Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]([S:17][CH3:18])=[C:4]([C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[CH3:15])[C:5]#[N:6].[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([Cl:30])[C:21]=1[NH:31][NH2:32]>C(O)C>[NH2:6][C:5]1[N:31]([C:21]2[C:22]([Cl:30])=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[CH:25][C:20]=2[Cl:19])[N:32]=[C:3]([S:17][CH3:18])[C:4]=1[C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[CH3:15]
Reactant: CSC(SC)=C(C#N)C(=O)c1cc(C)ccc1C
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1cc(C)ccc1C
Yield: 88.5 %

Procedure:
A suspension of 7.94 g (28.6 mmol) of the product of step C and 7.01 g (28.6 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 100 mL of ethanol was heated at reflux for 2 hours, solution occurring as the reaction mixture was warmed. Then the ethanol was mostly removed on the rotary evaporator and the residues were partitioned between dilute aqueous hydrogen chloride solution and ethyl acetate. The organic phase was washed once with water and with brine, then dried with magnesium sulfate and treated with decolorizing carbon. The filtered solution was evaporated and the residues crystallized from 10:1 hexane/ethyl acetate to give 12.00 g (88%) of the title product in two crops, m.p. 130-132° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:32])[N:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:33])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:32])[N:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[CH:21][CH:22]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)cc1)C(=O)O
Temperature: 42.5 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
To a suspension of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester (0.278 mmol, 131 mg) in ethanol (4 mL) was added aqueous 1.0 N sodium hydroxide (3 mL) at room temperature. The mixture was heated to 40-45° C. and the resulting clear solution was stirred for 2-3 h. The ethanol was removed under reduced pressure and the residue was diluted with water (20 mL) and NaOH (3 mL, 1.0N) to dissolve the sodium salt. The aqueous solution was washed with ether (50 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate afforded 107 mg (85%) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine as a white solid: mp 234-236° C. EI-HRMS m/e calcd for C23H22N3O5Cl (M+H) 456.1326, found 456.1326.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:36])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[C:25]([N+:30]([O-])=O)[CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]=2[C:33]([NH2:35])=[O:34])=[CH:17][CH:16]=1>CO.[Pd]>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[NH:23][C:22]([C:33]([NH2:35])=[O:34])=[C:21]2[C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:13]([NH:12][C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:9])[F:10])[CH:6]=[CH:7][C:2]=2[F:1])=[O:36])=[CH:20][CH:19]=1
Reactant: NC(=O)c1[nH]c2c([N+](=O)[O-])cccc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1[nH]c2c(N)cccc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 2 h
Yield: 40.4 %

Procedure:
3.28 g of palladium-on-charcoal are added to a suspension of 3.42 g (6.82 mmol) of 3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-7-nitro-1H-indole-2-carboxamide in 480 ml of methanol. The reaction mixture is hydrogenated at 30° C. under 3 bar for 2 h in an autoclave, and is then filtered over yridi. The filtrate is evaporated to dryness under reduced pressure. The residue obtained is triturated with ethyl acetate and a small amount of methylene chloride and then filtered. 1.30 g of 7-amino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-indole-2-carboxamide are obtained in the form of a gray solid.
Reaction SMILES: I.CO[CH:4](OC)[CH2:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)[CH2:14][CH2:13]1)=[NH:8].Cl.[OH-].[Na+]>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]2[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=[C:19]2[NH:18][CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][NH:9][C:7]3[NH:6][CH:5]=[CH:4][N:8]=3)[CH2:13][CH2:14]2)=[CH:26][CH:27]=1
Reactant: COC(CNC(=N)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)OC
Agent: Cl
Agent: I
Agent: [Na+]
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4ncc[nH]4)CC3)nc3ccccc32)cc1
Yield: 26 %

Procedure:
A mixture of 12.5 parts of N-(2,2-dimethoxyethyl)-N'-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]guanidine monohydroiodide and 100 parts of a hydrochloric acid solution 10% was stirred and refluxed for 1 hour. The reaction mixture was poured onto crushed ice. The whole was treated with a sodium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The solid residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 2.3 parts (26%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(1H-imidazol-2-ylamino)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 226.5° C. (compound 79).
Reaction SMILES: [I-].[K+].Cl.Cl[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]([N:18]([CH3:20])[CH3:19])[CH3:17])=[CH:11][CH:10]=1)=[O:7].[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].C1(S(O)(=O)=O)C(S(O)(=O)=O)=CC=C2C=1C=CC=C2>C(O)C>[CH2:21]([N:23]([CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]([N:18]([CH3:20])[CH3:19])[CH3:17])=[CH:11][CH:10]=1)=[O:7])[CH2:24][CH3:25])[CH3:22]
Reactant: CCNCC
Reactant: CC(=Nc1ccc(NC(=O)CCl)cc1)N(C)C
Agent: Cl
Agent: O=S(=O)(O)c1ccc2ccccc2c1S(=O)(=O)O
Agent: [I-]
Solvent: CCO
Product: CCN(CC)CC(=O)Nc1ccc(N=C(C)N(C)C)cc1

Procedure:
1 g of potassium iodide is added to a solution of 23.2 g of N'-(4-chloroacetylaminophenyl)-N,N-dimethylacetamidine hydrochloride in 250 ml of ethanol and 14.6 g of diethylamine are added dropwise at 20° C. The mixture is heated under reflux for 2 hours and evaporated in vacuo, the residue is dissolved in water, sodium hydroxide solution is added and the organic phase is extracted with ether/chloroform. After distilling the organic phase, 7.9 g of N'-(4-diethylaminoacetylaminophenyl)-N,N-dimethylacetamidine, boiling point0.2 185°-187° C, are obtained. Addition of 1 mol of naphthalenedisulphonic acid to 1 mol of the base gives the naphthalenedisulphonate, melting point >260° C (decomposition) (recrystallized from ethanol/H2O). The naphthalene-disulphonate is best prepared from the crude undistilled base and naphthalenedisulphonic acid.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:42][CH2:43][O:44]S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:33]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:34]=[CH:35][C:30]([C:28]2[O:29][C:25]([CH3:24])=[C:26]([CH2:42][CH2:43][O:44][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:14])([O:15][C:16]4[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=4)[C:4]([OH:23])=[O:3])=[CH:12][CH:11]=3)[N:27]=2)=[CH:31][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccc(-c5ccccc5)cc4)oc3C)cc2)C(=O)O)c1

Procedure:
A mixture of 2-(m-tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.095 g, 0.030 mmol) (see Ex. 48, Part C), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 2H, J=8.21 Hz), 7.70 (d, 2H, J=8.60 Hz), 7.64–7.62 (m, 2H), 7.48–7.45 (m, 2H), 7.41–7.37 (m, 1H), 7.18 (d, 2H, J=8.60 Hz), 7.12 (t, 1H, J=7.82 Hz), 6.86–6.81 (m, 3H), 6.72–6.68 (m, 2H), 4.22 (t, 2H, J=5.86 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.13 (d, 1H, J=14.08 Hz), 3.08 (t, 2H, J=5.86 Hz) 2.44 (s, 3H), 2.28 (s, 3H), 1.42 (s, 3H); HRMS (ES+) m/z exact mass calcd for C35H34NO5 548.2437, found 548.2459.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>O>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Sc1ccc(Br)cc1
Reactant: CCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCSc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A mixture of 4-bromothiophenol (30 g), pentyl bromide (26.4 g), sodium hydroxide (6-67 g) and water (30 ml) was heated at 90° C. and stirred for 48 hrs. The mixture was then poured into water, extracted with petroleum spirit, dried and distilled (bp 96° C. at 0.11 mmHG). Yield 27.3 g.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([Br:12])=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])C.[CH3:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]=1>>[CH3:14][C:15]1[CH:20]=[C:19]([NH:21][C:4]([C:6]2[C:11]([Br:12])=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=2)=[O:5])[CH:18]=[CH:17][N:16]=1
Reactant: CCOC(=O)c1nc(C)cnc1Br
Reactant: Cc1cc(N)ccn1
Product: Cc1cc(NC(=O)c2nc(C)cnc2Br)ccn1

Procedure:
The title compound, MS: m/e=307.2 (M+H+), was prepared in accordance with the general method of example 1, step 2 from 3-bromo-6-methyl-pyrazine-2-carboxylic acid ethyl ester and 2-methyl-pyridin-4-ylamine (Example B).
Reaction SMILES: [C:1](=[N:4][NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)([CH3:3])[CH3:2]>CO.[Pt]=O>[CH:1]([NH:4][NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)=NNC(=O)c1ccc(Cl)c(Cl)c1
Agent: O=[Pt]
Solvent: CO
Product: CC(C)NNC(=O)c1ccc(Cl)c(Cl)c1
Yield: 26.3 %

Procedure:
3,4-Dichlorobenzoic acid isopropylidenehydrazide (9.2 g, 0.040 mole) and 100 mg of platinum oxide in 100 mL of methanol in a Parr hydrogenation apparatus is shaken for one hour and 30 minutes under an initial hydrogen pressure of 40 psig. The filtered reaction mixture is concentrated under vacuum and the resulting solids are recrystallized three times from isopropyl alcohol to give 2.6 g of the title compound as a white crystalline product, mp 112.5°-115° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:31](=[CH:32][CH:33]=2)[C:15]2[NH:16][C:17]([C@@H:19]4[CH2:23][CH2:22][CH2:21][N:20]4[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:18][C:14]=2[CH:13]=[CH:12]3)O1.Br[C:36]1[C:37]([F:65])=[C:38]2[C:62](=[CH:63][CH:64]=1)[C:42]1[NH:43][C:44]([C@@H:46]3[CH2:50][CH2:49][CH2:48][N:47]3[C:51](=[O:61])[C@@H:52]([NH:56][C:57](=[O:60])[O:58][CH3:59])[CH:53]([CH3:55])[CH3:54])=[N:45][C:41]=1[CH:40]=[CH:39]2.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:65][C:37]1[C:36]([C:9]2[CH:10]=[C:11]3[C:31](=[CH:32][CH:33]=2)[C:15]2[NH:16][C:17]([C@@H:19]4[CH2:23][CH2:22][CH2:21][N:20]4[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[N:18][C:14]=2[CH:13]=[CH:12]3)=[CH:64][CH:63]=[C:62]2[C:38]=1[CH:39]=[CH:40][C:41]1[N:45]=[C:44]([C@@H:46]3[CH2:50][CH2:49][CH2:48][N:47]3[C:51](=[O:61])[C@@H:52]([NH:56][C:57]([O:58][CH3:59])=[O:60])[CH:53]([CH3:54])[CH3:55])[NH:43][C:42]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3c(F)c(Br)ccc3c2[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3c(F)c(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Temperature: 85 °C
Yield: 71.2 %

Procedure:
(S)-tert-butyl 2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (250 mg, 0.48 mmol) and methyl (S)-1-((S)-2-(7-bromo-6-fluoro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (200 mg, 0.4 mmol), Pd(PPh3)4 (46 mg, 0.04 mmol), Pd(dppf)2Cl2 (29 mg, 0.04 mmol), and K2CO3 (2M in H2O, 0.67 mL, 1.34 mmoL) were combined in DME (6 mL). The mixture was degassed with bubbling N2 for 10 min the heated to 85° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford (S)-tert-butyl 2-(6′-fluoro-2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (213 mg, 71%).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([CH3:49])[C:46]([OH:50])=[C:45]([CH3:51])[CH:44]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:52]=[CH:53][CH:54]=[CH:55][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([CH3:49])[C:46]([OH:50])=[C:45]([CH3:51])[CH:44]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:30][CH2:31][CH:32]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:52]=[CH:53][CH:54]=[CH:55][C:6]=2[NH:5]1
Reactant: CCOC(=O)CCC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(CCC(=O)O)CC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2.6 mg (0.11 mmol) LiOH in 1 mL water was added to a solution of 50 mg (0.07 mmol) (R)-2-[4-(2-ethoxycarbonyl-ethyl)-1,4′-bipiperidinyl-1′-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 3 mL THF and the reaction mixture was stirred for 4 h at RT. The THF was eliminated in a nitrogen current and the crude product was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[Cl:23])=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[C:19]([O:18][C:16]([NH:15][C@@H:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[C:6]([Cl:23])[CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1cc2c(cc1Cl)[C@@H](NC(=O)OC(C)(C)C)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)O)c(Cl)cc21
Yield: 87.1 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 6 using (S)-4-(tert-butoxycarbonylamino)-6-chlorothiochromane-7-carboxylic acid methyl ester (1.10 g) and potassium carbonate (847 mg), the objective (S)-4-(tert-butoxycarbonylamino)-6-chlorothiochromane-7-carboxylic acid (921 mg) was obtained as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:17]3([C:30]([O:32]CC)=[O:31])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:2]=1.[OH-].[K+]>C(O)C.O>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][C:17]([S:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:13][CH:12]=2)(=[O:15])=[O:16])([C:30]([OH:32])=[O:31])[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3cccnc3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)(S(=O)(=O)c2ccc(Oc3cccnc3)cc2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
1-(tert-butoxycarbonyl)-4-(4-(pyridin-3-yloxy)phenylsulfonyl)piperidine-4-carboxylic acid was prepared according to FIG. 3. A 250-mL round bottom flask was charged with 1.7 g ethyl ester (from step 1), 0.78 g (4 eq.) potassium hydroxide in 16 mL ethanol and 4 mL water. The reaction mixture was heated to 90° C. LCMS after 1 hour shows complete reaction. The mixture was partitioned between ethyl acetate and 10% aqueous KHSO4-Brine. The yellow organic phase was separated, dried, filtered and concentrated. The residue was vacuum dried overnight to produce 1.32 g off-white foam that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:21]([CH3:23])[CH3:22])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[O:20])C)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:24](O)[CH2:25][OH:26].[OH-].[Na+].O>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]([N:21]([CH3:22])[CH3:23])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]([O:26][CH2:25][CH3:24])=[O:20])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: CC(=O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 16 h

Procedure:
A mixture of 2-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}-N,N-3-oxapentamethyleneacetamide (4.9 g prepared as described in Example 214), ethylene glycol (30 ml) and 18N aqueous sodium hydroxide solution (10 ml) was heated under reflux for 21/2 hours and then cooled. Water (30 ml) was added and the aqueous mixture washed with ether. The ether extracts were washed with 5N aqueous sodium hydroxide solution and the alkaline washings combined with the aqueous reaction mixture and the resulting mixture neutralised by addition of concentrated hydrochloric acid. The neutralised mixture was evaporated and the residue dried by azeotropic distillation with methanol and then propan-2-ol. The residue was mixed with propan-2-ol and the mixture filtered. The filtrate was evaporated and the residue was heated at 63°/0.7 mm to remove excess ethyleneglycol and then dissolved in ethanol (50 ml). Thionyl chloride (3.5 ml) was added dropwise with stirring and the mixture allowed to stand for 16 hours under anhydrous conditions. The reaction mixture was then poured into a mixture of ice and excess aqueous sodium bicarbonate solution. The mixture was extracted with ether and the extracts were dried and evaporated to give an oil which was mixed with ether. The mixture was filtered and a solution of maleic acid in ether was added to the filtrate to produce a gum. The supernatent was decanted and the residual gum washed with ether, which was decanted, several times and then basified with sodium bicarbonate. The product was extracted with ether and the extracts were dried and evaporated to give ethyl 2-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}acetate. A sample of this material (2.8 g) was dissolved in methanol (300 ml). Ammonia gas was bubbled into the solution which was cooled in ice, saturated with ammonia gas and then evaporated and heated at 90°/20 mm to leave 2-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}acetamide a residual oil the boiling point of which was not determined.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:21]3[S:20](=[O:64])[CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:72]=[CH:71][NH:70][N:69]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:73][Si]([N-][Si](C)(C)C)(C)C.[Li+].COS(C(F)(F)F)(=O)=O.Cl>O1CCCC1.O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@H:21]3[S:20](=[O:64])[CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:72]([CH3:73])[CH:71]=[N:70][N:69]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCSc4nc[nH]n4)CS(=O)[C@H]23)cs1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: COS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cnnc1SCSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2S(=O)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (2.71 g: 2.63 mMol.) in tetrahydrofuran (50 ml) at -78° C. is added a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M: 2.9 ml), and the mixture is stirred at -78° C. for 10 minutes, mixed with trifluoromethanesulfonic acid methyl ester (0.33 ml: 2.92 mMol.), and stirred at -78° C. for 30 minutes. The reaction mixture is mixed with 10% hydrochloric acid (2.1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (ethyl acetate) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(4-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1 -oxide (0.73 g) as pale brown foam. Yield: 27%. NMR δ(CDCl3 -CD3OD) ppm: 1.51(s, 9H), 3.31(s, 3H), 3.85(s, 2H), 4.12, 4.70(ABq, J=14.6 Hz, 2H), 4.74(d, J=4.8 Hz, 1H), 6.26(d, J=4.8 Hz, 1H), 6.96(s, 1H), 7.01(s, 1H), 7.2-7.5(m, 25H), 8.11(brs, 1H). IR ν(CHCl3) cm-1 : 3400, 1805, 1722, 1690, 1545, 1507, 1497, 1450, 1372, 1040.