Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1cccc(CCBr)c1
Product: Fc1ccc(N(CCc2cccc(F)c2)N=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-(4-fluorophenyl)-hydrazine (200 mg, 0.69 mmol; Example 84A) and 1-(2-bromoethyl)-3-fluorobenzene (280 mg, 1.37 mmol; Aldrich) into the title compound: MS (DCI/NH3) 413 m/z (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][CH:39]([OH:41])[CH3:40]>>[CH:39]([O:41][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1)([CH3:40])[CH3:38]
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cnc2c(Sc3ccc(Nc4nnc(OC(C)C)c5ccccc45)cc3)ccnc2c1

Procedure:
In a 5 mL sealed tube, was dissolved 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (0.100 g, 0.224 mmol) in iPrOH (0.500 mL). To this was added cesium carbonate (0.110 g, 0.336 mmol) and the mixture was irradiated for 30 min at 140° C. in the microwave. When the reaction was determined to be complete by LC/MS, it was concentrated. The mixture concentrate was purified using Isco silica gel chromatography, using 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2, followed by reverse phase chromatography (Gilson, 10-90% TFA/acetonitrile in water over 15 min) The product-containing fractions were extracted into DCM, washed 1× sodium carbonate, 1×H2O, dried with Na2SO4, filtered through fritted funnel, and concentrated to yield 4-isopropoxy-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine as a light yellow solid. MS [M+H]+=470.0; Calc'd=469.6 for C26H23N5O2S
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7])[CH3:2].[C:10](Cl)(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][C:10](=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:2]
Reactant: CCN(CC)CCCN
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCCCN(CC)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of 3-diethylaminopropylamine (4.13 g, 31.7 mmole) in methylene chloride (50 mL) was added palmitoyl chloride (9.15 g, 33.3 mmole) in small portions. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in 1N aqueous sodium hydroxide (90 mL), chloroform (100 mL) and methanol (200 mL). The solution was transferred to a separatory funnel then chloroform (100 mL) and IN aqueous sodium hydroxide (100 mL) was added and the layers separated. The aqueous layer was extracted twice with chloroform (100 mL portions). The solution was transferred to a separatory funnel then chloroform. The organic layer was dried over magnesium sulfate and the salts removed by filtration. The solvent was removed under reduced pressure to give the title compound (11.6 g, 100%) as a gum. 1H NMR (300 MHz, CDCl3): δ0.881 (3H, t, J=6.6 Hz), 1.053 (6H, t, J= 7.1 Hz), 1.252 (24H, bs), 1.56 to 1.67 (2H, m), 2.129 (2H, t, J=7.7 Hz), 2.50 to 2.57 (6H, m), 3.31 to 3.37 (2H, m), and 7.392 (1H, bs). IR (neat): 3307, 3219, 3152, 3085, 2949, 2920, 2850, 1734, 1642, 1082 cm-1. Analysis calculated for C23H48N2O.3/4H2O: C, 74.94; H, 13.12; N, 7.59. Found: C, 74.68; H, 13.11; N, 7.52.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:3]=1[C:21]#[N:22].Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([O:8][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[O:28][C:29]=2[CH3:30])[N:7]=1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCl
Reactant: N#Cc1c(N)[nH]c(=O)c(C#N)c1-c1ccc(OCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(F)cc2)nc1COc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 70 °C
Reaction time: 2 h

Procedure:
250 mg (0.81 mmol) of the compound from Example 102A, 228 mg (1.013 mmol) of 4-(chloromethyl)-2-(4-fluorophenyl)-5-methyl-1,3-oxazole and 224 mg (1.62 mmol) of potassium carbonate are initially charged in 8.6 ml of dry DMF and stirred at 70° C. for 2 h. The solvent is then removed on a rotary evaporator and the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). The product is then purified once more by HPLC (column: Waters Sunfire C18 5 μm, 250 mm×20 mm; mobile phase gradient: water/ethanol 55:45→5:95; flow rate: 25 ml/min; temperature: 30° C.; detection: 210 nm).
Reaction SMILES: CC(=CC)C.[CH:6]([C:8]12[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:12]([CH2:13][CH2:14]1)[CH2:11][O:10][CH2:9]2)=[O:7].CC(=CC)C.C1C[O:31]CC1.[O-]Cl=O.[Na+].Cl>O.C(O)(C)(C)C.C1COCC1>[C:19]([O:18][C:16]([N:15]1[C:8]2([C:6]([OH:31])=[O:7])[CH2:14][CH2:13][CH:12]1[CH2:11][O:10][CH2:9]2)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1C2CCC1(C=O)COC2
Reactant: C1CCOC1
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1(C(=O)O)COC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
A 50 ml of flask fitted with magnetic stirrer was charged with 5 ml of THF and was cooled to −78° C., to which 2-methyl-2-butene (0.15 mL, 3 mmol) was added and stirred for 5 minutes. Another 50 ml of flask fitted with magnetic stirrer was charged with tert-butyl 5-formyl-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (71 mg, 0.3 mmol) and tert butanol (5 mL) and was stirred at 25° C., to which the above prepared 2-methyl-2-butene THF solution was added. The resulting mixture was cooled to 0° C., and then a solution of NaH2PO4 (81 mg, 0.52 mmol) in water (5 mL) and a solution of NaClO2 (20 mg, 0.22 mmol) in water (5 mL) were added subsequently. After stirring for 20 minutes at 0° C., the reaction mixture was diluted with water (10 mL), acidified to pH 5-6 using 1N HCl, and extracted with ethyl acetate (50 mL) three times. The combined organic phases were dried over Na2SO4, and concentrated in vacuo to afford 8-tert-butoxycarbonyl-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid 81k (40 mg, 51%), which was used for next step without further purification. MS: calc'd (MH+) 258, measured (MH+) 258
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][C:36]([NH2:38])=[O:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][C:36]([NH2:38])=[O:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H](N)CC(N)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](CC(N)=O)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.08 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 67-2 (15.5 mmol, crude form) as starting materials, 576 mg of the title compound (colorless amorphous) was obtained by a similar method to Step 4-2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[Mg]Br.[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C1COCC1>[C:11]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: O=C1CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1ccc(C2=CCCC2)c(F)c1
Temperature: 0 °C
Yield: 26.3 %

Procedure:
To a 0.497M solution of (2,4-difluorophenyl)magnesium bromide (32.4 g, 149 mmol) in THF at 0° C. was carefully added cyclopentanone (13.23 mL, 149 mmol). Upon the end of the addition, the reaction mixture was heated at reflux for 2 h. Ice (10 g) and 6N aqueous hydrochloric acid were added. The reaction mixture was extracted with ether. The combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen sulfite, a saturated aqueous solution of sodium bicarbonate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 1-cyclopentenyl-2,4-difluorobenzene (7.064 g, 39.2 mmol, 26.3% yield) as colorless oil. LC-MS (M+H)+=181.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.22-7.31 (1H, m), 6.75-6.85 (2H, m), 6.26-6.31 (1H, m), 2.68-2.74 (2H, m), 2.51-2.58 (2H, m), 1.93-2.02 (2H, m).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23](=O)[CH3:24])=[C:6]([CH3:22])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][C:11]=2[O:19][CH2:20][CH3:21])[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:26][NH2:27]>>[CH2:20]([O:19][C:11]1[CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=[CH:15][C:10]=1[N:7]1[C:8]([CH3:9])=[C:4]2[C:5]([C:23]([CH3:24])=[N:26][N:27]=[C:1]2[CH3:2])=[C:6]1[CH3:22])[CH3:21]
Reactant: NN
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(OCC)c1
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)c(OCC)c1

Procedure:
Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(2,4dihydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone prepared as in Example 70 (12 mg, 0.4 mmol) reacted with bromoethane (30 μL, excess), in the presence of K2CO3 (10 mg), to afford 1-[4-acetyl-1-(2,4-diethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 344 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(2,4-diethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (4 mg) and hydrazine (5 μL) reacted to give 6-(2,4-diethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as off-white solid: 1H NMR (CDCl3, 500 MHz) δ 7.03 (d, 1H), 6.67 (s, 1H), 6.64 (d, 1H), 4.15 (q, 1H), 4.04 (q, 1H), 2.89 (br s, 6H), 2.43 (s, 6H), 1.49 (t, 3H, 1.26 (t, 3H); MS (ESI) 340 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][N:20]([CH3:29])[C:21]4([C:25]([NH:27][CH3:28])=[O:26])[CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C=O.[CH:35](N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][N:20]([CH3:29])[C:21]4([C:25]([NH:27][CH3:28])=[O:26])[CH2:24][N:23]([CH3:35])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CNC1
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN(C)C1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
The hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methylazetidine-3-carboxamide (110 mg, 0.22 mmol Example 99), formaldehyde (54 μl of a 37% wt aqueous solution, 0.67 mmol) and diisopropylethylamine (78 μl, 0.45 mmol) were stirred at room temperature in 5% acetic acid in 1,2-dichloroethane (2 ml) with 3 Å molecular sieves. Sodium triacetoxyborohydride (95 mg, 0.45 mmol) was added portionwise over 0.5 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure and the residues purified preparative HPLC (standard basic conditions) to give the title product (68 mg, 65%) as a white powder. 1H NMR Spectrum: (CDCl3) 2.40 (s, 3H), 2.45 (m, 3H), 2.89 (s, 3H), 3.39 (brs, 2H), 3.60 (d, 2H), 3.95 (s, 2H), 3.98 (s, 3H), 7.17 (m, 2H), 7.25 (s, 1H), 7.44 (brs, 1H), 7.84 (brs, 1H), 8.00 (s, 1H), 8.51 (brs, 1H), 8.74 (s, 1H); Mass Spectrum: (M+H)+ 473.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([S:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:20][C:10]1[N:7]2[C:8]([CH3:9])=[C:3]([CH2:1][CH3:2])[C:4]([S:18][CH3:19])=[N:5][C:6]2=[N:12][C:11]=1[C:13](=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)C(=O)c1cn2c(C)c(CC)c(SC)nc2n1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)c1nc2nc(SC)c(CC)c(C)n2c1Br
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
A solution of 1.0 g (3.63 mmol) of 1-(6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-2-propen-1-one in 50 ml of chloroform was treated with 0.71 g (4.0 mmol) of N-bromo succinimide. After 20 minutes at room temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica, 25 g: dichloromethane) to obtain 1.1 g (87%) of 1-(3-bromo-6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-2-propen-1-one in the form of pale yellow crystals melting at 87°-9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4′-fluoroacetophenone (111.04 g) in concentrated H2SO4 (46 mL) was dropwise added a thoroughly mixed solution of fuming nitric acid (6.4 mL) and concentrated H2SO4 (118 mL) at 15° C. After the addition was complete, the reaction mixture was stiffed at −15° C. for 30 min and then poured into ice-water. The resulting mixture was extracted with CH2Cl2, and the organic layer was washed with water, dried over MgSO4 and concentrated in vacuo. The resulting residue was Purified by silica gel flash chromatography (30% ethyl acetate in hexane) to give 5.6 g of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1N
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc(N)c(C)c2)ccn1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
To the solution of 4-amino-m-cresol (125 mg, 1.01 mmol, 1.0 eq) in 1 mL of NMP was added 4-chloro-N-methylpicolinamide (189 mg, 1.11 mmol, 1.1 eq) and cesium carbonate (658 mg, 2.02 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at 75° C. for 12 hours, thereafter the mixture was diluted with water (ca. 50 mL) and aqueous layer extracted with ethyl acetate (ca. 50 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure to give sufficiently pure crude product which was carried to next step without further purification. LC/MS (m/z) [258.1] (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Br:25][CH2:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1onc(-c2ccccc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2ccccc2)c1CBr
Yield: 79.3 %

Procedure:
Ethyl 4-methyl-3-phenylisoxazole-5-carboxylate (0.2 g, 0.87 mmol), NBS (0.17 g, 0.95 mmol), and benzoyl peroxide (21 mg, 0.087 mmol) were added to 5 mL of carbon tetrachloride and the mixture was refluxed for 16 h. The mixture was diluted with CH2Cl2, and 5 g of silica gel was added. The solvent was removed in vacuo and the crude was purified by flash chromatography (0-20% EtOAc/hexanes) to give 214 mg of the title compound. MS: (+) m/z 310.31, 312.28 (M+1, 79Br/81Br).
Reaction SMILES: CC(OCC1CS[C@@H]2[C@H](N)C(=O)N2C=1C(O)=O)=O.CC1CS[C@@H]2[C@H](N)C(=O)N2C=1C(O)=O.[NH2:33][CH:34]1[C:59](=[O:60])[N:36]2[C:37]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[O:50])=[C:38]([O:41][S:42]([C:45]([F:48])([F:47])[F:46])(=[O:44])=[O:43])[CH2:39][CH2:40][C@H:35]12.[O:61]([CH2:68][C:69](Cl)=[O:70])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C(#N)C.N1C=CC=CC=1.C(N(CC)CC)C>[O:61]([CH2:68][C:69]([NH:33][CH:34]1[C:59](=[O:60])[N:36]2[C:37]([C:49]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[O:50])=[C:38]([O:41][S:42]([C:45]([F:48])([F:47])[F:46])(=[O:44])=[O:43])[CH2:39][CH2:40][C@H:35]12)=[O:70])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12
Reactant: O=C(Cl)COc1ccccc1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12

Procedure:
The N-acylations are carried out by using the methods employed for the acylation of the cephalosporin nuclei such as 7-ACA and 7-ADCA. In an example of the acylation benzyl 7-amino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate in acetonitrile is treated with phenoxyacetyl chloride in the presence of an acid-binding agent such as triethylamine or pyridine to provide benzyl 7-phenoxyacetylamino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH2:52][CH2:53][CH2:54][N:55]1[CH:59]=[C:58]([C:60]2[N:65]=[C:64]([C:66](=[O:69])[NH:67][CH3:68])[C:63]([NH:70][C:71]3[C:76]([C:77]([F:80])([F:79])[F:78])=[CH:75][N:74]=[C:73]([NH:81][C:82]4[CH:96]=[CH:95][C:85]([CH2:86][P:87](=[O:94])([O:91]CC)[O:88][CH2:89][CH3:90])=[CH:84][C:83]=4[O:97][CH3:98])[N:72]=3)=[CH:62][CH:61]=2)[CH:57]=[N:56]1>>[OH:50][CH2:51][CH2:52][CH2:53][CH2:54][N:55]1[CH:59]=[C:58]([C:60]2[N:65]=[C:64]([C:66](=[O:69])[NH:67][CH3:68])[C:63]([NH:70][C:71]3[C:76]([C:77]([F:80])([F:78])[F:79])=[CH:75][N:74]=[C:73]([NH:81][C:82]4[CH:96]=[CH:95][C:85]([CH2:86][P:87](=[O:91])([OH:94])[O:88][CH2:89][CH3:90])=[CH:84][C:83]=4[O:97][CH3:98])[N:72]=3)=[CH:62][CH:61]=2)[CH:57]=[N:56]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCCO)c4)nc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCCO)c4)nc3C(=O)NC)n2)c(OC)c1
Yield: 103.2 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({6-[1-(4-hydroxybutyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 15B, 95 mg, 0.13 mmol) to afford 91 mg of the title compound (99%). 1H NMR (400 MHz, CD3OD) δ 8.96 (d, J=6.1 Hz, 1H), 8.50 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.69 (d, J=9.1 Hz, 2H), 7.10 (s, 1H), 6.93 (dd, J=2.0, 8.1 Hz, 1H), 4.24 (t, J=6.9 Hz, 2H), 3.83-3.91 (m, 5H), 3.60 (t, J=6.4 Hz, 2H), 2.99-3.06 (m, 2H), 2.98 (s, 3H), 1.94-2.04 (m, 2H), 1.51-1.61 (m, 2H), 1.16 (t, J=7.1 Hz, 3H). MS (ESI): m/z 679.80 [M+H]+. UPLC: tR=1.11 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:20])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound (F) was prepared as described in the procedure of compound (C). The 3,4-dimethoxy-5-nitrobenzoyl chloride was prepared by the reaction of 3,4-dimethoxy-5-nitrobenzoic acid (585 mg, 2.57 mmol) with oxalyl chloride (0.36 mL, 4.1 mmol) in dichloromethane using N,N-dimethylformamide as a catalyst. The resulting mixture was stirred at room temperature for 1 h, the volatile liquids were removed and the resulting acid chloride was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][N:5]=1
Reactant: O=C(O)c1cc(I)ccn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(I)ccn1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 4-iodopicolinic acid 11a (7.0 g, 18.6 mmol) in MeOH (70 mL) at 23° C. was added concentrated sulfuric acid (350 μL), and the reaction mixture was refluxed for 48 h. The reaction mixture was cooled to room temperature and concentrated to yield the desired product 4-iodopicolinic acid methyl ester 11b (4.4 g, 90%) as a yellow oil; 1H NMR (300 MHz, CDCl3) δ 8.52 (t, J=0.6, 1.5, 1), 8.40 (d, J=5.1, 1), 7.86-7.88 (dd, J=0.6, 5.1, 1), 4.02 (s, 3); MS (ESPOS): 263.9 [M+H];285.9 [M+Na].
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:11][CH:10]([O:12][C:13]2[C:18](Br)=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:36]2[CH2:37][CH2:38][O:39][CH2:40][CH:41]=2)O1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:11][CH:10]([O:12][C:13]2[C:18]([C:36]3[CH2:41][CH2:40][O:39][CH2:38][CH:37]=3)=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CC(Oc2nc(Cl)ncc2Br)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC(Oc2nc(Cl)ncc2C2=CCOCC2)C1
Yield: 43.3 %

Procedure:
To a solution of [3-(5-bromo-2-chloro-pyrimidin-4-yloxy)-cyclobutyl]-carbamic acid tert-butyl ester (5.1 g, 13.3 mmol) in dioxane (80 mL) was treated with Na2CO3 (2.8 g, 26.6 mmol) in 15 mL of H2O as a solution, followed by additional of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (3.3 g 16.0 mmol) and Pd(dppf)Cl2 (974 mg, 1.33 mmol). The resulting mixture was heated at refluxing overnight under N2 atmosphere. TLC showed that most of the staring materials were consumed completely. The solution was filtered, and the filter was concentrated. And the residue was purified by silica gel chromatography to give the product (2.2 g, 5.76 mmol, 43%). ESI-MS (M+1): 382 calc. for C18H24ClN3O4 381.