Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: COc1ccc(B(O)O)cc1Cl
Product: COc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 84.1 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 4.4 g (13 mmol) of 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Step 2) was reacted with 3.1 g (17 mmol) of 3-chloro-4-methoxy phenylboronic acid (Example 5, Step 2). Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (3:7) and subsequent recrystallization from ethyl acetate/hexane gave 4.47 g (95%) of 1-(3-chloro-4-methoxyphenyl)-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 147.5°-148.5° C.; NMR (CDCl3) δ 3.05 (s, 3H), 3.88 (s, 3H), 6.75(d, J=9 Hz, 1H), 6.83 (dd, J=2, 9 Hz, 1H), 7.10(d, J=2 Hz, 1H), 7.17-7.32 (m, 4H), 7.83(d, J=9 Hz, 2H). MS (EI): m/e (rel intensity) 408 (33), 314 (15), 294 (52), 279 (63), 251 (100). Anal. Calc'd for C20H15ClF2O3 S.(0.27 ethyl acetate): C, 58.53; H, 3.99; F, 8.79. Found: C, 58.75; H, 3.71; F, 8.52.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[OH:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[N:37]1([CH2:43][CH2:44]O)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[O:34][CH2:44][CH2:43][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1OCCN1CCOCC1
Yield: 42.8 %

Procedure:
A solution of (2S)-(5-bromo-2-hydroxy-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (25 mg, 46 μmol, obtained by following similar procedure described for example 34), 2-morpholin-4-yl-ethanol (1.5 eq., 8.3 μL, 69 μmol) and triphenylphosphine (1.5 eq., 18 mg, 69 μmol) in anhydrous THF (1 mL) was treated with DIAD (1.5 eq., 13.5 μl, 69 μmol) as described in Procedure I. Flash column chromatography (4:1 hexanes:EtOAc) provided 13 mg of the title compound. LCMS for C35H35BrN2O6: 659, 661.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.Cl.[N:54]1([CH:60]2[C:72]3[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=3[C:66]3[C:61]2=[CH:62][CH:63]=[CH:64][CH:65]=3)[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C=O)C.C(OCC)C>[CH:62]1[C:61]2[CH:60]([N:54]3[CH2:59][CH2:58][N:57]([C:12]([C@@H:11]([NH:10][C:8]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:56][CH2:55]3)[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[C:66]=2[CH:65]=[CH:64][CH:63]=1
Reactant: c1ccc2c(c1)-c1ccccc1C2N1CCNCC1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N1CCN(C2c3ccccc3-c3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]4-methyl-pentanoic acid (0.300 g, 1.17 mmol, Example 1, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.816 mL, 4.68 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.444 g, 1.17 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 9-piperazinofluorene dihydrochloride (0.293 g, 1.17 mmol, Maybridge Chemical Co. Ltd., Tintagel Cornwall, U.K.) was then added. After stirring for, sequentially, 20 minutes at 0° C. and 20 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (50% EtOAc in hexane containing 1% MeOH to provide 0.21 g (37%) of the pure titled compound as a white foam: mp 63-73° C. APCI-MS m/z 489.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].Cl.[CH3:28][O:29][CH2:30][CH:31]([NH2:33])[CH3:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:33][CH:31]([CH3:32])[CH2:30][O:29][CH3:28])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Reactant: COCC(C)N
Agent: Cl
Product: COCC(C)Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-]
Yield: 34.1 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (1.0 g, 2.42 mmol), prepared substantially as described in Part C of Example 19a, and 2-methoxy-1-methyl-ethylamine HCl (0.61 g, 4.85 mmol) were treated substantially as described in Part C of Example 19a to produce 0.29 g (34%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 351.8 [(M+H)+, 100].
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH3:24].CC1(C)C(C)(C)OB(C2C=CC3OCOC=3C=2)O1>>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]=3[CH3:24])=[CH:4][C:3]=2[O:2][CH2:10]1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cc1[nH]c2ncccc2c1Br
Agent: CC1(C)OB(c2ccc3c(c2)OCO3)OC1(C)C
Product: Cc1[nH]c2ncccc2c1-c1ccc2c(c1)OCO2

Procedure:
3-Benzo[1,3]dioxol-5-yl-2-methyl-1H-pyrrolo[2,3-b]pyridine 142 was prepared using the same protocol as described in Example 8, substituting 3-Bromo-1H-pyrrolo[2,3-b]pyridine and 3,4-dimethoxy-phenyl boronic acid with 3-Bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine and 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole respectively.
Reaction SMILES: O.[C:2]1([CH3:13])[CH:7]=[CH:6][C:5]([S:8]([NH:11][NH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:15]1[C:24]2[C:19](=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1>C(Cl)Cl>[CH3:13][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][NH:12][C:15]2[C:24]3[C:19](=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NNc2ncnc3c([N+](=O)[O-])cccc23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
p-Toluene sulphonyl hydrazine hydrate (390 mg, 2.1 mmol) was added to a solution of 4-chloro-8-nitro-quinazoline 477 (400 mg, 1.91 mmol) in DCM at (10 ml) and the mixture was stirred at room temperature for 24 h. The mixture was concentrated in vacuo and washed with Et20 to give the title compound (650 mg, 95%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[C:17]3C(OC)=O)(=[O:11])=[O:10])[O:4][N:3]=1.[CH3:26][Mg]Br.CC[O:31][CH2:32][CH3:33]>O1CCCC1>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]3[C:18](=[C:17]([C:32]([OH:31])([CH3:33])[CH3:26])[CH:16]=[CH:15][CH:14]=3)[CH:19]=[CH:20][CH:21]=2)(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: C[Mg]Br
Reactant: COC(=O)c1cccc2c(S(=O)(=O)Nc3onc(C)c3C)cccc12
Reactant: CCOCC
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2cccc3c(C(C)(C)O)cccc23)c1C

Procedure:
To a solution of Example 32 (0.99 g, 2.75 mmol) in dry tetrahydrofuran (50 mL) was added methyl magnesium bromide (4.58 mL of a 3M solution in ether, 13.7 mmol). The solution was heated at reflux for 75 minutes, quenched with 5% aqueous potassium hydrogen sulfate and extracted with ethyl acetate and the organic phase was washed with brine, dried (magnesium sulfate) and evaporated. The residue was combined with the product of a previous reaction (0.55 mmol scale) to afford 1.26 g of off-white foamy solid. Chromatography on silica (flash; 75% ethyl acetate/hexanes) afforded 0.28 g (24%) of Example 35 as a white foamy solid (melting point 97°-101° C.) as well as 0.40 g of slightly less pure material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([F:33])=[CH:14][C:15]=1[C:16]1[C:21]2[S:22][C:23]([C:25]3[C:30]([F:31])=[CH:29][N:28]=[C:27](Cl)[N:26]=3)=[CH:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][NH:40][C:39]1=[O:43].C(N(CC)CC)C>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([F:33])=[CH:14][C:15]=1[C:16]1[C:21]2[S:22][C:23]([C:25]3[C:30]([F:31])=[CH:29][N:28]=[C:27]([NH:35][CH2:36][CH2:37][N:38]4[CH:42]=[CH:41][NH:40][C:39]4=[O:43])[N:26]=3)=[CH:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1cnc(F)cc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Reactant: NCCn1cc[nH]c1=O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(NC(=O)OC(C)(C)C)c1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4cc[nH]c4=O)ncc3F)sc12
Temperature: 130 °C
Yield: 44.9 %

Procedure:
Combine (1-{4-[2-(2-chloro-5-fluoro-pyrimidin-4-yl)-benzo[b]thiophen-7-yl]-6-fluoro-pyridin-3-yl}-ethyl)-carbamic acid tert-butyl ester (150 mg, 0.3 mmol), 1-(2-amino-ethyl)-1,3-dihydro-imidazol-2-one (70 mg, 0.55 mmol) and triethylamine (80 mg, 0.8 mmol) in N-methylpyrrolidone (1.0 mL) in a pressure tube. Heat the reaction mixture at 130° C. for 1 hour in a microwave reactor and then cool to room temperature. Dilute the reaction mixture with ethyl acetate, and wash with water and saturated aqueous sodium chloride. Separate the organic layer from the aqueous layer and dry over MgSO4. After filtration, evaporate the organic solvent to give the crude. Purify the crude by column chromatography (10% methanol in dichloromethane) to afford the desired product (80 mg, 74%). MS (ES) m/z 538 [M+t-Bu]+, 494 [M-Boc]−, 616 [M+Na]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[N:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.Cl.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)=[N:53][C:54]=1[NH2:55]>ClCCl>[NH2:55][C:54]1[C:49]([NH:48][C:10]([C:7]2([C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:50][CH:51]=[C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)[N:53]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O=C(O)C1(c2cccnn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cccnn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
To a mixture of 1-(pyridazin-3-yl)cyclopropanecarboxylic acid (160 mg, 0.97 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (445 mg, 1.17 mmol) and diisopropylethyl amine (330 mg, 2.4 mmol) in anhydrous dichloromethane (10 mL) was added (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (350 mg, 0.98 mmol) dissolved in anhydrous dichloromethane (10 mL) with diisopropylethyl amine (330 mg, 2.4 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted with dichloromethane and washed with water. The organics were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude was purified via column chromatography (100-200 silica gel mesh, 60-80% ethyl acetate in petroleum ether) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyridazin-3-yl)cyclopropanecarboxamide (100 mg, 23%). MS (ES+APCI) (M+H) 436.2; LCMS retention time: 3.390 min (Method W1).
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[C:7]([F:13])[CH:8]=2)[N:3]=1.CO[CH:17]([O:20]C)[CH2:18][NH2:19]>>[F:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[F:14])[N:3]1[CH:2]=[CH:11][N:19]=[C:18]1[C:17](=[O:20])[NH:10]2
Reactant: Fc1cc2nc(Cl)c(Cl)nc2cc1F
Reactant: COC(CN)OC
Product: O=c1[nH]c2cc(F)c(F)cc2n2ccnc12

Procedure:
By reacting 2,3-dichloro-6,7-difluoroquinoxaline with aminoacetaldehyde dimethyl acetal, following a procedure that is similar to that described in example 1, there is obtained 7,8-difluoroimidazo[1,2-a]quinoxalin-4(5H)-one (m.p. >300° C.) and, subsequently, 4-chloro-7,8-difluoroimidazo[1,2-]quinoxaline. By reacting this product with cyclopentylamine according to the method described in example 3, there is obtained 4-cyclopentylamino-7,8-dichloroimidazo[1,2-a]quinoxaline. m.p. (DSC)=146.0° C.(onset); IR (KBr): 3263, 2955, 1554 cm-1 ; 1H-NMR (CDCl3): δ7.7 (1H,s), 7.65÷7.15 (3H,m), 6.1 (1H,d), 4.6 (1H,m), 2.3÷1.3 (8H,m); UV (EtOH): λmax =225, 241, 270, 295, 323, 337 nm. Elementary analysis for C15H14F2N4 (m.w. 288.30): calcd. C 62.49, H 4.89, N 19.43%; found C 62.46, H 5.03, N 19.65%.
Reaction SMILES: S1C2C=CC=CC=2N=C1S[S:11][CH:12]1[N:15](/[C:16](=[C:20](/[O:22][CH3:23])\[CH3:21])/[C:17](Cl)=[O:18])[C:14](=[O:24])[CH:13]1[NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.S1C2C=CC=CC=2N=C1SSC1N(/C(=C(\OC)/C)/C(Cl)=O)C(=O)C1NC(=O)COC1C=CC=CC=1.C(N(CC)CC)C.[C:78]([OH:82])([CH3:81])([CH3:80])[CH3:79]>C(Cl)Cl>[C:78]([O:82][C:17]([CH:16]1[N:15]2[C:14](=[O:24])[C@@H:13]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:12]2[S:11][CH:21]=[C:20]1[O:22][CH3:23])=[O:18])([CH3:81])([CH3:80])[CH3:79]
Reactant: CO/C(C)=C(\C(=O)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Reactant: CC(C)(C)O
Agent: CO/C(C)=C(/C(=O)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 266 mg (0.5 mM) of a crude mixture consisting of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl ]-3-methoxy-crotonic acid chloride and 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid chloride in 5 ml of dry methylene chloride is added dropwise over the course of 15 minutes at 0° C., whilst stirring, to a solution of 0.10 ml of triethylamine in 0.5 ml of dry tert.-butanol and 3 ml of methylene chloride. After a further 15 minutes stirring, the reaction mixture is diluted with methylene chloride, washed with water, with dilute hydrochloric acid and again with water, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 10 g of acid-washed silica gel, using toluene/ethyl acetate (4:1) as the running agent. 7β-Phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid tert.butyl ester is obtained. IR spectrum (in CH2CL2): characteristic bands at 5.60, 5.77, 5.90 and 8.29 μ.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10](=[O:37])/[CH:11]=[CH:12]/[C:13]2[N:17]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[N:15][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(Cl)Cl.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:37])/[CH:11]=[CH:12]/[C:13]2[N:17]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=[N:15][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(C(=O)/C=C/c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc(C(O)/C=C/c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Reaction time: 1 h

Procedure:
To a solution of the product from Step G (8.89 g, 18.4 mmol) in methanol (200 mL)/methylene chloride (50 mL) at 0° C. was added sodium borohydride (695 mg, 18.4 mmol). After stirring for 1 hour, the reaction was quenched by the addition of sat. aq. NH4Cl until H2 evolution ceased. The solvents were removed in vacuo and the residue was partitioned between methylene chloride (200 mL) and water (200 mL). The layers were separated and the aqueous layer was washed with methylene chloride (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide the title compound as a yellow oil which was sufficiently pure for use in the next step.
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15](Br)=[N:14][C:13]=1[C:18]([F:21])([F:20])[F:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:22]([N:24](CC)CC)[CH3:23].C(N)C.O1CCCC1>C(OC(=O)C)C.O>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:24][CH2:22][CH3:23])=[N:14][C:13]=1[C:18]([F:21])([F:20])[F:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCN(CC)CC
Reactant: N#CC(NC(=O)c1sc(Br)nc1C(F)(F)F)c1cccs1
Agent: CCN
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCNc1nc(C(F)(F)F)c(C(=O)NC(C#N)c2cccs2)s1
Yield: 73 %

Procedure:
1.0g of 2-bromo-4-trifluoromethyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide, 0.36ml of triethylamine and 0.50ml of ethylamine were added to 10ml of tetrahydrofuran and the reaction mixture was stirred under reflux for 4 hours. Water and ethylacetate were added thereto to separate the layers. The separated organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was recrystallized from the mixed solvent of n-hexane and ethylacetate to obtain 0.67g (Yield 73%) of the title compound.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[CH3:30][C@H:31]1[O:36][C@@H:35]([CH3:37])[CH2:34][NH:33][CH2:32]1>>[ClH:20].[CH3:37][C@H:35]1[O:36][C@@H:31]([CH3:30])[CH2:32][N:33]([CH2:19][CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]4[CH:27]=[CH:28][CH:29]=[C:23]4[CH:22]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:34]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: C[C@@H]1CN(CCOc2ccc3oc(-c4cc5cccn5cn4)cc(=NO)c3c2)C[C@H](C)O1
Product: Cl

Procedure:
6-[2-(cis-2,6-dimethyl-morpholin-4-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 17% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and (cis)-2,6-dimethylmorpholine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1.C([O-])([O-])=O.[K+].[K+].[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30]>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cnn1-c1ccc(F)cc1
Reactant: CC(C)N=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)NC(=O)Oc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole, from Example 10, step 2, (0.30 g, 1.01 mmol) was combined with K2CO3 (0.418 g, 3.03 mmol) and THF (6 mL). The mixture was cooled in an ice bath and then isopropyl isocyanate (0.12 mL, 1.21 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with water, extracted into ethyl acetate: dried (MgSO4), filtered, and concentrated to dryness. The residue was stirred in methanol and dichloromethane for one hour then filtered to give 0.118 g of 5-amino-1-(4-fluorophenyl)-4-[3-isopropylaminocarbonyloxybenzoyl]pyrazole (mpt. 225.2-230.1° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].C(O[C:18](=O)[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](=[O:31])N(OC)C)[CH2:22][CH2:21]1)(C)(C)C.[O:33]=[C:34]1[NH:39][C:38]2[CH:40]=[C:41](C=O)[CH:42]=[CH:43][C:37]=2[O:36][CH2:35]1>>[CH2:1]([O:3][C:4]1[C:9]2[N:10]=[C:11]([C:26]([C@H:23]3[CH2:22][CH2:21][C@H:20]([NH:19][CH2:18][C:41]4[CH:42]=[CH:43][C:37]5[O:36][CH2:35][C:34](=[O:33])[NH:39][C:38]=5[CH:40]=4)[CH2:25][CH2:24]3)=[O:31])[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CCOc1cccc2scnc12
Product: CCOc1cccc2sc(C(=O)[C@H]3CC[C@H](NCc4ccc5c(c4)NC(=O)CO5)CC3)nc12

Procedure:
The title compound was prepared according to the same protocol as that described for example 1, steps 1.a to 1.c, starting from 4-ethoxy-benzothiazole (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.3 mmol). A yellowish solid (9 mg) was obtained.
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[H-].[Na+].[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=[O:16].CO>C1C=CC=CC=1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][C:4](=[O:6])[C:3]2[CH:2]=[CH:10][C:9]([Br:11])=[CH:8][CH:7]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: O=C(CC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 60 °C

Procedure:
In a 1-liter three neck round bottom flask, 43 g (0.2 mol) methyl 4-bromobenzoic acid and 17.6 g (0.4 mol) sodium hydride were dissolved in 200 ml dried benzene and heated to 60° C. Next, 39.8 g (0.2 mol) 4-bromoacetophenone in 100 ml dry benzene was slowly added through a dropping funnel, and 1 ml methanol was added to the flask to initiate the reaction. After the mixture was refluxed overnight, the reaction was quenched by adding methanol and pouring it into ice water. The pH of the mixture was brought down to 7.0 using 5 N sulfuric acid. A solid was collected, washed with water, and recrystallized from benzene to give a light yellow product. Characterization. Yield: 30.3 g (40%). 1H NMR (300 MHz, CDCl3, 20° C., δ): 7.84 (d, 4H, ArH); 7.62 (d, 4H, ArH); 6.77 (s, 2H, CH2). EI-MS: 382 (M+), 301, 225, 183, 157.