Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42](O)=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]1([CH:51]2[CH2:55][CH2:54][NH:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42]([N:53]1[CH2:54][CH2:55][CH:51]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:52]1)=[O:43])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)N4CCC(c5ccccc5)C4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 0.10 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1,2-dicarboxylic acid 1-benzyl ester (from example 3b) and 3-phenylpyrrolidine are reacted to afford the title compound as a colourless solid. Rf=0.15 (EtOAc-heptane 1:1); Rt=5.47.
Reaction SMILES: [Br:1][O-].[Na+].BrBr.[OH:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].Cl>[OH-].[Na+]>[Br:1][C:13]1[CH:14]=[N:15][C:7]([OH:6])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: [O-]Br
Reactant: O=C(O)c1cccnc1O
Agent: BrBr
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc(Br)cnc1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium hypobromide was made by adding Br2 (1.01 ml, 39.5 mmol, 1.1 eq) slowly over a period of 5 min to NaOH (5N, 40 ml) that was previously cooled to 0° C. in an ice bath. The solution was stirred for 10 min before adding 2-hydroxynicotinic acid (5.0 g, 35.9 mmol) and placed in a 50° C. oil bath and stirred. Concurrently, a second pot of sodium hypobromide solution was made by slowly adding Br2 (1.01 ml, 39.5 mmol, 1.1 eq) to a NaOH solution (5N, 40 ml) in an ice bath. The second pot of sodium hypobromide was added to the solution of 2-hydroxynicotinic acid after 24 h of heating then was stirred for an additional 24 h. The solution was cooled to RT, placed in an ice bath and acidified with concentrated HCl while stirring. The precipitate which formed was filtered, washed and dried to afford the desired compound as an off-white solid.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[N+:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]([OH:29])=O)([O-:16])=[O:15].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O.O1CCCC1>[CH2:30]([NH:37][C:27]([C:22]1[C:23]2[C:18](=[C:17]([N+:14]([O-:16])=[O:15])[CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccc2c([N+](=O)[O-])cccc12
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCc1ccccc1)c1cccc2c([N+](=O)[O-])cccc12
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
Triethylamine (0.16 ml, 1.15 mmol) and ethyl chloroformate (0.11 ml, 1.115 mmol) were added to a suspension of 5-nitronaphthalene-1-carboxylic acid (250 mg, 1.15 mmol) and anhydrous tetrahydrofuran (3 ml) under ice cooling, and the mixture was stirred for 0.5 hour. Benzylamine (0.13 ml, 1.20 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and after the mixture was stirred for 10 minutes, the resulting precipitate was collected. The precipitate was washed with water and isopropyl ether, and dried to give the title compound as a light brown solid (189 mg, 53.5%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CO[CH:14](OC)[CH2:15][CH:16](OC)OC>C(O)(=O)C>[N:5]1[N:6]2[CH:14]=[CH:15][CH:16]=[N:1][C:2]2=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=1
Reactant: COC(CC(OC)OC)OC
Reactant: CCOC(=O)c1cn[nH]c1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2cccnc12
Yield: 58.2 %

Procedure:
A stirred mixture of 10.88 g of 5-amino-4-pyrazolecarboxylic acid, ethyl ester, 11.51 g of malonaldehyde bis(dimethyl acetal) and 100 ml of glacial acetic acid was heated at reflux for 16 hours, then worked up as described in Example 50 to give 7.8 g of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:33][C:34]([CH3:38])([CH3:37])[C:35]#[CH:36]>COCCOC.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.C(OCC)(=O)C.CCCCCC>[CH3:33][C:34]([CH3:38])([CH3:37])[C:35]#[C:36][C:21]1[S:22][CH:23]=[CH:24][N:25]=1
Reactant: C#CC(C)(C)C
Reactant: Brc1nccs1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1nccs1
Temperature: 60 °C
Yield: 27.8 %

Procedure:
Triphenylphosphine (380 mg, 1.5 mmol) was dissolved in TBF (20 mL), then argon was bubbled through the solution for several minutes to deoxygenate it. Palladium(II) acetate (82 mg, 0.37 mmol) was added, and the reaction mixture was heated to 60° C. for 0.5 h, and then cooled to ambient temperature. CuI (210 mg, 1.1 mmol), 2-bromo-1,3-thiazole (1.6 g, 9.8 mmol), potassium carbonate (4.2 g, 31 mmol) and water (0.70 mL, 39 mmol) were dissolved in DME (30 mL) and argon was bubbled through the mixture for several minutes to deoxygenate the mixture. 3,3-dimethyl-1-butyne (1.0 g, 12.2 mmol) was then added to mixture. The catalyst solution of triphenylphosphine and palladium (II) acetate in THF was added to the reaction flask which was heated to 30° C. for 2 h. After this time heating was discontinued and the mixture was allowed to stir at ambient temperature. After stirring for 16 h, GC/MS analysis showed the reaction to be complete. The mixture was filtered through Celite.™., the filter pad was washed thoroughly with ethyl acetate, and the combined filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with water (200 mL), brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane, then 99:1 hexane:ethyl acetate to afford 2-(3,3-dimethyl-1-butynyl)-1,3-thiazole (0.45 g, 28% yield) as a yellow oil. 1H NMR (CDCl3, 300 MHz) Δ7.74 (d, J=3.0 Hz, 1H), 7.28 (d, J=3.0 Hz, 1H), 1.33 (s, 9H). MS (ESI) 166.1 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[N:11][CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[N:11][CH:10]=[CH:9][C:4]=1[CH:5]=[O:6]
Reactant: COC(=O)c1ccncc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1cnccc1C=O
Reaction time: 0.17 h

Procedure:
To an cooled solution (−78° C. internal temp) of 0.192 g of methyl 3-methoxyisonicotinate in 10 mL of toluene was added 2 mL of 1 M diisobutyl aluminum hydride in toluene. After stirring 10 min the reaction was quenched with 5 mL of methanol and concentrated under reduced pressure. To a stirred solution of the residue (0.15 g) in 50 mL of dichloromethane was added 1 mL of water, then 1 g of MgSO4. The mixture was filtered and 0.75 g of activated MnO2 was added. The mixture was heated to reflux under nitrogen for 5 h, then cooled and filtered. Concentration under reduced pressure gave a resin: MS (m+1)=138.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[N:18]=[C:17](S(C)(=O)=O)[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:35]#[N:36].[Na+]>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[N:18]=[C:17]([C:35]#[N:36])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(S(C)(=O)=O)n2)CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Yield: 83.7 %

Procedure:
4-[2-Methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (139 mg) and sodium cyanide (22 mg) were heated to 45° C. in dimethylsulphoxide for four hours. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (3×30 ml). Organics were separated, dried over sodium sulphate and solvent was evaporated to yield product 4-[2-cyano-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (104 mg). The above product was then dissolved in dichloromethane (1 ml) and cooled to 0° C. Trifluoroacetic acid (200 μL) was added and the mixture stirred for ten minutes. Solvent was evaporated under reduced pressure to yield crude product. Purification by preparative HPLC yielded product 4-[1,4]diazepan-1-yl-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (52 mg) as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[F:40])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[F:40])=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccccc3F)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccccc3F)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.07 g of 4,5-bis(4-methoxyphenyl)-2-(2-fluorophenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated under vacuum to dryness. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus obtaining 3.49 g of 4,5-bis(4-methoxyphenyl)-2-(2-fluorophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)N=Cc2cccc(Cl)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S1(=O)NCc2cccc(Cl)c21
Temperature: 0 °C
Yield: 97.4 %

Procedure:
A suspension of 17.9 g of 7-chloro-1,2-benzisothiazole-1,1-dioxide in 180 ml of absolute etnanol was cooled to 0° C. and treated with 3.33 g of sodium borohydride at such a rate that the temperature remained below 5° C. The mixture was warmed to room temperature for 30 minutes, recooled to 0° C. and treated with glacial acetic acid to destroy excess hydride. The mixture was concentrated to dryness, the resulting solid suspended in water, filtered, washed with water and dried in vacuo at 50° C. for 16 hours to give 17.6 g of the title compound as a white powder, m.p. 159°-161° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.[CH2:38]([O:41][C:42]1[CH:47]=[C:46]([CH2:48]Cl)[CH:45]=[CH:44][C:43]=1[CH3:50])[CH:39]=[CH2:40]>>[CH2:38]([O:41][C:42]1[CH:47]=[C:46]([CH:45]=[CH:44][C:43]=1[CH3:50])[CH2:48][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:3]1)[CH:39]=[CH2:40]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: C=CCOc1cc(CCl)ccc1C
Product: C=CCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C

Procedure:
Analogously to Method D, 3.00 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 10f) and 1.31 g of 2-allyloxy-4-chloromethyl-1-methylbenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.33 (1:2 EtOAc heptane); Rt=6.27.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Product: Fc1cc2c(c(-c3c(Cl)cccc3Cl)c1)OC(CN1CCCC1)C2

Procedure:
The title compound was prepared (0.069 g, 61%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.13 g, 0.28 mmol) and pyrrolidine (0.20 g, 2.8 mmol). mp 65-67° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39](=[O:53])[C@@H:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:33])=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:54][O:55][C:56]([NH:58][C@@H:59]([CH2:63][CH3:64])[C:60](O)=[O:61])=[O:57]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:60]([C@@H:59]([NH:58][C:56](=[O:57])[O:55][CH3:54])[CH2:63][CH3:64])=[O:61])=[O:18])=[CH:12][CH:11]=2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39](=[O:53])[C@@H:40]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:41]3[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]3)=[O:33])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1)[C@@H]1CCCN1
Reactant: CC[C@H](NC(=O)OC)C(=O)O
Product: CC[C@H](NC(=O)OC)C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1

Procedure:
The product from Example 114C (0.040 g, 0.056 mmol) and (S)-2-(methoxycarbonylamino)butanoic acid (0.011 g, 0.067 mmol) were processed as in Example 81A to give the title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.90 (t, J=7.37 Hz, 3 H) 1.29-1.37 (m, 2 H) 1.39-1.47 (m, 4 H) 1.47-1.58 (m, 1 H) 1.61-1.72 (m, 1 H) 1.75-2.06 (m, 6 H) 2.08-2.20 (m, 1 H) 3.39-3.50 (m, 1 H) 3.52 (s, 3 H) 3.56-3.64 (m, 1 H) 3.69-3.77 (m, 1 H) 3.79-3.90 (m, 1 H) 4.14-4.21 (m, 1 H) 4.24 (s, 1 H) 4.31 (dd, J=7.81, 4.23 Hz, 1 H) 4.43 (dd, J=7.92, 4.34 Hz, 1 H) 4.56 (s, 4 H) 6.64 (dd, J=9.27, 4.39 Hz, 2 H) 6.91 (t, J=8.89 Hz, 2 H) 7.17 (dd, J=8.51, 2.55 Hz, 4 H) 7.27-7.36 (m, 3 H) 7.42 (d, J=6.94 Hz, 2 H) 7.51 (dd, J=8.51, 3.74 Hz, 4 H) 9.95 (d, J=2.93 Hz, 2 H); MS ESI− m/z 858.6 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[C:27]([CH3:32])[CH:26]=[CH:25]2.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[C:27]([CH3:32])[CH:26]=[CH:25]2
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: Cc1ccc2cc(CCl)ccc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2ccc3nc(C)ccc3c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (434 mg, 1.75 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 6-(chloromethyl)-2-methylquinolinehydrochloride SLA 47080B (400 mg, 1.75 mmol) and a 2 N aq. LiOH solution (1.75 mL, 3.50 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided 6,7-dimethoxy-4-((2-methylquinolin-6-yl)methyl)-1-propylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((2-methylquinolin-6-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 80 as a yellow solid (28 mg, 3% yield).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29]>>[C:28]([CH2:30][C:31]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:8]3[C:7]4[CH2:6][CH2:5][O:4][C:12]=4[CH:11]=[CH:10][N:9]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:32])#[N:29]
Reactant: N#CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: N#CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (86 mg, 87%), MS (ISP) m/z=398.3 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and cyano-acetic acid.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCCC1>[CH:18]1([NH:17][C:16]([NH:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C

Procedure:
The half-ester of the formula (VI) may be converted into an "activated" ester prior to reaction with the 7-(α-aminoarylacetamido)-4-carboxy-Δ3 -cephem derivative using the preferred reagent N-hydroxysuccinimide in the presence of a dehydrating agent such as dicyclohexylcarbodiimide. The "activated" ester product of the formula: ##STR5## is conveniently then reacted with the Δ3 -cephem derivative in the reaction solution in which it has been formed, without isolation. In a typical procedure, a solution of the half-ester, N-hydroxysuccinimide and dehydrating agent in a reaction-inert organic solvent, e.g. tetrahydrofuran, is stirred for several hours at room temperature, after which the solid N,N'-dicyclohexylurea formed in the reaction may be removed, e.g. by filtration. To the solution containing the "activated" ester is then added a solution of the Δ3 -cephem derivative, and reaction generally goes substantially to completion in the presence of a tertiary amine or inorganic base, as hereinbefore examplified and preferably with stirring during a period from 1 to 12 hours at room temperature. The solvent may then be removed, e.g. by evaporation in vacuo, and the residue dissolved in water, the aqueous solution then being acidified, extracted with a water-immiscible organic solvent, e.g. ethyl acetate, and the organic phase subjected to a similar procedure to that described in Method (1) for the isolation and purification of the product.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]([CH2:35][NH:36][C:37](=[O:49])[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]#[C:47][CH3:48])=[CH:40][CH:39]=2)([C:31]([O:33][CH3:34])=[O:32])[C:27]([O:29][CH3:30])=[O:28])[CH2:22][CH2:21]1)=O)(C)(C)C>ClCCl>[CH2:45]([O:44][C:41]1[CH:40]=[CH:39][C:38]([C:37]([NH:36][CH2:35][C:26]([N:23]2[CH2:24][CH2:25][N:20]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:21][CH2:22]2)([C:27]([O:29][CH3:30])=[O:28])[C:31]([O:33][CH3:34])=[O:32])=[O:49])=[CH:43][CH:42]=1)[C:46]#[C:47][CH3:48]
Reactant: CS(=O)(=O)Cl
Reactant: CC#CCOc1ccc(C(=O)NCC(C(=O)OC)(C(=O)OC)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(C(=O)NCC(C(=O)OC)(C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.1 %

Procedure:
0.8 ml (5.7 mmol) of triethylamine then 0.4 ml (5.7 mmol) of methanesulphonyl chloride are added to a solution of 2.2 g (3.6 mmol) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzoylamino)methyl]malonate in 25 ml of dichloromethane. The reaction medium is then stirred at ambient temperature for 3 h, then the solvents are evaporated under vacuum and the crude product obtained is purified by chromatography over silica gel eluted with a 98/2 dichloromethane/methanol mixture. 2 g (80%) of dimethyl 2-[(4-but-2-ynyloxybenzoylamino)methyl]-2-(4-methane-sulphonylpiperazin-1-yl)malonate are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[C:4]([OH:6])=O.[NH2:19][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[C:20]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[CH:8]=2)=[CH:23][CH:22]=1)#[N:19]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COc1ccc2cc(C(OC)C(=O)O)ccc2c1
Product: COc1ccc2cc(C(OC)C(=O)NCc3ccc(C#N)cc3)ccc2c1

Procedure:
(RS)-Methoxy-(6-methoxy-naphthalen-2-yl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-(6-methoxy-naphthalen-2-yl)-acetamide. Off-white foam. MS 361.2 ([M+H]+)
Reaction SMILES: [S:1]([C:5]1[C:13]2[N:12]=[N:11][NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:20].O>C(O)C.O>[S:1]([C:5]1[C:13]2[N:12]=[N:11][NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[Ag:20]
Reactant: [Ag+]
Agent: O=S(=O)(O)c1cccc2[nH]nnc12
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [Ag]
Temperature: 25 °C

Procedure:
Forty grams of 4-sulfobenzotriazole and 8.0 g of sodium hydroxide were added to and dissolved in 500 ml of an ethanol-water (1:1) mixture liquid containing 40 g of polyvinyl pyrrolidone. To this solution were added dropwise 33 ml of a five-normal silver nitrate solution. At this time a five-normal sodium hydroxide solution also was simultaneouly added dropwise to maintain the pH at 7 to 8. To this solution, after being stirred for an hour at room temperature, was added water to make the whole quantity thereof 600 ml, whereby a silver 4-sulfobenzotriazole solution was obtained.