Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.C(OC([NH:43][CH2:44][C:45](O)=[O:46])=O)(C)(C)C.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[NH2:43][CH2:44][C:45]([N:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([Cl:1])=[CH:3][C:4]=3[C:32]([F:35])([F:34])[F:33])[N:8]=[CH:9]4)[C:18](=[O:29])[N:19]=2)[CH2:23][CH2:24]1)=[O:46]
Reactant: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCC(=O)N1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
A solution 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one (0.026 g, 0.05 mmol) and tert-butoxycarbonylamino-acetic acid (0.0087 g, 0.05 mmol) in dichloromethane (3 mL) was treated with EDCI (0.0104 g, 0.055 mmol) and triethylamine (0.006 g, 0.06 mmol). Reaction mixture was stirred at room temperature for 18 hours and was then partitioned between dichloromethane and an aqueous saturated hydrogencarbonate solution. The dichloromethane layer was then washed with aqueous 10% citric acid, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (26 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:19][CH3:20])=[C:16]([Cl:18])[CH:17]=1)[C:5]#[N:6].C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:19][CH3:20])=[C:16]([Cl:18])[CH:17]=1)[C:5]([NH2:6])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: COc1ncc(COc2ccc(C#N)cc2Cl)cc1Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ncc(COc2ccc(C(N)=O)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a suspension of 3-chloro-4-[(5-chloro-6-methoxypyridin-3-yl)methoxy]benzonitrile (Preparation 30, 64 mg, 0.21 mmol) and potassium carbonate (57 mg, 0.414 mmol) in DMSO (5 mL) was added hydrogen peroxide (141 mL, 4.14 mmol) and the reaction stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL). The organic layer was washed with water (2×10 mL), dried over sodium sulfate and concentrated in vacuo to afford a white solid, which was triturated with EtOAc to yield the title compound (30 mg, 44%).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:45]/[O:46][C:47]([C:50]([O:52]C(C)(C)C)=[O:51])([CH3:49])[CH3:48])/[C:15]([NH:17][C@@H:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:22]([CH2:25]Cl)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1)=O)(C)(C)C.[I-].[Na+].C(OC([NH:66][CH2:67][C:68]1[CH:69]=[N:70][N:71]([CH2:93][CH3:94])[C:72]=1[NH:73]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)(C)C.C(OCC)(=O)C>CN(C)C=O.O>[NH2:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:45]/[O:46][C:47]([C:50]([OH:52])=[O:51])([CH3:48])[CH3:49])/[C:15]([NH:17][C@@H:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O-:29])=[O:28])=[C:22]([CH2:25][N+:70]4[N:71]([CH2:93][CH3:94])[C:72]([NH2:73])=[C:68]([CH2:67][NH2:66])[CH:69]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)ns1
Reactant: CCn1ncc(CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(N)c(CN)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 47 h
Yield: 21.1 %

Procedure:
To a suspension of a mixture of benzhydryl 7β-[(Z)-2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (1 g) and sodium iodide (199 mg) in N,N-dimethylformamide (3 ml) was added 4-tert-butoxycarbonylaminomethyl-1-ethyl-5-tritylaminopyrazole (1.17 g), and the mixture was stirred at room temperature for 47 hours. The reaction mixture was added to a mixture of ethyl acetate (30 ml) and water (20 ml). The organic layer was separated, washed with brine (15 ml), and dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated to about 5 ml under reduced pressure. The concentrate was poured into diisopropyl ether (150 ml), and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the resulting solid in methylene chloride (4.5 ml) were added anisole (1.5 ml) and trifluoroacetic acid (3 ml). The resulting solution was stirred at room temperature for 3 hours and poured into diisopropyl ether. The resulting precipitate was collected by filtration and dried in vacuo. The obtained powder was dissolved in a phosphate buffer (pH 7) and adjusted to about pH 6 with saturated aqueous sodium hydrogencarbonate solution. The solution containing the objective compound was purified by preparative HPLC utilizing ODS column. The eluate containing a desired product was concentrated in vacuo. The concentrate was adjusted to about pH 2 with concentrated hydrochloric acid and chromatographed on Diaion® HP-20 (Mitsubishi Chemical Corporation) eluting with 20% aqueous 2-propanol. The eluate was evaporated in vacuo and lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(3-amino-4-aminomethyl-2-ethyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (155 mg) as an amorphous solid.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:25].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:11]2[CH2:10][CH2:9][C:8](=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13][CH2:12]2)=[CH:31][CH:30]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(CCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
A mixture of 99.9 g (0.4 mole) of 4-diphenylmethylenepiperidine, 88 g (0.44 mole) of 4-chloro-4'-fluorobutyrophenone, 64.0 g (0.64 mole) of potassium bicarbonate and a small amount of potassium iodide in 1500 ml of toluene was refluxed for 5 days. The reaction mixture was filtered, and the filtrate was concentrated at reduced pressure leaving a residue which was dissolved in about 800 ml of ethyl acetate. This solution was concentrated to about 500 ml and allowed to stand for one day. The resulting precipitate was recrystallized from methanolethyl acetate, made basic with sodium hydroxide solution, water washed, and the product recrystallized from 75°-90° petroleum ether to give the title compound, M.P. 111°-114° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH2:15]Br)=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:14][CH2:15][CH2:11][C:10](=[O:12])[C:8]=2[CH:9]=1
Reactant: CC(=O)c1cc(Br)ccc1OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCOc2ccc(Br)cc21
Reaction time: 20 h
Yield: 69.7 %

Procedure:
To a slurry of NaH (60% dispersion in mineral oil) (1.48 g, 37.1 mmol) in THF (˜50 mL) at room temperature was added 1-(5-bromo-2-(2-bromoethoxy)phenyl)ethanone (8.07 g, 25.1 mmol). The reaction mixture was slowly heated to reflux and allowed to stir for 20 h. The solvent was removed under vacuum pressure and the concentrated residue was absorbed onto silica gel and purified by column chromatography (4:1 ethyl acetate/petroleum ether). The product was afforded as a yellow oil after the solvents were removed, providing 4.22 g (70%) of 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one. 1H NMR (CDCl3) 7.87 (d, J=2.6 Hz, 1H), 7.50 (dd, J=2.6, 8.1 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 4.24 (t, J=6.6 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H), 2.15-2.29 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[ClH:14].[N:15]([O-])=O.[Na+]>O>[ClH:14].[NH:1]([C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[NH2:15]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Yield: 93 %

Procedure:
To an ice cooled solution of 2-amino-5-nitrobenzoic acid (50.0 g, 274.5 mmol) in water (350 mL) was added conc. HCl (404 mL). The reaction mixture was stirred until the salt had precipitated out. A solution of sodium nitrite (29.0 g, 411.8 mmol) in water (300 mL) was slowly added at 0° C. with stirring for 15 min. This reaction mixture was slowly added to ice-cold sulfurous acid (2.5 L) followed by stirring at RT for 12 h. The reaction mixture was again cooled to 0° C. and conc. HCl was added until solid separates out. The solid was filtered, washed with cold HCl and vacuum dried to afford the title compound as a yellow colored solid 60 g (93%), which was used without further purification. Rf=0.10 (10% MeOH in DCM).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:38])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:48][C:49]1[N:57]=[C:56]2[C:52]([N:53]=[CH:54][N:55]2[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)=[C:51](Cl)[N:50]=1>C(O)(C)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:38])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:32][CH2:33][C@H:34]([NH:37][C:51]2[N:50]=[C:49]([Cl:48])[N:57]=[C:56]3[C:52]=2[N:53]=[CH:54][N:55]3[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)[CH2:35][CH2:36]1)(=[O:3])[CH3:2]
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](N)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](Nc6nc(Cl)nc7c6ncn7C6CCCCO6)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Temperature: 25 °C

Procedure:
(2R,3R,4R,5R)-2-{6-[(trans-4-Aminocyclohexyl)amino]-2-chloro-9H-purin-9-yl}-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydrofuran-3,4-diyl diacetate (Intermediate 4) (7.9 g) was dissolved in isopropanol (200 ml) and stirred at room temperature under nitrogen. N,N-diisopropylethylamine (10 ml) was added followed by 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.92 g). The mixture was stirred at 60° C. under nitrogen for 18 h. The reaction mixture was allowed to cool to room temperature and evaporated down in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous extracted twice with ethyl acetate. The organic phases were combined, dried (MgSO4), and evaporated down in vacuo to give the title compound (10.35 g). Used without purification.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)[S:26][CH:27]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1cc(Cl)cs1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Cl)cs4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), 4-chlorothiophen-2-methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred at 60° C. for 4 h. The reaction mixture was concentrated in vacuo, and diluted with DCM. The organic layer was washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography, (MeOH/DCM) to afford the title compound (53 mg) as an off-white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23](SC)=[N:22][C:21]4=[O:27])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:30]([F:33])([F:32])[F:31])[CH:6]=1)(=[O:4])=[O:3].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][S:2]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23]([N:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[N:22][C:21]4=[O:27])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:30]([F:31])([F:32])[F:33])[CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3C(F)(F)F)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(S(C)(=O)=O)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(OCCO)cc[n+]([O-])c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(OCCCl)cc[n+]([O-])c1C

Procedure:
1.0 ml of thionyl chloride was gradually added to a solution of 0.92 g (5 mmol) of 4-(2-hydroxyethoxy)-2,3-dimethylpyridine N-oxide in 10 ml of chloroform under cooling with ice. The obtained mixture was heated under reflux for 2 hours, cooled by allowing to stand, neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with 100 ml of methyl ethyl ketone twice. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (solvent: chloroform/methanol=19:1) to obtain 0.56 g of 4-(2-chloroethoxy)-2,3-dimethylpyridine N-oxide as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:15]([NH:22][C:23](=[O:43])[CH2:24][NH:25][C:26](=[O:42])[C:27]2[CH:32]=[C:31]([NH:33][C:34]3[NH:35][CH2:36][CH:37]([OH:40])[CH2:38][N:39]=3)[CH:30]=[C:29]([OH:41])[CH:28]=2)[CH2:16][C:17]([O:19]CC)=[O:18])[CH:5]=[C:6]([C:8]([CH3:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.O.[OH-].[Li+].ClCCl>C(#N)C.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:15]([NH:22][C:23](=[O:43])[CH2:24][NH:25][C:26](=[O:42])[C:27]2[CH:32]=[C:31]([NH:33][C:34]3[NH:39][CH2:38][CH:37]([OH:40])[CH2:36][N:35]=3)[CH:30]=[C:29]([OH:41])[CH:28]=2)[CH2:16][C:17]([OH:19])=[O:18])[CH:5]=[C:6]([C:8]([CH3:13])([CH3:14])[C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C(C)(C)C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CC(C)(c1cc(Cl)cc([C@H](CC(=O)O)NC(=O)CNC(=O)c2cc(O)cc(NC3=NCC(O)CN3)c2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (3S)-ethyl 3-(3-chloro-5-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate (from step 2 above) (0.785 mmol, crude residue) in a mixture of acetonitrile/water (1:1) (6 mL) was added lithium hydroxide monohydrate (165 mg, 3.932 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo to afford a yellow-orange viscous residue and the residue was dissolved in water (25 mL) and stirred with dichloromethane (50 mL) for 15 min. The aqueous layer was separated, acidified with TFA (1 mL in 3 mL ACN) and evaporated in vacuo to afford a pale viscous residue. The crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column and a gradient 10-60% acetonitrile in water containing 0.05% TFA to afford the desired product, after lyophilization, as a colorless lyophilized powder (277.7 mg). LC-MS analysis of the residue shows the desired product: (3S)-3-(3-chloro-5-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid's mass: m/z 600 (35ClM+H), and m/z 602 (37ClM+H); Calcd for C26H29ClF3N5O6: 599.99.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:13]3)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>CS(C)=O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:23])([F:25])[F:24])(=[O:21])=[O:20])=[CH:13]4)=[CH:26][CH:27]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=S(=O)(Nc1ccc2c(OCc3ccc(Br)cc3)cccc2c1)C(F)(F)F
Solvent: CS(C)=O
Product: O=S(=O)(Nc1ccc2c(OCc3ccc(-c4ccc(F)cc4)cc3)cccc2c1)C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 1 and 4-florophenyl boronic acid according to the procedure of Example 2, m.p. 139-140° C. DMSO: δ 12.0 broad (s, 1H), 7.0-8.3(m, 14H, arom), 5.36 (s, 2H). CHN 60.63, 3.60, 2.94. Found 60.60, 3.50, 2.83.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[C:12]=2[N:19]([C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=C.CC1C=CC=C(C)N=1.[O:43]1CCOCC1>O.O=[Os](=O)(=O)=O>[F:34][C:28]1[CH:29]=[C:30]([I:33])[CH:31]=[CH:32][C:27]=1[N:19]([C:12]1[N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH:16][C:11]=1[NH:10][S:7]([C:4]1([CH2:1][CH:2]=[O:43])[CH2:5][CH2:6]1)(=[O:9])=[O:8])[C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25]
Reactant: C=CCC1(S(=O)(=O)Nc2ccc(=O)n(C)c2N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)CC1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: Cc1cccc(C)n1
Product: Cn1c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)c(NS(=O)(=O)C2(CC=O)CC2)ccc1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of tert-butyl (3-{[(1-allylcyclopropyl)sulfonyl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)(2-fluoro-4-iodophenyl)carbamate (140 mg, 0.232 mmol) in dioxane (2.30 ml) under a nitrogen atmosphere was added H2O (0.51 ml). Then NaIO4 (4 eq, 198 mg, 0.928 mmol) and 2,6-dimethyl pyridin (2 eq, 0.054 ml, 0.464 mmol) were added and the mixture was cooled to 0° C. At this temperature OsO4 (4% in H2O, 0.05 eq, 71 μl, 0.012 mmol) was added. The mixture was allowed to come to room temperature and then stirred for 18 hours. The mixture was diluted with H2O (4 ml) to form a fine suspension. After stirring for 30 min the precipitate was filtered off to afford the title compound (140 mg, 88%) in sufficient purity for the next transformation (88% UV) as a mixture of the aldehyde and a cyclised 1,2-thiazolidin-3-ol 1,1-dioxide form.
Reaction SMILES: [C:1]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C@@H:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[C@H:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[C@H:19]1[C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])([O:3]C(C)(C)C)=[O:2]>C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1.C(OCC)(=O)C>[C:1]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C@@H:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[C@H:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[C@H:19]1[C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])([OH:3])=[O:2]
Reactant: C=CCOC(=O)[C@H]1[C@H](c2ccc(OC)cc2OCC(=O)OC(C)(C)C)c2cc(OCCC)ccc2[C@@H]1c1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)[C@H]1[C@H](c2ccc(OC)cc2OCC(=O)O)c2cc(OCCC)ccc2[C@@H]1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.7 %

Procedure:
Allyl(1S,2R,3S)-3-(2-carbo-tert-butoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (765 mg, 1.24 mmol) was dissolved in TFA (5 ml) containing a few drops of anisole. The reaction mixture was stirred at RT for 20 min. The solvent was eliminated, the residue was diluted with ethyl acetate, washed with water, brine and dried (MgSO4 anhyd.), filtered and evaporated. The product was purified by column chromatography to provide the title compound (575 mg, 83%) as a colorless oil.
Reaction SMILES: C1(OC2C=C(S)[CH:10]=[CH:11][C:12]=2OC)CCCC1.[CH2:16]([Li])CCC.[CH:21]1([O:26][C:27]2[CH:28]=[C:29]([S:35][CH:36]([CH2:41][CH2:42][CH2:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:37][C:38]([OH:40])=[O:39])[CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1.CCCCCC.O>[C:11]([O:39][C:38](=[O:40])[CH2:37][CH:36]([S:35][C:29]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([O:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:28]=1)[CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)([CH3:10])([CH3:12])[CH3:16]
Reactant: COc1ccc(S)cc1OC1CCCC1
Reactant: [Li]CCCC
Reactant: COc1ccc(SC(CCCCc2ccccc2)CC(=O)O)cc1OC1CCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(SC(CCCCc2ccccc2)CC(=O)OC(C)(C)C)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 3-cyclopentyloxy-4-methoxybenzenethiol (0.5 g, Reference Example 2) in anhydrous tetrahydrofuran (20 ml), at 0° C. and under nitrogen, was treated with a solution of n-butyllithium in hexane (0.03 ml, 2.5M). After stirring for 15 minutes the mixture was treated dropwise with a solution of t-butyl 7-phenyl-2-heptenoate (0.39 g, Reference Example 5) in tetrahydrofuran (5 ml) and then the mixture was allowed to warm to room temperature. After stirring at room temperature for 18 hours the reaction mixture was diluted with water (50 ml) and then extracted three times with ether (30 ml). The combined organic extracts were washed with brine (50 ml), then dried over magnesium sulphate and then evaporated. The residual pale yellow oil was subjected to flash chromatography on silica eluting with a mixture of petroleum ether and ethyl acetate (97:3, v/v) to give the title compound (0.5 g) as a colourless oil. NMR (CDCl3): δ1.44 (s,9H), 1.55 (m,8H), 1.95 (m,6H), 2.41 (m,2H), 2.60 (app t,2H), 3.25 (m,1H), 3.81 (s,3H) 4.74 (m,1H), 6.79 (d, 1H), 6.99 (dd,2H), 7.10-7.30 (m,5H). Mass spectrum (FAB): m/z 484 M+.