Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:6](Cl)=[O:7].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][C:35](=[O:37])[CH3:36]>>[C:35]([N:34]([CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=1)[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1OC
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1OC
Yield: 27.7 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 1.09 g product from Example 48, 0.450 g of product from Example 12, 0.144 g of 50% washed sodium hydride and 12 ml of dry tetrahydrofuran. The residue is purified by column chromatography (silica gel:35% ethyl acetate/hexane) to give 0.391 g of the desired product as yellow crystals.
Reaction SMILES: [Cl-].[Ba+2:2].[Cl-].[Na+].[C:5]([NH:18][CH2:19][CH2:20][S:21]([O-:24])(=[O:23])=[O:22])(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[Ba:2].[C:5]([NH:18][CH2:19][CH2:20][S:21]([OH:24])(=[O:22])=[O:23])(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCC(=O)NCCS(=O)(=O)[O-]
Reactant: [Ba+2]
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCCCCCC(=O)NCCS(=O)(=O)O
Product: [Ba]

Procedure:
Similar to the procedure described in Production Examples 1 and 2, a 5% by weight aqueous solution of barium chloride was added dropwise to a homogeneous solution of N-lauroyltaurine sodium salt. Thus, the target compound N-lauroyltaurine barium was obtained as white crystals (yield: 98.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH:7]=O)[CH3:2].[OH2:22].Cl.[NH2:24]O>CO.N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH:7]=[N:24][OH:22])[CH3:2]
Reactant: O
Reactant: NO
Reactant: CCOc1cc(C=O)ccc1OCc1ccc(OC)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCOc1cc(C=NO)ccc1OCc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred solution of 3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde (3.40 g, 11.83 mmol) in methanol (50 mL), pyridine (1.5 mL), and water (5 mL) was added hydroxylamine hydrochloride (1.23 g, 17.75 mmol). The reaction mixture was heated to reflux. After 2 h, the colorless solution was allowed to cool to room temperature and was concentrated. The residue was suspended in water (50 mL) and filtered. The solids were washed with water and then dissolved in ethyl acetate (150 mL). The solution was dried over magnesium sulfate, filtered, and concentrated to provide 3.05 g (85%) of 3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde oxime as an off-white solid.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25]CC)=[O:24])[CH:13]=[C:14]([Cl:21])[C:15]=3[O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:7]=[CH:6][C:5]=12.CO.O.O[Li].O>C1COCC1>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])[CH:13]=[C:14]([Cl:21])[C:15]=3[O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC2CC2)c(-c2ccc3nonc3c2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(OCC2CC2)c(-c2ccc3nonc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a stirred solution of ethyl 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.25 g, 0.565 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (118.7 mg, 2.828 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography to afford compound-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid (152 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.92 (s, 1H), 7.85 (m, 1H), 7.72 (m, 1H), 7.46 (s, 1H), 7.25 (s, 1H), 3.65 (t, 1H), 3.48 (d, 2H), 1.95 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H), 1.22 (m, 1H0, 0.93 (d, 6H), 0.39 (d, 2H), 0.0 (m, 2H).
Reaction SMILES: [C:1]([O:14]CC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:17]([NH2:20])[CH2:18][NH2:19]>O1CCCC1>[NH2:19][CH2:18][CH2:17][NH:20][C:1](=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCCN
Reactant: CCCCCCCCCCCC(=O)OCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)NCCN
Temperature: 100 °C
Yield: 44.6 %

Procedure:
A solution of 23 g of ethyl dodecanoate and 62.7 g of ethylenediamine in 100 ml of tetrahydrofuran (THF) was refluxed for 3 hours and the excess THF was distilled off. The reaction mixture was heated at 100° C. for 16 hours, cooled to room temperature, poured into cold water and extracted with ether. After drying, the organic solution was concentrated to give 15.7 g of crude product and this was recrystallized from ether-hexane to give 10.9 g of pure product, m.p. 64°-66° C.
Reaction SMILES: CNC1CCC(C2C3C(=CC=C(NC(C4SC=CC=4)=N)C=3)NC=2)=CC1.[CH2:26]([O:28]C(=O)CN1C2C(=CC=C([N+]([O-])=O)C=2)C=C1)C.CN1[CH2:50][CH:49]=[C:48]([C:51]2[C:59]3[C:54](=[CH:55][CH:56]=[C:57]([N+:60]([O-:62])=[O:61])[CH:58]=3)[NH:53][CH:52]=2)[CH2:47][CH2:46]1>>[N+:60]([C:57]1[CH:58]=[C:59]2[C:54](=[CH:55][CH:56]=1)[NH:53][CH:52]=[C:51]2[C:48]1[CH2:47][CH2:46][C:26](=[O:28])[CH2:50][CH:49]=1)([O-:62])=[O:61]
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reactant: CCOC(=O)Cn1ccc2ccc([N+](=O)[O-])cc21
Agent: CNC1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Product: O=C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1

Procedure:
Compound 120 (0.26 g, 0.557 mmol) was treated with 1 N aqueous HCl solution at room temperature and the resulting solution was refluxed for 2 h. The reaction was brought to room temperature, filtered and washed with water (5 mL). The solvent was evaporated and crude was recrystallised from ethanol/ether to obtain compound 121 (0.23 g, 94%) as a solid in 2:3 ratio of diastereomers. 1H NMR (DMSO-d6) δ 1.22-1.29 (m, 3H), 1.53-1.62 (m, 2H), 1.80-2.16 (m, 6H), 2.74-3.23 (m, 4H), 7.08 (d, 1H, J=8.4 Hz), 7.24-7.52 (m, 3H), 7.68-7.72 (m, 1H), 8.14-8.18 (m, 2H), 8.59 (s, 1H), 8.97-9.09 (m, 2H), 9.64 (s, 1H), 11.20, 11.27 (2s, 1H), 11.42 (s, 1H); ESI-MS m/z (%): 367 (MH+ for free base, 18), 322 (100), 184 (19), 119 (39); ESI-HRMS calculated for C21H27N4S (MH+, free base), calculated: 367.1959; observed: 367.1950.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]2.[CH3:46][N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CS(C)=O>[C:23]1([C:19]2[CH:18]=[C:17]([C:10]3[N:9]=[C:8]([NH:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[N:35]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[N:34]=[CH:33]5)[C:7]4[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:50]5[CH2:51][CH2:52][CH2:53][N:47]([CH3:46])[CH2:48][CH2:49]5)[CH:6]=4)[N:11]=3)[CH:22]=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Reactant: CN1CCCNCC1
Solvent: CS(C)=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN1CCCN(C)CC1
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
A mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.25 g, 0.402 mmole), 1-methyl-1,4-diazepane (0.23 g, 0.25 mL, 2.00 mmoles) in DMSO was stirred at 85° C. for 2.5 h. The suspension was poured onto ice-water, filtered and re-dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (SiO2, 10% CH2Cl2/CH3OH— with 0.1% NH4OH) to give tert-butyl 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate which taken on directly to the next step. HPLC retention time 5.96 mins.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[CH:27][S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:28]([CH3:29])=[CH:27][S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)[C@@H:6]([C@H:8]1[CH2:17][C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2Br)[CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[OH:7])(=[O:3])[CH3:2].ClCCl.[I-].[CH2:41]([Zn+])[C:42]([CH3:45])([CH3:44])[CH3:43].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:1]([NH:4][C@@H:5]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)[C@@H:6]([C@H:8]1[CH2:17][C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[OH:7])(=[O:3])[CH3:2]
Reactant: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)C2
Reactant: CC(C)(C)C[Zn+]
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CC(C)(C)C)c2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
Dissolve tert-butyl 3(R)-[(1S,2S)-2-(acetylamino)-3-(3,5-difluorophenyl)-1-hydroxypropyl]-5-bromo-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (46.0 mg, 0.0808 mmol) in tetrahydrofuran (1.00 mL) in a sealed tube flushed with nitrogen. Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (3.3 mg, 0.0040 mmol) and 0.500 M of neopentyl zinc iodide in tetrahydrofuran (0.808 mL) dropwise at room temperature. Stir the resulting green solution at room temperature for six hours. Heat to 50° C. for three days. Add saturated ammonium chloride solution (2 mL) and dilute with ethyl acetate (30 mL). Add water (10 mL) and separate the layers. Extract the aqueous layer (1×30 mL) with ethyl acetate. Combine the organic layers and dry over magnesium sulfate. Purify (Biotage medium pressure chormatography eluting with 1.5% methanol:dichloromethane) to give desired product (21.8 mg, 46%) as an off-white foam.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([OH:25])=O)=[CH:21][N:22]=2)[CH2:14][C@@H:13]1[F:26])=[O:10].CN([C:30]([O:34][N:35]1N=NC2C=CC=N[C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CNOC>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([N:35]([O:34][CH3:30])[CH3:36])=[O:25])=[CH:21][N:22]=2)[CH2:14][C@@H:13]1[F:26])=[O:10]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1[nH]c(C(=O)N[C@@H]2CCN(c3ncc(C(=O)O)s3)C[C@@H]2F)c(Cl)c1Cl
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cnc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](F)C2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (10 mg, 0.024 mmol) was dissolved in dry DMF (10 ml), HATU (9.1 mg, 0.024 mmol), triethylamine (7.27 mg, 0.072 mmol) and N,O-dimethylhydroxyamine (4.65 mg, 0.048 mmol) were added. The mixture was stirred at room temperature for 30 minutes, then was poured into cold water (30 ml), the precipitate was filtered, washed with water and collected as the desired product (off white solid, 10 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([O-])(=O)C.[Na+].[Br:16]Br.S(=O)(=O)(O)[O-].[Na+]>ClCCl>[Br:16][C:7]1[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH:8]=1
Reactant: Clc1ccc2sccc2c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc2scc(Br)c2c1
Yield: 85.2 %

Procedure:
In a 250 mL 2-neck round flask, 5-chlorobenzothiophene (2 g, 11.8 mmol) was dissolved in dichloromethane (10 mL), and sodium acetate (NaOAc) (1.95 g, 23.6 mmol) and Br2 (1.89 g, 11.8 mmol) were gradually added to the mixture for 5 minutes at 0□. After the reaction, a 10% sodium bisulfate (NaHSO3) solution (20 mL) was poured to the mixture, and then the resulting mixture was extracted with ethyl acetate (20 mL), dried over MgSO4, and distilled in vacuum to give 2.49 g of yellow solid (85% yield).
Reaction SMILES: [Na+:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][C@@H:11]1[C:23](=[O:24])[N:13]2[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]12)=[O:9].C(N(CC)CC)C.[CH2:32]=[C:33]1[O:37][C:35](=[O:36])[CH2:34]1.Cl>CN(C)C=O>[Na+:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][C@@H:11]1[C:23](=[O:24])[N:13]2[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][O:19][C:35](=[O:36])[CH2:34][C:33](=[O:37])[CH3:32])[CH2:16][S:17][C@H:12]12)=[O:9]
Reactant: C=C1CC(=O)O1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In N,N-dimethylformamide (20 ml) was dissolved 7β-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid sodium salt (3.86 g) and, at -5° C., triethylamine (1.40 ml) and diketene (1.50 ml) were added. The reaction was carried out at -5°-0° C. for 1 hour, after which time the reaction mixture was poured in ice-water (200 ml). The mixture was adjusted to pH 2.0 with 4 N-hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was rinsed with water, diluted with water, brought to pH 7.0 with 5% aqueous sodium hydrogen carbonate solution and separated. The water layer was taken, concentrated and subjected to column-chromatography on Amberlite XAD-2, elution being carried out with water-methanol. The eluate was lyophilized. The above procedure provided 7β-(2-thienylacetamido)-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid sodium salt (4.48 g).
Reaction SMILES: O[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]#[N:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]#[N:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccc2c(c1)[nH]c1ncnc(O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2c(c1)[nH]c1ncnc(Cl)c12
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-9H-pyrimido[4,5-b]indole-7-carbonitrile (215 mg, 1.02 mmol) in 5 mL POCl3 (5 mL) was heated at 100° C. for 18 hours. Upon cooling to room temperature the reaction mixture was evaporated to dryness and the residue treated with saturated sodium bicarbonate solution and ethyl acetate. The organic phase was dried over sodium sulphate and concentrated to the title compound as an orange solid. LC-MS (1) Rt 1.66 min; (100% UV), m/z (ES−) 227/229. The product was used without further purification.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25].[CH3:26][N:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[CH:29]=[N:28]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:32]([C:30]5[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=5)=[O:33])[CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25]
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCNC4)c3)ccc21
Reactant: Cn1cc(C(=O)O)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCN(C(=O)c5cnn(C)c5)C4)c3)ccc21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a solution of 1-methyl-6-[5-((S)-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one hydrochloride (0.04 g, 0.111 mmol, example 60), 1-methyl-1H-pyrazole-4-carboxylic acid (0.021 g, 0.167 mmol) and Hunig's base (0.036 g, 0.278 mmol) in EtOAc (2 mL) was added propylphosphonic acid anhydride (cyclic trimer) solution (50% in EtOAc, 0.177 mL, 0.25 mmol) dropwise and the reaction mixture was stirred at room temperature over night. The mixture was diluted with EtOAc, poured into a sat. NaHCO3 solution (5 mL) and extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH-DCM gradient to give the title compound (0.036 g, 75.1%) as a colorless amorphous solid. MS: 432.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([NH2:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11].C(N(CC)CC)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([NH:9][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:6][N:5]1[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCOC(=O)N1C[C@H](N)C[C@H]1C(=O)OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCOC(=O)N1C[C@H](NS(=O)(=O)c2ccc(C)cc2)C[C@H]1C(=O)OC
Yield: 80 %

Procedure:
A 3 ml solution of N-α-butoxycarbonyl-trans-4-amino-L-proline methylester 49 mg (0.20 mmol), triethylamine 0.042 ml (0.30 mmol), p-toluenesulfonyl chloride 42 mg (0.22 mmol) in chloroform was stirred at room temperature for 16 hours. To the reaction solution was added water and the mixture was extracted with chloroform and dried on magnesium sulfate. After filtration and concentration of the mixture, the residue was purified by a column chromatography on silica gel (eluted with a mixed solvent of ethyl acetate and hexane) to give 64 mg (0.16 mmol) of the title compound (yield: 80%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[C:10]([CH3:24])[CH:9]=1)=[O:6].CC(C)([O-])C.[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:24][C:10]1[CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH:13]=[CH:12][C:11]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(NC(=O)CCCCl)cc2C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2C)cc1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
Methyl 4'-((4-chlorobutanoyl)amino)-2'-methylbiphenyl-4-carboxylate (D3) (1.65 g, 4.8 mmol) was stirred in dry dimethylformamide (DMF) (20 ml) as potassium t-butoxide (0.70 g, 5.7 mmol) was added. The mixture was stirred for 30 min, diluted with ethyl acetate (200 ml), washed successively with brine, water and brine, dried (Na2SO4) and evaporated to give a light brown gum. Chromatography on silica gel, eluting with 0-50% ether/dichloromethane, gave the title compound (1.15 g, 71%) as a light yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])=[O:7].[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC=CC=1>C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[O:19][CH2:18][CH2:17][O:7]1
Reactant: OCCO
Reactant: COc1ccc(Cl)cc1C(=O)CCCCCl
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1C1(CCCCCl)OCCO1
Yield: 95.4 %

Procedure:
A mixture of 5-chloro-1-(5-chloro-2-methoxyphenyl)-1-pentanone (2 g, 7.66 mmol), prepared as in Example 7, ethylene glycol (1.25 g, 20 mmol), 2-napthalenesulfonic acid (50 mg, 0.24 mmol) and toluene (approximately 80 mL) was heated 4-5 hours at reflux (removing water with a Dean-Stark trap) and then additional ethylene glycol (1 g, 16 mmol) was added. The mixture was heated approximately 16 hours at reflux and then washed with saturated sodium bicarbonate, water (3×) and brine (1×), dried (K2 CO3), filtered and concentrated to give 5-chloro-1-(5-chloro-2-methoxyphenyl)-1,1-ethylenedioxypentane (2.23 g, 7.31 mmol) as an oil.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:19]=[C:18]2[C:10]([CH:11]=[CH:12][C:13]3[O:14][C:15](=[O:22])[C:16]([CH3:21])([CH3:20])[C:17]=32)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].N1C=CC=CC=1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].Cl>O>[CH3:21][C:16]1([CH3:20])[C:15](=[O:22])[O:14][C:13]2[CH:12]=[CH:11][C:10]3[C:18]([C:17]1=2)=[CH:19][C:7]([CH:2]([O:1][S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[C:3]([F:4])([F:6])[F:5])=[CH:8][CH:9]=3
Reactant: CC1(C)C(=O)Oc2ccc3ccc(C(O)C(F)(F)F)cc3c21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(c2ccc3ccc4c(c3c2)C(C)(C)C(=O)O4)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 8-(1-hydroxy-2,2,2-trifluoroethyl)-1,1-dimethyl-2(1H)-naphtho[2,1-b]furanone (0.04 g), pyridine (0.5 ml) and tosyl chloride (0.04 g) was stirred at room temperature for 18 h and then heated at 50° for 6 h. The mixture was cooled to room temperature, treated with water (10 ml) and the mixture was stirred at room temperature for 5 minutes and acidified with 2N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the extract was dried and evaporated to dryness under reduced pressure to give the required starting material, 1,1-dimethyl-8-(2,2,2-trifluoro-1-tosyloxyethyl)-2(1H)-naphtho[2,1-b]furanone, which was used without further purification. ##STR3##
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7](O)(=[O:11])/[CH:8]=[CH:9]/[CH3:10]>O>[CH3:10][CH:9]1[C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=2[C:7](=[O:11])[CH2:8]1
Reactant: C1=CCCCC1
Reactant: C/C=C/C(=O)O
Solvent: O
Product: CC1CC(=O)C2=C1CCCC2
Yield: 65.8 %

Procedure:
Cyclohexene (27.3 g, 0.33 mol), crotonic acid (28.7 g, 0.33 mol) and polyphosphoric acid (300 mL) were mechanically stirred under a nitrogen atmosphere at 60° C. for 30 minutes. The slurry was poured into water and the aqueous solution extracted with diethyl ether. The diethyl ether extract was washed successively with a 10 percent NaHCO3 solution and a saturated NaCl solution. The organic extract was dried over anhydrous MgSO4. The solution was filtered and the solvent removed under reduced pressure. The crude product was purified via vacuum distillation (bp 87°-92° C. at 5 mm) to give 32.6 g (66 percent) of purified material.