Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:11]=[C:12](I)[C:5]=12)[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[N:35]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:11]=[C:12]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([F:33])[N:35]=3)[C:5]=12)[CH3:2]
Reactant: CCOc1ncnc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OB(c2cccc(F)n2)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1ncnc2c1c(-c1cccc(F)n1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
4-ethoxy-3-iodo-1-trityl-pyrazolo[3,4-d]pyrimidine (590 mg, 1.11 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (296.7 mg, 1.33 mmol) and Na2CO3 (1.662 mL of 2 M, 3.324 mmol) were suspended in anhydrous Dioxane (25 mL) and degassed (vacuum/nitrogen cycles×5). Pd[P(tBu)3]2 (56.62 mg, 0.11 mmol) was added and the reaction mixture was degassed again (vacuum/nitrogen cycles×5) and stirred at 60° C. for 3 hours. After this time, the reaction mixture was allowed to cool to ambient temperature. DCM, saturated aqueous Na2CO3 and brine were added and the aqueous layer was extracted with DCM (4×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 120 g column, eluting with EtOAc/petroleum ether) to give the sub title compound (139.1 mg, 25% Yield). 1H NMR (400 MHz, DMSO) δ 8.17 (1H, s), 7.77 (1H, m), 7.63 (1H, m), 7.24-7.11 (15H, m), 6.89-6.81 (1H, m), 4.50 (2H, q) and 1.44 (3H, t).
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:40]=[CH:39][C:32]2[CH:33](O)[O:34][CH:35]([CH:36]=[CH2:37])[C:31]=2[CH:30]=1>CCOCC.CCCCCC>[F:27][C:28]([F:42])([F:41])[C:29]1[CH:40]=[CH:39][C:32]([CH:33]=[CH2:2])=[C:31]([CH:35]([OH:34])[CH:36]=[CH2:37])[CH:30]=1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CC1OC(O)c2ccc(C(F)(F)F)cc21
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C=Cc1ccc(C(F)(F)F)cc1C(O)C=C
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Triphenylmethylphosphonium bromide (1.71 g, 4.78 mmol) was dissolved in ether (20.00 mL). After cooling to 0° C., a 1.60 M solution of n-butyllithium in hexane (2.72 mL) was added rapidly by syringe and the resulting orange mixture was warmed to room temperature and stirred overnight. The stirring was stopped to allow the solids to settle and then the ylid was transferred via cannula to a solution of 5-(trifluoromethyl)-3-vinyl-1,3-dihydro-2-benzofuran-1-ol (1.00 g, 4.34 mmol) in ether (10.00 mL) while stirring at 0° C. Following the addition, the ice bath was removed and the mixture was heated to reflux overnight. The reaction was allowed to cool and then the solids filtered off and washed with a small amount of ether. Most of the solvents were evaporated and the crude product was loaded onto silica gel and eluted with hexane/EtOAc (10:1) to give the desired product (0.81 g, 82%), LC-MS [M+1]=229.2.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])[CH3:3].[Na+].O1CCCC1.[I-].C[S+](C)C.OC(C1[C:24]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[N:40]=[C:41]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[O:42][C:43]=3[CH3:44])=[CH:33][CH:32]=2)=[N:25][CH:26]=[CH:27][CH:28]=1)S([O-])(=O)=O.[Na+]>CS(C)=O.O>[CH3:44][C:43]1[O:42][C:41]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[N:40][C:39]=1[CH2:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:24]2[C:3]([CH:2]3[CH2:5][O:4]3)=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C(O)S(=O)(=O)[O-])cc1
Agent: C[S+](C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C2CO2)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Sodium t-butoxide (2.86 g) was added to dimethyl sulfoxide (20 ml), and after stirring at room temperature for 50 min., tetrahydrofuran (30 ml) was added and ice-cooled. Trimethylsulfonium iodide (4.04 g) was added to the mixture, and after stirring under ice-cooling for 10 min., a solution of sodium hydroxy[2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)pyridin-3-yl]methanesulfonate (5 g) in dimethyl sulfoxide (15 ml) was dropwise added under ice-cooling and the mixture was stirred under ice-cooling for 1 hr. and at room temperature for 1 hr. The reaction solution was poured into iced water (100 ml) and extracted twice with t-butylmethyl ether (50 ml). The organic layers were combined, washed 4 times with water (50 ml) and concentrated under reduced pressure to give 2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)-3-oxiran-2-ylpyridine.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:16](=[O:25])[O:15][C:14]([CH3:27])([CH3:26])[C:13]=3[CH:28]=2)=[CH:5][CH:4]=1)#[N:2].[Br:29]N1C(=O)CCC1=O.N1C=CC=CC=1.O>C1COCC1>[Br:29][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[N:7]([CH3:8])[C:6]=1[C:9]1[CH:10]=[CH:11][C:12]2[N:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:16](=[O:25])[O:15][C:14]([CH3:27])([CH3:26])[C:13]=2[CH:28]=1
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C#N)cc(Br)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2C(=O)OC(C)(C)C

Procedure:
To a solution of tert-butyl 6-(5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylate (1 eq, 1.94 g, 5.10 mmol) in THF (150 mL) at −78° C. was added N-bromosuccinimide (1.1 eq, 1.0 g, 5.61 mmol). The solution was allowed to warm and stir for 16 hours Pyridine (1 mL) was added and the mixture was poured into water (150 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The product, tert-butyl 6-(3-bromo-5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylate was obtained by crystallization from 20% ethyl acetate/hexane as a white crystalline solid. 1H NMR (300 MHz, d6-DMSO) δ 1.56 (s, 9H), 1.71 (s, 6H), 3.65 (s, 3H), 7.30 (s, 1H), 7.44 (d, 1H, J=8.4 Hz), 7.52 (d, 1H, J=8.4 Hz), 7.55 (s, 1H). M/z (ESI (+)) 461 (M+H)+. Anal. calcd for C21H22N3O4, C, 54.8,H, 4.82, N, 9.13. Found, C, 54.9, H, 4.86, N, 9.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]#[N:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:15])[CH3:16])[C:11]([C:17]#[N:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-cyano-5-dimethylamino-phenyl)-carbamic acid tert-butyl ester (Example J23) (276 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl)-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (320 mg, 64%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH:14]([C:17]([O:19]CC)=[O:18])[CH:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:12]4[C:28](=[O:30])[NH:29][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:31])[O:4][N:3]=1.O.[OH-].[Li+]>CO.O.CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH:14]([C:17]([OH:19])=[O:18])[CH:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:12]4[C:28](=[O:30])[NH:29][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: CCOC(=O)C1Oc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n(c23)C1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OC(C(=O)O)C3c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate (0.150 g, 0.358 mmol) from Example 23 was dissolved in MeOH (3.0 mL) and lithium hydroxide, monohydrate (0.030 g, 0.72 mmol) dissolved in water (1.0 mL) was added. The reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed with saturated water ammonium chloride, brine, dried over magnesium sulfate and concentrated to give a mixture of the diastereoisomers of the title compound as a solid residue (0.145 g, 100%). LCMS calc. for C21H18N3O5 (M+H)+: m/z=392.1. found: 392.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[C:27]1[NH:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>CCN(CC)CC.C(OCC)(=O)C>[NH:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[O:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccn(-c2cccc(O)c2)nc1-c1ccnn1-c1ccccc1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=c1ccn(-c2cccc(Oc3nc4ccccc4[nH]3)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 120 °C
Reaction time: 14 h
Yield: 21.6 %

Procedure:
A mixture of 1-(3-hydroxyphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (0.113 g, 0.342 mmol) and 2-chlorobenzimidazole (0.075 g, 0.49 mmol) in Et3N (1 mL) was sealed and stirred at 120° C. for 14 h and then at 160° C. for 64 h. After this time, the reaction was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate aqueous solution (40 mL), and then with 2 N sodium hydroxide (3×20 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Flash chromatography (silica, methylene chloride to 1:19 methanol/methylene chloride) afforded 1-[3-(1H-benzimidazol-2-yloxy)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (33 mg, 18%) as a light-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([OH:37])[CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[N:26]=[C:25]([C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=5)[O:24][N:23]=4)[CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH3:40]I.O>C1(C)C=CC=CC=1>[CH3:40][O:37][CH:13]([CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[O:24][N:23]=2)[CH2:19][CH2:20]1)[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1
Reactant: Cc1nc2cc(OCC(O)CN3CCN(Cc4noc(-c5ccc(C(F)(F)F)cc5)n4)CC3)ccc2s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(COc1ccc2sc(C)nc2c1)CN1CCN(Cc2noc(-c3ccc(C(F)(F)F)cc3)n2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[4-(trifluoromethyl)phenyl]-(1,2,4-oxadiazol-3-yl)}methyl)piperazinyl]propan-2-ol (0.10 g) in toluene (6 ml) was added to a suspension of sodium hydride (0.09 g) in toluene (2 ml) at 0° C. The mixture was stirred at 100° C. for 2 hours, then cooled to 0° C. Methyl iodide (0.14 ml) was then added, and the mixture stirred overnight at room temperature. After slow addition of water the mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and the solvent removed under reduced pressure. The residue was purified by flash chromatography (3% methanol in methylene chloride), to provide 5-{2-methoxy-3-[4-({5-[4-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methyl)piperazinyl]propoxy}-2-methylbenzothiazole (0.0075 g).
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)[S:24][CH:25]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccncc4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccncc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-[2-(4-pyridyl)-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (864 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (3 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(4-pyridyl)-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionic acid (771 mg, yield: 94%). This was recrystallized from ethanol. Melting point: 149–150° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:20][C:21]([F:24])([F:23])[F:22])[S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[C:4]([F:25])[CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[F:25][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]([CH2:20][C:21]([F:24])([F:23])[F:22])[S:10]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Cc1ccccc1)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=S(=O)(Cc1ccccc1)N(Cc1ccc(-c2ccncc2)cc1F)CC(F)(F)F
Temperature: 80 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide (Example 2, Step 2) (2 g, 4.54 mmol), 4-pyridylboronic acid (931 mg, 6.81 mmol) dichlorobis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) (161 mg, 0.23 mmol) potassium acetate (669 mg, 6.81 mmol) and sodium carbonate (722 mg, 6.81 mmol) were combined and the reaction was purged with nitrogen. Acetonitrile (15 mL) and water (4.5 mL) were then added and the reaction was stirred at 80° C. for 16 hours. The reaction was filtered through diatomaceous earth, concentrated and purified by silica gel column chromatography (20-100% EtOAc in heptane) to give N-[[2-fluoro-4-(4-pyridyl)phenyl]methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide (1.85 g, 93% yield). 1H NMR (400 MHz, DMSO) δ 8.69-8.62 (m, 2H), 7.79-7.74 (m, 2H), 7.74-7.66 (m, 2H), 7.57 (t, J=8.1 Hz, 1H), 7.50-7.36 (m, 5H), 4.68 (s, 2H), 4.53 (s, 2H), 4.04 (q, J=9.3 Hz, 2H); LCMS (m/z) ES+ 439.0 [M+1]+.
Reaction SMILES: Cl.[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH2:26])[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44](/[C:46](=[N:50]/[O:51][CH3:52])/[C:47](O)=[O:48])[N:45]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCl>[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH:26][C:47](=[O:48])/[C:46](/[C:44]4[N:45]=[C:41]([NH:40][C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[S:42][CH:43]=4)=[N:50]\[O:51][CH3:52])[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(C)(=O)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Yield: 71.9 %

Procedure:
To a suspension of 7β-amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (994 mg: 2 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-methoxyiminoacetic acid (662 mg: 2.2 mMol.) in dichloromethane (16 ml) is added at -30° C. N-methylmorpholine (0.72 ml: 6.6 mMol.) and phenyl dichlorophosphate (0.33 ml: 2.2 mMol.), and the mixture is stirred at the same temperature for 2.5 hours. The reaction mixture is quenched by adding 10% hydrochloric acid (5 ml) and extracted with ethyl acetate. The extract is washed with water, 5% aqueous sodium hydrogen carbonate, and water, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=2:1 containing 0.5% of acetic acid) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-methoxyiminoacetyl]amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (1.07 g). Yield: 72%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#N>>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)Cc1nc2ccccc2s1
Temperature: 120 °C
Yield: 72 %

Procedure:
Ethyl 2-(benzothiazol-2-yl)acetate was prepared by the method of Abbotto, Bradamante et. al. ( J. Org. Chem. 2002, 16, 5753). A neat mixture of 2-aminothiophenol (6.94 g, 50 mmol) and ethyl cyanoacetate (5.65 g, 50 mmol) was heated at 120° C. for 3 hours at which time TLC analysis indicated that the reaction was complete as judged by the disappearance of starting material. The dark orange mixture was diluted with ethyl acetate/hexanes and purified by flash chromatography using 10-20% ethyl acetate/hexanes (Rf0.35, 10% ethyl acetate/hexanes) as an eluant. After concentration by rotary evaporator, ethyl 2-(benzothiazol-2-yl)acetate could be obtained as a yellow oil in 72% yield (7.97 g). LCMS: 222.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5](O)=[O:6].C(C1NC=CN=1)([C:15]1[NH:16][CH:17]=CN=1)=O.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5]([N:16]([CH3:17])[CH3:15])=[O:6]
Reactant: CNc1ccc(C(=O)O)cc1Cl
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1ccc(C(=O)N(C)C)cc1Cl
Reaction time: 1 h

Procedure:
To 3-chloro-4-methylamino-benzoic acid (387 mg) in dry N,N-dimethylformamide (10 mL) was added carbonyl diimidazole (440 mg). After one hour, dimethylamine. HCl (221 mg) and triethylamine (0.38 mL) were added. The reaction mixture was stirred overnight, then diluted with ethyl acetate, washed with brine, dried (MgSO4) and the solvent removed in vacuo. Purification using flash chromatography yielded 3-chloro-N,N-dimethyl-4-methylamino-benzamide.
Reaction SMILES: C(O)=O.[NH2:4][C:5]1[C:10]([NH:11][C:12](=O)[O:13]C)=[C:9]([CH3:16])[N:8]=[C:7]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:18]=2)[N:6]=1.O>O1CCCC1>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][N:19]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[C:17]([C:7]2[N:6]=[C:5]3[C:10]([NH:11][C:12](=[O:13])[NH:4]3)=[C:9]([CH3:16])[N:8]=2)=[N:18]1
Reactant: COC(=O)Nc1c(C)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: C1CCOC1
Solvent: O
Solvent: O=CO
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)[nH]c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, 245 mg (0.60 mmol) of the compound from example 69A were initially charged in tetrahydrofuran (2.6 ml) and cooled to 0° C., and 0.90 ml (0.90 mmol) of bis(trimethylsilyl)sodium amide (1.0 M in tetrahydrofuran) was added dropwise. The mixture was stirred at 0° C. for 1 h and then at RT overnight. Subsequently, the mixture was stirred at 60° C. for 8 h. Thereafter, water was added and the reaction mixture was concentrated. The residue was extracted twice with ethyl acetate, and the collected organic phases were washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. This gave 110 mg (85% purity, 41% of theory) of the title compound in solid form. A solid likewise precipitated out of the aqueous phase, which was filtered off, washed with water and dried under high vacuum. This gave a further 100 mg (44% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:14]1(B(O)O)[CH2:16][CH2:15]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:14]1([C:2]2[C:7]3[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15]1
Reactant: OB(O)C1CC1
Reactant: CSc1ncc2ccnc(Cl)c2n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ncc2ccnc(C3CC3)c2n1
Temperature: 95 °C
Yield: 63.6 %

Procedure:
A solution of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 33, 20 mg, 0.094 mmol), cyclopropyl boronic acid (11 mg, 0.128 mmol), PCy3 (3 mg, 10.70 μmol), and Pd(OAc)2 (1 mg, 4.45 μmol) was dissolved in toluene/water 6:1 (1 mL) and heated to 95° C. for 18 hours. The mixture was diluted with EtOAc and quenched with brine. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 20% EtOAc in cyclohexane to give the title compound (13 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=S)[C:6]3([F:16])[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.[NH3:17]>>[NH2:17][C:7]1[C:6]2([F:16])[CH2:13][CH2:14][CH2:15][CH:5]2[C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: N
Reactant: FC12CCCC1c1cc(Cl)ccc1NC2=S
Product: NC1=Nc2ccc(Cl)cc2C2CCCC12F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
90 mg (0.35 mmol) of 8-chloro-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione is dissolved in 20 ml of 7 M methanolic ammonia solution. After 2 hours of stirring at room temperature, the batch is concentrated by evaporation in a vacuum, and the residue is purified by column chromatography on silica gel with ethyl acetate: 73 mg of product, melting point 223° C.