Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:30][C:29]([C:31]([O:33]C(C)(C)C)=[O:32])=[CH:28][C:9]=3[N:10]3[CH2:17][C:16](=O)[N:15]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:14][C:13]4[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=4[C:11]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.CSC.Cl.CO>C1COCC1>[CH:1]1([C:7]2[C:8]3[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][C:9]=3[N:10]3[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:14][C:13]4[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=4[C:11]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCN1Cc2ccccc2-c2c(C3CCCCC3)c3sc(C(=O)OC(C)(C)C)cc3n2CC1=O
Agent: B
Agent: Cl
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: CN(C)CCN1CCn2c(c(C3CCCCC3)c3sc(C(=O)O)cc32)-c2ccccc2C1
Reaction time: 0.05 h

Procedure:
A solution of tert-butyl 13-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydrothieno[2′,3′:4,5]pyrrolo[2,1-a][2,5]benzodiazocine-11-carboxylate (1 eq., prepared as described in Example 1, Step 5) in dry THF (0.14 M) was treated with borane-dimethylsulfide complex (20 eq., 2 M solution in THF) overnight at RT. A solution of HCl in methanol (40 eq., 1.25 M) was added to the reaction mixture, which was then heated to reflux for 1 h. All volatiles were evaporated in vacuo and the residual material was subjected to RP-HPLC purification (column: Waters XTERRA PREP MS C18, 10 μm; solvents: A: water+0.1% trifluoroacetic acid; B: MeCN+0.1% trifluoroacetic acid; 25% B in A isocratic for 3 min, linear to 20% A in B in 12 min) afforded the title compound after lyophilisation as a colourless powder (33%). 1H-NMR (500 MHz, DMSO-d6, 330 K, δ) 7.91 (s, 1H), 7.63 (d, J 7.1, 1H), 7.52-7.46 (m, 2H), 7.37 (d, J 6.3, 1H), 4.40 (dd, J 15.3, 4.9, 1H), 3.86 (d, J 13.9, 1H), 3.70-3.10 (m, 4H, hidden by the H2O signal), 3.05 (d, J 13.9, 1H), 3.04-2.84 (m, 2H), 2.84 (m, 6H), 2.69-2.60 (m, 1H) 2.55-2.50 (m, 1H, partially hidden by the DMSO signal), 2.02-1.09 (m, 10H). MS (ES+) m/z: 452 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[B:16]([O:25]C(C)C)([O:21]C(C)C)[O:17]C(C)C.C([Li])CCC>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][B:16]([OH:25])[OH:21])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OB(O)Oc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
4-Bromochlorobenzene (70.6 g) is added into a four mouth flask connecting with a mechanical stirring apparatus, two constant pressure funnels and a temperature probe. Toluene (588.3 ml) and tetrahydrofuran (THF) (147 ml) are added under stiffing at room temperature under argon, and dissolved to obtain a colorless transparent liquid. Then triisopropyl borate (109.2 ml) and n-butyllithium (176.4 ml, 2.5M in hexane) are respectively added into two constant pressure funnels, and cooled the inner temperature to below −78° C., then n-butyllithium solution is dropped to the flask under controlling a dropping speed to keep the inner temperature below −78° C. After addition, the mixture is kept at the temperature for 1 hour, then triisopropyl borate is dropped into the mixture under the temperature below −78° C., and kept at the temperature for 1 hour after addition, and then the cooling system is removed to naturally warm up to −20° C. HCl solution (360.4 ml, 2.2M) is added to the mixture to warm up to about 10° C., and then placed for layer separation. The aqueous phase is reextracted with toluene (58.8 ml, 2 times). The organic phase is combined together and washed with saturated brine to pH=7 to obtain a colorless transparent liquid, dried with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove most of solvents and the white solid is finally precipitated, filtered to obtain a crystal of 4-chlorophenylboric acid (48 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:8]1=[O:23].C([Li])(CC)C.I[CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41].O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)([CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:8]1=[O:23]
Reactant: COc1cc(CN2CCC(Cc3ccc(C(F)(F)F)cc3)C2=O)cc(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)OCCI
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1cc(CN2CCC(CCO[Si](C)(C)C(C)(C)C)(Cc3ccc(C(F)(F)F)cc3)C2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)phenylmethyl)-2-oxopyrrolidine (1.55 g, 3.66 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of sec-butyllithium (3.1 mL, 1.3 M in hexane, 4.0 mmol). After 30 minutes, add a solution of 1-iodo-2-(t-butyldimethylsilyloxy)ethane (1.15 g, 4.0 mmol) in tetrahydrofuran (1 mL). After 2 hours, warm to ambient temperature. After 12 hours, add water (5 mL). Separate the layers and extract the aqueous layer three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/4 ethyl acetate/hexane to give the title compound: Rf=0.79 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C1COCC1.[CH:16]12[O:21][CH:20]1[CH2:19][CH2:18][CH2:17]2.[NH4+].[Cl-]>[Cu]I>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:19]1[CH2:18][CH2:17][CH2:16][CH:20]1[OH:21]
Reactant: C1CC2OC2C1
Reactant: COc1ccccc1[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C1CCCC1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of (2-methoxyphenyl)magnesium bromide in THF (47.4 ml, 47.4 mmol) was added Copper(I) iodide (0.632 g, 3.32 mmol). The resulting solution was stirred at RT for 10 min. 6-oxabicyclo[3.1.0]hexane (4.11 ml, 47.4 mmol) was slowly added and the reaction mixture was stirred at RT overnight. Sat. NH4Cl was slowly added and the mixture was stirred at RT for 30 min. The product was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (SG, 0% to 60% EtOAc/Hex) to get 2-(2-methoxyphenyl)cyclopentanol (9.03 g, 47.0 mmol, 99% yield). LC-MS (M+Na)+=215.1. 1H NMR (500 MHz, CDCl3) δ 7.21 (t, J=5.8 Hz, 2H), 6.97 (t, J=7.3 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 4.24 (q, J=5.9 Hz, 1H), 3.79 (s, 3H), 3.38-3.27 (m, 2H), 2.23-2.10 (m, 1H), 2.09-1.97 (m, 1H), 1.95-1.85 (m, 1H), 1.85-1.71 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:13])[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:11]=2[CH:12]=1.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[C:5]([NH:13][C:22]([NH:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:27])[F:26])=[CH:25][CH:24]=2)=[O:23])[CH:4]=1
Reactant: COc1cc(N)c2ccncc2c1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: COc1cc(NC(=O)NCc2ccc(C(F)(F)F)cc2)c2ccncc2c1

Procedure:
Prepared from 7-methoxyisoquinolin-5-amine (Description 82) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 376 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:38][N:39]([CH3:44])[S:40](Cl)(=[O:42])=[O:41]>CN(C)C=O>[CH3:38][N:39]([CH3:44])[S:40]([N:26]1[CH2:25][CH2:24][N:23]([S:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([C:2]([F:29])([F:1])[F:30])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:19][CH:18]=2)(=[O:22])=[O:21])[CH2:28][CH2:27]1)(=[O:42])=[O:41]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=S(=O)(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of [[4-[(7-trifluoromethyl-4-quinolinyl)amino]phenyl]sulfonyl]piperazine (prepared as in Example 9, part D) and triethylamine, in dimethyl formamide, is added dropwise an equimolar quantity of dimethylsulfamoyl chloride. The reaction mixture is stirred at room temperature for 15 to 25 hours and is then partitioned with methylene chloride-aqueous sodium carbonate. The organic phase is dried over sodium sulfate and is concentrated and purified by conventional methods to give 1-(dimethylaminosulfonyl)-4-[[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][CH:24]=[C:25]([CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:26]=2)=[CH:18][CH:17]=1.Cl>>[N:28]1([CH2:27][C:25]2[N:26]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:9]4[CH:10]=[CH:11][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=4)=[CH:17][CH:18]=3)[O:23][CH:24]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Brc1ccc(-c2nc(CN3CCCC3)co2)cc1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(-c2ccc(-c3nc(CN4CCCC4)co3)cc2)cc1

Procedure:
The titled compound is prepared substantially in accordance with the procedure of Example 4 using 4-(methylsulfonylamino)phenylboronic acid and 2-(4-Bromo-phenyl-4-pyrrolidin-1-ylmethyl-oxazole; hydrochloride (See Example 2). MS (m/e) 398.2 (M+1)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:46])[N:28]5[CH2:31][O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.FC(F)(F)C(O)=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:46])[N:28]5[CH2:31][O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:23][CH:22]=4)[CH2:14][CH2:15]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CCCCCCCCCCCC(=O)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCC(=O)OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.4 %

Procedure:
To a solution (5 ml) of dodecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester (150 mg) synthesized in the same manner as in Example 21 in THF was added trifluoroacetic acid (TFA) (0.11 ml), then to a solution (3 ml) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.27 g) in THF was added, and the mixture was stirred at room temperature for 3 days. To the reaction mixture were added water and sodium carbonate, and the mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate) to give the title compound (yield 50 mg, 33.4%) as a brown oil.
Reaction SMILES: [CH2:1](Cl)[CH2:2]Cl.C1C=CC2N(O)N=NC=2C=1.C(O)(=O)C.[NH:19]([C:21]1[N:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[C:24]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:25]([C:31]1[CH:36]=[CH:35][C:34]([C:37]3([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:40][CH2:39][CH2:38]3)=[CH:33][CH:32]=1)=[N:26]2)[NH2:20].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O.O.C(Cl)Cl>[CH3:1][C:2]1[N:30]2[C:21]([C:22]3[CH:23]=[C:24]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:25]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:40][CH2:39][CH2:38]5)=[CH:33][CH:32]=4)=[N:26][C:27]=3[CH:28]=[CH:29]2)=[N:19][N:20]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Reactant: ClCCCl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3ccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask was added EDC (4.63 g, 24.17 mmol), HOBt (3.27 g, 24.17 mmol), anhydrous DCM (50 mL) and acetic acid (13.2 mL, 13.86 mmol). The reaction mixture was then stirred at room temperature under an atmosphere of nitrogen for 30 minutes. Then added tert-butyl {1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) (10.58 g, 21.97 mmol). The reaction mixture was then permitted to stir overnight (18 hours) at room temperature under an atmosphere of nitrogen, then heated to 80° C. for 2 hours. The reaction mixture was then suspended in ethyl acetate, slowly poured into a saturated solution of sodium bicarbonate, followed by water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography 1-20% IPA/DCM. The appropriate fractions were combined and the solvent was removed in vacuo to give tert-butyl {1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6f) as a tan solid. MS (M+H)+: observed=506.2, calculated=506.6.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[NH:12]C(=O)C)[CH3:2].OS(O)(=O)=O>O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[NH2:12])[CH3:2]
Reactant: CCc1cccc([N+](=O)[O-])c1NC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1cccc([N+](=O)[O-])c1N
Yield: 25.1 %

Procedure:
A mixture of crude N-(2-ethyl-6-nitrophenyl)acetamide (2.4 g, 12 mmol), H2SO4 (3.4 g, 36 mmol), and H2O (10 mL) was refluxed for 2 hours and steam distilled. The distillate was extracted with Et2O and the organic phase was washed with brine and dried over Na2SO4. The solvent was evaporated to give the title compound as a yellow liquid (0.5 g, 25%). 1H NMR (400 MHz, CD3OD) δ 7.95 (1H, d, J=8.8 Hz), 7.31 (1H, d, J=6.8 Hz), 6.62 (1H, dd, J=8.8, 7.6 Hz), 2.63 (2H, q, J=7.6 Hz), 1.27 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][NH2:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][NH:25][S:16]([C:14]1[O:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: NCc1cc(F)cc(F)c1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3cc(F)cc(F)c3)o2)c(C)[nH]c1=O
Yield: 10 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-sulfonyl chloride is reacted with 3,5-difluoro-benzylamine as described in Steps 5 and 6, Example 24 to give the title compound as a solid (10% yield). MS: m/e 409 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.CCO[C:42]([CH3:44])=O>>[C:3]1([CH2:8][CH2:9][C:42]2[CH:44]=[CH:16][C:17]([CH2:23][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[N:13]=[C:12]([N:14]4[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]4)[CH:11]=[CH:10][CH:9]=3)=[CH:18][CH:19]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(CCc4ccccc4)cc3)n2)c1C(F)(F)F
Reaction time: 2 h

Procedure:
A vial was charged with the title compound from Example 1 Step B (36.0 mg, 0.095 mmol), cesium carbonate (62.2 mg, 0.191 mmol), and 4-chloromethyl dibenzyl (33.0 mg, 0.143 mmol). DMF (0.5 mL) was added, and the resulting suspension was stirred vigorously. After 2 h, the reaction mixture was diluted with EtOAc and washed with brine. The organic phase was separated and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 25% EtOAc in hexanes, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 572.5 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.98 (dd, J=7.5, 1.5 Hz, 1H), 7.86 (t, J=7.5 Hz, 1H), 7.53 (d, J=7.0 Hz, 1H), 7.39-7.36 (m, 1H), 7.29-7.26 (m, 4H), 7.22-7.17 (m, 5H), 7.11 (t, J=7.5 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 5.13 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 2.93 (app s, 4H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].O.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>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3F)cnc2n1
Temperature: 65 °C

Procedure:
A mixture of 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (256 mg, 1.0 mmol) and 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid (352 mg, 1.5 mmol) in tetrahydrofuran (3 ml) and sodium carbonate (1.25 ml of a 2M solution in water, 2.5 mmol) was degassed with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) was added and this mixture was heated at 65° C. for 24 h. The reaction was cooled to ambient temperature then partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate. The organics were dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-5%) gave 2-[3-(2,4-difluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a pale yellow oil which solidified on standing (200 mg, 44%). Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, d6-DMSO) 1.56 (6H, s), 7.62 (1H, t, J 9), 7.79-7.84 (1H, m), 7.86 (1H, s), 7.88 (1H, s), 8.32 (1H, d, J 8), 8.54 (1H, s), 8.80 (1H, d, J 5), 8.98 (1H, s), 9.27 (1H, dd, J 7 and 3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH:8]([CH2:14][C:15]([OH:17])=O)[CH2:7][CH2:6]2.[NH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]3[CH:8]([CH2:14][C:15](=[O:17])[N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:19]=3)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCC(CC(=O)O)C2=O
Reactant: NNc1ccccn1
Solvent: CCO
Product: COc1ccc2c(c1)CCC1CC(=O)N(c3ccccn3)N=C21
Yield: 81.9 %

Procedure:
A mixture of 20 g of 6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-acetic acid, 10.9 g of 2-hydrazinopyridine and 150 ml of ethanol is heated under reflux for 2 hours. The resulting crystals are collected, whereto 50 ml of acetic acid is added. The mixture is heated under reflux for 30 minutes. Acetic acid is distilled off under reduced pressure, and water is added to the residue. The resultant crystals are collected and recrystallized from chloroform - ethanol to give 21.5 g of 8-methoxy-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one as white crystals, m.p. 194°-196° C.
Reaction SMILES: [C:1]([O:4][CH:5](Br)[CH3:6])(=[O:3])[CH3:2].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:35]/[O:36][CH3:37])/[C:15]([NH:17][C@@H:18]2[C:33](=[O:34])[N:20]3[C:21]([C:30]([O-:32])=[O:31])=[C:22]([C@@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:35]/[O:36][CH3:37])/[C:15]([NH:17][C@@H:18]2[C:33](=[O:34])[N:20]3[C:21]([C:30]([O:32][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])=[O:31])=[C:22]([C@@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C
Yield: 79.8 %

Procedure:
A solution of (RS)-1-acetoxyethylbromide (267 mg) in 1-methyl-2-pyrrolidinone (2 ml) was added dropwise, over 1 hour, to an ice cold mixture of sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (190 mg) and potassium carbonate (110 mg) in 1-methyl-2-pyrrolidinone (1 ml). After 15 minutes the mixture was diluted with ethyl acetate, washed with water, brine, dried (MgSO4), concentrated and flash chromatographed on silica gel eluting with 50,70,80 and 90% ethyl acetate in hexane to give the title compound (172 mg); νmax (CHCl3) 3019, 2929, 1786, 1683, 1520, 13176 and 1135 cm-1 ; δH (CDCl3, 250 MHz) 1.45-1.75 (4H,m), 1.90-2.10 (2H,m), 2.09 and 2.10 (together 3H, 2s), 2.30-2.50 (1H,m), 3.36 and 3.65 (2H, ABq, J 18.8 Hz), 4.93-5.10 (2H,m), 5.90-6.05 (1H,m), 6.94 and 7.07 (together 1H,q,J 5.8 Hz), 7.10 and 7.15 (together 1H, 2s) and 7.60 and 7.67 (together 1H,2d, J 7.4 Hz); [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (562)].
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH2:13][C:14]([OH:16])=[O:15])=[CH:7][CH:6]=1)(=O)C.Cl.[CH3:18]O.S(=O)(=O)(O)O>[OH-].[K+].CCCCCC.C(OCC)(=O)C>[NH2:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[CH2:13][C:14]([O:16][CH3:18])=[O:15])=[CH:9][CH:10]=1
Reactant: CO
Reactant: CC(=O)Nc1ccc(/C=C/CC(=O)O)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C/C=C/c1ccc(N)cc1

Procedure:
7.5 g of (E)-4-(4-(acetylamino)phenyl)-3-butenoic acid was dissolved in a 1N aqueous solution of potassium hydroxide. The obtained solution was heated under reflux for 4 hours and cooled by allowing to stand. After the pH of the solution had been adjusted to about 3 by the addition of concentrated hydrochloric acid, the resulting solution was concentrated under a reduced pressure, followed by the addition of benzene. The obtained mixture was concentrated and freed from the water by azeotropic distillation to obtain a solid. 300 ml of methanol and 1 ml of concentrated sulfuric acid were added to the solid. The obtained mixture was heated under reflux for 3 hours, cooled by allowing to stand and concentrated under a reduced pressure. An aqueous solution of potassium carbonate was added to the residue and the obtained mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of common salt successively and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (2:1)3 to obtain 5.38 g of the title compound as a lightly orange-colored oil (yield: 82%).