Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:12])[C@:4]1([CH3:11])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>CCOCC>[CH3:10][C:6]1([CH3:9])[O:5][C@:4]([CH3:11])([C:3]([Cl:12])=[N:2][O:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:8][O:7]1
Reactant: CC1(C)OC[C@@](C)(C(Cl)=NO)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@@](C)(C(Cl)=NOS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
(S)-N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoyl chloride (5.5 g, 28.4 mmol) was dissolved in Et2O (150 mL) and methanesulfonyl chloride (2.21 ml, 28.4 mmol) was added. Triethylamine (3.96 ml, 28.4 mmol) was added dropwise and the reaction was stirred at ambient temperature for 1 hour. The resulting solids were filtered and the filtrate concentrated. The residue was purified over silica gel (100% CH2Cl2) to afford (S)-2,2,4-trimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (4.7 g, 17.3 mmol, 60.9% yield) as an amber oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[NH:6][C:7](=O)[C:8]=1[CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])[CH3:2].P(Cl)(Cl)([Cl:26])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:26][C:7]1[C:8]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:3]([CH2:1][CH3:2])[N:4]=[C:5]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(C(=O)OC)c1c(CC)nc(N2CCCCC2)[nH]c1=O
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1CC

Procedure:
To a suspension of methyl 2-(4-ethyl-6-oxo-2-(piperidin-1-yl)-1,6-dihydropyrimidin-5-yl)pentanoate (2.53 g; 7.86 mmol) in dry toluene (15 mL) under nitrogen atmosphere were 5carefully added phosphorus oxychloride (7.30 mL; 79 mmol) and dimethylaniline (0.794 mL; 6.29 mmol) and the reaction mixture was heated under reflux for 3 h. The volatiles were removed under reduced pressure (while the reaction mixture was still at elevated temperature), the residue was cooled in an ice-bath and quenched by adding crushed ice and a saturated solution of sodium hydrogen carbonate until neutralization. The aqueous layer was extracted with ethyl acetate, the organics were collected, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.352 g (8.6%, over 3 last steps) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CC(C)=O>[CH2:30]([O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:20][CH3:21])[N:12]=[CH:11][N:10]=[C:9]2[NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc2c(Nc3ccc(Cl)cc3)ncnc2cc1OC
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-chloro-phenylamino)-7-methoxy-quinazolin-6-ol (0.61 g, 2.02 mmol) (from Example 16, Step B, supra) in acetone (50 mL) was added K2CO3 (0.84 g, 6.06 mmol), and allyl bromide (0.52 mL, 6.06 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.01) as eluent to give the desired (6-allyloxy-7-methoxy-quinazolin-4-yl)-(4-chloro-phenyl)-amine as a white solid. (Yield 0.5 g, 72%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH3:21])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:22]([O:24]C)=[O:23])[CH:12]=3)[N:7]=2)=[CH:2]1.[OH-].[Na+]>CO.O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH3:21])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:22]([OH:24])=[O:23])[CH:12]=3)[N:7]=2)=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccoc3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccoc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of methyl 2-(furan-3-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (111 mg, 0.33 mmol) in methanol (20 mL) and water (1.0 mL) was added sodium hydroxide (52.9 mg, 1.32 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL), adjusted pH to 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(furan-3-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylic acid as a light yellow solid (72 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12]([CH3:20])([CH3:19])[CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:29][N:30]1[CH:34]=[C:33]([S:35](Cl)(=[O:37])=[O:36])[N:32]=[CH:31]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([CH3:19])([CH3:20])[CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)[S:35]([C:33]2[N:32]=[CH:31][N:30]([CH3:29])[CH:34]=2)(=[O:37])=[O:36])=[CH:21][CH:22]=1
Reactant: CC1(C)CNC(=O)c2cc(NCc3ccc(Cl)cc3)ccc21
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: Cn1cnc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2ccc3c(c2)C(=O)NCC3(C)C)c1
Temperature: 150 °C
Yield: 54.5 %

Procedure:
To a stirred solution of 7-(4-chloro-benzylamino)-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (20 mg, 0.06 mmol) and pyridine (12 μl, 0.14 mmol) in anhydrous acetonitrile (1 ml) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (25 mg, 0.14 mmol) and the reaction heated to 150° C. in a microwave for 0.5 hrs. The solvent was evaporated in vacuo and the crude residue purified by preparative HPLC (Method A) to afford the title compound as a colourless solid (15 mg, 21%). HPLC retention time 4.07 min. Mass spectrum (ES+) m/z 459 (M+H).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](Cl)=[O:65])=[CH:62][C:61]=1[CH3:69]>>[F:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:65])=[CH:62][C:61]=1[CH3:69]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: Cc1cc(C(=O)Cl)ccc1F
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)c(C)c4)cc3)cc2C1=O
Yield: 85 %

Procedure:
The compound of example 161 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-fluoro-3-methyl benzoyl chloride.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[C:25]([CH2:37][CH2:38][CH3:39])[N:24]=1.C(O)(C)C>CO>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[C:25]([CH2:37][CH2:38][CH3:39])[N:24]=[C:23]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1
Reactant: CCCc1nc(Cl)c2cc(OC)c(OC)cc2n1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Solvent: CO
Solvent: CC(C)O
Product: CCCc1nc(N2CCC(n3c(=O)c4cc(C)ccc4n(C)c3=O)CC2)c2cc(OC)c(OC)cc2n1
Yield: 35 %

Procedure:
The procedure similar to that described in Example 40 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used, 4-chloro-6,7-dimethoxy-2-propylquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline, and isopropyl alcohol was used as a reaction solvent in place of methanol. As a result, 174.3 mg (yield: 35%) of Compound 82 was obtained as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([CH:21]([CH3:23])[CH3:22])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:33]>C(#N)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([CH:21]([CH3:23])[CH3:22])=[C:18]([NH2:33])[N:19]=2)=[N:6]1
Reactant: CC(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Reactant: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
900 mg (5.138 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-isopropyl-1,2,4-triazin-5-ol were admixed with 12 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 50 ml of dry acetonitrile and, with ice-cooling, stirred into 173 ml of concentrated aqueous ammonia solution (25% strength). The reaction mixture was stirred for 2 h at RT and for 6 h at 50° C. After cooling, concentration on a rotary evaporator was carried out.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:6][C:7](=O)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:2].[ClH:22]>O1CCCC1.C(O)C>[ClH:22].[CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:13][S:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:2]
Reactant: CCOC(=O)C(CSc1ccccc1)NC(=O)CC(C)C
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(CSc1ccccc1)NCCC(C)C
Reaction time: 1 h
Yield: 15 %

Procedure:
A solution of N-isovaleryl-3-(phenylthio)-DL-alanine ethyl ester (1.0 g) in anhydrous tetrahydrofuran (3.2 ml) is added to a 1 M solution of a borane-tetrahydrofuran complex salt in tetrahydrofuran (4.85 ml) dropwise under a nitrogen atmosphere and ice cooling, and the mixture is refluxed with stirring for one hour. A 3 N solution of hydrogen chloride in ethanol (2 ml) is added to the reaction mixture under ice cooling, and the mixture is further refluxed for one hour. The reaction mixture is concentrated under reduced pressure, 5% sodium hydrogencarbonate is added to the concentrate, and the whole is extracted with ether. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, and the resulting oily matter is dissolved in ether. A 4.6 N solution of hydrogen chloride in ethyl acetate is added thereto under ice cooling, and the resulting precipitate is filtered off to give 163 mg (15%) of the titled compound (Reference compound No. 5-1) as crystals.
Reaction SMILES: [OH:1][C@H:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1.[Cl-:33].[NH4+].O>C(O)(C)C>[ClH:33].[OH:1][C@H:2]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1.[OH:1][C@H:2]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1
Reactant: [Cl-]
Agent: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1O
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: Cl
Reaction time: 20 h

Procedure:
In a 200 mL roundbottom flask, compound 1 (200 mg, 0.46 mmol) was dissolved in 40 mL isopropyl alcohol. The solution was stirred and vortexed at room temperature until it became homogeneous. A 7% (w/w) solution of ammonium chloride in water (20 mL, 26 mmol)) was then added dropwise to the stirring solution. The stirring was stopped and the solution was permitted to stand at room temperature for 20 h. White crystals formed. The crystals were collected on a Bülchner funnel, washed with 1:1 isopropanol:water (3 mL), and dried for 30 minutes. The crystals were collected to yield the monohydrochloride salt of compound 1 (27 mg, 12% yield).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:38]=[C:39]=[O:40])[CH2:35][CH2:36][CH3:37]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([NH:38][CH2:34][CH2:35][CH2:36][CH3:37])=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCCN=C=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 61.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, n-butyl isocyanate (0.27 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))1,3-dioxoisoindolin-4-yl]methyl}(butylamino)carboxamide (0.44 g, 61%) as a white solid: mp 172-174° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86-7.68 (m, 3H), 6.42 (t, J=5.9 Hz, 1H), 6.12 (t, J=5.4 Hz, 1H), 5.18-5.11 (dd, J=5.2 and 12.4 Hz, 1H), 4.63 (d, J=5.9 Hz, 1H), 3.03-2.83 (m, 3H), 2.64-2.51 (m, 2H), 2.08-2.04 (m, 1H), 1.37-1.22 (m, 4H), 0.86 (t, J=7.0 Hz, 3H); 13C NMR (DMSO-d6) δ 172.70, 169.77, 167.54, 167.00, 157.98, 141.14, 134.56, 133.33, 131.47, 126.94, 121.58, 48.80, 38.98, 38.70, 32.01, 30.90, 21.95, 19.46, 13.64; Anal. Calcd. For C19H22N4O5: C, 59.06; H, 5.74; N, 14.50. Found: C, 59.24; H, 5.53; N, 14.37.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:16]=2)[CH:12]=[N:11]1)[CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)#[N:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:5]1([CH:4]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[O:27])=[CH:29][CH:30]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:3][C:1]#[N:2])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3ccc(C(=O)O)cc3)n2)cn1
Reactant: CN1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(Nc3nccc(-c4cnn(C(CC#N)C5CCCC5)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)benzoic acid (30 mg, 0.07 mmol), 1-methyl-piperazine (8.3 μL, 0.074 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.4 mg, 0.089 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (31 μL, 0.18 mmol). The reaction was stirred at room temperature for 1 h, quenched with water, purified on HPLC to give the desired product as a racemic mixture (28 mg, 82%). LCMS (M+H) 485.5.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccccc1)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 97.7 %

Procedure:
6.8 g (29 mmol) of 4-bromo-N-methyl-2-nitroaniline were dissolved into 20 mL of pyridine. Furthermore, 5.0 g (35 mmol) of benzoyl chloride were added, and the whole was stirred under heating at 90° C. for 7 hours in an argon atmosphere. After the completion of the reaction, 200 mL of ethyl acetate were added, and the whole was washed with 10-mass % hydrochloric acid, 10-mass % K2CO3, and a saturated sodium chloride solution, and dried with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by means of silica gel column chromatography to obtain 9.5 g of 4′-bromo-N-methyl-2′-nitro-benzanilide as a greenish white solid (96% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([OH:17])[CH2:15][S:16][C@H:11]12)=[O:8].CC(N(C)C)=O.C1OC1C.[CH2:43]([S:45](Cl)(=[O:47])=[O:46])[CH3:44]>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([O:17][S:45]([CH2:43][CH3:44])(=[O:47])=[O:46])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: CCS(=O)(=O)Cl
Agent: CC1CO1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
By following the procedure described by Example 4, 4.7 g. (10 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate was reacted for about 3 hours in 50 ml. of dimethylacetamide containing about 2 ml. of propylene oxide with a stoichiometric amount of ethanesulfonyl chloride. The reaction mixture was dissolved in ethyl acetate and the solution washed with a saturated solution of sodium chloride. The organic phase was dried and evaporated to dryness to provide the reaction product. The product was purified by preparative thin layer chromatography on silica gel by employing 65 percent ethyl acetate/hexane for development. The purified product, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-ethylsulfonyloxy-3-cephem-4-carboxylate, gave the following percent elemental composition on microanalysis for the formula C22H21N3O9S3 :
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][C:40]=1[F:41])[NH:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:37])=[CH:23][C:24]=2[O:26][CH2:27][C@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33](=[O:36])[CH2:34][OH:35])[N:19]=[CH:18][N:17]=1.O>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][C:40]=1[F:41])[NH:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:37][CH2:2][CH2:3][OH:4])=[CH:23][C:24]=2[O:26][CH2:27][C@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33](=[O:36])[CH2:34][OH:35])[N:19]=[CH:18][N:17]=1
Reactant: O=C(CO)N1CCC[C@@H]1COc1cc(O)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CO)N1CCC[C@@H]1COc1cc(OCCO)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 70 °C
Yield: 45 %

Procedure:
2-Bromoethanol (51 μl) and potassium carbonate (86 mg) were added to a mixture of 4-[3-chloro-4-fluoroanilino]-5-{[(2R)-1-glycoloylpyrrolidin-2-yl]methoxy}-quinazolin-7-ol (70 mg) in DMF and the reaction mixture was heated at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and then water (5 ml) was added to leave a white precipitate. The precipitate was filtered, washed with water and then purified by column chromatography using 2-5% methanol in DCM as eluent. The product was purified further by acidic reverse phase HPLC, and then the combined fractions were reduced to a third of the initial concentration, basified with sodium carbonate and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (35 mg, 45%); NMR Spectrum (DMSO-d6 at 373 K) 9.80 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1M, 7.33 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.0 (m, 2H), 3.75 (m, 2H), 3.60 (m, 1H), 3.50-3.37 (m, 2H), 2.10-1.85 (m, 4H); Mass spectrum MH+ 491.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:27][CH:24]3[CH2:26][CH2:25]3)[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1C1CCC(=O)CC1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NC2CC2)CC1

Procedure:
from 4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-cyclohexanone and cyclopropylamine. Colourless oil. Rf value: 0.51 (alumina, petroleum ether/ethyl acetate=4:1, v:v).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:27][C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>>[CH:15]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:18]([C:20]2[CH:25]=[N:24][C:23]([N:29]3[CH:30]=[CH:31][N:32]=[C:28]3[CH3:27])=[N:22][CH:21]=2)=[O:19])[CH2:16][CH2:17]1
Reactant: Cc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Product: Cc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1

Procedure:
The title compound is prepared from 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester and 2-methyl-1H-imidazole following procedures analogous to those described in Intermediate 16 and Intermediate 17. LC (method 10): tR=0.56 min; Mass spectrum (ESI+): m/z=327 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[C:14]([NH:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[C:14]1[N:19]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]2=[N:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC[C@@H]1c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of Intermediate 83a (375 mg, 1.10 mmol), Ph3P (578 mg, 2.20 mmol) and Et3N (614 μL, 4.41 mmol) in THF (11.0 mL) at 0° C. was added hexachloroethane (523 mg, 2.20 mmol). The reaction was stirred at RT overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (297 mg, 84%). LCMS (Method 1): Rt 2.73, m/z 323.2 [MH+].