Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:16][C:17]([C:19]2[CH:20]=[C:21]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[CH:22]=[CH:23]C=2O)=[O:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].Cl>O1CCCC1.N1C=CC=CC=1>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[C:21]1[CH:22]=[CH:23][C:5]2[O:4][C:2](=[O:3])[N:16]([C:10]3[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=3)[C:17](=[O:18])[C:19]=2[CH:20]=1
Reactant: COc1ccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)cc1OC
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)cc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 43 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 11 (1.54 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 23.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[N:3]=1.[CH2:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:23][CH3:24]>>[CH2:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:19]2[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:4]4[N:3]=[C:2]([CH3:1])[O:6][N:5]=4)=[CH:8][CH:9]=3)[CH2:17][CH2:18]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:23][CH3:24]
Reactant: Cc1nc(-c2ccc(CC(=O)N3CCNCC3)cc2)no1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)N2CCN(C(=O)Cc3ccc(-c4noc(C)n4)cc3)CC2)cc1

Procedure:
Similarly to Example 1, reaction of 2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-1-piperazin-1-ylethan-1-one (“B”) and 4-propylphenylsulphonyl chloride gives the compound 1-[4-(4-propylphenylsulphonyl)piperazin-1-yl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]ethan-1-one and, after hydrogenation, 4-{2-oxo-2-[4-(4-propylphenylsulphonyl)piperazin-1-yl]ethyl}benzamidine, FAB 429.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:32])[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[C:18]([N+:29]([O-])=O)[CH:17]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1.O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH2:29][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][C:23]1=[O:28])[C:15]([NH:14][C@H:9]([C:7]1[NH:6][C:5]2[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1)[CH2:10][CH2:11][S:12][CH3:13])=[O:32]
Reactant: CSCC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1)c1nc2cc(Cl)ccc2[nH]1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CSCC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(N)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
65 mg (0.13 mmol) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide dissolved in 2 ml of ethyl acetate are combined with 143 mg (0.63 mmol) tin(II)chloride-dihydrate and 130 mg (1.55 mmol) sodium hydrogen carbonate and refluxed for 2 hours. The reaction solution is combined with ice water, stirred for 10 minutes and then the precipitate formed is filtered off. After drying for 3 days the residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol 100:0->91:9).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:11][CH:10]=[N:9][C:8]=1[S:12]CCC(OC)=O)=[O:6]>CO>[CH3:3][O:4][C:5]([C:7]1[S:11][CH:10]=[N:9][C:8]=1[SH:12])=[O:6]
Reactant: COC(=O)CCSc1ncsc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1scnc1S
Temperature: 75 °C
Yield: 64.2 %

Procedure:
Sodium hydroxide (0.29 g, 7.27 mmol) is added to a solution of 4-(2-methoxycarbonyl-ethylsulfanyl)-thiazole-5-carboxylic acid methyl ester (2.0 g, 7.27 mmol) in MeOH (30 ml). The mixture is refluxed at 70-80° C. for 1 h and then concentrated in vacuo. The residue is dissolved in EtOAc/water (1:1) (80 ml) and the pH is adjusted to 2 with 2M hydrochloric acid. The organic layer is dried over sodium sulfate and concentrated yielding 4-mercapto-thiazole-5-carboxylic acid methyl ester (0.82 g, 4.67 mmol, 46%).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[NH:8][CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([F:22])[CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:11]=[N:10][C:9]3[NH:8][CH2:7][CH2:6][O:5][C:4]=3[CH:3]=2)=[C:15]([F:22])[CH:14]=1
Reactant: Brc1cnc2c(c1)OCCN2
Reactant: OB(O)c1ccc(Cl)cc1F
Product: Fc1cc(Cl)ccc1-c1cnc2c(c1)OCCN2

Procedure:
Prepared in a manner similar to that found in Example 1 using of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine with (4-chloro-2-fluorophenyl)boronic acid. 1H NMR (400 MHz, CDCl3) δ 7.84 (m, 1H), 7.35-7.28 (m, 1H), 7.20-7.14 (m, 3H), 4.29-4.25 (m, 2H), 3.64-3.58 (m, 2H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:7].Br[CH2:26][C:27]([CH3:29])=[CH2:28]>CN(C=O)C>[Br:3][C:4]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:5]=1[C:6]([N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH2:28][C:27]([CH3:29])=[CH2:26])=[O:7]
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2Br)cc1
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CN(Cc1ccc(OC)cc1)C(=O)c1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of NaH (1.22 g) in DMF (130 ml) was added 2-bromo-N-(4-methoxy-benzyl)-5-nitro-benzamide (6.2 g) in DMF (60 ml) at −78 C. The mixture was warmed to 0° C., 3-bromo-2-methyl-propene (4.57 g) was added and the mixture was stirred for 2 h at 0° C. The reaction was poured into ice water, extracted with EtOAc (2×400 ml), dried over MgSO4, filtered and concentrated to a DMF solution which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39](O)=[O:40])[S:33]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[N:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[O:19][C:20]=4[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)=[O:40])[S:33]1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)CC1SC(=O)NC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(CC(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)S1
Yield: 90.1 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (60.1 mg, 0.149 mmol), (2,4-dioxo-thiazolidin-5-yl)-acetic acid (26.2 mg, 0.149 mmol), triethylamine (63 uL, 0.448 mmol) and BOP (63.2 mg, 0.149 mmol) in 1 mL DMF were reacted as above. The crude product was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[2-(2,4-dioxo-thiazolidin-5-yl)-acetyl]-piperidin-4-yl}-phenyl)-amide as a white solid (76.9 mg, 90%). ES-MS calcd for C27H23F3N4O5S (m/e) 572.57, obsd 573 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH2:18])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](Cl)=[O:28].O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)=[O:28])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)c1ccccn1
Yield: 31.6 %

Procedure:
A solution of amine 8 (0.145 g, 0.57 mmol) and picolinoyl chloride hydrochloride (0.180 g, 1.01 mmol) in dry pyridine (5 ml) was stirred at room temperature overnight. After addition of water the brown solid was filtered and passed through a SiO2 gel, eluting with CH2Cl2: MeOH (100:5) affording the desired product 21 (0.065 g, 31%).
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 55.1 %

Procedure:
A solution of 4-chloro-3-nitro aniline (2.0 g, 11.16 mmol), 4-benzyloxyphenol (2.55 g, 12.76 mmol), powdered potassium hydroxide (0.94 g, 16.80 mmol) in dimethylformamide (15 ml) was heated at 120° C. for 20 hours. Afterwards ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a dark red solid as the title compound, (2.07 g, 53%).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.[OH:17][CH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([C:23]2[CH:24]=[C:19]([CH2:18][OH:17])[CH:20]=[CH:21][CH:22]=2)=[N:11][CH:12]=1
Reactant: Cc1ccc(Br)nc1
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cccc(CO)c2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
92 mg (0.08 mmol) of tetrakis(triphenylphosphine)palladium are added to a suspension, kept under nitrogen, of 849 mg (4.0 mmol) of tripotassium phosphate, 344 mg (2.0 mmol) of 2-bromo-5-methylpyridine and 304 mg (2.0 mmol) of 3-hydroxymethylbenzeneboronic acid in 12 ml of dioxane and 1 ml of water, and the mixture is heated at the boil with stirring for 18 hours. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate, evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent: [3-(5-methylpyridin-2-yl)phenyl]methanol as yellowish oil; LCMS 200.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[O:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:50]1[CH:55]=[CH:54][C:53]([C@H:56]([NH2:59])[CH2:57][OH:58])=[CH:52][CH:51]=1>>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[O:15][C:14]([C:16]([NH:59][C@H:56]([C:53]3[CH:54]=[CH:55][CH:50]=[CH:51][CH:52]=3)[CH2:57][OH:58])=[O:18])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: N[C@H](CO)c1ccccc1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)O)o2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)N[C@@H](CO)c3ccccc3)o2)s1
Reaction time: 8 h

Procedure:
To 5 mL of the crude 4.49 millimolar solution of 5-(2-acetamido-4-methylthiazol-5-yl)furan-2-carboxylic acid was added 200 mg of TBTU and 1 mL of Hunig's base. To the stirred reaction mixture was then added 200 mg of S-phenylglycinol. The reaction was allowed to stir overnight and was then concentrated to dryness and dissolved in 1 mL of DMSO and filtered. The filtrate was purified via reverse phase chromatography to yield 4.1 mg of (R)-5-(2-acetamido-4-methylthiazol-5-yl)-N-(2-hydroxy-1-phenylethyl)furan-2-carboxamide as a white solid. LC/MS: 386.2 (M+H)/2.0 min.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].Cl[CH2:14][C:15](=[O:17])[CH3:16].O>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH2:14][C:15](=[O:17])[CH3:16])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CC(=O)CCl
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cn1c(Cl)nc2ccccc21
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloro-1H-benzimidazole (1.53 g) in DMF (20 ml) was added sodium hydride (60% in oil, 0.480 g) at 0° C. by small portions. After stirring for 10 min, chloroacetone (1.19 mL) was added, and the obtained mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give the title compound (1.73 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18]C2CCCCO2)=[CH:10][CH:9]=[CH:8][C:7]=1[O:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32]C)=[O:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[C:7]([O:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOC2CCCCO2)c1CCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)CCCOc1cccc(CCCCCCO)c1CCC(=O)OC
Yield: 92.4 %

Procedure:
A solution of 9.74 g (ca. 20 mmol) of rac-2-(4-ethoxy-4-oxobutoxy)-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester from the preceding example, and 0.53 g of p-toluenesulfonic acid monohydrate, in 270 mL of methanol was stirred and refluxed for 21.5 hr. Most of the solvent was removed in vacuo and the residue was dissolved in ether. The ether solution was washed with saturated sodium bicarbonate solution and processed in the usual manner giving an oil. This material was chromatographed on 200 g of silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 7.03 g (92.5%) of 2-(6-hydroxyhexyl)-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([CH3:25])[CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([CH3:25])[CH:16]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2cc(C)nc3ccccc23)c2ccccc12
Temperature: 80 °C
Reaction time: 60 h

Procedure:
1 mmol (175 mg) of 1H-indole-3-carboxylic acid methyl ester, 1.1 mmol (195 mg) of 4-chloro-2-methyl-quinoline and 1.2 mmol (390 mg) of Cs2CO3 are suspended in 3 ml of dry DMF. The mixture is stirred for 60 h at 80° C. under argon, allowed to cool to room temperature, and diluted with water (20 ml). Part of the product precipitates and is filtered off, the filtrate is extracted twice with ethyl acetate (20 ml portions). The combined extracts are dried over anhydrous Na2SO4 and evaporated. The residue is combined with the precipitate and purified by prep. HPLC to yield 1-(2-methyl-quinolin-4-yl)-1H-indole-3-carboxylic acid methyl ester (MS molpeak 316.12 (M+H, electrospray ionisation)) as an off-white foam after freeze-drying.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC>C1(C)C=CC=CC=1.O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=c1[nH]cnc2cc(-c3ccccn3)ccc12
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a solution of 7-bromo-3H-quinazolin-4-one (100 mg, 0.444 mmol) in toluene/dioxane (3:1), add 2-tributylstannanyl-pyridine (162 mg, 0.444 mmol) followed by tetrakis-(triphenylphosphine)-palladium(0) (26 mg, 0.022 mmol). Bubble dry nitrogen through the solution for 10 minutes then heat the stirring solution to 115° C. under a nitrogen atmosphere. After several minutes the reaction mixture becomes homogeneous. After 16 hours, cool the reaction vessel and collect the precipitate via filtration. Wash the solid with 25% EtOAc/hexanes followed by hexanes to give 7-pyridin-2-yl-3H-quinazolin-4-one as a beige solid.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:51])/[C:16](/[N:24]2[CH:27]([S:28]S(C3C=CC(C)=CC=3)(=O)=O)[CH:26]([NH:39][C:40](=[O:49])[CH2:41][O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:25]2=[O:50])=[C:17](\N2CCCC2)/[CH3:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(OCC)(=[O:61])C>C(#N)C>[C:1]1([CH:7]([O:14][C:15]([C@@H:16]2[N:24]3[C:25](=[O:50])[C@@H:26]([NH:39][C:40](=[O:49])[CH2:41][O:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C@H:27]3[S:28][CH2:18][CH:17]2[OH:61])=[O:51])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: C/C(=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1)N1CCCC1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1SCC(O)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 139.32 g (160 mmol) of a mixture consisting of the 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-(1-pyrrolidinyl)-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 1350 ml of dry acetonitrile is heated at 80° for approximately 6 hours under nitrogen until it is no longer possible to detect any starting material by thin layer-chromatography (silica gel; toluene/ethyl acetate 1:1). The heating bath is removed, the reaction mixture containing the 7β-phenoxyacetamido-3-(1-pyrrolidinyl)-3-cephem-4-carboxylic acid diphenylmethyl ester is left to cool for a further 11/2 hours, 550 ml of 0.1 N hydrochloric acid are added and the mixture is further stirred for 81/2 hours at room temperature. The reaction mixture is diluted with ethyl acetate, the water is separated off, the organic phase is washed twice with 2 N hydrochloric acid and three times with water, dried over sodium sulphate, concentrated by evaporation in vacuo and dried under a high vacuum. The residue, containing the 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, is used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[OH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[C:32](I)[CH:31]=3)=[CH:24][C:23]=2[C:39]([F:42])([F:41])[F:40])[CH2:17][CH2:16]1>>[OH:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([C:2]#[C:1][C:3]4[N:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:31]=3)=[CH:24][C:23]=2[C:39]([F:42])([F:41])[F:40])[CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CCO)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc2cccnn12
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CCO)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and N-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 14, The product was obtained as a solid: 563 m/z (M+H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[ClH:13].[NH2:14][CH2:15][C:16](=[O:22])[CH2:17][CH2:18][C:19](O)=[O:20]>>[ClH:13].[NH2:14][CH2:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
From 4-(trifluoromethyl)benzyl alcohol (4.9 g; 28 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 2 h. The yield was 1.24 g (64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:19])[C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20]#[N:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:8]([CH3:23])([CH3:22])[C:7]=2[CH:24]=1.C1C(=O)N([Br:32])C(=O)C1.O>CC#N>[Br:32][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[C:20]#[N:21])[NH:10][C:9]1[C:8]([CH3:22])([CH3:23])[C:7]3[CH:24]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[C:18](=[O:19])[C:17]2=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)c(Br)cc3c1C2=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A5-2, 50 mg, 0.158 mmol) was dissolved in CH3CN (1 mL), added with NBS (56 mg, 2 eq.), and stirred at 80° C. overnight. The reaction solution was added to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with MeOH and the solid remained after dissolution was filtered to obtain the target compound (yellow powder, 20 mg, 38%).