Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:92]=[CH:93][CH:94]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[C:67]([CH3:81])[CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:92]=[CH:93][CH:94]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:75][CH2:76]5)=[C:67]([CH3:81])[CH:66]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)c(C)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)ccc1N1CCN(C[C@H](C)O)CC1
Yield: 68 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methylphenyl)piperazin-1-yl)propan-2-ol (183 mg, 0.269 mmol) was hydrolyzed with lithium hydroxide (57 mg, 1.347 mmol) in THF/methanol/water (20/10/5 mL) to yield 96 mg (55.8% yield) of desired product. 1H NMR (CD3OD, 300 MHz): δ 8.63-8.62 (d, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 7.65-7.63 (d, 1H), 7.60-7.56 (dd, 1H), 7.42-7.32 (q, 1H), 7.26-7.24 (d, 1H), 7.12-7.10 (d, 1H), 7.06-7.00 (m, 2H), 5.44 (s, 2H), 4.30-4.20 (m, 1H), 3.77-3.68 (t, 2H), 2.44 (s, 3H), 1.32-1.23 (m, 3H). MS: m/z=525.4 (M+1), HPLC: 90.77% in method B.
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH2:5][CH2:4]1.Cl>C(O)C>[O:3]1[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:7][CH2:8]1
Reactant: COC(=O)CCN1CCOCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCN1CCOCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 109.4 %

Procedure:
Potassium hydroxide (485 mg, 8.6mmol) was added to a solution of methyl 3-morpholinopropionate (1 g, 5.7 mmol) in ethanol (20 ml) and the mixture stirred for 2 hours at 80° C. The solution was allowed to cool and adjusted to pH1 with 6M hydrochloric acid. Insoluble material was removed by filtration and the volatiles removed from the filtrate by evaporation. The resulting oil was triturated with ether, the solid product collected by filtration, washed with methylene chloride and dried under vacuum to give 3-morpholinopropionic acid (993 mg, 89%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:15][O:16][CH3:17])[CH:10]([N+:12]([O-])=O)[CH3:11].Cl>[Zn].CC(O)C>[NH2:12][CH:10]([CH3:11])[CH:9]([NH:15][O:16][CH3:17])[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CONC(c1ccc(Cl)cc1Cl)C(C)[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CC(C)O
Product: CONC(c1ccc(Cl)cc1Cl)C(C)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
N-[1-(2,4-dichloro-phenyl)-2-nitro-propyl]-O-methyl-hydroxylamine (0.123 g, 0.44 mmol), was dissolved with i-PrOH (9 ml) and treated with 1N HCl (4.4 ml, 4.4 mmol). Zinc dust (0.58 g, 8.8 mmol) was then added in small portions over 15 minutes and the solution allowed to stir for two hours at ambient temperature. The suspension was quenched by addition of saturated NaHCO3 (15 ml), stirred for 15 minutes and filtered through a small plug of Celite, washing with ethylacetate (40 ml). The organic extract was separated, dried over anhydrous MgSO4 an filtered and the solvent was removed under reduced pressure. 110 mg (100% of theory) of N-[2-Amino-1-(2,4-dichloro-phenyl)-propyl]-O-methyl-hydroxylamine (compound Z1.14) was obtained in the form of a colourless oil as a mixture of diastereomeres.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=O)[NH:7][O:8][C:4]=2[C:3]=1[F:12].O=P(Cl)(Cl)[Cl:15]>CCOCC>[Cl:15][C:6]1[C:5]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]([F:12])[C:4]=2[O:8][N:7]=1
Reactant: O=c1[nH]oc2c(F)c(F)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: Fc1ccc2c(Cl)noc2c1F
Temperature: 140 °C
Yield: 74 %

Procedure:
TEA (5.6 ml, 40.2 mmol) was added to an ice bath cooled mixture of 6,7-difluoro-1,2-benzisoxazol-3(2H)-one (Intermediate 528, 6.88 g, 40.2 mmol) and POCl3 (13.1 ml, 141 mmol) (exotherm results) in a microwave reactor vessel and the mixture was heated at 140° C. for 6 hours in a microwave reactor. The mixture was taken up in ether and washed with Na2CO3 (2×) and brine. The combined aqueous layers were twice more extracted with ether, which was washed with Na2CO3 and brine. The combined ether layers were dried (MgSO4) and concentrated to give an oil that slowly solidified. The material was chromatographed on silica gel (hexanes followed by gradient elution to 50% CH2Cl2 in hexanes) to afford 5.64 g of product as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:21])=[C:6]([CH:10]=[C:11]2[C:15](=[O:16])[NH:14][N:13]=[C:12]2[O:17][CH:18]([CH3:20])[CH3:19])[NH:7][C:8]=1[CH3:9])([OH:3])=[O:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:33][N:34]([CH2:36][CH2:37]O)[CH3:35]>ClCCl>[CH3:33][N:34]([CH3:35])[CH2:36][CH2:37][O:2][C:1]([C:4]1[C:5]([CH3:21])=[C:6]([CH:10]=[C:11]2[C:15](=[O:16])[NH:14][N:13]=[C:12]2[O:17][CH:18]([CH3:19])[CH3:20])[NH:7][C:8]=1[CH3:9])=[O:3]
Reactant: CN(C)CCO
Reactant: Cc1[nH]c(C=C2C(=O)NN=C2OC(C)C)c(C)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1[nH]c(C=C2C(=O)NN=C2OC(C)C)c(C)c1C(=O)OCCN(C)C
Reaction time: 24 h

Procedure:
A mixture of 4-[(4-carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one (200 mg, 0.68 mmol) in dichloromethane (20 ml) and a drop of DMF, was treated with oxalyldichloride (0.2 ml). The stirring was continued for 24 h and a solution of dimethylaminoethanol (0.6 g, 6.7 mmol) in dichloromethane (5 ml) was added. The stirring was continued for 24 h. The solvent was evaporated to dryness, the solid residue was treated with NaHCO3 (5%) and extracted with dichloromethane. The solid obtained after elimination of the solvent was recrystallized from n-heptane.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].[CH3:11][Si:12]([CH2:15][Mg]Cl)([CH3:14])[CH3:13]>CCOCC>[C:2]1([CH:1]([OH:8])[CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C[Si](C)(C)CC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To benzaldehyde (2.17 g, 20.4 mmol) in 20 mL of ether, 1 M (trimethylsilyl)methyl magnesium chloride solution in ether (28.6 mL) was added at 0° C. After two hours of stirring at 0° C., a saturated NH4Cl solution was added and the mixture was extracted with ether (3×). The combined organic extract was dried (Na2SO4), filtered, and concentrated to give the title product (4.12 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:71]=[CH:70][C:53]2[NH:54][C:55]([C@@H:57]([NH2:69])[CH2:58][C:59]3[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[C:61]([O:67][CH3:68])[CH:60]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:71]=[CH:70][C:53]2[NH:54][C:55]([C@@H:57]([NH:69][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[C:61]([O:67][CH3:68])[CH:60]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: COc1ccc(C[C@H](N)c2nc3cc(Cl)ccc3[nH]2)cc1OC
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C[C@H](NC(=O)c2ccc(C(=O)N3CCCC3)c(C)c2)c2nc3cc(Cl)ccc3[nH]2)cc1OC

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-(3,4-di-methoxyphenyl)ethylamine in tetrahydrofuran. Yield: %; Rf value: 0.38 (silica gel: dichloromethane/ethanol=9:1); C30H31ClN4O4 (547.06); mass spectrum: (M+H)+=547/549 (chlorine isotope).
Reaction SMILES: [I-].[C:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N+:14]([CH3:17])([CH3:16])C)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1C=CN=[CH:19]1.[ClH:23]>C(O)C.CCOCC>[ClH:23].[C:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N:14]2[CH:16]=[CH:19][N:18]=[CH:17]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](C)(C)Cc1cccn1-c1ccccc1
Reactant: c1c[nH]cn1
Agent: Cl
Agent: [I-]
Solvent: CCO
Solvent: CCOCC
Product: c1ccc(-n2cccc2Cn2ccnc2)cc1

Procedure:
A solution of [1-phenyl-pyrrol-2-yl]methyl trimethylammonium iodide (J.A.C.S., 73, 4921, (1951) (3.42 g) and imidazole (0.68 g) in ethanol (70 ml) was heated under reflux for 7 hours. The solution was evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave an oil which was dissolved in ether. Addition of an excess of ethereal hydrogen chloride gave a precipitate which was filtered off and crystallised from methanol/ethyl acetate to give 1-phenyl-2-(imidazol-1-ylmethyl) pyrrole hydrochloride (0.65 g), m.p. 140°-141°.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[CH3:29][O:30][C:31](=[O:38])[C@H:32]([C@H:34]([CH2:36][CH3:37])[CH3:35])[NH2:33]>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:38])[CH:32]([NH:33][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9])[CH:34]([CH3:35])[CH2:36][CH3:37]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C)C(NC(=O)c1cccnc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70.2 %

Procedure:
To a solution of nicotinic acid (2.0 g, 16.5 mmol) in DCM (20 mL), was added N-methylmorpholine (6.9 mL, 49.5 mmol), EDCI.HCl (6.3 g, 33.0 mmol) and isoleucine methyl ester (3.0 g, 16.5 mmol). The mixture was allowed to stir at room temperature (25° C.) over 2.5 h under nitrogen atmosphere. The resulting mixture was diluted with DCM (200 mL), washed with water (3×100 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was further purified by silica gel column chromatography to obtain product as yellow solid (2.9 g, 72%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].C(OP([CH:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(OCC)=O)C.C=O>O>[CH2:1]=[C:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Agent: C=O
Agent: [K+]
Solvent: O
Product: C=C(CC)C(=O)OCC
Temperature: 85 °C
Reaction time: 0.75 h

Procedure:
Potassium carbonate (5.5 g) was dissolved in water (15 mL). To the solution, ethyl 2-(diethoxyphosphoryl)butyrate (5.0 g) and a 37% aqueous formaldehyde (6.2 g) were added at room temperature, and the mixture was stirred at 85° C. for 45 minutes. Organic matter was extracted with diethyl ether, dried over anhydrous sodium sulfate, and filtered, and the solvent in the filtrate was distilled off under reduced pressure to obtain a crude product.
Reaction SMILES: [OH-:1].[Na+].BrBr.[CH3:5][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:7][C:8](=[O:10])C>>[CH3:11][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:5])[CH2:7][C:8]([OH:10])=[O:1]
Reactant: [OH-]
Reactant: CC(=O)CC(C)(C)c1ccccc1
Agent: BrBr
Agent: [Na+]
Product: CC(C)(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of NaOH (47.2 g, 1.18 mole) in ice/H2O (270 g) maintained at 4°-5° C. was added Br2 (68.7 g, 0.43 mole) followed by 4-methyl-4-phenyl-2-pentanone (23.7 g, 0.135 mole). The reaction was stirred for 18 hours at room temperature. The crude reaction mixture was extracted with CCl4 (discarded), acidified to pH 1-2 with concentrated HCl solution and extracted with ethyl acetate. The combined organics were washed with saturated NaCl solution, dried over Na2SO4 and evaporated in vacuo to obtain 22.5 g of the title B compound as an off-white solid. This was used in the next step without further purification. MS: (M+NH4)+ @ 196.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:22][CH:23]2[CH2:28][CH2:27][C:26](=O)[NH:25][CH2:24]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)=O>O1CCOCC1.O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:22][CH:23]2[CH2:24][N:25]3[C:26](=[N:1][C:2]4[C:3]([C:4]3=[O:6])=[CH:7][CH:8]=[C:9]([Br:11])[CH:10]=4)[CH2:27][CH2:28]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=C1CCC(OS(=O)(=O)c2ccc(Br)cc2)CN1
Reactant: Nc1cc(Br)ccc1C(=O)O
Solvent: C1COCCO1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2ccc(Br)cc2nc2n1CC(OS(=O)(=O)c1ccc(Br)cc1)CC2
Temperature: 25 °C

Procedure:
A solution of 2-amino-4-bromobenzoic acid (1.4 g, 6.6 mmol, 1.1 equiv), 6-oxopiperidin-3-yl 4-bromobenzenesulfonate (2 g, 6.0 mmol, 1 equiv), and phosphoryl trichloride (4 mL) in 1,4-dioxane (100 mL) was stirred at 80° C. for two hours. After it was cooled to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CO[C:38](=[O:77])[C@H:39]([CH2:68][S:69]CC1C=CC=CC=1)[NH:40][C:41]([C:43]1[NH:44][C:45]2[C:50]([CH:51]=1)=[CH:49][C:48]([O:52][CH2:53][CH2:54][O:55][CH3:56])=[CH:47][C:46]=2[N:57]([CH3:67])[S:58]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=1)(=[O:60])=[O:59])=O.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+].COCCOC1C=C2C(=C(N(C)S(C3C=CC=CN=3)(=O)=O)C=1)NC(C1SC[C@@H](C(OC)=O)N=1)=C2.[BH4-].[Na+]>ClCCl.O1CCCC1.O.CO>[OH:77][CH2:38][C@@H:39]1[CH2:68][S:69][C:41]([C:43]2[NH:44][C:45]3[C:50]([CH:51]=2)=[CH:49][C:48]([O:52][CH2:53][CH2:54][O:55][CH3:56])=[CH:47][C:46]=3[N:57]([CH3:67])[S:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=2)(=[O:59])=[O:60])=[N:40]1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)N[C@@H](CSCc3ccccc3)C(=O)OC)cc2c1
Agent: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](C(=O)OC)CS3)cc2c1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CSc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
To a solution of triphenylphosphine oxide (2.7 g) in dichloromethane (6 mL) was added dropwise trifluoromethanesulfonic anhydride (1.2 mL) at 0° C., and the mixture was stirred at 0° C. for 15 min. The obtained suspension was diluted with dichloromethane (19 mL), and a solution of S-benzyl-N-({5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}carbonyl)-L-cysteine methyl ester (1.0 g) and thioanisole (1.5 mL) in dichloromethane (25 mL) was added. The reaction mixture was stirred at 0° C. for 1 hr, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was concentrated. The residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1, volume ratio) to give a mixture of methyl (4R)-2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-4-carboxylate and triphenylphosphine oxide. The obtained mixture of the ester and triphenylphosphine oxide was dissolved in tetrahydrofuran (5 mL), sodium borohydride (0:053 mg) was added at 0° C., and methanol (2.5 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, and then at room temperature for 3 hr. Water was added, the mixture was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-0:1, volume ratio) to give the title compound (0.27 g, yield 36%) .as a colorless amorphous solid. MS:477(MH+).
Reaction SMILES: [Na].[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([NH:26][C:25]3[CH:27]=[CH:28][C:22]([F:21])=[CH:23][CH:24]=3)=[O:20])[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1
Agent: [Na]
Product: O=C(Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1)Nc1ccc(F)cc1

Procedure:
The product is prepared by following the procedure described in step 3b of example 1b, but using 670 mg of the sodium salt of [4-(2-fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid and 762 mg of 4-fluoroaniline. 300 mg of 2-[4-(2-fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(4-fluorophenyl)acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]2[NH:9][C:10]([NH:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+].Cl.C(OCC)(=O)C>CO>[C:23]1([CH2:22][CH2:21][CH2:20][N:17]2[CH2:16][CH2:15][CH:14]([CH2:13][NH:12][C:10]3[NH:9][C:8]4[CH:29]=[CH:30][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=4[N:11]=3)[CH2:19][CH2:18]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2[nH]c(NCC3CCN(CCCc4ccccc4)CC3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc2[nH]c(NCC3CCN(CCCc4ccccc4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
After suspending 2-{[1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-5-carboxylic acid methyl ester (3.2 mmol) in methanol (10 ml), a 4N lithium hydroxide aqueous solution (5.4 ml, 21.4 mmol) was added. The reaction mixture was stirred at 50° C. for 2 hours and then cooled to room temperature. Next, 1N hydrochloric acid was added dropwise to adjust the pH to approximately 6.0. Ethyl acetate (1 ml) was added to the aqueous solution and the mixture was stirred for 3 hours, and then the precipitate was filtered out to obtain 2-{[1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-5-carboxylic acid. The compound was identified by LC-MS.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[F:22][C:23]1[CH:24]=[C:25]([CH2:29]C#N)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([C:29]2[O:3][N:1]=[C:4]3[CH:5]=[CH:6][C:7]([C:10]4[N:14]([C:15]5[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=5)[N:13]=[CH:12][CH:11]=4)=[CH:8][C:9]=23)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: N#CCc1cccc(F)c1
Product: Cc1ccc(-n2nccc2-c2ccc3noc(-c4cccc(F)c4)c3c2)cc1

Procedure:
The title compound, light green solid (95 mg, 72%), MS (ISP) m/z=370.2 [(M+H)+], mp 207° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8])[CH:3]1[C:13]([OH:15])=[O:14].[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH:10]2[CH2:17][CH2:12][CH2:11]2)=[O:8])[CH:3]1[C:13]([OH:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCOC(=O)C=CC1C(C(=O)O)C1(C)C
Solvent: Cc1ccccc1
Product: CC1(C)C(C=CC(=O)OC2CCC2)C1C(=O)O
Reaction time: 2 h

Procedure:
A mixture of 2.3 g of the product of Step A, 25 ml of toluene and 250 mg of p-toluene sulfonic acid was refluxed for 15 minutes and was cooled. The mixture was stirred for 2 hours at 0° to 5° C. and was filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 1.8 g of (1R, cis, ΔZ) 2,2-dimethyl-3-(3-cyclobutoxy-3-oxo-1-propenyl)-cyclopropane-carboxylic acid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+].O.O.[Br-].[Ca+2].[Br-]>CO>[CH3:1][O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Br-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 87.7 %

Procedure:
2 g of sodium 3-acetoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate were dissolved in 20 ml of 50% v/v aqueous methanol, and 20 g of calcium bromide dihydrate were added to the resulting solution. The mixture was then stirred at 70° C. for 50 minutes, after which it was treated as described in Example 2, to give 1.55 g of 3-methoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylic acid, in the form of a yellow solid.
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2(C(O)=O)[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.Cl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH2:15])[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN1CCC(C(=O)O)(c2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCC(N)(c2ccc(F)cc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
TEA (1.3 mL) and diphenylphosphorylazide (0.98 mL) were added to a suspension of 4-(4-fluorophenyl)-1-methyl-4-piperidinecarboxylic acid hydrochloride (500 mg) in dry toluene (40 mL) under nitrogen atmosphere. The reaction mixture was heated at 90° C. and stirred overnight. Then it was cooled to rt and washed with an aqueous std K2CO3 solution. The aqueous layer was separated and the organic phase was dried and concentrated under vacuum to give a white solid. This material was suspended in HCl 5M (10 mL) and the reaction mixture was heated to reflux and stirred overnight. Then it was cooled to 0° C. and treated with aqueous 4M NaOH solution until pH=9. The aqueous layer was extracted with AcOEt, the combined organic extracts were washed with water and brine, dried and concentrated under vacuum to a residue which was purified by silica cartridge (from DCM to DCM/MeOH/TEA 90:5:5) to give the title compound (70 mg) as a white foam.