Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.[OH:34][CH2:35][C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[ClH:33].[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:35](=[O:34])[C:36]([CH3:41])([CH3:40])[CH2:37][OH:38])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CC(C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CO)C(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 15 h
Yield: 141.4 %

Procedure:
A solution of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 3-hydroxy-2,2-dimethylpropanoic acid (68 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (132 mg) and triethylamine (0.40 mL) in N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→methanol:ethyl acetate=15:85). After concentration under reduced pressure, ethyl acetate (2.0 mL) and 4N hydrochloric acid/ethyl acetate (0.5 mL) were added, and the mixture was stirred at room temperature for 15 hrs. After concentration under reduced pressure, the precipitated crystals were collected by filtration. To a solution of the collected crystals in ethanol (2.0 mL) was added 1N aqueous sodium hydroxide solution at room temperature, and the mixture was stirred for 2 days. The mixture was concentrated under reduced pressure and a solution of the residue in ethyl acetate was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, 4N hydrochloric acid/ethyl acetate (0.5 mL) was added to a solution of the residue in ethyl acetate (1.0 mL). After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the title compound (119 mg) as colorless crystals.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C>O1CCCC1.O>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 55.4 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (282) (1.6 g. 3.48 mmol) in a mixture of tetrahydrofuran:water (2:1) (90 mL), was added lithium-hydroxide monohydrate (2.9 g, 69.57 mmol) and the reaction mixture was refluxed for 18 h. After completion of the reaction, all volatiles were evaporated, added water (30 mL) and washed with ethyl acetate (2×20 mL) to remove non acidic impurities. The separated aqueous part was acidified with 1N HCl to reach a pH of about 5 to 6. The acidified aqueous part was extracted with ethyl acetate (4×50 mL), dried and concentrated to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (780 mg, 55.44%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.C(O)C.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:31])=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:24]=1>>[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH:31][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:24]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(N)c(-c2ccccc2)c1
Solvent: CCO
Product: CCCc1ccc2c(Nc3ccc(C)cc3-c3ccccc3)ccnc2n1
Temperature: 100 °C

Procedure:
The product from Example 2g as a 4.1M solution in ethanol (0.10 mL, 0.40 mmol) was reacted with the product from Example 219c (0.0724 g, 0.40 mmol) for 66 h at 100° C. following the procedure from Example 1g. Consumption of starting material required a second addition of the product from Example 2g (0.03 mL, 0.12 mmol) and continued heating at 100° C. (19 h). The crude title compound was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.060 g, 32%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J=7.35 Hz, 3H) 1.70-1.89 (m, 2H) 2.46 (s, 3H) 2.88-3.00 (m, 2H) 6.28 (d, J=6.99 Hz, 1H) 7.11-7.53 (m, 8H) 7.76 (d, J=8.82 Hz, 1H) 8.30 (d, J=6.99 Hz, 1H) 8.91 (d, J=8.82 Hz, 1H) 10.98 (s, 1H); MS (ESI+) m/z 354.2 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13]CC)=O)=[CH:3][CH:2]=1.[H-].[K+].Cl>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:13])[CH2:7][CH2:6][CH:5]2[CH2:4][CH2:3][CH2:2][NH:1][CH2:10]2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccnc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [K+]
Product: O=C(CCC1CCCNC1)c1ccnc2ccccc12

Procedure:
On operating as in Example 1, but starting from 4.4 g of ethyl quinoline-4-carboxylate, 5.6 g of ethyl 3-[3-(N-benzoyl)piperidyl]propionate and 12 ml of a 20% suspension of potassium hydride in oil, 2.7 g of crude product are isolated, which are absorbed on a column containing 270 g of silica. After elution with a 9/1 chloroform-diethylamine mixture, 1.2 g of 1-(4-quinolyl)-3-(3-piperidyl)-1-propanone are obtained, which is converted into its monohydrochloride. This monohydrochloride melts at 163° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([F:14])([F:13])([F:12])([F:11])[F:10].Cl.Cl.[NH:17]1[CH2:22][CH2:21][CH:20](/[CH:23]=[C:24]2/[C:25]([NH:30][CH2:31][C:32]#[CH:33])=[N:26][C:27](=[O:29])[S:28]/2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:10][S:9]([F:14])([F:13])([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:17]1[CH2:22][CH2:21][CH:20](/[CH:23]=[C:24]2/[C:25]([NH:30][CH2:31][C:32]#[CH:33])=[N:26][C:27](=[O:29])[S:28]/2)[CH2:19][CH2:18]1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: FS(F)(F)(F)(F)c1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccccc2S(F)(F)(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 2-(bromomethyl)-1-(pentafluorosulfanyl)benzene (213 mg) in DMF (5 mL) were added (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (210 mg) and potassium carbonate (362 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (164 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[C:4]([CH2:10][CH3:11])[N:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O>[CH2:10]([C:4]1[N:3]=[C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=1)[CH3:11]
Reactant: CCc1nc(Cl)cc(NN)n1
Reactant: CN1CCNCC1
Solvent: O
Product: CCc1nc(NN)cc(N2CCN(C)CC2)n1
Yield: 70.2 %

Procedure:
A mixture of 8.3 g (0.05 mole) of 4-chloro-2-ethyl-6-hydrazinylpyrimidine and 11 g (0.10 mole) of 1-methylpiperazine in 250 ml of water was heated at reflux for 16 hours and was then cooled and extracted with chloroform. The extracts were dried over magnesium sulfate and were then evaporated to provide 8.3 g (70%) of 2-ethyl-6-hydrazinyl-4-(4-methyl-1-piperazinyl)pyrimidine.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32])[CH:26]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:26][C:25]1[CH:28]=[CH:29][C:30]([C:31]([F:32])([F:33])[F:34])=[C:23]([F:22])[CH:24]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Product: O=C(C=Cc1ccc(C(F)(F)F)c(F)c1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and 3-fluoro-4-(trifluoromethyl)benzaldehyde (91 ul, 0.633 mmol) similar to Example 18 as a yellow solid (164 mg, 53%). 1H NMR (CDCl3): 7.65-7.60 (m, 2H), 7.52 (d, J=15.9 Hz, 1H), 7.43-7.37 (m, 2H), 7.32 (d, J=3.3 Hz, 1H), 7.15 (dd, J=3.3, 8.7 Hz, 1H), 6.92 (d, J=9.0 Hz, 1H), 4.45-4.32 (m, 4H).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([NH2:32])(=[O:30])=[O:31])=[CH:27][CH:28]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NCCc2ccc(S(N)(=O)=O)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 45.4 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), 4-(2-aminoethyl)benzenesulfonamide (0.139 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.122 g, 45%). 1H NMR (500 MHz, d8-THF): δ 7.70-7.65 (m, 2H), 7.58-7.52 (m, 2H), 7.51-7.45 (m, 3H), 6.90-6.84 (m, 2H), 6.53-6.47 (m, 1H), 6.38-6.34 (m, 1H), 3.19-3.12 (m, 2H), 2.64-2.58 (m, 1H), 1.70 (s, 9H); 13C NMR (125 MHz, d8-THF): δ 159.7, 143.3, 142.4, 135.2, 132.0, 129.4, 128.8, 128.6, 126.4, 126.3, 107.2, 60.6, 44.7, 35.6, 27.0; Mass Spectrum: M−H+ 464.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=O)[C@@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[S:33])[C@@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@@H]2F)CC1
Solvent: c1ccccc1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@@H]2F)CC1
Yield: 175.7 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3-(R)-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone (4.825 g, 15.11 mmol) was dissolved in dry benzene (150 ml), and the solution was mixed with Lawesson's reagent (3.085 g, 7.625 mmol) and heated under reflux for 30 minutes. After cooling, benzene was evaporated under a reduced pressure, and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=5:1, to thereby obtain 4.494 g (88.7%) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH2:11])[CH:5]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(N=Cc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 3-amino-4-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-4-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C18H11BrClNO2 353.62, obsd. (ESI+) [(M+H)+]351.9 & 353.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[CH:8][C:9]=1[NH:10]C(=O)C(F)(F)F)=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])=[CH:8][C:9]=1[NH2:10])=[O:4]
Reactant: COC(=O)c1sc(C(=O)C(C)C)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1sc(C(=O)C(C)C)cc1N

Procedure:
5-Isobutyryl-3-(2,2,2-trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester and potassium carbonate were reacted by method X. The product with the molecular weight of 227.28 (C10H13NO3S) was obtained in this way; MS (ESI): 228 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH:12]1([CH2:15][O:16]/[N:17]=[C:18](/[C:22]2[N:23]=[C:24]([NH:27][C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:25][CH:26]=2)\[C:19]([OH:21])=O)[CH2:14][CH2:13]1.[NH2:47][C@@H:48]1[C:63](=[O:64])[N:50]2[C:51]([C:60]([OH:62])=[O:61])=[C:52]([CH2:55][O:56][C:57](=[O:59])[NH2:58])[CH2:53][S:54][C@H:49]12>C(Cl)Cl.O.C(N(CC)CC)C>[C:57]([O:56][CH2:55][C:52]1[CH2:53][S:54][C@@H:49]2[C@H:48]([NH:47][C:19](=[O:21])/[C:18](=[N:17]\[O:16][CH2:15][CH:12]3[CH2:13][CH2:14]3)/[C:22]3[N:23]=[C:24]([NH:27][C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:25][CH:26]=3)[C:63](=[O:64])[N:50]2[C:51]=1[C:60]([OH:62])=[O:61])(=[O:59])[NH2:58]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)/C(=N\OCC1CC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC3CC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78.7 %

Procedure:
Oxalyl chloride (0.37 ml.) was added to a solution of N,N-dimethylformamide (0.38 ml) in methylene chloride (10 ml) with stirring under nitrogen at -20°. After ten minutes with ice water cooling, the mixture was recooled to -20° and (Z)-2-cyclopropylmethoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (1.94 g) was added and the solution was stirred with ice-water cooling for 10 minutes. The solution was recooled to -20° and added to a solution of (6R,7R)-7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylic acid (1.09 g) in industrial methylated spirits (12 ml) and water (3 ml) containing triethylamine (2.4 ml) at -10° and with vigorous stirring. After five minutes, the solution was partitioned between water and methylene chloride. Dilute hydrochloric acid was added to adjust the aqueous layer to pH >2. The aqueous layer was extracted with more methylene chloride and the combined organic layers were washed with water, dried with magnesium sulphate and evaporated. The residue was triturated with diethyl ether to give the title compound (2.32 g); [α]D21 +15.88° (c 0.69, CHCl3); νmax (Nujol) 3540 to 3100 (NH, NH2, OH, and water), 1785 (β-lactam), 1720 (acid and carbamate) and 1683 and 1510 cm-1 (amide).
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][C:10]1[CH:11]=[C:12](I)[CH:13]=[C:14]([CH3:16])[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCCCCCCCCCCC>[Cu]I.CC1C=CC=CC=1C>[CH2:1]([O:8][C:12]1[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:9])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Cc1cc(C)cc(I)c1
Reactant: CCCCCCCO
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1C
Solvent: CCCCCCCCCCCC
Product: CCCCCCCOc1cc(C)cc(C)c1
Temperature: 120 °C

Procedure:
A screw cap test tube was charged with n-heptanol (283 μL, 2.00 mmol), 3,5-dimethyliodobenzene (144 μL, 1.00 mmol), CuI (19.0 mg, 0.100 mmol), ligand (0.200 mmol), Cs2CO3 (977 mg, 3.00 mmol) and o-xylene (1 mL). The test tube was sealed with a screw cap. The reaction mixture was stirred magnetically and heated at 120° C. for 19 hours. The reaction mixture was allowed to reach room temperature. Dodecane (227 μL, 1.00 mmol; internal standard) was added and a GC sample was filtered through Celite and eluted with CH2Cl2. The yield of the desired product was determined using GC analysis; the results are tabulated below.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH:15]=[C:16]([F:18])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[F:33].[OH-].[Na+].Cl>CO.C1COCC1.O>[CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:15]=[C:16]([F:18])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[F:33]
Reactant: COC(=O)CCc1cc(F)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(F)c(-c2ccc(COc3cc(F)cc(CCC(=O)O)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.6 %

Procedure:
To a solution of methyl 3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-fluorophenyl)propanoate (380 mg) in methanol (4.0 mL) and THF (3.0 mL) was added a solution of sodium hydroxide (183 mg) in water (4.0 mL), and the mixture was stirred at room temperature for 15 hr. 2N Hydrochloric acid was added to the reaction to mixture to adjust to pH<2, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (290 mg) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]O.Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1.[I-].[K+]>C(N(CC)CC)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCCCCCO
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NCCCCCN2CCCCC2)nc1

Procedure:
Synthesis and purification were performed according to the procedure stated in example 152 using reagents 5-aminopentanol (15 mmol), 2-chloro-5-nitropyridine (15 mmol), 5 ml of triethylamine, and catalytic amounts of potassium iodide in the first step. The final product was purified by column chromatography (eluent: ethyl acetate/triethylamine (90/10)). The solvent was removed under reduced pressure. The residue was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:14])[N:8]3[CH3:13])[CH2:3][CH2:2]1.[Br-:15].[K+].BrBr>O.ClCCl.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:15][C:12]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:13])[C:7](=[O:14])[CH2:6]2
Reactant: CN1C(=O)Cc2c(C3CC3)cccc21
Reactant: [Br-]
Agent: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)Cc2c1ccc(Br)c2C1CC1
Temperature: 70 °C

Procedure:
Water (14 mL) was added to 4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one (0.74 g, 3.94 mmol) and the resulting mixture was placed at 70° C. In a separate flask potassium bromide (1.03 g, 8.7 mmol) in water (14 was treated with bromine (0.225 mL, 4.3 mmol), the resulting orange solution was added dropwise to the 4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one mixture over ca. 10 minutes. The resulting heterogeneous mixture was permitted to stir at 70° C. for an additional hour and then cooled to room temperature. The reaction was then diluted with dichloromethane and saturated aqueous sodium bicarbonate. The solution was then further diluted with saturated aqueous sodium thiosulfate. The layers were separated and the aqueous layer eras extracted two additional times with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was preadsorbed onto silica gel and purified by silica gel flash chromatography (ethyl acetate-heptane 0 to 50%) to provide 5-bromo-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 266.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[C:4]([CH3:20])[CH:3]=1.FC(F)(F)C(O)=O.ClCCl>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cc(F)ccc1NC1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)ccc1NC1CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To an ice cooled solution of tert-butyl 3-((4-fluoro-2-methylphenyl)amino)azetidine-1-carboxylate (D30) (300 mg, 1.07 mmol) in dichloromethane (2 ml), a mixture of trifluoroacetic acid/dichloromethane (4.5 ml/1.5 ml) was added and the mixture stirred at room temperature for 1 h. Solvents were evaporated in vacuo and the resulting residue was purified by SPE-SCX cartridge (10 g). Collected ammonia fractions, after solvent evaporation afforded the title compound (D55) (0022/107/1) (190 mg)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[C:18]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.Cl>[C:24]([O:23][C:21](=[O:22])[CH2:20][C:18]1[CH:17]=[CH:16][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)=[C:3]([CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH:19]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CNS(C)(=O)=O)cc1
Reaction time: 12 h
Yield: 67.7 %

Procedure:
The product of step B (1.87 g, 5.03 mmol) was diluted with methylene chloride (2 mL) followed by the addition of pyridine (0.489 mL, 6.04 mmol) and methanesulfonyl chloride (0.779 mL, 10.1 mmol). After stirring for 12 hours, the reaction mixture was diluted with methylene chloride and 2N HCl, the layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 40M cartridge eluting with hexanes:ethyl acetate (1:1) to yield methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-(methylsulfonamidomethyl)phenoxy)benzoate (1.53 g, 67.6% yield) as a clear oil.