Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:30])[C:5]1[C:6](=[CH:11][C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22]C(OC(C)(C)C)=O)=[CH:13][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8]>C(OCC)C.CO>[CH3:2][O:3][C:4](=[O:30])[C:5]1[C:6](=[CH:11][C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])=[CH:13][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(Cc2ccccc2NC(=O)OC(C)(C)C)cc1C(=O)OC
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccc(Cc2ccccc2N)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
2N hydrogen chloride in diethyl ether (1 ml) was added to a solution of 4-(2-(tert-butoxycarbonylamino)benzyl)phthalic acid dimethyl ester (100 mg, 0.25 mmol) in methanol (1 ml). The mixture was stirred for 2 hours at room temperature and evaporated to dryness in vacuo. The crude product was recrystallized from diethyl ether/ethyl acetate to give light, golden crystals of 4-(2-aminobenzyl)phthalic acid dimethyl ester (yield: 69 mg (86%)). 1H—NMR (CDCl3) in ppm: δ 7.74 (1H,d); 7.60 (1H,s); 7.54 (1H,d); 7.27 (2H,d); 7.13 (1H,m); 7.05 (1H,d); 4.12 (2H,s); 3.8 (6H,2xs); 2.5 (3H,s). LC-MS: m/e 322 (M+Na), 300 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C(O)CCC>[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1ccccc1-c1cc2c(Cl)ncnc2[nH]1
Solvent: CCCCO
Product: COc1ccccc1-c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reaction time: 1.5 h

Procedure:
6.6 g (25.4 mmol) of 4-chloro-6-(2-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 5.34 ml (50.8 mmol) of 3-chloro-aniline in 100 ml of n-butanol are heated at boiling for 1.5 hours. The reaction mixture is cooled, then filtered and washed with diethyl ether and hexane. Flash chromatography (SiO2 ; applied dry; hexane/ethyl acetate [2:1] ethanol/acetone [1:1]) yields the title compound; m.p. 221-222° C.; TLC-Rf =0.3 (hexane/ethyl acetate [1:1]); FAB-MS: (M+H)+ =351.
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].[N+:7]([C:10]1[CH:27]=[CH:26][C:13]([CH2:14][CH:15]([C:21](=O)[CH2:22][CH2:23][CH3:24])[C:16](OCC)=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(O)C>[CH2:22]([C:21]1[N:6]=[C:3]([CH3:4])[N:5]=[C:16]([OH:17])[C:15]=1[CH2:14][C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:27][CH:26]=1)[CH2:23][CH3:24]
Reactant: CC(=N)N
Reactant: CCCC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCc1nc(C)nc(O)c1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.6 %

Procedure:
3.5 g of sodium are dissolved in 175 ml of ethanol. 9.5 g of acetamidine hydrochloride are added to this solution and the mixture is stirred for 5 minutes at room temperature. 20 g of ethyl 2-(4-nitrobenzyl)-3-oxohexanoate, prepared in Example 3, are then added and the mixture is stirred for 4 days at room temperature. The solvents are then evaporated off under vacuum and the residue is taken up with hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and then evaporated under vacuum to give an oily residue which crystallises in an acetone/ether mixture. The crystals are drained and dried and give 10.9 g of 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of crystals of melting point 200° C.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([OH:20])[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].C(=O)([O-])[O-].[K+].[K+].F[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1.O>CN(C)C=O>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
To a suspension of 3-(1-cyanocyclopropyl)-N-(3-hydroxy-4-methoxyphenyl)-benzamide (1.54 mg, 5.00 mmol) and potassium carbonate (0.69 g, 5.00 mmol) in N,N-dimethylformamide (5 mL) was added 1-fluoro-4-nitrobenzene (0.78 g, 5.50 mmol), and the mixture was stirred at 60° C. for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (1.90 g, 89%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:10]1[CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:2]=2[Cl:1])[C:7]([NH2:12])=[N:8][CH:9]=1
Reactant: Nc1ncccc1OCc1c(Cl)cccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(Br)cc1OCc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
A stirring solution of 3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (32.4 g, 0.11 mol) in acetonitrile was cooled to 0° C. using an ice bath. To this solution was added N-bromosuccinimide (19.5 g, 0.11 mol) portionwise. The reaction was stirred at 0° C. for 15 min. The reaction was concentrated to dryness under vacuum. The resulting dark oil was dissolved in EtOAc (500 mL) and partitioned with H2O (250 mL). The organic was then washed with sat'd NaHCO3 (2×200 mL) and brine (1×200 mL). Activated charcoal was added to the organic layer and warmed to reflux. The solution was then cooled to room temperature and filtered through a pad of celite. The organic was then concentrated to dryness under vacuum to one third the original volume. The solids were then filtered off to yield 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (22.0 g, 0.07 mol, 64%) as a tan solid. The remaining filtrate was concentrated under vacuum to yield crude 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (12.1 g, 0.04 mol, 35%) as a brown solid.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:22](OC(C)(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>CN(C=O)C>[CH3:22][N:23]([CH:25]=[C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13][C:12]1=[O:16])[CH3:24]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)Nc2cc(-c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
6-Phenyloxindole (0.053 mg, 0.25 mmol) and dimethylformamide di-t-butylacetal (0.08 mL, 0.32 mmol) were combined and dissolved in DMF. The reaction mixture was stirred at room temperature for 4 hours. The volatiles were removed in vacuo and the resulting residue was triturated with diethyl ether. The solids were collected by filtration (50 mg, 75% yield). 1H NMR 400 MHz (DMSO-d6) mixture of E and Z isomers: δ 10.09 (s, 1H); 10.02 (s, 1H); 7.59–7.51 (m, 4H); 7.45–7.22 (m, 10H); 7.10–7.05 (m, 2H); 6.98 (s, 1H); 6.91 (s, 1H); 3.29 (s, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[Si]([C:17]#[N:18])(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1(C)C=CC=CC=1.[Zn+2].[I-].[I-]>[NH2:18][CH2:17][C:8]1([OH:12])[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: O=C1CCCc2cc(Br)ccc21
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: Cc1ccccc1
Product: NCC1(O)CCCc2cc(Br)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (5.00 g, 22.0 mmol) and ZnI2 (300 mg) in toluene (50 mL) was added TMSCN (4.36 g, 44.0 mmol) at rt. The mixture was heated at 60° C. overnight. The reaction mixture was cooled to rt, and a solution of LAH (20.0 mL, 2.4 M in THF, 44.0 mmol) was added slowly. The reaction stirred at 40° C. for 2 h. The reaction was cooled to 0° C. was quenched with addition of EtOAc (10 mL) at 0 OC, and then water (5 mL) and aqueous 10% NaOH (5 mL). The mixture was filtered through Celite and concentrated to give the 4.5 g (79%) of the crude 1-(aminomethyl)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-ol intermediate as a brown oil. To a solution of this intermediate (4.5 g, 17.4 mmol) in toluene (100 mL) was added 4N HCl/dioxane (20 mL) solution, and the mixture was stirred at reflux for 10 min. The mixture was cooled to room temperature and concentrated to give 3.6 g (75%) of the title compound as a tan solid. [M+H] calc'd for C11H12BrN, 237, 239. found 237, 239.
Reaction SMILES: CC1C=C(C2C(F)=C(F)C3C(=O)C([C:23]([OH:25])=[O:24])=CN4C(C)COC=2C=34)C=C(C)N=1.Br[C:30]1[C:35]([F:36])=[C:34]([F:37])[C:33]([Br:38])=[C:32]([F:39])[C:31]=1[F:40].C([Li])CCC.C(=O)=O>>[Br:38][C:33]1[C:34]([F:37])=[C:35]([F:36])[C:30]([C:23]([OH:25])=[O:24])=[C:31]([F:40])[C:32]=1[F:39]
Reactant: Fc1c(F)c(Br)c(F)c(F)c1Br
Reactant: Cc1cc(-c2c(F)c(F)c3c(=O)c(C(=O)O)cn4c3c2OCC4C)cc(C)n1
Agent: O=C=O
Agent: [Li]CCCC
Product: O=C(O)c1c(F)c(F)c(Br)c(F)c1F

Procedure:
The above Flow Sheet A illustrates the preparation of 10-(2,6-dimethyl-4-pyridinyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine6-carboxylic acid. 1,4-Dibromo-2,3,5,6-tetrafluorobenzene (III) is metalated with butyllithium and then caused to react with carbon dioxide to give 4-bromo-2,3,5,6-tetrafluorobenzoic acid (IV). The latter is converted to its acid chloride (V) which reacts with a half ester of malonic acid in the presence of butyllithium to afford an alkyl 4-bromo-2,3,5,6-tetrafluorobenzoylacetate (VI). The benzoylacetate (VI) is then treated with molar equivalent amounts of dimethylformamide (DMF) dimethyl acetal and 2-amino-1-alkanol to produce an alkyl N-(1-hydroxy-2-alkyl)-3-amino-2-(4-bromo-2,3,5,6-tetrafluorobenzoyl)propenoate (VII). The latter is then cyclized by heating with a base, preferably potassium carbonate, to give a compound of Formula II (R'=F). The alkyl 10-bromo-8,9-difluoro-3-alkyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate (II) is then caused to react with a 2,6-dimethyl-4-(trialkylstannyl)pyridine in the presence of a palladium complex catalyst thereby producing a compound of Formula I where R'=F and X=O. The latter can then be converted to the free acid (I; R=H, R'=F, X=O) by a conventional hydrolysis reaction with base or acid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[O:15])=[N:2]1.[C:25](P(=O)(OCC)OCC)#[N:26].CN.C(N(CC)CC)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:26][CH3:25])=[O:22])=[CH:18][N:17]=2)=[O:15])=[N:2]1
Reactant: O=C(O)c1ccc(C(=O)NCCNc2nsc3ccccc23)nc1
Reactant: CCOP(=O)(C#N)OCC
Agent: CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(C(=O)NCCNc2nsc3ccccc23)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(2-(benzo[d]isothiazol-3-ylamino)ethylcarbamoyl)nicotinic acid (62 mg, 0.13 mmol), diethyl cyanophosphonate (21 μL, 0.14 mmol), methylamine (2.0M soln in THF, 15 μL, 0.14 mmol) and triethylamine (20 μL, 0.14 mmol) in dichloromethane (5 mL) was allowed to stir at room temperature overnight. The solution was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 30% ethyl acetate in hexanes, and selected fractions were combined and concentrated under reduced pressure to yield N2-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-N5-methylpyridine-2,5-dicarboxamide as a white solid, (50 mg). 1H NMR (300 MHz, DMSO-d6): 9.16 (broad s, 1H), 8.99 (s, 1H), 8.79 (m, 1H), 8.37 (d, 1H), 8.23 (t, 2H), 7.91 (d, 1H), 7.58 (s, 1H), 7.49 (t, 1H), 7.39 (t, 1H), 3.61 (m, 3H), 3.34 ppm (m, 4H). MW=355 confirmed by LC-MS, tr=2.98 min (Method B) MH+=356.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17]([F:20])([F:19])[F:18])=[C:6]([NH:21][C:22](=O)[CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH:5]=1.Cl.O>O1CCOCC1>[S:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:23][C:22]1[N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17]([F:19])([F:18])[F:20])[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:30])=[CH:5][C:6]=2[N:21]=1
Reactant: COC(=O)c1ccc(NC2CCCCC2C(F)(F)F)c(NC(=O)Cc2cccs2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2c(c1)nc(Cc1cccs1)n2C1CCCCC1C(F)(F)F
Yield: 107.8 %

Procedure:
0.75 g 3-(2-Thiophen-2-yl-acetylamino)-4-(2-trifluoromethyl-cyclohexylamino)-benzoic acid methyl ester with 10 ml of 4M hydrochloric acid in dioxane were heated in a microwave reactor to 110° C. for 5 h. 3 ml water was added to the reaction mixture, which was reacted again to 110° C. for 2 h. The mixture was then concentrated in vacuo, the residue taken up in ethyl acetate and water, and the pH of the aqueous phase was brought to 4. The phases were separated, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, concentrated and 0.75 g (100%) of 2-Thiophen-2-ylmethyl-1-(2-trifluoromethyl-cyclohexyl)-1H-benzoimidazole-5-carboxylic acid were obtained.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH2:35]([N:37]([CH2:43][CH3:44])[CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)[CH3:36]>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:40]4[CH2:41][CH2:42][CH:38]([N:37]([CH2:43][CH3:44])[CH2:35][CH3:36])[CH2:39]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCN(CC)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(F)(F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3-diethylaminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.56 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 3H), 3.34 (m, 2H), 3.26 (m, 1H), 2.63 (m, 4H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 2H), 1.27-1.32 (m, 2H), 0.98 (m, 5H). m/z: 496 [M+H]
Reaction SMILES: [ClH:1].C[O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[OH:18].[OH-].[NH4+].Cl>CO>[ClH:1].[OH:18][C:6]1[CH:7]=[C:8]([CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:9]=[CH:10][C:5]=1[C:4]([OH:19])=[O:3]
Reactant: COC(=O)c1ccc(CN2CCOCC2)cc1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN2CCOCC2)cc1O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 2-hydroxy-4-morpholin-4-ylmethyl-benzoic acid methyl ester hydrochloride (75 mg, 0.26 mmol) in MeOH (0.5 mL) was treated with ammonium hydroxide (1 mL) and stirred in a sealed vial for 2 h at 60° C. After cooling, the reaction mixture was concentrated under a stream of nitrogen to approximately ¼ the original volume and was treated with 1 M HCl (0.25 mL, 0.25 mmol). The solid that formed was collected by filtration and recrystallized from water to yield the white crystalline product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][C:16](=[O:18])[O:15][O:14][C@H:13](/[CH:19]=[CH:20]/[CH2:21][CH2:22][SH:23])[CH2:12][C:11](=[O:24])[NH:10][C@H:9]([CH:25]([CH3:27])[CH3:26])[C:8](=[O:28])[NH:7][C@H:6]([CH3:29])[C:5](=[O:30])[NH:4][C@@H:3]1[CH:31]([CH3:33])[CH3:32].C(N(C(C)C)CC)(C)C.[C:43](Cl)(=[O:45])[CH3:44].Cl>C(Cl)Cl.CCOC(C)=O>[OH:1][C@H:2]1[CH2:17][C:16](=[O:18])[O:15][O:14][C@H:13](/[CH:19]=[CH:20]/[CH2:21][CH2:22][S:23][C:43](=[O:45])[CH3:44])[CH2:12][C:11](=[O:24])[NH:10][C@H:9]([CH:25]([CH3:27])[CH3:26])[C:8](=[O:28])[NH:7][C@H:6]([CH3:29])[C:5](=[O:30])[NH:4][C@@H:3]1[CH:31]([CH3:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(C)[C@H]1NC(=O)[C@@H](C)NC(=O)[C@@H](C(C)C)NC(=O)C[C@@H](/C=C/CCS)OOC(=O)C[C@@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)SCC/C=C/[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N[C@H](C)C(=O)N[C@H](C(C)C)[C@@H](O)CC(=O)OO1
Yield: 41 %

Procedure:
To a solution of 9 (24.7 mg, 0.035 mmol) in CH2Cl2 (1.4 mL) was added triethylsilane (28 μL, 0.175 mmol) followed by the dropwise addition of TFA (0.35 mL, 25% v/v). After stirring for 1 h the reaction mixture was concentrated in vacuo and put under high vacuum for 2 h to give the crude thiol 10. At 0° C. to a solution of thiol 10 in CH2Cl2 (0.45 mL) was added diisopropylethylamine (30 μL, 0.172 mmol) followed by acetyl chloride (2.43 μL, 0.034 mmol) in CH2Cl2 (0.1 mL). After stirring for 2 h 10 min 1M HCl (1 mL) was added followed by EtOAc (10 mL) the layers were separated and the organic layer was washed with sat. brine (10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography (eluent 1:0-98:2-96:4-94:6-92.8 CH2Cl2/MeOH) gave the product 11 (7.3 mg, 0.014 mmol, 41%) as a white solid: Rf 0.47 MeOH/CH2Cl2 (1:9).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][C@@H:11]1[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:27]
Reactant: CCOC(=O)CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
To a stirred solution of tert-butyl (2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-ethoxy-3-oxopropyl)pyrrolidine-1-carboxylate (500 mg, 1.2 mmol, step 1 of Example 8) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 1.36 mL, 1.4 mmol) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 6 h. The mixture was diluted with ethyl acetate (100 mL), washed with water (20 mL), brine (20 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (2:1) to give 338 mg (95%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[N:5]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[CH2:7][OH:8]>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[N:3]=[C:4]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[N:5]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:14])[CH3:15])[C:6]=1[CH:7]=[O:8]
Reactant: CNS(=O)(=O)c1nc(Cl)c(CO)n1COCC[Si](C)(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CNS(=O)(=O)c1nc(Cl)c(C=O)n1COCC[Si](C)(C)C
Temperature: 40 °C
Yield: 48 %

Procedure:
A solution of the above alcohol, MnO2 (0.42 g, 4.86 mmol) in CH2Cl2 (5 mL) was stirred at RT for 1 h. Additional MnO2 (0.42 g, 4.86 mmol) was added and the reaction mixture was heated at 40° C. overnight and then evaporated and purified by silica gel chromatography (0-35% EtOAc/hex) to afford the title compound (0.083 g, 48%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.93 (s, 1H), 6.00 (s, 2H), 5.33 (br. s., 1H), 3.60-3.69 (m, 2H), 2.90 (s, 3H), −0.02 (s, 9H).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([N:16]([C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].[K+]>>[C:1]([NH:11][C@H:12]([C:14]([N:16]([C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCOC(=O)CN(C(=O)[C@H](C)NC(=O)OCc1ccccc1)c1ccsc1
Agent: [K+]
Agent: [OH-]
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)c1ccsc1

Procedure:
An ethanolic solution of ethyl N-carbobenzyloxy-L-alanyl-N-(3-thienyl)glycinate was treated with two equivalents of potassium hydroxide to yield N-carbobenzyloxy-L-alanyl-N-(3-thienyl)glycine.
Reaction SMILES: [O:1]=[C:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][CH:6]1[CH2:22][C:23]([O:25]C)=[O:24].[OH-].[Na+].O1CCOCC1.O>C(OCC)C>[O:1]=[C:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][CH:6]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2ncc(F)c(C(=O)CCC3CCN(CCSc4cc(F)ccc4F)CC3CC(=O)O)c2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A mixture of 0.3 g of methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylsulfanyl)ethyl]piperidine-3-acetate in 1.34 cm3 of a 1N aqueous sodium hydroxide solution and 5 cm3 of dioxane is brought to a temperature in the region of 60° C. with stirring and under an inert atmosphere for 1 hour. After cooling to around 20° C., the reaction medium is evaporated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. The evaporation residue obtained is taken up with 20 cm3 of water and 20 cm3 of diethyl ether, and the aqueous phase is separated after settling out and neutralized with 1.3 cm3 of 1N aqueous hydrochloric acid solution and is then extracted with 70 cm3 of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, and then evaporated according to the same conditions above. 0.23 g of (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-1-[2-(2,5-difluoro-phenylsulfanyl)ethyl]piperidine-3-acetic acid, in the form of a beige-colored solid, is obtained.