Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][CH2:11][C:10]=1[C:14]1[CH:15]=[C:16]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH:17]=[C:18]([CH:22]=1)[C:19]([OH:21])=[O:20].[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH2:31]Br>CC(C)=O>[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH2:31][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:14]([C:10]2[CH2:11][CH2:12][CH2:13][C:9]=2[C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[O:1][CH2:31][C:30]2[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:29]=2[F:28])[CH:15]=[C:16]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH:17]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CCC(=O)Nc1cc(C(=O)O)cc(C2=C(c3cc(C)ccc3O)CCC2)c1
Solvent: CC(C)=O
Product: CCC(=O)Nc1cc(C(=O)OCc2ccc(F)cc2F)cc(C2=C(c3cc(C)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure 5 but using 5-[2-(2-hydroxy-5-methylphenyl)cyclopent-1-enyl]-3-(propionamido)benzoic acid instead of 6-[2-(5-chloro-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylic acid, 2,4-difluorobenzyl bromide instead of 4-chlorobenzyl bromide and acetone instead of 2-butanone.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[C:41]=1[OH:55].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[Cl:39][C:40]1[C:41]([OH:55])=[C:42]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[CH:44][CH:45]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cccc(Cl)c2O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc(Cl)c3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 55 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.30 mmol), sodium carbonate (32 mg, 0.30 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 0.01 mmol) in 1,2-dimethoxyethane (900 μl) and water (225 μl) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 35%, hexane-ethyl acetate) to give 58 mg (55% yield, 77% purity) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)C1C=CC=CC=1.O>ClCCl>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:10]2[S:11][C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:9]=2[OH:8])=[CH:24][CH:23]=1
Reactant: COc1ccc(Cc2sc(C(F)(F)F)cc2OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cc2sc(C(F)(F)F)cc2O)cc1
Reaction time: 0.08 h
Yield: 90.2 %

Procedure:
To a solution of (3-benzyloxy-2-(4-methoxybenzyl)-5-trifluoromethylthiophene (170.5 mg, 0.45 mmol) in dichloromethane (4.5 mL), a solution of boron tribromide-dimethylsulfide complex in dichloromethane (0.47 mL, 0.47 mmol) was added at −78° C. in a nitrogen stream. The reaction mixture was stirred at the same temperature for five minutes and then at 0° C. for 11 hours. To the reaction mixture, water was added and the resulting mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried (anhydrous sodium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (117.0 mg, 90%).
Reaction SMILES: C(O[C:6]([NH:8][C:9]1([CH2:15][C:16]([OH:18])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@@:26]2([OH:34])[CH2:31][CH2:30][NH:29][CH2:28][C:27]2([CH3:33])[CH3:32])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2N=N1>CN(C=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@@:26]2([OH:34])[CH2:31][CH2:30][N:29]([C:16](=[O:18])[CH2:15][C:9]3([NH:8][C:6](=[O:7])[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[CH2:28][C:27]2([CH3:32])[CH3:33])=[CH:22][CH:21]=1
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)O)CCOCC1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)CC2(NC(=O)c3ccccc3)CCOCC2)CC[C@]1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
To a solution of 2-(4-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-yl)acetic acid (step 2, 0.125 g, 0.48 mmol) in anhydrous DMF (1 mL) was sequentially added (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (0.182 g, 0.48 mmol), diisopropylethylamine (0.17 mL, 0.96 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.225 g, 0.50 mmol) at room temperature. Upon completion of addition, the reaction mixture was stirred at room temperature for 20 h and then partitioned between ethyl acetate (20 mL) and 1N HCl (10 mL). The ethyl acetate layer was separated, washed sequentially with 1N NaOH (10 mL), brine (10 mL), dried over sodium sulfate and concentrated to yield a residue. The residue was purified using a pre-packed silica gel column (40 g) employing hexane and ethyl acetate. The desired fractions were collected and concentrated under reduced pressure to yield the title compound (0.175 g) as a foamy solid. MS (ESI+)=481.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:16][CH2:17][CH2:18][OH:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:16][CH2:17][CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCCSc1cccc(Br)c1
Temperature: 50 °C
Yield: 98.1 %

Procedure:
A solution of 3-bromobenzenethiol (5.00 g, 26.4 mmol) in anhydrous DMF (30 mL) was treated with Cs2CO3 (17.2 g, 52.9 mmol) followed by 3-bromopropan-1-ol (4.40 g, 31.6 mmol). The mixture was heated to 50° C. under nitrogen for 12 h. DMF was distilled out completely, and the residue was dissolved in DCM and washed with water, brine and dried over Na2SO4. The solvent was evaporated to afford 6.4 g (98%) of the title compound as pale yellow liquid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[C:8]([O:23][CH3:24])[CH:7]=2.[NH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>C(#N)C>[CH3:21][CH:20]([S:17]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:23][CH3:24])[N:5]=[C:4]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=1)[C:3]([CH2:2][N:35]1[CH2:40][CH2:39][CH:38]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH2:37][CH2:36]1)=[C:12]2[C:13]([O:15][CH3:16])=[O:14])(=[O:19])=[O:18])[CH3:22]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(N3CCOCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Reaction time: 3 h
Yield: 64.8 %

Procedure:
A suspension of methyl 3-(bromomethyl)-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.025 g, 1.83 mmol) and 4-(4-piperidinyl)morpholine (0.405 g, 2.379 mmol) in acetonitrile (10 mL) was stirred for 3 h. The solvent was removed under reduced pressure, and the residue was dissolved in DMSO and purified via HPLC (Biotage RP, 0-50% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl 6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.77 g, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ8.37 (s, 1H), 7.98 (s, 1H), 7.87-7.94 (m, 2H), 7.81 (s, 1H), 7.79 (d, J=7.78 Hz, 1H), 4.09 (s, 3H), 4.01 (s, 3H), 3.83 (quin, J=6.78 Hz, 1H), 3.61 (s, 2H), 3.53 (br. s., 4H), 2.59-2.69 (m, 2H), 2.38 (br. s., 4H), 2.00 (t, J=10.54 Hz, 1H), 1.77-1.86 (m, 2H), 1.62 (d, J=11.04 Hz, 2H), 1.24-1.30 (m, 2H), 1.22 (s, 3H), 1.21 (s, 3H); MS (m/z) 650.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:7][C:5]([NH2:6])=[C:4]([N+:18]([O-])=O)[CH:3]=1.Cl>C(O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:6])=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Nc1cc(Oc2ccc(F)cc2F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: Nc1cc(Cl)c(Oc2ccc(F)cc2F)cc1N
Temperature: 85 °C
Reaction time: 4 h
Yield: 51.3 %

Procedure:
To a solution of 2,4-difluorophenol (1.9 g, 14.61 mmol) in DMSO (20 ml) was added 4,5-dichloro-2-nitroaniline (3 g, 14.49 mmol) and potassium carbonate (4 g, 28.94 mmol) with stirring overnight at 90° C. Then the reaction was quenched with water (200 ml) and extracted with ethyl acetate (3×100 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The organic layers were concentrated under vacuum to give a residue, which was purified by a silica gel column with 2%˜5% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-fluoro-2-methylphenoxy)-2-nitroaniline as a yellow solid (1.3 g, 30%). Next, to a solution of 4-chloro-5-(2,4-difluorophenoxy)-2-nitroaniline (1.3 g, 4.32 mmol) in ethanol (20 ml) was added hydrogen chloride (conc. 1 ml) followed by the addition of Zn powder (1.7 g, 25.92 mmol) in portions at room temperature. The resulting solution was stirred for 4 h at 85° C. The resulting mixture was concentrated under vacuum and dissolved in water (150 ml), adjusted pH to 8 with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 ml), dried and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(2,4-difluorophenoxy)benzene-1,2-diamine as a light yellow solid (600 mg, 51%). Finally, a solution of 4-chloro-5-(2,4-difluorophenoxy)benzene-1,2-diamine (100 mg, 0.37 mmol) in hydrogen chloride (conc. 2 ml) and TFA (10 ml) was stirred overnight at 80° C. The solution was quenched with water (100 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×50 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%˜10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-difluorophenoxy)-2-(trifluoromethyl)-1H-1,3-benzodiazole as a white solid (73.5 mg, 57%).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:15]=[C:14]1[S:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:5])C.[OH-].[Na+]>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:16]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:15]=[C:14]1[S:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])([OH:5])=[O:3]
Reactant: CCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCCCC(=O)O

Procedure:
1-(7-Ethoxycarbonylheptyl)-2-octylthio-4,5-diphenylimidazole (1 g) was reacted with 2N sodium hydroxide in a method similar to Example 10 to give, after chromatography on silica gel eluted with a dichloro-methane:methanol gradient, 1-(7-carboxyheptyl)-2 octylthio-4,5-diphenyl-imidazole (0.47 g, 49%) as an oil. Found: C, 73.56; H, 8.59; N, 5.60; S, 6.47%; C31H42N2O2S requires: C, 73.47; H, 8.35; N, 5.53; S, 6.33%.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:9][CH2:8]1.[CH3:30][O:31][CH2:32][CH2:33][N:34]1[CH2:43][CH2:42][C:41]2[C:40]([C:44](O)=[O:45])=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]1=[O:47].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][C@H:3]([NH:2][C:44]([C:40]1[C:41]2[CH2:42][CH2:43][N:34]([CH2:33][CH2:32][O:31][CH3:30])[C:35](=[O:47])[C:36]=2[CH:37]=[CH:38][CH:39]=1)=[O:45])[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:9][CH2:8]1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: COCCN1CCc2c(C(=O)O)cccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cccc2C1=O
Reaction time: 20 h
Yield: 30 %

Procedure:
Poured into a suspension of 242 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 104 mg of 2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 8 mg of hydroxybenzotriazole, 99 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 7 cm3 of dichloromethane is 0.28 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The reaction mixture is kept stirring for 20 h at a temperature close to 20° C. The suspension obtained is filtered and the precipitate is washed 3 times with 5 cm3 of ethyl ether, then dried under vacuum. 79 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a white powder.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]1[CH:27]=[N:26][C:25]([S:4][CH2:1][CH2:2][CH3:3])=[N:24][CH:23]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCS
Reactant: Clc1ccc(OCc2ccccc2)c(-c2cnc(Cl)nc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCSc1ncc(-c2cc(Cl)ccc2OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Propanethiol (3.1 ml) was added to a stirred suspension of sodium hydride (1.4 g, 60% in oil) in DMF (30 ml). After 1 hour a solution of the product from step (i) (2.4 g) in DMF (10 ml) was added. The reaction mixture was stirred at RT for 1 hour then partitioned between EtOAc and water. The organics were washed with water, brine, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5% EtOAc/isohexane. Yield 1.87 g
Reaction SMILES: [I-].[C:2]1([CH:8]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:29])[C@@H:19]([NH:20][C:21](=[O:28])[CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[CH2:30][P+:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+].C[C:60](C)=[O:61]>>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][C:21]([NH:20][C@:19]1([O:61][CH3:60])[C:18](=[O:29])[N:17]2[C:12]([C:10]([O:9][CH:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:11])=[C:13]([CH:30]=[P:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:14][S:15][C@H:16]12)=[O:28]
Reactant: CC(C)=O
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CO[C@@]1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@@H]21

Procedure:
To a solution of [4-diphenylmethoxycarbonyl-7β-thiopheneacetamido-ceph-3-em-3-ylmethyl]triphenylphosphonium iodide (0.1 g) in acetone:water (12 ml:2 ml) is added in an ice-bath and the pH adjusted to pH 11 with 2 N sodium hydroxide. The reaction mixture is diluted with an equal volume of solvent and filtered. The precipitate is washed with acetone and ether and dried to give benzhydryl 7β-thiopheneacetamido-7-methoxy-3-(triphenylphosphoranylidenemethyl)-ceph-3-em-4-carboxylate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[C:10]2/[C:11](=O)[CH2:12][CH2:13][C:14]3[C:19]/2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:24][OH:25].N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:24]\[OH:25])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(/C=C2/C(=O)CCc3ccccc32)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one (50 mg, 0.16 mmol) and hydroxylamine hydrochloride salt (22 mg, 0.32 mmol) was added into pyridine (2.0 ml) and then stirred overnight at reflux condition. Cooled to room temperature, dichloromethane (40 ml) was added, washed twice using 2 N hydrochloric acid (40 ml) and again washed twice using the saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was made to solid by adding diisopropylether and n-hexane, filtrated and dried. As a result, 36.7 mg of the present compound (productive yield 70%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[I-].[Na+].[H-].[Na+].Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33](=[O:41])[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1>CN(C=O)C>[F:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[S:10]([C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)(=[O:12])=[O:11])[CH2:28][CH2:29]2)=[O:41])=[CH:39][CH:38]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCl)CC1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
In an atmosphere of argon, N-(2-methoxyphenyl)-p-toluenesulfonamide (277 mg, 1.0 mmol) and a catalytically effective amount of sodium iodide were dissolved in DMF (3 ml) to which was subsequently added sodium hydride (44 mg, 60%, 1.1 mmol) at room temperature. After stirring at the same temperature for 30 minutes and then at 60° C. for 10 minutes, 1-(2-chloroethyl)-4-(4-fluorobenzoyl)piperidine (324 mg, 1.2 mmol) which has been divided into 3 portions, each being dissolved in DMF (1 ml), was added to the reaction solution at 1 hour intervals at 60° C. After 1.5 hours of additional stirring at the same temperature, DMF was removed by evaporation. The thus obtained residue was diluted with water (10 ml) and extracted with ether. The resulting organic layer was washed with water and saturated brine, and dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by a silica gel column chromatography (ether:hexane=2:1) to obtain 467 mg (91.5%) of the title compound in the form of colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)#[N:2].[OH-].[Li+]>CO.O1CCCC1>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)#[N:2]
Reactant: COC(=O)c1ccc2c(C#N)n[nH]c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1n[nH]c2cc(C(=O)O)ccc12
Temperature: 50 °C
Yield: 36.5 %

Procedure:
To a solution of methyl 3-cyano-1H-indazole-6-carboxylate (1.47 g, 7.31 mmol) in methanol (36 mL) and tetrahydrofuran (20 mL) was added 2 N aqueous lithium hydroxide (16 mL, 32 mmol). The reaction was heated to 50° C. for 72 hours. The reaction was cooled to room temperature and concentrated. The residue was diluted with water and the pH was adjusted to 4 with 1 N aqueous hydrochloric acid. The resulting precipitate was filtered off, rinsed with water, and dried under vacuum to provide the title compound (500 mg, 37%) as a tan solid. +ESI (M+H) 188.2.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([NH:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[O:13])=[N:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[ClH:32]>>[ClH:32].[NH2:17][CH2:16][CH2:15][NH:14][C:12]([C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][O:10][N:9]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1nocc1-c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NCCNC(=O)c1nocc1-c1ccccc1
Yield: 94.1 %

Procedure:
5.0 g (15.1 mmol) of t-butyl [2-(4-phenyl-3-isoxazolecarboxamido)ethyl]carbamate were stirred at room temperature for 16 hours with trifluoroacetic acid analogously to Example 13. After concentration there was obtained a residue which was converted into the hydrochloride. Recrystallization of the crude product from methanol/ether yielded 3.8 g (94.1%) of N-(2-aminoethyl)-4-phenyl-3-isoxazolecarboxamide hydrochloride as white crystals, melting point 211°-212°.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][CH:25]([F:34])[CH2:26][C@@H:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH2:28])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[N+:35]([C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1)([O-:37])=[O:36]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][CH:25]([F:34])[CH2:26][C@@H:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH:28][S:44]([C:41]1[CH:40]=[CH:39][C:38]([N+:35]([O-:37])=[O:36])=[CH:43][CH:42]=1)(=[O:45])=[O:46])=[O:21])[CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CCOC(=O)[C@@H](N)CC(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](CC(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
To a solution of the material from Step 4 (170 mg, 0.359 mmol) in pyridine (1.5 mL) at room temperature were added 4-nitrobenzenesulfonyl chloride (119 mg, 0.539 mmol) and DMAP (8.77 mg, 0.072 mmol). The reaction mixture was stirred at 85° C. overnight. Upon cooling to rt, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel using ethyl acetate-hexanes (0:100 to 90:10) to afford 50 mg of the title compound as a yellow foam. LCMS (M+1)=659.