Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:23]([O:25]C)=[O:24])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:11][C:10]3([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[CH2:9]2)[CH2:4][CH2:3]1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[CH2:11]1[C:10]2([CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:9][CH:8]1[N:5]1[CH2:6][CH2:7][C:2]([F:1])([C:23]([O:25][CH2:27][CH3:29])=[O:24])[CH2:3][CH2:4]1
Reactant: COC(=O)C1(F)CCN(C2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(F)CCN(C2CC3(CCNC3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[4-fluoro-4-(methoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.300 g, 0.81 mmol) was dissolved in DCM (4 mL) and TFA (1 mL) was added. The reaction mixture was stirred at rt overnight under nitrogen, then the solvents were removed in vacuo, to give ethyl 1-(6-azaspiro[3.4]oct-2-yl)-4-fluoropiperidine-4-carboxylate trifluoroacetate, as a dark yellow oil which was used directly without further purification. The residue was dissolved in DCM (8 mL) at rt. NEt3 (0.246 g, 0.34 mL, 2.43 mmol) and ethyl chloroformate (0.176 g, 0.16 mL, 1.62 mmol) were added and the reaction mixture was stirred at rt overnight under nitrogen. The reaction mixture was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl 2-[4-fluoro-4-(methoxycarbonyl) piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.440 g, 158% impure) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:16]([CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][C:11]2[N:15]=[CH:14][NH:13][CH:12]=2)=[O:18])[CH2:28][CH2:29]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of N-t-butoxycarbonylhistidine (2 g, 7.05 mmol) in THF (30 mL) was added 1-ethoxycarbonylpiperazine (1.36 mL, 1.3 eq.), EDCl (1.65 g, 1.2 eq.), HOBt (1.2 g, 1.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 2%–6% MeOH in CH2Cl2 afforded 4-ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (820 mg). 4-Ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (200 mg, 0.5 mmol) was treated with trifluoroacetic acid/methylene chloride (1:1, 2.0 mL) with stirring at ambient temperture for 1 hour. Evaporation gave 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, which was treated with methylene chloride and triethylamine (0.5 mL), and the solvents evaporated to again afford 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine. To a solution of 2-carboxy-4-methoxyquinoline (124 mg, 0.61 mmol) in THF (4 mL) was added a mixture of 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, THF (2 mL), and triethylamine (0.1 mL), followed by addition of EDCl (136 mg, 1.4 eq.), HOBt (98 mg, 1.4 eq.). The resulting mixture was stirred overnight. The crude product (245 mg, foam) was isolated from the reaction mixture by the same methods employed above. Flash column chromatography with 25%–6% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline; NMR (CDCl3) 1.25 (t, 3), 3.10–3.30 (m, 2), 3.20–3.65 (m, 9), 4.10 (m, 5), 5.40 (m, 1), 6.90 (s, 1), 7.55–7.60 (m, 3), 7.70 (t, 1), 8.02 (d, 1), 8.20 (d, 1), 9.0 (d, 1) ppm.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][C:24]([OH:26])=O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C1CCN2C(=NCCC2)CC1.Cl>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:23][C:24]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:26])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CC(=O)NS(C)(=O)=O)c1ccccc1
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
To a solution of 100 mg of (3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridin-3-yl]carbonyl}amino)-3-phenylpropanoic acid in 1 mL of DMF was added 43 mg of 1,1′-carbonyldiimidazole, followed by stirring for 30 minutes. To the reaction solution were added 24 mg of methanesulfonamide and 0.039 mL of 1,8-diazabicyclo[5.4.0]-7-undecene, followed by stirring for 5 hours. To the reaction mixture were added 1 M hydrochloric acid and ethyl acetate to carry out a layer separation operation. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. To the purified product were added ethyl acetate and hexane, and the resulting solid was collected by filtration and dried to obtain 41 mg of 8-(cyclohexylmethoxy)-2-methyl-N-{(1S)-3-[(methylsulfonyl)amino]-3-oxo-1-phenylpropyl}imidazolo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCSc3ccc(Cl)c(Cl)c3)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(3,4-dichloro-phenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:21]=[C:19]([OH:20])[C:17]([OH:18])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[CH2:23]([N+:27]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>CO>[CH2:36]([N+:27]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:37][CH2:38][CH3:39].[OH:20][C:19]1[CH:21]=[C:14]([CH2:13][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:10]([O-:12])=[O:11])[CH:15]=[CH:16][C:17]=1[OH:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)[O-]
Temperature: 4 °C
Yield: 83 %

Procedure:
A solution of N-Boc-(L)-Dopa (175 g, 0.59 mol) in methanol (1 L) was cautiously mixed with a methanolic solution of tetrabutylammonium hydroxide (1.0 M, 0.55 L) at 0° C. for 30 min. The mixture was then concentrated under reduced pressure and dried by azeotroping with toluene twice. The residue was crystallized after cooling at 4° C. for 16 h. The resulting crystalline solid was washed with acetone (400 mL×3), collected on a Buchner funnel, and then dried under high vacuum to afford 245 g (83% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 0.94 (t, J=7.6 Hz, 12H), 1.30 (m, 17H), 1.60 (m, 8H), 3.18 (m, 8H), 4.58 (m, 1H), 5.68 (d, J=5.6 Hz, 1H), 6.30 (d, J=7.6 Hz, 1H), 6.46 (d, J=8.0 Hz, 1H), 6.51 (s, 1H), 8.85 (s, 1H); 8.94 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21]([C:23]1[N:27]([CH3:28])[C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:21]([C:23]1[N:27]([CH3:28])[C:26]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=2)=[CH:25][CH:24]=1)#[N:22]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CCN(CC)S(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCN(CC)S(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 41.4 %

Procedure:
According to general procedure B, 4-bromo-N,N-diethyl-2-(trifluoromethoxy)benzenesulfonamide (225 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromethoxy)benzenesulfonamide (98 mg, 42%) was provided after purification. MS (ESI) m/z 401. HPLC purity 100.0% at 210-370 nm, 10.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][CH:16]1Br)(=[O:13])[CH3:12]>C(Cl)Cl.C(#N)C.[N-]1C=CN=C1.[Ag+].[Cl-].[Zn+2].[Cl-]>[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:16]1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])(=[O:13])[CH3:12]
Reactant: CC(=O)c1ccccc1O
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Agent: [Ag+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1C(C)=O
Yield: 13.3 %

Procedure:
If the procedure described in Preparation LXXXIII is followed starting from 3.45 g (25.3.10-3 mol) of 1-(2-hydroxyphenyl)ethanone, 6 g (16.9.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 3 g (17.10-3 mol) of silver imidazolate and 4.6 g (33.7.10-3 mol) of zinc chloride in 90 ml of methylene chloride and 30 ml of acetonitrile, 0.92 g (yield: 13.5%) of the expected product is obtained after purification by chromatography on silica gel using a toluene/ethyl acetate mixture (6/1 v/v) as the eluent, and crystallization from ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[C:21]=1[C:30]([OH:32])=[O:31])(=[O:18])=[O:17]>C(O)(=O)C.[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[C:21]=1[C:30]([OH:32])=[O:31])(=[O:18])=[O:17]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2NCCc2ccccn2)ccc2c1CCCC2
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2NCC[C@@H]2CCCCN2)ccc2c1CCCC2
Reaction time: 80 h

Procedure:
A mixture of Example 384 (0.16 g, 0.35 mmol), and platinum oxide (0.20 g) in acetic acid (35 mL) was shaken in a reactor pressurized with 60 psi of H2 at 25° C. for 80 hours, filtered, and concentrated to provide the desired product. MS (DCI) m/e 458 (M+H)+.
Reaction SMILES: C[C@:2]1([CH2:18][CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:4][C@@:3]1([C:8]1[N:9]=[CH:10][N:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:5]([OH:7])=[O:6].[ClH:36]>>[ClH:36].[ClH:36].[NH2:21][CH2:20][CH2:19][CH2:18][C@H:2]1[CH2:4][C@@:3]1([C:8]1[N:9]=[CH:10][N:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: CC(C)(C)OC(=O)N(CCC[C@@]1(C)C[C@]1(C(=O)O)c1cn(-c2cccs2)cn1)C(=O)OC(C)(C)C
Agent: Cl
Product: NCCC[C@H]1C[C@]1(C(=O)O)c1cn(-c2cccs2)cn1

Procedure:
The compound (4.1 mg) obtained in Step 1 of this Example was heated to reflux for 3 hours in 5 N hydrochloric acid (3 mL). The reaction solution was concentrated under reduced pressure and then freeze-dried to obtain the title compound (2.6 mg).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([C:8]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[C:11]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:10]2[N:9]=1)[CH2:5][CH2:6][CH3:7].CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[CH2:4]([C:8]1[C:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=2)=[C:11]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:3])=[O:17])=[CH:15][N:10]2[N:9]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCc1nn2cc(C(=O)O)ccc2c1Cc1ccc(Br)cc1
Reactant: C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nn2cc(C(=O)OC)ccc2c1Cc1ccc(Br)cc1

Procedure:
100 ml of a solution of diazomethane in methylene chloride were added at ambient temperature to a suspension of 4 g of the product of Example 11 in 100 ml of methylene chloride and the solvent was eliminated at 40° C. under reduced pressure. Chromatography on silica was carried out (hexane: 80/ethyl acetate: 20) to obtain 3.7 g of the expected product melting at < or=50° C.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]=[C:5]([C:34]1[N:35]=[C:36]([NH:39]C=O)[S:37][CH:38]=1)[C:6]([NH:8][CH:9]1[C:32](=[O:33])[N:11]2[C:12]([C:29]([OH:31])=[O:30])=[C:13]([CH2:16][S:17][C:18]3[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:21]=[N:20][N:19]=3)[CH2:14][S:15][C@H:10]12)=[O:7]>CO>[CH3:2][O:3][N:4]=[C:5]([C:34]1[N:35]=[C:36]([NH2:39])[S:37][CH:38]=1)[C:6]([NH:8][CH:9]1[C:32](=[O:33])[N:11]2[C:12]([C:29]([OH:31])=[O:30])=[C:13]([CH2:16][S:17][C:18]3[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:21]=[N:20][N:19]=3)[CH2:14][S:15][C@H:10]12)=[O:7]
Reactant: CCCCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: CCCCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
Conc. hydrochloric acid (2.1 g.) was added under ice-cooling and stirring to a solution of 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-hexyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (6.0 g.) in methanol (60 ml.), and the mixture was stirred for 4 hours at ambient temperature. The solvent was removed from the reaction mixture and ethyl acetate (50 g.) was added thereto. The mixture was adjusted to pH 7.0 under stirring with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 3.5 with conc. hydrochloric acid. Precipitates were collected by filtration, washed with water and dried under reduced pressure to give powder of 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-hexyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (4.62 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[NH:22][CH2:21][CH2:20][CH2:19]3)=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:29]CCCCCC.C(OCC)(=O)C>>[Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]([CH3:29])[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[NH:22][CH2:21][CH2:20][CH2:19]3)=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: O=C(Nc1cccc2c1NCCC2)c1cnccc1Oc1cc(Cl)ccc1Cl
Reactant: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl)c1cccc2c1NCCC2

Procedure:
The title compound was prepared in analogy to Example 12, from 4-(2,5-dichloro-phenoxy)-N-(1,2,3,4-tetrahydro-quinolin-8-yl)-nicotinamide (Example 22) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Colorless foam (42%). MS (ESI): m/z=428.092 [M+H]+.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:12]2=[N:13][C:14]([O:17][CH3:18])=[CH:15][N:16]=[C:11]2[CH:10]=[CH:9][C:8]1=[O:19].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:18][O:17][C:14]1[N:13]=[C:12]2[N:7]([CH2:6][CH:2]=[O:1])[C:8](=[O:19])[CH:9]=[CH:10][C:11]2=[N:16][CH:15]=1
Reactant: COc1cnc2ccc(=O)n(CC3OCCO3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CC=O)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.1 %

Procedure:
To 0.12 g of 5-(1,3-dioxolan-2-ylmethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-one, 5 mL of a 90% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 3 hours 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture, the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.12 g of (3-methoxy-6-oxopyrido(2,3-b)pyrazin-5(6H)-yl)acetaldehyde as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=1)[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](=O)(OC1C=CC([N+]([O-])=O)=CC=1)[O:29]C1C=CC([N+]([O-])=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C@@H:8]([N:13]1[CH2:14][CH2:15][N:16]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=2)[C:28]1=[O:29])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cccc(CNCCN[C@H](C(=O)OC(C)(C)C)C(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of the product from Example 17C (10.27 g, 27.1 mmol), bis (4-nitrophenyl) carbonate (8.24 g, 27.1 mmol), in toluene (100 mL) was heated at 110° C. for 16 hours, cooled to 25° C., treated with 1M sodium bicarbonate, and extracted with ethyl acetate. The organic phase layer was concentrated and the residue was purified by flash chromatography on silica gel eluting with 60% ethyl acetate in hexane to give the title compound as a white solid (9.44 g, 64% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCc1ccccc1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Solvent: CCO
Product: N#Cc1c(NCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and benzylamine in ethanol. EI-MS m/e (%): 291 (M+, 100), 290 ([M—H]+, 36), 106 (64), 91 (48).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OCC)OCC)[C:6](=[O:18])[CH:5]2[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:18])[CH:5]2[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1
Reactant: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCOC)c(OC)cc23)c2cc(F)ccc21
Agent: Cl
Solvent: CCO
Product: COCCOc1cc2ncnc(C3C(=O)Nc4ccc(F)cc43)c2cc1OC
Temperature: 80 °C
Yield: 24.6 %

Procedure:
A solution of 4-(5-fluoro-1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (255 mg, 0.52 mmol), (prepared as described in Example 9), in ethanol (25 ml) containing 2M hydrochloric acid (2.6 ml) was heated at 80° C. for 1 hour. The solid formed was collected by filtration, washed with ethanol and dried under vacuum. The solid was dissolved in hot DMF, the solution was diluted with ethyl acetate and thoroughly washed with water. The organic layer was dried (MgSO4), the volatiles removed by evaporation and the resulting solid was dried under vacuum at 70° C. to give 4-(5-fluorooxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (49 mg, 25%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[CH:15])[CH:9]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]([O:18][CH3:17])=[O:28])=[CH:22][CH:23]=2)[CH:9]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cccc(C(C)(C)C(=O)OCC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)c1cccc(C#Cc2ccc(CC(=O)OC)cc2)c1

Procedure:
Following General Procedure B and using 2-(3-ethynyl-phenyl)-2-methyl-propionic acid ethyl ester (Intermediate 132, 0.101 g, 0.47 mmol), 4-iodo phenyl acetic acid methyl ester (0.129 g, 0.47 mmol), triethyl amine (8 mL), copper(I)iodide (0.01 g, 0.05 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.035 g, 0.05 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 10–15% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.14 g, 82%).