Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[C:25]([CH3:31])=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[C:25]([CH3:31])=[C:26]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Cc1c(N)cccc1F
Product: Cc1nc(NCc2ccccn2)nc(Nc2cccc(F)c2C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (3-fluoro-2-methylphenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.94 (s, 3H), 2.06 (s, 3H), 2.14 (s, 3H), 4.32 (bs, 2H), 6.76 (bs, 1H), 6.86-6.95 (m, 1H), 7.01-7.13 (m, 3H), 7.17 (t, J=6.4 Hz, 1H), 7.63 (t, J=8.4 Hz, 1H), 7.75 (s, 1H), 8.43 (d, J=4.2 Hz, 1H); MS (ESI) m/z 338.2 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[OH:12][CH2:13][CH2:14][O:15][C:16]1[C:21]([Br:22])=[CH:20][C:19](I)=[CH:18][N:17]=1>>[Br:22][C:21]1[CH:20]=[C:19](/[CH:8]=[CH:7]/[C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:1])[CH3:11])=[CH:4][CH:5]=2)[CH:18]=[N:17][C:16]=1[O:15][CH2:14][CH2:13][OH:12]
Reactant: OCCOc1ncc(I)cc1Br
Reactant: C=Cc1ccc(N(C)C)cc1
Product: CN(C)c1ccc(/C=C/c2cnc(OCCO)c(Br)c2)cc1

Procedure:
Compound 14a was prepared from 4-dimethylaminostyrene (0.031 g, 0.212 mmol) and 9b (0.073 g, 0.212 mmol) as a light yellow solid (0.022 g, 29% yield). 1H NMR δ 8.07 (d, 1H, J=2.1 Hz), 8.03 (d, 1H, J=2.1 Hz), 7.39 (d, 2H, J=8.8 Hz), 6.94 (d, 1H, J=16.3 Hz), 6.78-6.69 (m, 3H), 4.57-4.52 (m, 2H), 3.99 (t, 2H, J=4.3 Hz), 3.21 (br s, 1H), 3.00 (s, 6H). 13C NMR δ 158.3, 150.4, 143.0, 138.2, 129.9, 129.8, 127.6, 124.9, 118.3, 112.3, 107.5, 69.6, 62.1, 40.3. HRMS calcd for C17H19BrN2O2 (M+), 362.063. found, 362.0629.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24](O)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:28][C:29]1[CH:34]=[CH:33][C:32]2[C:35]3([CH2:41][O:42][C:31]=2[CH:30]=1)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24]([N:38]3[CH2:39][CH2:40][C:35]4([C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][C:31]=5[O:42][CH2:41]4)[CH2:36][CH2:37]3)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)O)cnc12
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 74.5 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.130 g, 0.363 mmol) obtained in Example 90, step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.082 g, 0.399 mmol), the title compound (0.148 g, 74%) was obtained.
Reaction SMILES: [C:1]1(/[CH:11]=[CH:12]/[C:13]2[N:14]=[C:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[S:16][CH:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:31][C:32]1[N:36]([CH2:37][C:38]([OH:40])=O)[N:35]=[C:34]([C:41]([F:44])([F:43])[F:42])[CH:33]=1>>[CH3:31][C:32]1[N:36]([CH2:37][C:38]([N:21]2[CH2:22][CH2:23][CH:18]([C:15]3[S:16][CH:17]=[C:13](/[CH:12]=[CH:11]/[C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[N:14]=3)[CH2:19][CH2:20]2)=[O:40])[N:35]=[C:34]([C:41]([F:44])([F:43])[F:42])[CH:33]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(/C=C/c3cccc4ccccc34)cs2)CC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(/C=C/c3cccc4ccccc34)cs2)CC1

Procedure:
tert-Butyl 4-{4-[(E)-2-(naphthalen-1-yl)ethenyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IV-2, 171 mg) is deprotected analogously to Example II-2 and then reacted analogously to Example I-81 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (100 mg). After chromatographic purification, this gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[(E)-2-(naphthalen-1-yl)ethenyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (180 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17](=[O:19])[N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cc2cc(CCC(=O)O)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(CCC(=O)N3CCCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a solution of 5-(2-carboxy-ethyl)-1H-indole-2-carboxylic acid ethyl ester (1.3 g, 5 mmol) in 10 mL of dimethylformamide, was added 1,1′-carbonyldiimidazole (973 mg, 6 mmol). The mixture was stirred under nitrogen at room temperature for 30 mins. To the reaction mixture was added pyrrolidine (1.3 mL, 15 mmol) dropwise. After stirring at room temperature for overnight, the reaction was diluted with dichloromethane (300 mL), washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, brine, dried and concentrated to give 1.5 g (95%) of 5-(3-oxo-3-pyrrolidin-1-yl-propyl)-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[NH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43].O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][NH:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CC(C)(N)CO
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(CO)NCCCOc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1Cl)CNC2=O
Yield: 38.2 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (90.6 mg, 0.158 mmol) was dissolved in N,N-dimethylacetoamide (0.9 mL), and the solution was treated with 2-amino-2-methyl-1-propanol (0.159 mL, 1.58 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-(1-hydroxy-2-methyl-2-propylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (37.7 mg, yield 38%).
Reaction SMILES: Br[C:2]1[S:11][C:5]2[S:6][C:7](Br)=[C:8]([CH3:9])[C:4]=2[C:3]=1[CH3:12].B([O-])[O-].[CH2:16]([C:22]1[CH:23]=[CH:24][S:25][CH:26]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Na+].[Na+].[Na]>COCCOC.C(OCC)C>[CH2:16]([C:22]1[CH:23]=[C:24]([C:2]2[S:11][C:5]3[S:6][C:7]([C:24]4[S:25][CH:26]=[C:22]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:23]=4)=[C:8]([CH3:9])[C:4]=3[C:3]=2[CH3:12])[S:25][CH:26]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCc1ccsc1
Reactant: Cc1c(Br)sc2sc(Br)c(C)c12
Agent: [Na+]
Agent: [Na]
Agent: [O-]B[O-]
Solvent: COCCOC
Solvent: CCOCC
Product: CCCCCCc1csc(-c2sc3sc(-c4cc(CCCCCC)cs4)c(C)c3c2C)c1

Procedure:
To a solution of 2,5-dibromo-3,4-dimethylthieno[2,3-b]thiophene (3.02 g, 9.28 mmol) and sodium 4-hexylthiophene boronate (5.14 g, 20.4 mmol) in degassed DME (200 ml) was added tetrakis(triphenyl-phosphine)palladium(0) (0.5 g, 5 mol %). The solution was heated to reflux and a saturated solution of sodium hyodrogen carbonate (4.2 g, 49 mmol) was added slowly. The reaction was refluxed for 16 h, cooled and diluted with diethyl ether. The layers were separated and the organics washed with 5% HCl, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography over silica (eluent: petrol) to afford the product after recrystallisation from petroi (1.03 g, 22%). :M/Z 500 (M+). Found C, 66.9.1, H, 6.9, S, 25.3. Calc. for C28H36S4 C, 67.2; H 7.2, S, 25.6. NMR gave the expected signals.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[N+](C1C=CC([O:18][C:19](=O)[C@H:20]([CH:32]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]([OH:35])=[O:34])[NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=CC=1)([O-])=O>CN(C)C=O>[C:22]([NH:21][C@H:20]([C:19]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:18])[CH:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:33](=[O:34])[OH:35])([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(N[C@H](C(=O)Oc1ccc([N+](=O)[O-])cc1)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1

Procedure:
L-Proline (2.8 Kg) and N-carbobenzoxy-β-benzyl-L-aspartic acid p-nitrophenyl ester (10.5 Kg) are dissolved in a mixture of dimethylformamide (25-30 L) and distilled water (9-13 L). The pH of the solution is adjusted to 7.5-8.0 and maintained in this range by addition of diisopropylethylamine. The mixture is stirred at 20°-30° C. until the reaction is complete. The solution is diluted with ethyl acetate (45-55 L) and extracted with dilute hydrochloric acid (15-20 L). The aqueous layer is back extracted with ethyl acetate (8-12 L). The combined organic layers are washed three times with dilute hydrochloric acid (10-15 L). The organic layer is extracted with dilute sodium bicarbonate. Ethyl acetate (40-60 L) is added to the aqueous layer and the pH is adjusted to about 3.0 by addition of dilute hydrochloric acid. The organic layer is washed two times with dilute hydrochloric acid (10-30 L) and concentrated in vacuo below 55° C. to 20-30 L.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[NH:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH:9]=[CH:8]1>C(#N)C.O>[Cl:3][C:7]1[N:12]=[N:11][C:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[CH:9][CH:8]=1
Reactant: CCCCOC(=O)c1ccc(=O)[nH]n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CCCCOC(=O)c1ccc(Cl)nn1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a mixture of phosphorus oxychloride (20 ml) and acetonitrile (40 ml) heated at reflux was added a solution of n-butyl 6-oxo-1,6-dihydropyridazine-3-carboxylate (20 g) in acetonitrile (80 ml). The reaction was heated at reflux for 30 minutes, cooled and added to an ice cooled solution of K2C03 (87.8 g) in water (600 ml) with vigorous stirring. The product was filtered off, washed with water and dried at 60° C. to give n-butyl 6-chloropyridazine-3-carboxylate (17.5 g, 80% yield), mpt 110-111° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([Cl:12])[C:4]=1[F:13].[CH:14]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[CH2:15].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:12][C:5]1[C:4]([F:13])=[C:3]([C:19]2([OH:22])[CH2:20][CH2:21][CH:16]([CH:14]=[CH2:15])[CH2:17][CH2:18]2)[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][CH3:11]
Reactant: CCOc1ccc(Br)c(F)c1Cl
Reactant: C=CC1CCC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC1CCC(O)(c2ccc(OCC)c(Cl)c2F)CC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 133 %

Procedure:
1.5 g of well dried magnesium and 30 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 40° C. 15.3 g of the compound (1) dissolved in 30 mL of THF was slowly added dropwise thereto at a temperature range of from 35 to 49° C., followed by stirring for 30 minutes. Thereafter, 5.0 g of the compound (23) dissolved in 5 mL of THF was slowly added dropwise thereto at a temperature range of from 30 to 40° C., followed by stirring for 30 minutes. After cooling the resulting reaction mixture to 25° C., the reaction mixture was poured into and mixed with a mixture of 100 mL of 1N hydrochloric acid and 100 mL of toluene. The mixture was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 16.0 g of 1-(3-chloro-4-ethoxy-2-fluorophenyl)-4-vinylcyclohexanol (24) as a yellow liquid.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([CH2:16][CH3:17])=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[N:11]2)=O.[CH:19]1([NH:22][C:23]([NH2:25])=[NH:24])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:19]1([NH:22][C:23]2[N:25]=[C:5]([C:7]3[C:8]([CH2:16][CH3:17])=[N:9][N:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[N:11]4)[CH:4]=[CH:3][N:24]=2)[CH2:21][CH2:20]1
Reactant: CCc1nn2ncccc2c1C(=O)/C=C/N(C)C
Reactant: N=C(N)NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nn2ncccc2c1-c1ccnc(NC2CC2)n1
Temperature: 135 °C
Yield: 360 %

Procedure:
To a solution (2E)-3-(dimethylamino)-1-(2-ethylpyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one (75 mg, 0.31 mmol) in DMF (2.0 mL) was added N-cyclopropylguanidine.0.5H2SO4 (181 mg, 0.92 mmol) and potassium carbonate (212 mg, 1.54 mmol). The reaction was heated at an oil bath temperature of 135° C. for about 18 hours. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was dissolved in chloroform and filtered. The filtrate was concentrated in vacuo then disolved in CH2Cl2 and triturated with diethylether and hexanes to give the title compound as an orange solid (32 mg, 360% o). 1H-NMR (300 MHz, CDCl3) δ 8.96 (d, 1H, J=8.7 Hz), 8.38 (d, 1H, J=5.4 Hz), 8.34 (dd, 1H, J=4.4, 1.9 Hz), 7.14 (dd, 1H, J=9.0, 4.5 Hz), 6.92 (d, 1H, J=5.4 Hz), 5.47 (s, 1H), 3.23 (q, 2H, J=7.5 Hz), 2.88 (m, 1H), 1.50 (t, 3H, J=7.5 Hz), 0.91 (m, 2H), 0.67 (m, 2H); MS (ESI) (M+H)+ 281.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][N:5]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]([CH2:19][C:20]([OH:22])=[O:21])[CH2:3]1.[Li+].[OH-].[CH3:25][CH2:26]OC(C)=O>O1CCOCC1.CO>[O:1]=[C:2]1[NH:8][CH2:7][CH2:6][N:5]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]([CH2:19][C:20]([O:22][CH2:25][CH3:26])=[O:21])[CH2:3]1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)CC2CC(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)CC1CC(=O)NCCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
A solution of the product of step A (1.34 g, 5.44 mmol) was stirred in THF (30 ml) at 0*C. Bu3SnOTf (90%, 2.73 g, 5.60 mmol) in THF 8.0 ml was added dropwise over 6 min, and the mixture was heated to reflux for 22 h. The reaction was cooled to 0° C., and triethylamine (1.52 ml, 10.9 mmol) and dimethylaminopyridine (0.135 g, 1.11 mmol) were added followed by p-toluenesulfonyl chloride (2.09 g, 11.0 mmol) in THF 4.0 ml. The reaction was allowed to r.t. and after 4 h concentrated under reduced pressure. AcOEt (100 ml) was added to the residue and washed with 0.1 N HCl aq. (100 ml×2), sat'd NaHCO3 aq. (100 ml×2) and sat'd NaCl aq. (100 ml×2), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica (AcOEt→AcOEt/-MeOH=80/1) to yield the title compound. MS:355.2 C. 2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)acetic acid (3) To a solution of the product of step B (0.416 g, 1.17 mmol) in 1,4-dioxane (24 ml) and MeOH (24 ml), 0.13 N LiOH (28 ml, 3.6 mmol) was added, and the mixture was heated to reflux for overnight. The reaction was cooled to r.t. and AcOEt (400 ml) was added and washed with sat'd NaCl (400 ml×5), dried over Na2SO4 and concentrated under reduced pressure to yield the title compound. MS: 327.1 D. (R)-2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide. To a mixture of 2-(7-oxo-4-tosyl-1,4-diazepan-5-yl)acetic acid (0.115 g, 0.352 mmol), (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (0.0945 g, 0.387 mmol) and HOBt (<5% H2O, ˜0.398 mmol) in DMF (3.0 ml) was added EDCI*HCl (0.0805 g, 0.420 mmol), and stirred overnight under N2. AcOEt (60 ml) was added and washed with sat'd NaHCO3 aq. (60 ml×3) and sat'd NaCl aq. (60 ml×3), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica (CH2Cl2/MeOH with 2N NH3=10/1) to yield the title compound. MS: 553.1
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][C:34]1([CH3:41])[C:38]([CH3:40])([CH3:39])[O:37][BH:36][O:35]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([B:36]2[O:37][C:38]([CH3:40])([CH3:39])[C:34]([CH3:41])([CH3:33])[O:35]2)=[C:20]([CH3:25])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)c(C)c1)NC(=O)OCc1ccccc1
Reactant: CC1(C)OBOC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1)NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a mixture of methyl (2S)-2-[(benzyloxy)carbonyl]amino-3-(4-bromo-3-methylphenyl)propanoate (1.23 g, 3.03 mmol), 1,4-dioxane (8 mL), triethylamine (1.69 mL, 12.1 mmol), palladium acetate (17 mg, 76 μmol), O-(dicyclohexylphosphino)biphenyl (106 mg, 0.303 mmol) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10 mL, 7.57 mmol) dropwise. The greenish reaction mixture was stirred at 80° C. for 30 min. The reaction was quenched with saturated NH4Cl solution. The aqueous solution was extracted with ethyl acetate twice. The organic solutions were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.25 g, 91%). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, 1H), 7.3 (m, 5H), 6.9 (m, 2H), 5.22 (d, 1H), 5.10 (m, 2H), 4.64 (m, 1H), 3.70 (s, 3H), 3.06 (m, 2H), 2.48 (s, 3H), 1.33 (s, 12H); MF=C25H32BNO6; LCMS found for C25H33BNO6 (M+H)+: m/z=454.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:28])=[C:14]([CH:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8].C1([O:51]C)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH:17]([O:19][C:20](=[O:51])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: COc1ccccc1
Reactant: CC(OCc1ccccc1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(OC(=O)c1ccccc1)C1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
To a solution of diphenylmethyl 7-(2-thienylacetamido)-3-(1-benzyloxyethyl)-3-cephem-4-carboxylate (stereoisomer A: 160 mg) in methylene chloride (1.6 ml) are added anisole (0.32 ml) and trifluoroacetic acid (0.32 ml). After 15 minutes, the reaction mixture is evaporated to dryness, and the obtained residue is dissolved in ethyl acetate. The solution is extracted with aqueous sodium hydrogen carbonate solution. The extract solution is evaporated with ethyl acetate, cooled with ice, stirred and neutralized with 1N-hydrochloric acid to pH 2.0, and is extracted with ethyl acetate. The extract solution is washed with saline, dried over sodium sulfate, and evaporated to give 7-(2-thienylacetamido)-3-(1-benzoyloxyethyl)-3-cephem-4-carboxylic acid (stereoisomer A: 60 mg). m.p. 114°-118° C. RF: same with the benzylamine salt described below.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.CCN(C(C)C)C(C)C.[CH:23]1([CH2:26][NH2:27])[CH2:25][CH2:24]1>CCO>[CH:23]1([CH2:26][NH:27][CH2:2][C:3]2[NH:4][C:5](=[O:13])[C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=3[N:8]=2)[CH2:25][CH2:24]1
Reactant: NCC1CC1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Temperature: 65 °C
Reaction time: 18 h
Yield: 19.6 %

Procedure:
To a solution of 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (1 g, 5 mmol, 1 eq.) and DIEA (4.35 mL, 24.9 mmol, 5 eq.) in 7 mL of EtOH was added cyclopropylmethylamine (1.4 g, 20 mmol, 4 eq.). The resulting mixture was heated at 65° C. overnight. After 18 h, the reaction mixture was concentrated in vacuo to give an oil that was purified by silica gel column chromatography (100% CH2Cl2) to give the title compound as a white solid (0.23 g, 20%). 1H NMR (400 MHz, chloroform-d) δ ppm 4.37-4.42 (m, 2H), 3.95 (s, 1H), 3.80-3.88 (m, 3H), 2.63-2.72 (m, 1H), 2.54-2.63 (m, 3H), 0.89-1.05 (m, 1H), 0.42-0.54 (m, 2H), 0.14-0.26 (m, 2H). Exact mass calculated for C12H18N3O2 236.1. MS (ESI) m/z 236.9 (M+H)+. Retention time: 0.56 min (5-95% CH3CN/H2O over 2 min with 0.1% formic acid, Inertsil 3×3 mm C-8-3 column with flow rate of 2 mL/min).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: C1CCNC1
Reactant: O=C(O)CNc1ccc(-c2ccc(F)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ccc(-c2ccc(F)cc2)nc1)N1CCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 98 mg (0.27 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 38.7 mg (0.54 mmol) pyrrolidine. Yield: 4 mg.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:13][CH:12]=2)[CH:7]=1)=O)C.[NH3:28]>>[F:27][C:25]1[CH:24]=[CH:23][C:21]2[N:22]=[C:18]([NH:17][C:14]3[CH:13]=[CH:12][C:11]([C:8]4[CH:7]=[C:6]([C:4]([NH2:28])=[O:3])[O:10][N:9]=4)=[CH:16][CH:15]=3)[S:19][C:20]=2[CH:26]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Reactant: N
Product: NC(=O)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Yield: 97.4 %

Procedure:
A mixture of 3-[4-(6-fluoro-benzothiazol-2-ylamino)-phenyl]-isoxazole-5-carboxylic acid ethyl ester (4.0 g; 10.44 mmol) and saturated methanolic ammonia (250 ml) was stirred to obtain a white solid. The solvent was evaporated, and the residue was stirred with light petroleum and filtered. The residue was washed with light petroleum and dried to obtain 3.6 g (97.4%) of the title compound. Mass (ES+), 355 (M++1); IR (KBr): 3463, 3123 (br), 1700, 1607, 1553 (br); 1447 (br); 1H NMR (DMSO-d6) δ: 7.18 (m, 1H), 7.54 (s, 1H), 7.64 (m, 1H), 7.76 (m, 1H), 7.87-7.90 (br, 4H), 7.98, 8.37(2×br, 2H, NH2).