Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.BrCC1OC(C(F)(F)F)=CC=1.[F:21][C:22]1[C:23]([F:40])=[CH:24][C:25]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[C:26]=2[CH:27]=1.CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]3([C:26]4[CH:27]=[C:22]([F:21])[C:23]([F:40])=[CH:24][C:25]=4[O:39][CH2:38]3)[C:29]2=[O:37])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc(Br)cc2)c2ccccc2C12COc1cc(F)c(F)cc12

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 4-bromobenzyl bromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 1′-(4-bromobenzyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (54%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ7.51 (s, 1H), 7.48 (s, 1H), 7.23-7.04 (m, 5H), 6.82-6.77 (m, 2H), 6.50 (dd, J=8.9, 8.9 Hz, 1H), 5.03-4.96 (m, 2H), 4.84-4.72 (m, 2H); MS (ES+) m/z 442.1 (M+1), 444.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.CCN(C(C)C)C(C)C.[Cl:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>CN(C=O)C.CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:27]2[N:28]=[C:23]([Cl:22])[N:24]=[CH:25][N:26]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: Clc1ncnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
(3-Amino-phenyl)-acetic acid methyl ester was prepared by reacting 3-aminophenylacetic acid with acetyl chloride in MeOH to afford the corresponding methyl ester, HCl salt, (3.09 g, 15.324 mmol). The ester was dissolved in DMF (5 ml) with DIEA (2.67 ml, 15.324 mmol) and cooled to 0° C. To this solution was added dropwise a 0° C. solution of DMF (5 ml) containing 2,4-dichloro-1,3,5-triazine (2.297 g, 15.324 mmol) and DIEA (2.67 ml, 15.324 mmol). The reaction was stirred at ODC for 15 min and then at RT for 1 h. The reaction mix was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed 4 times with brine and dried over Na2SO4. The crude was concentrated down and dried under reduced pressure, giving [3-(4-chloro-[1,3,5]triazin-2-ylamino)-phenyl]-acetic acid methyl ester (4.3 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH2:39][CH3:40]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[C:38](=[O:41])[CH2:39][CH3:40])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: CCC(=O)Cl
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N(C)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by propanoyl chloride (32 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 108 mg, 63%. 1H NMR (mix of rotomers, 400 MHz, DMSO-D6) δ ppm 8.52 (2 H, d, J=6.06 Hz) 7.57-7.76 (2 H, m), 7.30 (2 H, dd, J=8.46, 5.68 Hz, 7.15 (2 H, t, J=8.84 Hz), 6.52 (1 H, s), 5.05-5.43 (2 H, m), 4.46-4.62 (0.5 H, m), 4.38 (1 H, d, J=12.63 Hz), 3.85-4.00 (3.5 H, m), 3.05-3.23 (1 H, m), 2.77 (2 H, s), 2.65 (1 H, s), 2.55-2.63 (1 H, m), 2.39 (1 H, q, J=7.33 Hz), 2.29 (1 H, q, J=7.33 Hz), 1.41-1.80 (4 H, m), 0.98 (3 H, q, J=7.49 Hz); m/z (APCI+) for C26H30N5O2F 464.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(O)[CH3:19])[C:5]=2[CH2:4][CH2:3]1.OS(O)(=O)=O.[OH-].[K+]>O>[F:27][C:24]1[CH:23]=[CH:22][C:21](/[C:18](/[CH3:19])=[CH:17]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)=[CH:26][CH:25]=1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(F)cc2)CCN(C)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The title compound was prepared by following general procedure 6. 1-(3,9-Dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol (100 mg, 0.273 mmol) was taken into 2.0 mL of 25% H2SO4 in water, and stirred at 90° C. for 2 h. The reaction was monitored by TLC and LCMS. The reaction mixture was cooled and basified with aq. KOH solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse phase chromatography to afford 10 mg of product as the TFA salt along with 6-(2-(4-fluorophenyl)allyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:4]=2[CH:3]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: Brc1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2cc3cnc(Br)cc3n2-c2ccccn2)cn1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 27 mg 0.10 mmole) and 2-bromopyridine (24 mg, 15 uL, 0.15 mmole) were dissolved in DMA (0.7 ml) and potassium carbonate (20 mg, 0.14 mmole) and copper(I) iodide (4.0 mg, 0.022 mmole) were added. The reaction was placed under argon and heated by microwave at 180° C. for 60 minutes followed by 210° C. for 45 minutes. The reaction was taken up in ethyl acetate (25 mL) and the solution washed with water (3×7 mL) and brine. The aqueous solutions were backwashed with a single portion of ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified using preparative TLC eluting with ethyl acetate to afford the title compound 17 mg (48%). 1H-NMR (CDCl3, 500 MHz): 3.88 (s, 3H), 6.72 (d, J=0.95 Hz, 1H), 7.18 (d of t, J=0.95, 7.88 Hz, 1H), 7.24 (s, 1H), 7.26 (d, J=0.63 Hz, 1H), 7.44 (ddd, J=0.95, 4.73, 7.57 Hz, 1H), 7.51 (t, J=0.95 Hz, 1H), 7.86 (t of d, J=1.89, 7.57 Hz, 1H), 8.66 (d, J=0.95 Hz, 1H), 8.73 (ddd, J=0.95, 1.89, 4.73 Hz, 1H).
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]1([CH2:13][N:14]([C@@H:22]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:23]([OH:30])[CH2:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[O:44]1[C:48]2[CH:49]=[CH:50][C:51]([S:53](Cl)(=[O:55])=[O:54])=[CH:52][C:47]=2[O:46][CH2:45]1.C(OCC)(=O)C>O.O1CCOCC1>[O:44]1[C:48]2[CH:49]=[CH:50][C:51]([S:53]([N:25]([CH2:24][C@@H:23]([OH:30])[C@@H:22]([N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:54])=[O:55])=[CH:52][C:47]=2[O:46][CH2:45]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: CC(C)CNC[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
To a 5000 mL, 3-necked flask fitted with a mechanical stirrer was added N-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine-oxalic acid salt (354.7 g, 0.7 mole) and 1,4-dioxane (2000 mL). A solution of potassium carbonate (241.9 g, 1.75 moles) in water (250 mL) was then added. The resultant heterogeneous mixture was stirred for 2 hours at room temperature followed by the addition of 1,3-benzodioxole-5-sulfonyl chloride (162.2 g, 0.735 mole) dissolved in 1,4-dioxane (250 mL) over 15 minutes. The reaction mixture was stirred at room temperature for 18 hours. Ethyl acetate (1000 mL) and water (500 mL) were charged to the reactor and stirring continued for another 1 hour. The aqueous layer was separated and further extracted with ethyl acetate (200 mL). The combined ethyl acetate layers were washed with 25% brine solution (500 mL) and dried over anhydrous magnesium sulfate. After filtering and washing the magnesium sulfate with ethyl acetate (200 mL), the solvent in the filtrate was removed under reduced pressure yielding the desired sulfonamide as an viscous yellow foamy oil (440.2 g 105% yield). HPLC/MS (electrospray) (m/z 601 [M+H]+].
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([CH3:25])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(C)c1OC
Temperature: 160 °C
Yield: 18.5 %

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.332 g), potassium methyltrifluoro borate (0.0675 g), palladium chloride dppf adduct with DCM (0.066 g) and cesium carbonate (0.786 g) in THF (9 ml) and water (1 ml) was sealed in a microwave vial and degassed. The mixture was then heated in the microwave at 160° C. for 30 minutes. After cooling, the mixture was dried (MgSO4) and filtered through Celite, and the pad was washed with ethyl acetate. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-50% to give ethyl 6-(benzenesulphonylmethyl)-2-methoxy-3-methylbenzoate (0.05 g) as a colourless gum.
Reaction SMILES: [Br:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2[N:8]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35](=[O:36])[CH2:34][NH:28][C:25]1[CH:26]=[CH:27][C:22]([N:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:11]=[C:7]2[CH2:6][C:5]2[CH:31]=[CH:32][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(C(F)(F)F)cc3)nc2Cc2ccc(Br)cc2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(F)(F)F)cc3)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-1-(4-Nitro-phenyl)-4-(4-trifluoromethyl-phenyl)-1H-imidazole (2.5 g, 5 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {-4-[2-(4-bromo-benzyl)-4-(4-trifluoromethyl-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [P:1]([O-:42])([O-:41])([O:3][C:4](C(C)(C)C)(C(C)(C)C)[N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:7][C:6]1=[O:32])=[O:2]>CC#N.O.CC(O)=O>[P:1]([OH:42])([OH:41])([O:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C:13]2[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[CH:15][C:14]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:7][C:6]1=[O:32])=[O:2]
Reactant: CC(C)(C)C(OP(=O)([O-])[O-])(n1ccc(NC(=O)c2cc(C(F)(F)F)ccc2Oc2ccc(F)cc2)cc1=O)C(C)(C)C
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccn(COP(=O)(O)O)c(=O)c1)c1cc(C(F)(F)F)ccc1Oc1ccc(F)cc1
Yield: 55.5 %

Procedure:
A solution of di-tert-butyl [4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (22) (67 mg, 0.1090 mmol) in CH3CN (1.340 mL), water (1.340 mL) and AcOH (1.340 mL) was refluxed for 1 hour then evaporated to dryness. The material was then co-evaporated with CH3CN (3×), triturated with CH3CN, filtered, washed with CH3CN and desiccated to give [4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (18) (32 mg, 0.06052 mmol, 55.5%) as a white solid. ESI-MS m/z calc. 502.0553, found 503.4 (M+1)+; Retention time: 1.39 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.35-7.23 (m, 4H), 7.00 (d, J=8.7 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.45 (dd, J=7.6, 2.3 Hz, 1H), 5.53 (d, J=9.7 Hz, 2H) ppm. 31P NMR (162 MHz, DMSO-d6-85% H3PO4 aq. as internal standard—0 ppm) δ −2.11 (t, J=9.6 Hz) ppm.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=[C:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]=1)=[S:6].Cl>O.CCOCC>[CH2:17]([C:9]1[N:8]=[C:7]([C:5]([OH:4])=[S:6])[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(Cc2ccccc2)nc1C(=S)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc(Cc2ccccc2)nc1C(O)=S
Temperature: 40 °C
Reaction time: 4 h

Procedure:
15.0 g (0.375 mol) sodium hydroxide are dissolved in 40 ml water and added to a stirred mixture of 7.3 g (0.023 mol) 6-benzylthiopyridine-2,3-dicarboxylic acid dimethyl ester in 40 ml ether. It is stirred for 4 hours at 40° C., the aqueous phase is acidified with concentrated hydrochloric acid, and the product is extracted with ethyl acetate, the solvent then being dried across magnesium sulfate and compressed. The product crystallizes from the residue.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[C:8]([Cl:23])=[C:7]([CH3:24])[C:6]=1[C:25](=[O:27])[CH3:26].Cl.[OH:29][CH:30]1[CH2:33][NH:32][CH2:31]1>>[Cl:23][C:8]1[C:7]([CH3:24])=[C:6]([C:25](=[O:27])[CH3:26])[C:5]([O:4][CH2:3][CH2:2][N:32]2[CH2:33][CH:30]([OH:29])[CH2:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[O:21][CH3:22]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccccc1
Reactant: OC1CNC1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CC(O)C2)c1OCCCc1ccccc1
Yield: 16 %

Procedure:
Example 34b (207 mg, 0.46 mmol), CsCO3 (2.48 eq.) and 3-hydroxyazetidine hydrochloride (1.4 eq.) were reacted as described under General Procedure L and the crude product was purified by flash chromatography (silica gel, hexane/Et2O 1:1) to afford the title compound as a pale yellow oil (34 mg, 16%). 1H NMR (300 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 4.40 (quintet, J=5.7 Hz, 1H), 4.07 (t, J=6.5 Hz, 2H), 3.98 (t, J=5.7 Hz, 2H), 3.88 (s, 3H), 3.67-3.62 (m, 2H), 2.96-2.91 (m, 2H), 2.85-2.80 (m, 2H), 2.73 (t, J=5.7 Hz, 2H), 2.51 (s, 3H), 2.19 (s, 3H), 2.13-2.03 (m, 2H). MS (ES+) m/z 448.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[N:19]=[C:18]([NH:28][C:29]3([C:32]([O:34]CC)=[O:33])[CH2:31][CH2:30]3)[N:17]=2)=[CH:11][CH:10]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[N:19]=[C:18]([NH:28][C:29]3([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]3)[N:17]=2)=[CH:11][CH:10]=1)=[O:8]
Reactant: CCOC(=O)C1(Nc2nc(Nc3ccc(C(=O)NCCCCN)cc3)nc(OCC(F)(F)F)n2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: NCCCCNC(=O)c1ccc(Nc2nc(NC3(C(=O)O)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.5 %

Procedure:
Ethyl 1-(4-(4-(4-aminobutylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropanecarboxylate (80 mg) and potassium carbonate (64.8 mg) were dissolved in acetone (3 mL)/water (2 mL). After stirring at r.t. for 16 hours and then heated to 90° C. for 2 hours, the mixture was acidified with 1N HCl to pH=3. All the solvents were then removed under vacuum. The residue was purified by perp. HPLC to give 1-(4-(4-(4-aminobutylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropanecarboxylic acid (20 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[Na].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[N:3]=1
Reactant: c1nc[nH]n1
Reactant: Brc1cccc(Br)n1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: Brc1cccc(-n2cncn2)n1
Temperature: 25 °C
Yield: 45 %

Procedure:
A stirred solution of 2,6-dibromopyridine (2.0 g, 8.3 mmol) and 1,2,4-triazole sodium salt (1.0 g, 9.9 mmol) in dimethylsulfoxide (10 ml) was heated at 60° C. for 5 h. After cooling to ambient temperature the reaction was diluted with water and extracted into dichloromethane. Combined organic extracts were washed with water and saturated brine then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel eluting with dichloromethane, then dichloromethane containing 5% methanol, gave 2-bromo-6-(1H-[1,2,4]triazol-1-yl)pyridine (0.84 g) as a white solid: δH (400 MHz, CDCl3) 7.49 (1H, d, J 8), 7.74 (1H, dd, J 8 and 8), 7.87 (1H, d, J 8), 8.09 (1H, s), 9.15 (1H, s); m/z (ES+) 224/226 (M++H).
Reaction SMILES: [F:1][C:2]1([F:15])[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([SH:12])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1.Cl.Cl[CH:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][N:21]=1)[CH3:19].[OH-].[Na+].O>C(O)C>[F:15][C:2]1([F:1])[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([S:12][CH:18]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][N:21]=4)[CH3:19])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1
Reactant: COc1ccnc(C(C)Cl)c1
Reactant: FC1(F)Oc2cc3nc(S)[nH]c3cc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccnc(C(C)Sc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c1
Yield: 68 %

Procedure:
4 g of 2,2-difluoro-5H-[1,3]-dioxolo[4,5-f]benzimidazole-6-thiol, 3.6 g of (±)-2-(1-chloroethyl)-4-methoxy-pyridine hydrochloride, 1.4 g of sodium hydroxide, 3 ml of water and 50 ml of ethanol are stirred for 4 h at 65° C. The reaction mixture is concentrated to dryness, the residue is dissolved in 100 ml of 2N hydrochloric acid, impurities are extracted by shaking with ethyl acetate, and the aqueous phase is adjusted with sodium hydroxide solution to pH 10 and extracted with ethyl acetate. The organic phase is dried and concentrated. Recrystallisation from toluene gives 4.3 g (80.5%) of the title compound of m.p. 173°-175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].[Br:11]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(N)c(F)c1
Solvent: ClCCl
Product: N#Cc1cc(F)c(N)c(Br)c1
Reaction time: 15 h
Yield: 80.4 %

Procedure:
To a stirred mixture of 4-amino-3-fluorobenzonitrile (5 g, 37 mmol) in anhydrous CH2Cl2 (40 mL) under Ar at rt was added dropwise N-bromosuccinimide (6.5 g, 37 mmol). After 15 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 50% EtOAc in hexanes to afford 4-amino-3-bromo-5-fluorobenzonitrile (6.4 g, 81%) as a tan solid. 1H NMR (500 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.62 (dd, J=1.5, 11.1 Hz, 1H), 6.44 (s, 2H); LCMS (ESI) m/z 214, 216 (M+H)+.
Reaction SMILES: O[CH:2]([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13].O=S(Cl)[Cl:17]>O1CCOCC1>[Cl:17][CH:2]([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13]
Reactant: CC(O)Cn1c(=O)[nH]c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CC(Cl)Cn1c(=O)[nH]c2ccccc21

Procedure:
13.2 gm of N-(2-hydroxy-propyl)-benzimidazolone were issolved in 150 ml of dioxane, and after addition of 8 ml of SOCl2 the mixture was refluxed for one hour. After evaporation in vacuo, the residue was dissolved in ethyl acetate, and the solution was washed with a sodium bicarbonate solution and water, and dried over Na2SO4. After distilling off the solvent, 13.4 gm of N-(2-chloro-propyl)-benzimidazolone were obtained.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)[N:3]=1.P(Cl)(Cl)(Cl)=O.Cl.[NH2:20][CH:21]1[C:46](=[O:47])[N:23]2[C:24]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:25]([CH:28]=[CH2:29])[CH2:26][S:27][C@H:22]12.C[Si](CC(N)=O)(C)C>C(Cl)Cl.C(OCC)(=O)C.O.CN(C)C=O>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:20][CH:21]2[C:46](=[O:47])[N:23]3[C:24]([C:30]([O:32][CH:33]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:31])=[C:25]([CH:28]=[CH2:29])[CH2:26][S:27][C@H:22]23)=[O:10])[N:3]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1noc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3noc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 39.1 %

Procedure:
To a suspension of 2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetic acid (syn isomer) (2.23 g) in methylene chloride (70 ml) was added phosphorus oxychloride (7.2 g), followed by stirring at ambient temperature for 45 minutes. Thereto was added N,N-dimethylformamide (4.4 g) at -10° C., and the mixture was stirred at -10° to 0° C. for an hour to prepare the activated acid solution. This solution was added to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (4.7 g) and trimethylsilylacetamide (8.6 g) in ethyl acetate (50 ml) at -20° C., and the mixture was stirred at -20° to 0° C. for an hour. After ethyl acetate (200 ml) and water (200 ml) were added to the reaction mixture, the ethyl acetate layer was separated out, washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was chromatographed on silica gel eluting with a mixed solvent of ethyl acetate and benzene (6:4 by volume). Fractions containing a desired compound firstly eluted were collected and evaporated to obtain benzhydryl 7-[2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.4 g).