Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH2:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[O:19]=[C:20]1[NH:24][C:23](=[O:25])[CH:22]([CH2:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=2)[S:21]1.C(P(=O)(OCC)OCC)#N>C(N(CC)CC)C.O1CCCC1>[C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH:17][C:33](=[O:34])[CH2:32][O:31][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH:22]2[S:21][C:20](=[O:19])[NH:24][C:23]2=[O:25])=[CH:37][CH:36]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1ccc(N)c(N(C)C(=O)OC(C)(C)C)c1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ccc(NC(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
To a mixture of N-(2-amino-5-methylthiophenyl)-N-methylcarbamic acid t-butyl ester (2.0 g) (obtained in Reference Example 4), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (2.31 g) (obtained in Reference Example 6), triethylamine (1.14 ml) and anhydrous tetrahydrofuran (40 ml) was added diethyl cyanophosphonate (1.34 g) and the resulting mixture was stirred at room temperature for 4 hours and allowed to stand overnight. To the reaction mixture were further added 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.84 g), triethylamine (0.3 g) and diethyl cyanophosphate (0.49 g) and the resulting solution was stirred at room temperature for 1.5 hours. At the end of this time the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was chromatographed on a silica gel column using n-hexane/ethyl acetate (2/1) as the eluant to give the desired product (3.54 g).
Reaction SMILES: N1C=CN=CC=1C1C=CN=C([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)N=1.C[N:25](/C=C/C(C1C=NC=CN=1)=O)C.[C:37]([NH:44][C:45]1[S:46][C:47]([C:51](=O)/[CH:52]=[CH:53]/[N:54]([CH3:56])C)=[C:48]([CH3:50])[N:49]=1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[C:40]([O:39][C:37]([NH:44][C:45]1[S:46][C:47]([C:51]2[CH:52]=[CH:53][N:54]=[C:56]([NH:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=3)[N:25]=2)=[C:48]([CH3:50])[N:49]=1)=[O:38])([CH3:41])([CH3:42])[CH3:43]
Reactant: O=C(O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Reactant: CN(C)/C=C/C(=O)c1cnccn1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)/C=C/N(C)C
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(NCc2ccc(C(=O)O)cc2)n1
Yield: 18 %

Procedure:
Following the procedure described for the synthesis of the acid 25a (scheme 6, step 3) but substituting enamino ketone 23a for the enamino ketone 338, title compound was obtained in 18% yield and was used for the next steps without further purification. MS (m/z): 441.50 (calc) 442.3 (MH+) (found).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:44]=[CH:45][C:46]=1[Cl:47])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH:41]3[CH3:43])=[O:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[Cl:47][C:46]1[CH:45]=[CH:44][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH:41]4[CH3:43])=[O:39])[N:36]=3)[N:33]=2)=[CH:25][C:24]=1[NH:23][C:8]([C:6]1[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=1)=[O:10]
Reactant: CC1CC1C(=O)Nc1cn2nc(Oc3ccc(Cl)c(N)c3)ccc2n1
Reactant: CCc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5C)cn4n3)ccc2Cl)n(C)n1
Yield: 49.9 %

Procedure:
Using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (181 mg, 1.17 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (102 μL, 1.17 mmol), N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide (300 mg, 0.84 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 249, the title compound (207 mg, 50%) was obtained as a white powder.
Reaction SMILES: [C:1]([C:3]([C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[OH:5])#[N:2].[N+](=[CH2:24])=[N-]>C1COCC1>[C:1]([C:3]([C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])=[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[O:5][CH3:24])#[N:2]
Reactant: CC(C)(C)C(=O)C(C#N)=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=C(C#N)C(=O)C(C)(C)C)c1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
To a solution of 1.0 g of 2-cyano-4,4-dimethyl-1-hydroxy-3-oxo-(2-nitro-4-chlorophenyl)-1-pentene dissolved in 3 ml of dry THF was cautiously added an ethereal solution of diazomethane. The excess starting material was removed by washing the reaction mixture with cold 3% K2CO3, separating the phases, drying the organic phase over MgSO4, filtering, and concentrating under reduced pressure. The crude product was crystallized from hot hexane/THF to yield 250 mg of the product, m.p. 130°-1° C.
Reaction SMILES: [OH:1][C:2]1[C:26]([CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[C:25]([O:32][CH2:33][O:34][CH3:35])[CH:24]=[C:23]([O:36][CH2:37][O:38][CH3:39])[C:3]=1[C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:8]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:25]([O:32][CH2:33][O:34][CH3:35])[CH:24]=[C:23]([O:36][CH2:37][O:38][CH3:39])[C:3]=1[C:4](=[O:22])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:8]=1
Reactant: COCOc1ccc(C=CC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2O)cc1CC=C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(CCC(=O)c2c(OCOC)cc(OCOC)c(CCC(C)C)c2O)cc1CCC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
Then, 80 ml of an ethyl acetate solution of 7.22 g of 2'-hydroxy-4,4',6'-tris(methoxymethoxy)-3,3'-bis(3-methyl-2-butenyl)chalcone was added to a suspension of 1.67 g of 5% palladium/carbon in 50 ml of ethyl acetate, in which a hydrogen gas had been sufficiently absorbed in advance, and the mixture was stirred at room temperature under atmospheric pressure in a hydrogen gas atmosphere for 4 hours. After the reaction, the suspension was filtered and the solvent was removed from the filtrate by distillation to obtain 6.23 g (yield=85.3%) of 1-[2-hydroxy-4,6-bis(methoxymethoxy)-3-isopentylphenyl]-3-(3-isopentyl-4-methoxymethoxyphenyl)-1-propanone in the form of a syrup.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:9](=[O:19])[N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.Br[C:28]1[CH:29]=[C:30]2NC(=O)N(C(OC(C)(C)C)=O)[C:31]2=[N:32][CH:33]=1.[C:45]1([C@@H](O)C)[CH:50]=CC=[CH:47][CH:46]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:13]1([C@H:11]([N:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:47]4[CH:46]=[CH:45][CH:50]=[C:31]5[C:30]=4[CH:29]=[CH:28][CH:33]=[N:32]5)[CH:3]=3)[NH:8][C:9]2=[O:19])[CH3:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Br)cnc21
Reactant: C[C@H](c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ncc(Br)cc21
Reactant: C[C@H](O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
(R)-tert-Butyl 6-bromo-2-oxo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate. To a solution of tert-butyl 6-bromo-2-oxo-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate (1.6 g, 5.09 mmol), (S)-1-phenylethanol (0.75 g, 6.11 mmol) and triphenylphosphine (1.6 g, 6.11 mmol) in tetrahydrofuran (45 mL) was added diisopropyl azodicarboxylate (1.19 mL, 6.11 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography to afford the title compound (0.60 g, 28% yield). MS (ESI) m/z 418.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[C:4]([C:17]([O:19]C)=[O:18])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH:32]1([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][O:11][CH2:12][C:13]([N:38]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:15])=[C:4]([CH:3]=1)[C:17]([OH:19])=[O:18]
Reactant: c1ccc(NC2CCCCC2)cc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: O=C(COCC(=O)N(c1ccccc1)C1CCCCC1)Nc1ccc(Cl)cc1C(=O)O
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
1.21 g (4.0 mmol) of (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i), 32 mg (0.44 mmol) of DMF, and 0.41 mL (4.8 mmol) of oxalyl chloride were added to 12 mL of THF, and stirring was conducted at 0° C. for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure and dried. 0.84 g (4.8 mmol) of N-cyclohexylaniline and 8.4 mL of DMA were added to this residue and stirred at room temperature overnight. After completion of the reaction, an aqueous sodium bicarbonate solution was added, extraction was carried out using ethyl acetate, and washing was conducted with a saturated sodium chloride solution. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography, thereby giving 1.77 g of 5-chloro-2-[((2-[cyclohexyl(phenyl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 96%).
Reaction SMILES: C([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])N=2)[N:10]=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.ClCC1N(C)C(C)=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:8][C:9]3[N:10]([CH3:5])[C:14]([CH3:15])=[N:12][N:11]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Cc1nnc(CCl)n1C
Agent: Cl
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CC(F)(F)C(F)(F)C4)c3n2)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole hydrochloride and isolated as white solid. MS (m/e): 428.3 (MH+).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=[O:8])=CC=1.[Br:12][C:13]1[CH:14]=[N+:15]([O-])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[CH:17]=2>CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>[Br:12][C:13]1[C:14](=[O:8])[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[CH:17]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2cc(Br)c[n+]([O-])c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc2cc(Br)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
p-Toluenesulfonyl chloride (1.68 g, 8.83 mmol) was added to a solution of 3-bromo-7-methoxyquinoline 1-oxide (2.04 g, 8.03 mmol) in EtOAc (50 mL) and 15% aqueous K2CO3 (15 mL) at RT. The reaction mixture was stirred vigorously at RT for 18 h, at which time the product was collected by filtration and washed with EtOAc. The solid was dried under vacuum and used with no further purification. LRMS (M+H)+=254.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:15][CH3:16])[CH:10]([N+:12]([O-])=O)[CH3:11]>C1COCC1.[Ni].CCO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:15][CH3:16])[CH:10]([NH2:12])[CH3:11]
Reactant: COC(c1ccc(Cl)cc1Cl)C(C)[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(c1ccc(Cl)cc1Cl)C(C)N
Reaction time: 23 h
Yield: 100 %

Procedure:
2,4-dichloro-1-(1-methoxy-2-nitro-propyl)-benzene (132.2 g, 0.500 mol), was dissolved in THF (3.6 l). The solution was deaerated, RaNi-EtOH (133 g) catalyst was added, and the mixture was hydrogenated at 50 bar at ambient temperature for 23 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure. 117.1 g (100% of theory) of 2-(2,4-dichlorophenyl)-2-methoxy-1-methyl-ethylamine (compound Z1.14) was obtained in the form of a colourless oil as a mixture of diastereomeres.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:25]([CH:33]=O)[NH:24][C:23]=2[CH3:35])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:25]([CH:33]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:24][C:23]=2[CH3:35])=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)NCCN1CCCC1
Yield: 27 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (44 mg, 0.21 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (70 mg, prepared in the same manner as the isopropyl analog, above) to give 0.03 g (27%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23](OCC)=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5]>C(OCC)(=O)C.CCCCCC>[OH:24][CH2:23][CH2:22][CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:29]([CH3:30])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:33])([CH3:1])[CH3:34])[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)[CH3:28]
Reactant: CCOC(=O)CC(C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)CCO)cc1)CO2
Yield: 85 %

Procedure:
Using ethyl 3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)butanoate obtained in Example 182, the title compound was synthesized in the same manner as in Example 193. Yield: 85%. Melting point: 145-147° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>C(#N)C.[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>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])[C:9]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(COc2cnc(COC(C)=O)cc2OS(=O)(=O)C(F)(F)F)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(COc2cnc(COC(C)=O)cc2C#C[Si](C)(C)C)cc1
Temperature: 45 °C
Yield: 95.8 %

Procedure:
(5-({[4-(Methyloxy)phenyl]methyl}oxy)-4-{[(trifluoromethyl)sulfonyl]oxy}-2-pyridinyl)methyl acetate (10 g, 23 mmol) (for a synthesis see WO2004058144, Example 60(d)) was dissolved in acetonitrile (400 ml) and triethylamine (65 ml) and treated with trimethylsilyl acetylene (10 ml, 69 mmol). The mixture was then degassed several times and put under an atmosphere of argon. Copper(I) iodide (0.44 g, 2,3 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.645 g, 0.9 mmol) was added and the mixture heated at 45° C. for 18 h. The mixture was allowed to cool and filtered. The filtrate was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was dried then evaporated to dryness. Chromatography on silica gel eluting with 40-60 petrol and ethyl acetate gradient provided the desired compound (8.45 g, 96%).
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C([N:39]1[C:43](=[S:44])[NH:42][N:41]=[N:40]1)C.[CH2:45](N(CC)CC)[CH3:46].Cl>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C.O>[CH2:45]([CH:2]([S:44][C:43]1[NH:42][N:41]=[N:40][N:39]=1)[C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:46]
Reactant: CCn1nn[nH]c1=S
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 0.08 h

Procedure:
A solution of diphenylmethyl 3-bromomethyl-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate (11.67g) and 1-ethyltetrazoline-5-thione (2.6 g) in dry tetrahydrofuran (150 ml) was stirred at 0° and a solution of triethylamine (2.8 ml) in tetrahydrofuran (25 ml) was added, dropwise, over 5 minutes. The resulting suspension was stirred for a further 25 minutes, during which time the temperature was allowed to rise to ca. 20°, and was then added, over 5 minutes, to a stirred mixture of 2N-hydrochloric acid (50 ml), water (350 ml), brine (350 ml), and ethyl acetate (600 ml). The organic phase was separated, and washed with 2 N-hydrochloric acid, saturated sodium bicarbonate, water, and brine, and dried and evaporated to a foam (11.71 g). A solution of this foam in benzene (25 ml) was purified by chromatography on kieselgel (200 g), with benzene:ethyl acetate= 5:1 as eluant. Appropriate fractions were combined and the solvents evaporated in vacuo. The residue was dissolved in methylene dichloride, and the solution run into petroleum ether to give the ester as a pale-yellow, amorphous solid (8.585 g, 68%); [ α]D23 - 131° (c 0.97, CHCl3); λmax. (EtOH) 264 nm (ε 7,300), τ (CDCl3) values include 4.12 (7-H, dd, J 5 and 9 Hz.), 5.04 (6-H, d, J 5 Hz.), 5.83 (CH3CH2 --,q, J 7 Hz.), and 8.57 (CH3CH2 --, t, J 7 Hz.).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)#[CH:25].C(NCC)C>CN(C=O)C.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>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]#[C:25][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][C:6]4[CH2:23][C:13]5([C:21]6[C:16](=[N:17][CH:18]=[CH:19][CH:20]=6)[NH:15][C:14]5=[O:22])[CH2:12][C:7]=4[CH:8]=3)[N:3]=2)=[CH:27][CH:28]=1
Reactant: O=C1Nc2ncccc2C12Cc1cc3ccc(Cl)nc3cc1C2
Reactant: C#Cc1ccc(C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cc1ccc(C#Cc2ccc3cc4c(cc3n2)CC2(C4)C(=O)Nc3ncccc32)cc1
Temperature: 120 °C

Procedure:
A stirred mixture of (±)-2-chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (15 mg, 0.047 mmol, described in Intermediate 20), 4-ethynyltoluene (7 mg, 0.061 mmol), PdCl2(PPh3)2 (4 mg, 0.006 mmol), and diethylamine (0.073 mL, 0.70 mmol) in DMF (0.5 mL) was heated at 120° C. in a microwave reactor for 5 min. The cooled mixture was partitioned between saturated aqueous NaHCO3 (3 mL) and EtOAc (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined and concentrated to give a crude product. This was further purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to give the title compound. MS: m/z=402 (M+1). HRMS: m/z=402.1609; calculated m/z=402.1601 for C27H20N3O.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:7][CH:6]=1)=[O:4].[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>C(#N)C>[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][NH:12][S:13]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)(=[O:15])=[O:14])=[CH:7][CH:6]=3)=[O:4])[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: Cc1ccc(S(=O)(=O)NCc2ccc(C(=O)CBr)cc2)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)NCc2ccc(C(=O)CN3CCN(c4ccncc4)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A solution of N-([4-bromoacetylphenyl]methyl)-4-methylphenylsulphonamide (470 mg) in acetonitrile (10 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (400 mg) in acetonitrile (10 ml) and the mixture stirred for 18 hours. The solvent was evaporated in vacuo and the residue purified by flash chromatography on silica, eluting with 10% v/v methanol/dichloromethane. On evaporation of the eluant fraction to a small volume crystallisation occurred. These crystals, on filtration and washing with dichloromethane gave the title compound, 130 mg, as a solid: m.p. 215°-219° C. dec.; NMR(d6DMSO) δ8.14(3H,m), 7.91(2H,d), 7.69(2H,d), 7.38(4H,d), 6.82(2H,d), 4.03(2H,d), 3.89(2H,s), 3.32(4H,t), 2.62(4H,t), 2.39(3H,s); m/e 465(M+H)+ ; calculated for C25H28N4O3S: C, 64.6; N, 6.1; N, 12.1. found C, 64.7; H, 6.2; N, 12.0%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].O>C(N(CC)CC)C.CN(C)C=O.[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]1[CH:14]=[C:13]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(I)cc1OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1OCC
Temperature: 50 °C
Yield: 90.3 %

Procedure:
Ethyl 2-ethoxy-4-iodobenzoate (0.763 g, 2.38 mmol, example 14), copper(I) iodide (0.0227 g, 0.119 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.167 g, 0.238 mmol) and (trimethylsilyl)acetylene (0.404 mL, 2.86 mmol) were dissolved under nitrogen in a flame-dried flask in a mixture of triethylamine (3.5 mL) and dimethylformamide (3.5 mL). The reaction mixture was heated at 50° C. for 2 h and then allowed to cool. Water (100 mL) was added and the mixture was extracted with diethyl ether (3×100 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried over Sodium sulfate and evaporated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 10% ethyl acetate in hexanes) gave ethyl 2-ethoxy-4-trimethylsilanylethynyl-benzoate as a yellow oil (0.624 g, 90%).