccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1c(F)cccc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
2-Amino-6-fluorobenzonitrile (18.0 g, 132 mmol) was dissolved in hot 1,4-dioxane (20 mL), 48% hydrobromic acid (200 mL) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (10.5 g, 152 mmol) in water (20 mL) over 1.5 h. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (56.8 g, 396 mmol) in 48% hydrobromic acid (50 mL). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (1200 mL) and extracted with ethyl acetate (2×400 mL). The combined organics were washed with 10% aqueous ammonia solution (400 mL), water (400 mL) and brine (500 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give an orange oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (2-4%) gave 2-bromo-6-fluorobenzonitrile (18.5 g, 70%) as a white solid: δH (400 MHz, CDCl3) 7.17-7.23 (1H, ddd, J 8, 8 and 1), 7.44-7.52 (2H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]Br.Br[C:14]1[C:15](=[O:31])[NH:16][C:17](=[O:30])[C:18]=1[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[NH:21][CH:20]=1>C1C=CC=CC=1.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:14]2[C:15](=[O:31])[NH:16][C:17](=[O:30])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[NH:21][CH:20]=2)=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1ccc2[nH]cc(C3=C(Br)C(=O)NC3=O)c2c1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: c1ccccc1
Product: COc1ccc2[nH]cc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c2c1
Reaction time: 0.5 h
Yield: 2.7 %

Procedure:
To a suspension of 105 mg of indole in 20 ml of benzene were added 0.6 ml of a 3M solution of methylmagnesium bromide in diethyl ether under nitrogen. The mixture was stirred for 0.5 hour. 100 mg of 3-bromo-4-(5-methoxy-3-indolyl)-1H-pyrrole-2,5-dione were added and the mixture was heated to reflux for 5 days. After cooling the residue was partitioned between dichloromethane and 2M hydrochloric acid. The organic extracts were washed with water, dried and evaporated. The residue was purified on silica gel with 1% methanol in dichloromethane and then with 50% methanol/0.1% trifluoroacetic acid/water on Spherisorb to give 3 mg of 3-(3-indolyl)-4-(5-methoxy-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 280° C.
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[CH3:22][O:23][C:24]1[CH:25]=C([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)CN>>[CH3:22][O:23][C:24]1[CH:25]=[C:2]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Product: COc1cc(CNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc(OC)c1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using 3,5-dimethoxybenzylamine instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 409 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.30 (1H, s) 8.65 (1H, t, J=5.95 Hz) 8.03 (1H, d, J=5.42 Hz) 7.80 (1H, d, J=5.42 Hz) 7.50 (1H, d, J=5.42 Hz) 7.30 (1H, dd, J=3.32, 2.20 Hz) 6.84 (1H, d, J=5.47 Hz) 6.48 (2H, d, J=2.25 Hz) 6.42 (1H, dd, J=3.44, 1.44 Hz) 6.37 (1H, t, J=2.27 Hz) 4.39 (2H, d, J=6.00 Hz) 3.70 (6H, s)
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Mg].C(O[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C.Cl>O1CCCC1>[O:28]=[C:22]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCC(=O)C(=O)OCC

Procedure:
A slurry of 40 ml of hexadecyl bromide in 250 ml of tetrahydrofuran containing 3.64 g of magnesium chips is put in a sonic bath. This solution is added dropwise to a stirred solution of 35.3 ml of diethyloxalate in 70 ml of tetrahydrofuran at -15° C. over 1 hour. The reaction mixture is poured into 3N hydrochloric acid and extracted with methylene chloride. The extract is dried and evaporated. The concentrate is purified by chromatography on silica gel using 5% ethyl acetate:petroleum ether. Fractions containing product are combined and evaporated. The residue is crystallized from petroleum ether to give 21.9 g of the desired product as a solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C@H:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:15]O.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C.O1CCCC1>[CH3:13][C@H:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:15][N:26]1[C:22](=[O:32])[C:23]2[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:25]1=[O:27]
Reactant: C[C@@H](CO)CC(F)(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](CN1C(=O)c2ccccc2C1=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
Diethyl azodicarboxylate (15.4 ml) was added to a 20 C., stirred slurry of (R)-2-methyl-4,4,4-trifluorobutan-1-ol (about 12.0 g), phthalimide (13.4 g), and triphenylphosphine (23.7 g) in diethyl ether (about 6.5 g, see above) and dry tetrahydrofuran (110 ml), warmed to room temperature overnight, and stirred an additional 8 h. The mixture was evaporated, methylene chloride was added to the residue, and the slurry was filtered. The filtrate was purified by flash chromatography, eluting with 1:1 methylene chloride:hexanes, to give (R)-2-(2-methyl-4,4,4-trifluorobutyl)-1H-isoindol-1,3(2H)-dione (17.1 g, 75%) as a white solid; m.p. 45°-47° C.; partial NMR (400 MHz, CDCl3): 1.08 (d, 3H, CH3), 1.94-2.07 (m, 1H, CF3CH2), 2.14-2.31 (m, 1H, CF3CH2), 2.36-2.50 (m, 1H, CHCH3), 3.58 (dd, 1 H, CH2N), 3.64 (dd, 1H, CH2N).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:15]=[C:16](I)[C:3]=12.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:15]=[C:16]([C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)[C:3]=12
Reactant: CN1CCN(CCn2nc(I)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(CCn2nc(-c3cnn(C)c3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
Nitrogen was bubbled through a suspension of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (75 mg, 0.16 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (37 mg, 0.18 mmol) and K3PO4 (99 mg, 0.47 mmol) in DMF (1.2 mL) and water (0.4 mL) for 20 min. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (13 mg, 0.016 mmol) was added and the tube sealed and heated using microwave irradiation to 60° C. for 30 min. The crude reaction mixture was filtered and purified by preparative HPLC to provide Compound Ic (42 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].N1CC[O:38]CC1>>[O:38]1[CH2:2][CH2:1][N:3]([C:4](=[O:32])[CH:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C:6]([NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)(=[O:10])=[O:11])=[O:7])[CH2:33][CH2:34]1
Reactant: C1COCCN1
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: O=C(NS(=O)(=O)c1ccc2ccccc2c1)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)N1CCOCC1

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (500 mg) obtained in Example 6 (4) and morpholine (204 μL). This was purified by silica gel column chromatography to give the title compound (304 mg) as a white powder.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:46]1[CH:47]=[CH:48][C:49]([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[N:50][CH:51]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]2[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:43])([CH3:44])[CH3:42])=[CH:37][CH:36]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:46]4[CH:47]=[CH:48][C:49]([C:52]5[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=5)=[N:50][CH:51]=4)=[CH:18][CH:17]=3)[N:24]=2)=[CH:30][CH:29]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: Brc1ccc(-c2ccncc2)nc1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccncc5)nc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
Under a stream of argon, 2.1 ml of a hexane solution containing 3.2 mmol of butyl lithium was slowly added to 50 ml of tetrahydrofuran cooled to −78° C. in which 1.50 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained in Reference Example 1 had been dissolved. After stirring at −78° C. for 15 minutes, 0.83 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 30 ml portion of tetrahydrofuran prepared by dissolving 0.74 g of 5-bromo-2,4′-bipyridyl and 0.14 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 13 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was purified by a silica gel column chromatography (eluting solution hexane:chloroform=2:1 to chloroform) and an alumina gel column chromatography (eluting solution hexane:chloroform=1:1) and then recrystallized from dichloromethane-methanol to obtain a white solid of the intended 5-{4-[4,6-bis(4-tert-butylphenyl)-1,3,5-triazin-2-yl]phenyl}-2,4′-bipyridyl (0.97 g, yield 56%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[Cl:11][C:12]1[CH:35]=[CH:34][CH:33]=[CH:32][C:13]=1[CH:14]=[CH:15][CH2:16][C:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:23](=[O:25])[CH3:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21].[OH-].[Na+]>C(O)C.O>[Cl:11][C:12]1[CH:35]=[CH:34][CH:33]=[CH:32][C:13]=1[CH:14]=[CH:15][CH2:16][C:17]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:23](=[O:25])[CH:24]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CC(=O)C(CC=Cc1ccccc1Cl)(CCC(=O)O)c1ccccc1
Reactant: COc1ccccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccccc1C=CC(=O)C(CC=Cc1ccccc1Cl)(CCC(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
o-Methoxybenzaldehyde (2.72 g., 0.02 mole) in ethanol (10 ml.) is added to a solution of 4-(o-chlorocinnamyl)-4-phenyl-5-oxohexanoic acid (3.57 g., 0.01 mole) and sodium hydroxide (0.56 g., 0.014 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (200 ml.), and extracted with ether to remove the excess o-methyoxybenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (10 ml.), and the yellow solid which precipitates is collected and air-dried. Several recrystallizations from ethanol yields a pale yellow material with m.p. 206.5°-209.5°C.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15](O)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:25])=O>>[Cl:25][CH:15]([CH2:14][O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CCCCCCCCCCCCOCC(O)Cn1ccnc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCCOCC(Cl)Cn1ccnc1

Procedure:
Thionyl chloride (10 ml.) and 1.55 g. of 1-[3'-(n-dodecyloxy)-2'-hydroxypropyl]imidazole are warmed gently for a period of 2 hours and the solution is then evaporated to dryness. The residue is dissolved in 100 ml. of dichloromethane and rendered basic with aqueous potassium carbonate solution. The organic layer is separated, dried over magnesium sulfate and evaporated to yield 1-[2'-chloro-3'-(n-dodecyloxy)propyl]imidazole.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[CH:25]([C:28]1[CH:29]=[C:30]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[O:31][C:32]1[C:39]([Cl:40])=[CH:38][C:35](CO)=[CH:34][C:33]=1[Cl:41])([CH3:27])[CH3:26]>C(OCC)C>[Cl:40][C:39]1[CH:38]=[C:35]([CH:34]=[C:33]([Cl:41])[C:32]=1[O:31][C:30]1[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:28]([CH:25]([CH3:26])[CH3:27])[CH:29]=1)[CH2:20][Br:24]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: COc1ccc(Oc2c(Cl)cc(CBr)cc2Cl)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
To a stirred solution of triphenylphosphine (0.42 g, 1.61 mmol) and CBr4 (0.534 g, 1.61 mmol) in diethyl ether (15.0 mL) at room temperature was added 4-(3′-iso-propyl-4′-methoxyphenoxy)-3,5-dichlorobenzyl alcohol (0.50 g, 1.46 mmol). The reaction mixture was stirred at room temperature for 16 h, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (1:9) to afford 3,5-dichloro-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl bromide (0.320 g, 54%): 1H NMR (300 MHz, DMSO-d6): δ 7.77 (s, 2 H), 6.82 (m, 2 H), 6.38 (m, 1 H), 4.75 (s, 2 H), 3.75 (s, 3 H), 3.22 (m, 1 H), 1.13 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (1:4); Rf=0.46.
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[N:5]1[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[CH:25]=[N:24][S:23][N:22]=3)[C@H:4]1[S:3]2.[Br-].[Al+3].[Br-].[Br-]>ClCCl>[CH3:1][CH:2]1[CH:15]=[C:6]([C:7]([O:9][CH2:10][C:11]([Cl:13])([Cl:14])[Cl:12])=[O:8])[N:5]2[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[CH:25]=[N:24][S:23][N:22]=3)[C@H:4]2[S:3]1
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3cnsn3)[C@H]1S2
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cnsn3)[C@H]2S1
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-{2-(1,2,5-thiadiazol-3-yl)acetamido}-penam-3-carboxylate (16.5 g.) in dried dichloromethane (100 ml.) was gradually dropwise added to a solution of aluminum bromide (17.5 g.) in dichloromethane (100 ml.) at below -10° C. Then, the mixture was stirred for 2 hours at below 0° C. and stirred for further 2 hours at room temperature. After the reaction, the reaction mixture was washed in turn with 2% hydrochloric acid (100 ml.) twice, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After drying, the solvent was distilled off to give powdery 2,2,2-trichloroethyl 2-methyl-7-{2-(1,2,5-thiadiazol-3-yl)acetamido}-3-cephem-4-carboxylate (13.2 g.), mp 180° to 185° C. (dec.).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:15][C:16]1[C:24]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:22]=[C:21]([F:29])[C:17]=1[C:18](O)=[O:19]>>[F:15][C:16]1[C:24]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:22]=[C:21]([F:29])[C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3]1)=[O:19]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1F
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Product: CS(=O)(=O)c1ccc(F)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1F

Procedure:
Prepared in analogy to example 5 from 4-piperazin-1-yl-benzonitrile and 2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m/e): 406.3 (MH+, 84%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[N:9]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26]CC)=[O:25])=[C:17]3[N:16]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+].Cl.O1CCOCC1>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[N:9]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[C:17]3[N:16]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3[C@H](CO)CC[C@@H]3c3cncc(F)c3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cnn2ccc(N3[C@H](CO)CC[C@@H]3c3cncc(F)c3)nc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 90.6 %

Procedure:
A mixture of ethyl 5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.250 g, 0.649 mmol) and 2M sodium hydroxide (3.24 mL, 6.48 mmol) in MeOH (10 mL) was stirred at ambient temperature for 4 days followed by 50° C. for 5 hours. The reaction was cooled to ambient temperature and 4M HCl in dioxane (1.78 mL, 7.14 mmol) was added. The mixture was concentrated and the residue was purified by reverse phase column chromatography (0-40% acetonitrile/water) to afford 5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (210 mg, 90% yield) as a white solid. MS (apci) m/z=358.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=3)[S:13][C:6]=12.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH2:18][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[CH:16][N:15]=3)[S:13][C:6]=12
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
A mixture of 400 (451 mg, 1.14 mmol) and 1-methylpiperazine (152 μL, 137 mg, 1.37 mmol) in DCM (7 mL) was stirred at room temperature for 10 min. It was then treated with NaBH(OAc)3 (340 mg, 1.60 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3 solution (20 mL). The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using the gradient 30-50% MeOH (with 2% Et3N) in EtOAc to afford 401 (308 mg, 52% yield). MS (m/z): (M+1) 480.0 (100%).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([OH:46])=[O:45])=[CH:40][C:39]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O[CH2:52][C:53]([O:55][CH3:56])=[O:54].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([O:46][CH2:52][C:53]([O:55][CH3:56])=[O:54])=[O:45])=[CH:40][C:39]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:4]=[C:3]([C:2]([F:1])([F:49])[F:50])[CH:8]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: COC(=O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid (EXAMPLE 30, 200 mg, 0.281 mmol), methyl hydroxyacetate (0.022 mL, 0.281 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (81 mg, 0.422 mmol) and triethylamine (0.059 ml; 0.422 mmol) were stirred in DCM (2.811 mL) at room temperature overnight. LCMS of aliquot indicated formation of the desired product and complete consumption of starting material. Volatiles were evaporated from the reaction crude. The pot residue was purified by prep HPLC to afford a light yellow solid as the titled compound. LCMS (ESI) calc.=783.19; found=784.0 (M+1)+. 1H NMR (CDCl3, 400 MHz, 1:1 mixture of atropisomers): δ 7.99 (d, J=6.8 Hz, 1H), 7.92 (d, J=8 Hz, 1H), 7.85 (s, 1H), 7.72-7.68 (m, 1.5H), 7.67-7.61 (m, 2.5H), 7.45-7.36 (m, 2H), 7.32-7.26 (m, 1H), 7.13 (s, 1H), 7.08 (d, J=5.6 Hz, 0.5H), 7.06 (d, J=5.6 Hz, 0.5H), 5.59 (d, J=8 Hz, 0.5H), 5.30 (d, J=8 Hz, 0.5H), 4.97 (d, J=14 Hz, 0.5H), 4.93 (d, J=14 Hz, 0.5H), 4.87 (s, 2H), 4.16 (d, J=15.6 Hz, 0.5H), 3.95 (d, J=16 Hz, 0.5H), 3.86 (s, 3H), 3.80 (s, 3H), 3.80-3.75 (m, 1H), 2.37 (s, 1.5H), 2.32 (s, 1.5H), 0.54 (d, J=6.8 Hz, 1.5H), 0.42 (d, J=6.8 Hz, 1.5H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[C:28]([CH3:42])=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([CH3:42])=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1C
Product: CCOc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-ethoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 85.1.1) to give the title compound as a white solid. (HPLC: tR 2.22 min (Method A); M+H=429 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.19-8.17 (m, 1H), 8.13-8.09 (m, 2H), 8.02-7.98 (m, 1H), 7.61-7.59 (m, 1H), 7.30-7.28 (m, 1H), 4.20-4.12 (m, 2H), 3.89 (s, 3H), 3.58 (s, 3H), 2.39 (s, 3H), 1.97 (s, 3H), 1.43 (t, 3H))