Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C@@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]([OH:46])[CH:37]=3)[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:48][CH:49]([CH3:51])[CH3:50].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]([CH2:25][C@@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]([O:46][CH2:48][CH:49]([CH3:51])[CH3:50])[CH:37]=3)[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CI
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)cc1OCC(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of the compound of Example 181 (0.097 g, 0.0015 mmol, 1.0 eq.) in N,N-dimethylformamide (0.5 mL) were added 1-iodo-2-methylpropane (0.10 ml) and potassium carbonate (0.10 g). The reaction mixture was stirred at 60° C. for 16 hours. The mixture was diluted with distilled water (2 mL) and extracted with ethyl acetate (3×2 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as clear oil (0.076 g, 74%). LC-MS: 705.3 (MH+), retention time: 4.01 min.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38]([F:41])([F:40])[F:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38]([F:39])([F:40])[F:41])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(F)(F)F)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(F)(F)F)c3csc(N)n3)[C@H]2SC1
Yield: 48 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.), conc. hydrochloric acid (0.4 g.) and methanol (13 ml.) was treated in a similar manner to that of Example 17 (2) to give 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.55 g.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[CH2:4][CH2:3]1.[ClH:28]>CO.C(O)(C)C.[Pd]>[ClH:28].[NH:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[CH:9]([O:8][CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1
Reactant: CN1CCC(OC(c2ccc([N+](=O)[O-])cc2)c2nc3ccccc3[nH]2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CN1CCC(OC(c2ccc(N)cc2)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[(1-methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1H-benzimidazole (example 447, 200 mg) in methanol (5 mL) and a solution of 5N hydrochloric acid in isopropanol (0.2 mL) is added 10% palladium on carbon (50 mg). The flask is evacuated and filled with hydrogen (balloon) and stirred overnight at room temperature. The reaction mixture is filtered on celite and the solvents are evaporated under reduced pressure to dryness. The residual solid is triturated twice with diethyl ether and the solid is filtered and dry to afford 4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]aniline hydrochloride as a cream-colored solid melting at 185° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]=[N:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12]C1C=C(C#CC=O)C=CC=1>>[Cl:12][C:3]1[CH:2]=[C:1]([C:7]#[C:8][CH:9]=[N:10][OH:11])[CH:6]=[CH:5][CH:4]=1
Reactant: ON=CC#Cc1ccccc1
Reactant: O=CC#Cc1cccc(Cl)c1
Product: ON=CC#Cc1cccc(Cl)c1
Yield: 96.4 %

Procedure:
The title compound was prepared following the method here described for Compound 1a, using Compound 31d instead of phenylpropiolaldehyde. The pale brown residue was used in the next step without further purification. Yield: 96.4%.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:30])[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C[O-].[Na+].CO>C(Cl)(Cl)Cl>[CH2:23]([N:20]1[CH2:21][CH2:22][C:17](=[CH:16][C:15]([C:12]2[CH:11]=[CH:10][C:9]([NH2:8])=[CH:14][CH:13]=2)=[O:30])[CH2:18][CH2:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)C=C2CCN(Cc3ccccc3)CC2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1ccc(C(=O)C=C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
4.12 g of N-t-butoxycarbonyl-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline was added to 50 ml of chloroform, and then 10 ml of trifluoroacetic acid was added thereto. The mixture was stirred at room temperature for 4 hours. After the reaction, the reaction mixture was condensed under reduced pressure, and the residue was dissolved in chloroform. Then, the solution was neutralized by adding a 28% sodium methylate·methanol solution thereto. The residue obtained by condensation under reduced pressure was applied to silica gel column chromatography to obtain 2.33 g of the title compound as bluish green powder.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH:4]1[CH2:19][CH2:20][N:21]=[N+:22]=[N-:23].C1(O)CCCCC1.[OH-].[Na+].Cl[C:34]1[N:39]=[C:38]([N:40]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH:37]=[C:36]([Cl:47])[N:35]=1>>[N:40]1([C:38]2[CH:37]=[C:36]([Cl:47])[N:35]=[C:34]([NH:2][CH:3]3[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[O:10])[CH:4]3[CH2:19][CH2:20][N:21]=[N+:22]=[N-:23])[N:39]=2)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1
Reactant: Clc1cc(N2CCCCCC2)nc(Cl)n1
Reactant: [N-]=[N+]=NCCC1C(N)CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OC1CCCCC1
Product: [N-]=[N+]=NCCC1C(Nc2nc(Cl)cc(N3CCCCCC3)n2)CCCN1C(=O)OCc1ccccc1
Yield: 40.9 %

Procedure:
The compound 16 (118 mg), cyclohexanol (0.16 mL), aqueous 5N sodium hydroxide solution (0.25 mL) and 1-(2,6-dichloropyrimidin-4-yl)azepan (83.5 mg) were stirred at 120° C. for 6 hours. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to obtain the title compound (71.2 mg) having the following physical properties.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[O:7]=[C:8]1[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:24][CH2:23]2)[C:16](=[O:42])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1>>[O:7]=[C:8]1[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([O:28][CH:29]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:26][CH2:27]2)[C:16](=[O:42])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]1[CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CBr
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Product: COC(=O)Cn1c(=O)n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c(=O)c2ccccc21
Yield: 44 %

Procedure:
Using the method similar to that in Example 57 and methyl bromoacetate instead of 1-bromo-2-phenylethane and starting from 2,4-dioxo-3-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline (1.52 g) obtained in Example 80, the title compound (760 mg, 44%) was obtained as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH2:36][C:37]([NH:39][C:40]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:14]([N:16]([CH2:26][C:27]1[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[S:30][CH:31]=1)[C@@H:17]([CH3:25])[CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[O:15]>>[S:30]1[CH:31]=[C:27]([CH2:26][N:16]([C@@H:17]([CH3:25])[CH:18]([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])[C:14](=[O:15])[C@@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH2:36][C:37](=[O:38])[NH:39][C:40]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NOCC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 37 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11]Cl)[CH:7]=1.[CH3:13][NH2:14]>CO>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][NH:14][CH3:13])[CH:5]=[N:4][CH:3]=1
Reactant: ClCCCOc1cncc(Br)c1
Reactant: CN
Solvent: CO
Product: CNCCCOc1cncc(Br)c1
Temperature: 102 °C

Procedure:
Crude 3-bromo-5-(3-chloropropoxy)pyridine (4.07 g) from the previous step was dissolved in CH3OH (28 mL) and added to a 40 wt % solution of methylamine (35 mL) in a heavy-walled pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 102° C. for 4 h. After cooling, the solution was concentrated by rotary evaporation, a saturated NaCl solution (15 mL) was added, and the mixture was basified with 10% NaOH solution (5 mL). The mixture was extracted with CHCl3 (4×30 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 2.07 g of a brown oil. The product was purified by column chromatography on silica gel (100 g) eluting with CHCL3—CH3OH (9:1, v/v) to remove impurities, followed by CHCL3—CH3OH—Et3N (75:25:2, v/v/v) to collect the product. Selected fractions containing the product (Rf 0.13) were combined and concentrated by rotary evaporation. The resulting brown oil was dissolved in CHCL3 (25 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 0.79 g (29.5% based upon 5-bromo-3-hydroxypyridine) of an amber-brown oil, which tended to crystallize as light amber crystals. 1H NMR (CDCl3, 300 MHz): δ8.27 (d, 1H, J=1.85 Hz), 8.24 (d, 1H, J=2.48 Hz), 7.38 (dd, 1H, J=1.91, 1.91 Hz), 4.09 (t, 2H, J=6.22 Hz), 2.78 (t, 2H, J=6.84Hz), 2.47 (s, 3H), 1.99 (p,2H, J=6.56 Hz), 1.53 (br s, 1H).
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C@@H:13]1[CH2:16][C@H:15](O)[CH2:14]1.F[C:19]1[C:24]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:23][C:22]([F:31])=[CH:21][N:20]=1.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C@H:13]1[CH2:16][C@H:15]([C:19]2[C:24]([CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][C:22]([F:31])=[CH:21][N:20]=2)[CH2:14]1
Reactant: Fc1cnc(F)c(C2CCOCC2)c1
Reactant: O[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cnc([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (81.8 mg, 2.0 mmol) was added to a solution of cis-3-(benzothiazol-2-ylamino)-cyclobutanol (150 mg, 0.68 mmol) in DMF (3 mL) under argon and the mixture was stirred for 1 h at RT. Then 2,5-difluoro-3-(tetrahydro-pyran-4-yl)-pyridine (162 mg, 0.82 mmol) was added and the mixture was heated to 100° C. for 2 h. It was cooled to RT and EtOAc (25 mL) and saturated NH4Cl (15 mL) were added. The organic layer was separated, washed with water (2×25 mL), brine (25 mL), dried over MgSO4, filtered and concentrated in vacuo to give an oil, which was purified by prep-HPLC to give trans-benzothiazol-2-yl-{3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yl]-cyclobutyl}-amine (30 mg, yield 10%). [M+1] 400. IC50 (uM) 0.0001.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].O[C@@H:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:25]=[CH:24][C:23]([O:26][C@H:28]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:22][CH:21]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Reactant: CCCCCc1ccc(CCn2c(C)ccc2-c2ccc(O)cc2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Yield: 23 %

Procedure:
A solution of 4-[1-(4-pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenol (1.82 g, 5.2 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.0 g, 5.1 mmol), 1,1′-(azodicarbonyl)dipiperidine (1.29 g, 5.1 mmol) and triphenylphosphine (1.34 g, 5.1 mmol) in toluene (5 ml) was stirred at 80° C. for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give the object compound as an oily substance. 660 mg, (yield 23%)
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=O.[BH4-].[Na+].Cl>C1COCC1.CO>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1Cc2c(cccc2-c2ccccc2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=Cc2cccc(-c3ccccc3)c2C1
Temperature: 0 °C

Procedure:
50 g (0,226 mol) of 2 were dissolved in 450 cm3 of THF/MeOH (2:1) and, while stirring at 0° C., 12.8 9 (0.34 mol) of sodium borohydride were added a little at a time. The mixture was stirred for a further 18 hours. The reaction mixture was poured onto ice, acidified with concentrated HCl to a pH of 1 and extracted a number of times with Et2O. The combined organic phases were washed with saturated aqueous NaHCO3 solution and NaCl solution and then dried (MgSO4). The solvent was removed under reduced pressure and the crude product was, without further purification, taken up in 1 dm3 of toluene, admixed with 2 g of p-toluenesulfonic acid and heated unider reflux for 2 hours. The reaction mixture was washed with 200 cm3 of saturated aqueous NaHCO3 solution and the solvent was removed under reduced pressure. The crude product was purified by filtration through 500 g of silica gel (hexane/CH2Cl2). This gave 42 g (90%) of 3 as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:4][C:3]=1[NH2:25].[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:5]2[N:6]=[N:7][C:2]([C:31]3[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)=[C:3]([NH2:25])[N:4]=2)=[N:9]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1COCCO1
Product: COc1ccc(-c2nnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2N)cn1
Reaction time: 0.17 h

Procedure:
Under an argon atmosphere, 140 mg (purity 65%, 0.256 mmol) of 6-chloro-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5-amine were suspended in 5 ml of absolute dioxane. 117 mg (0.767 mmol) of (6-methoxypyridin-3-yl)boronic acid, 1.023 ml (1.023 mmol) of 1N aqueous potassium carbonate solution and 14 mg (0.051 mmol) of tricyclohexylphosphine were added and argon was passed through the suspension for 10 min with stirring. Then, 28 mg (0.038 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride were added and the reaction mixture was stirred for 30 min in the microwave at 140° C. After cooling, the mixture was filtered over an Extrelut cartridge and after-washed with a mixture of dichloromethane/methanol (v/v=20:1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80→100:0). This gave 58 mg of the target compound (purity 85%; 36% of theory).
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:26]=[CH:25][C:8]([NH:9][C:10]2[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:11]=2[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])=[C:7]([F:27])[CH:6]=1>CCO.[Pd]>[NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:26]=[CH:25][C:8]([NH:9][C:10]2[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:11]=2[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])=[C:7]([F:27])[CH:6]=1
Reactant: NCC#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: NCCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 46 %

Procedure:
The product of Example 9, 2-[4-(3-amino-1-propynyl)-2-fluoroanilino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide was dissolved in absolute EtOH and hydrogenated in the presence of 5% Pd/C by the general procedure of Example 1, Step D. Purification of the resulting oil was carried out by column chromatography on silica gel (1% NH4OH in 25% MeOH/CH2Cl2 as eluant) to give 2-[4-(3-aminopropyl)-2-fluoroanilino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a cream solid (46%); m.p. (MeOH/CH2Cl2) 178–181° C. 1H NMR [400 MHz, (CD3)2SO] δ 7.61–7.53 (m, 1 H), 6.97–6.87 (m, 2 H), 6.78 (dd, J=8.2, 1.3 Hz, 1 H), 6.60 (dd, J=15.1, 8.6 Hz, 1 H), 4.10 (br s, 1 H), 3.77 (t, J=5.0 Hz, 2 H), 3.56 (t, J=5.0 Hz, 2 H), 2.70 (t, J=7.3 Hz, 2 H), 2.53 (t, J=8.0 Hz, 2 H), 1.75 (pentet, J=7.5 Hz, 2 H). Not all exchangeable protons observed. Anal. calcd. for C18H20F3N3O3: C, 56.4; H, 5.3; N, 11.0. Await Found.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[CH:26][O:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:20]([NH:38][C:39](=[O:69])[C:40](=[N:66][O:67][CH3:68])[C:41]1[N:42]=[C:43]([NH:46]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:44][CH:45]=1)[C:19]2=[O:70])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:46][C:43]1[S:44][CH:45]=[C:41]([C:40](=[N:66][O:67][CH3:68])[C:39]([NH:38][CH:20]2[C:19](=[O:70])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([CH:25]=[CH:26][O:27][S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=2)(=[O:29])=[O:30])=[C:17]3[C:15]([O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])=[O:69])[N:42]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Yield: 40.2 %

Procedure:
A mixture of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(tritylamino-thiazol-4-yl)-acetamido]-8-oxo-3-(2-tosyloxy-vinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (0.494 g), acetone (20 cc) and p-toluenesulphonic acid hydrate (10 mg) is heated under reflux for 20 hours. It is then concentrated to dryness under 20 mm Hg at 20° C., the residue is taken up in ethyl acetate (30 cc) and a 5% strength sodium bicarbonate solution (20 cc), and the organic phase is decanted, dried over sodium sulphate, filtered and concentrated to dryness under 20 mm Hg at 20° C. The residue is chromatographed on a column (column diameter: 3 cm, height: 27 cm) of Merck silica gel (0.06-0.2 mm) (50 g). Elution is carried out with ethyl acetate (0.4 liter), 20 cc fractions being collected. Fractions 8 to 10 are a mixture of the starting material and of the expected product; fractions 11 to 17 are concentrated to dryness under 20 mm Hg at 20° C. 7-[2-(2-amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxy-vinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (0.15 g) is obtained in the form of a cream-coloured solid.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][C@@:8]23[CH2:15][C@H:14]([NH2:16])[CH2:13][N:12]2[C:11](=[O:17])[N:10]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]3=[O:26])=[CH:5][CH:4]=1)#[N:2].[C:29](OC(=O)C)(=[O:31])[CH3:30]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@@:8]23[CH2:15][C@H:14]([NH:16][C:29](=[O:31])[CH3:30])[CH2:13][N:12]2[C:11](=[O:17])[N:10]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]3=[O:26])=[CH:27][CH:28]=1)#[N:2]
Reactant: N#Cc1ccc(C[C@@]23C[C@H](N)CN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(C#N)cc2)C1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of (5S,7S)-5-(4-cyanobenzyl)-3-(3,5-dichlorophenyl)-7-amino-1,3-diazabicyclo[3.3.0]octane-2,4-dione (78.5 mg) in THF (5 mL) was added acetic anhydride (1.0 mL). The reaction mixture was stirred for 2 hours at 45° C., and the mixture was concentrated and purified by preparative thin-layer chromatography (silica gel; CH2Cl2) to afford the titled compound (84 mg). MS (m/z) 478.8 (MNa+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([N:7]([CH3:9])[CH3:8])[N:3]=1.C(O)(=O)C.O=[C:15]1[CH2:20][CH2:19][CH2:18][S:17][CH:16]1[C:21](OCC)=[O:22]>CN(C)C=O>[CH3:8][N:7]([CH3:9])[C:4]1[N:3]=[C:2]2[NH:1][C:15]3[CH2:20][CH2:19][CH2:18][S:17][C:16]=3[C:21](=[O:22])[N:6]2[N:5]=1
Reactant: CN(C)c1n[nH]c(N)n1
Reactant: CCOC(=O)C1SCCCC1=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(C)c1nc2[nH]c3c(c(=O)n2n1)SCCC3
Reaction time: 0.67 h
Yield: 65.3 %

Procedure:
To the solution of 6.35 g (0.05 mole) of 5-amino-3-dimethylamino-1H-1,2,4-triazole, 2.5 ml of acetic acid and 12.5 ml of dimethylformamide, 9.4 g (0.05 mole) of ethyl 3-oxo-3,4,5,6-tetrahydro-2H-thiopyrane-2-carboxylate are added and the reaction mixture is boiled for 40 minutes. The precipitated product is filtered off from the hot solution, then washed with acetic acid and i-propanol and recrystallized from dimethylformamide. Thus 8.2 g (65.2%) of 2-dimethylamino-5,7,8,9-tetrahydrothiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained. M.p.: higher than 350° C.