Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:40](=[O:41])[CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)Cc1ccccc1
Yield: 67.4 %

Procedure:
In a manner analogous to that described in Example 21, from 223 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester, 77 mg of phenylacetyl chloride and 65 mg of diisopropylethylamine there were obtained 190 mg of N-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(phenylacetyl)-L-asparaginyl]amino]butyl]-L-proline tert.butyl ester as a white solid (from ethyl acetate/n-hexane); MS: m/e 567 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9][C:8]2[N:7]=[CH:6][C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][C:3]1=2.C(=O)(O)[O-].[Na+]>ClCCl.C(O)(C(F)(F)F)=O>[F:21][C:19]([F:20])([F:22])[C:5]1[CH:6]=[N:7][C:8]2[CH2:9][CH2:10][NH:11][C:2](=[O:1])[C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ncc(C(F)(F)F)cc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCc2ncc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl 5-oxo-3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (as prepared in the previous step, 2.7 g, 8.54 mmol, 1.00 equiv) in dichloromethane (20 g) and CF3COOH (4 g). The reaction mixture was stirred for 2 h at room temperature. The pH value of the solution was adjusted to 8 with sodium bicarbonate. The resulting solution was extracted with 3×30 mL of dichloromethane, and the combined organic layers was washed with 1×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The title compound was obtained a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[N:21]1([CH2:30][C:31]2[C:32](=[O:38])[NH:33][C:34](=[S:37])[NH:35][CH:36]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:37][C:34]3[NH:35][CH:36]=[C:31]([CH2:30][N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22]4)[C:32](=[O:38])[N:33]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: O=c1[nH]c(=S)[nH]cc1Cn1ccc2ccccc21
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cn1ccc2ccccc21
Temperature: 80 °C
Yield: 8.9 %

Procedure:
A mixture of 1-chloro-4-(4-(chloromethyl)phenoxy)-2-(trifluoromethyl)benzene (200 mg, 0.623 mmol), 5-(1H-indol-1-ylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (160 mg, 0.623 mmol), and K2CO3 (200 mg, 1.447 mmol) in DMF (5 mL) was heated at 80° C. for 3 h. Purification via MDAP then afforded the title compound (30 mg, 8.44% yield). LCMS: rt=4.19 min, [M+H+]=542
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:32]=[N:33][N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:35]=2)[CH:19]=[CH:18]3)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].Cl.[OH-].[Na+].O>CO>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)[CH:19]=[CH:18]3)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3-c3nnn[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
852 mg (1.21 mmol) of 2-ethyl-5,7-dimethyl-3-{[2-[2-(2-(triphenylmethyl)-2H-tetrazol-5-yl)phenyl]quinolin-6-yl]methyl}-3H-imidazo[4.5-b]pyridine obtained in Example 14 were suspended in 12 ml of methanol and 12 ml of concentrated hydrochloric acid were added thereto over an iced water bath. After stirring at room temperature for 24 hours, the reaction mixture was cooled with ice and acidified with a 10 N sodium hydroxide solution. 10 ml of water was added thereto followed by filtration and the filter cake were washed with 10 ml of a 1N sodium hydroxide solution. The filtrate was acidified by adding concentrated hydrochloric acid dropwise thereto with stirring and then extracted with 100 ml of ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain 518 mg of 2-ethyl-5,7-dimethyl-3-{[2-[2-(1H-tetrazol-5-yl)phenyl]quinolin-6-yl]methyl}-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Cl>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:20][C:19]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:17]([Cl:16])[CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccc(Cl)c(Cl)c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 3,4-dichlorobenzyl chloride
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([OH:13])[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>>[CH2:1]([C:8]1[N:12]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:11](=[O:13])[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Oc1nc(Cc2ccccc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)OC(=O)n1c(Cc2ccccc2)noc1=O

Procedure:
17.6 parts of 3-benzyl-5-hydroxy-1,2,4-oxadiazole, 6.9 parts of potassium carbonate and 12.3 parts of isopropyl chloroformate are heated for 5 hours at 60° C. After the mixture has cooled, the precipitated potassium chloride is removed by suction filtration and the filtrate concentrated. The residue is recrystallized from n-propanol. There is obtained 15.5 parts (59% of theory) of the desired product; m.p.: 80° C.
Reaction SMILES: [C:1]([NH:5][C@H:6]([C:16]([O:18]C)=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:4])[CH:2]=[CH2:3].[OH-].[Na+:21]>CO>[C:1]([NH:5][C@H:6]([C:16]([O-:18])=[O:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)(=[O:4])[CH:2]=[CH2:3].[Na+:21]
Reactant: C=CC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)[O-]
Yield: 97 %

Procedure:
The same procedures as in Example 60 were carried out from the compound obtained in Example 34 (1.9 g), 1 mol/L of an aqueous sodium hydroxide solution (11 mL), and methanol (70 mL), to give the captioned compound (1.9 g, 97%) as crystals.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1>[C:9]([C:2]1[N:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1nc(Br)cs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1csc(C=O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 3.7 %

Procedure:
A solution of 4-bromo-2-thiazolecarboxaldehyde (14.8 g), 1-dodecyne (14.1 g), and triethylamine (23.5 g) in dry tetrahydrofuran (85 m) was chilled to 5° C. and degassed under nitrogen. bis(Triphenylphosphine)palladium (II) chloride (0.54 g) and copper (I) iodide (0.07 g) were added to the mixture, which was degassed, and stirred, under nitrogen, at room temperature for 2.5 hrs. The reaction mixture was heated at 40° C. for 7 hrs, during which time additional amounts of 1-dodecyne (3.9 g), bis(triphenylphosphine)palladium (II) chloride (0.11 g), and copper (I) iodide (0.02 g) were added. The mixture was cooled to room temperature, the precipitate was collected, and the filter cake was washed with ethyl acetate. The filtrate was diluted with ethyl acetate (300 ml). Water was added in portions, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with heptane to heptane:1% ethyl acetate. A portion (1.05 g) of the residue was rechromatographed, eluting with hexane:(0.3 to 1%) ethyl acetate. The appropriate fractions were collected and evaporated to yield 0.79 g (76.5% yield) of product, mp 25.5°-26° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:16](Cl)(Cl)=[O:17].C1(C)C=CC=CC=1>>[F:1][C:2]1[CH:8]=[C:7]([S:9][C:10]([F:15])([F:14])[CH:11]([F:12])[F:13])[CH:6]=[CH:5][C:3]=1[N:4]=[C:16]=[O:17]
Reactant: Nc1ccc(SC(F)(F)C(F)F)cc1F
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(SC(F)(F)C(F)F)cc1F

Procedure:
To 140 ml of 4% phosgen-toluene solution was added 3.6 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethylthio)aniline, and the mixture was heated under reflux for 3 hours. After the conclusion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to give 2-fluoro-4-(1,1,2,2-tetrafluoroethylthio)phenyl isocyanate as an oily material. The oily material was dissolved in 50 ml of xylene, and 1.5 g of 2,6-difluorobenzamide was added to the solution, followed by heating under reflux for 20 hours. After the conclusion of the reaction, the reaction mixture was cooled (0° C.), and the crystals which separated out were recovered by filtration, and further recrystallized from acetone to give N-(2,6-difluorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoroethylthio)phenyl]urea (Compound No. 1) as crystals having a m.p. of 177°-179° C. The resulting compound was found to show no decrease in melting point even when admixed with the authentic sample as obtained in Example 2.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.[CH3:28][C@@H:29]([NH:38][CH3:39])[C@H:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([N:38]([C@H:29]([CH3:28])[C@H:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:39])=[O:18])=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CN[C@H](C)[C@H](O)c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pivaloyl chloride (7.8 ml, 63.3 mmol) was added dropwise to a DCM/THF solution (100 ml/20 ml) containing 4-bromophenylacetic acid (13.59 g, 63.2 mmol). DIEA (11.0 ml, 63.1 mmol) was then added dropwise (exotherm). After stirring at room temperature for 1 hour the solution was poured slowly into a DCM/THF solution (100 ml/20 ml) containing (1R,2R)-(−)-pseudoephedrine (10.5 g, 63.5 mmol) and DIEA (11.0 ml, 63.1 mmol). After stirring overnight at room temperature the solution was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with aqueous 1N NaOH (2×), aqueous 1N HCl (3×), brine and dried over MgSO4. The solution was filtered and concentrated. The oil residue was diluted with 100 ml of toluene and concentrated. The residue was then dissolved in ethyl ether and triturated with hexanes to give the title compound as a white solid. The compound is a 3:1 mixture of amide rotational isomers by proton NMR: 1H NMR (400 MHz, asterisk denotes minor rotamer, CDCl3): δ 7.42 (d, J=8.3 Hz, 2H); 7.39-7.27 (m, 5H); 7.11 * (d, J=8.4 Hz, 2H); 7.04 (d, J=8.3 Hz, 2H); 4.64-4.42 (m, 1H); 4.07-3.94 (m, 1H); 3.82-3.70 (m, 1H); 2.94 * (s, 3H); 3.63 (s, 2H); 2.82 (s, 3H); 1.12 (d, J=7.0 Hz, 3H); 0.86 * (d, 3H, J=7.0 Hz). LC1 3.23 min. (M+H)=362
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([CH3:26])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].[OH:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>CN(C)C=O>[CH3:28][O:27][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:39]1[CH2:40][CH2:41][CH:36]([OH:35])[CH2:37][CH2:38]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([CH3:26])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][N:20]=2
Reactant: OC1CCNCC1
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCN1CCC(O)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (compound 398) (32 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (34 mg) and 4-hydroxypiperidine (25 mg) were added to the suspension, and the mixture was stirred at 80° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (22 mg, yield 60%).
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[C:22]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])=[C:14]([C:37](=[O:41])[N:38]([CH3:40])[CH3:39])[CH:13]=1)C1C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH3:39][N:38]([CH3:40])[C:37]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[NH:18][C:19]([C:21]1[C:22]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=2)=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20])[O:11][CH2:10][C:9]([OH:42])=[O:8])=[O:41]
Reactant: CN(C)C(=O)c1cc(OCC(=O)OCc2ccccc2)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cc(OCC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 53.8 %

Procedure:
{3-Dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenoxy}acetic acid benzyl ester (260 mg) was dissolved in ethyl acetate (5 mL), and thereto was added 7.5% palladium carbon (250 mg). The mixture was stirred for 1 hour under hydrogen atomosphere. The reaction solution was filtered through a Celite and the filtrate was concentrated to give {3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenoxy}acetic acid (118 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20](OCCCC)=[O:21])[O:17][C:16]2=[O:27])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH3:28]>CO>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20]([NH2:28])=[O:21])[O:17][C:16]2=[O:27])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CCCCOC(=O)[C@H]1CN(c2cc(F)c(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: N
Solvent: CO
Product: NC(=O)[C@H]1CN(c2cc(F)c(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The butyl(5R)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate (Step 1, 350 mg, 0.910 mmol) is treated with 7N ammonia in methanol (9.1 mL) under N2, and the mixture is stirred at ambient temperature for 30 mins. The reaction mixture is then concentrated under reduced pressure, and the residue is recrystallized from EtOAc/hexanes to give the title compound, mp 181-183° C.; MS (ESI+) for C14H15N3O4F2 m/z 328 (M+H)+; [α]25D−23 (c 0.94, DMSO).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])(=[N:15][CH:12]2[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: CS(=O)Nc1ccc(Br)cc1
Product: CS(=O)(=NC1CC1)Nc1ccc(Br)cc1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and cyclopropylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.93 min; Mass spectrum (ESI+): m/z=289, 291 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.[NH:13]([CH2:17][CH2:18]O)[CH2:14][CH2:15]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]2[O:9][CH2:18][CH2:17][NH:13][CH2:14][CH2:15][O:10]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: OCCNCCO
Product: COc1ccc(Cl)cc1B1OCCNCCO1
Yield: 47 %

Procedure:
The title compound (47%, crystals) was prepared from 5-chloro-2-methoxyphenylboronic acid and diethanolamin.
Reaction SMILES: C(OC([C:6]1[O:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=O)C>Cl.O>[O:14]1[C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7](=[O:15])[CH2:6]1
Reactant: CCOC(=O)c1oc2cnccc2c1O
Agent: Cl
Solvent: O
Product: O=C1COc2cnccc21
Temperature: 25 °C

Procedure:
A suspension of 3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester (10 mmol) in 10 mL 25% HCl solution and 5 mL H2O was heated to reflux overnight. After cooling to RT, the reaction mixture was quenched with sat. aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as brown solid;
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9])[CH3:2].Cl[CH2:11][C:12](=O)[CH3:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:2][O:1][C:3]1[C:4]2[S:9][CH:11]=[C:12]([CH3:13])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)CCl
Reactant: COc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc2c(C)csc12
Temperature: 100 °C
Yield: 53.5 %

Procedure:
A mixture of 2-methoxylthiophenol (915 mg, 6.5 mmol), chloroacetone (1.1 mL, 13.8 mmol) and K2CO3 (1.8 g, 13 mmol) in acetone (15 mL) was refluxed for 2 h. The mixture was filtered and the solvent evaporated. The crude product was dissolved in chlorobenzene (30 mL) and polyphosphoric acid (PPA, 0.5 g) was added (Plé et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). The resulting mixture was heated at 100° C. over night, and then refluxed for 5 h. The solvent was decanted from the PPA-residue. The residue was then treated with CH2Cl2 and the combined organic extracts were washed with water and dried before the solvents were evaporated. The crude product was purified on silica using heptane as eluent, to give the title compound (620 mg, 53% yield over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 2.43 (d, J=1.13 Hz, 3 H) 4.01 (s, 3 H) 6.77-6.83 (m, 1 H) 7.06 (qd, J=1.17, 0.53 Hz, 1 H) 7.32-7.39 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][O:33]C(=O)C)=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH3:26])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.O[Li].O>C1COCC1.CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][OH:33])=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH3:26])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: C=CC(=O)N[C@@H](C)COc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Agent: [Li]O
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=CC(=O)N[C@@H](C)COc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
To a mixture of 108d (70 mg, 0.1 mmol) in THF (6 mL), i-PrOH (2 mL) and H2O (2 mL) was added LiOH.H2O (42 mg, 1 mmol). The reaction mixture was stirred at rt for 16 h and concentrated. The residue was purified by prep-HPLC to give 108 (20 mg, 8% for two steps) as yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 8.61 (d, J=10 Hz, 2H), 8.49 (s, 1H), 8.04-8.03 (m, 1H), 7.52-7.50 (m, 2H), 7.40-7.35 (m, 2H), 6.87 (d, J=8 Hz, 1H), 6.21-6.15 (m, 2H), 6.05-6.02 (m, 1H), 5.54 (d, J=10 Hz, 1H), 4.73 (bs, 1H), 4.30 (bs, 2H), 4.15 (bs, 2H), 4.02 (bs, 1H), 3.61 (s, 3H), 2.93 (bs, 2H), 2.84 (bs, 2H), 1.86 (bs, 4H), 0.97 (bs, 3H). ESI-LCMS: m/z=657.3 [C34H33FN6O5S+H]+
Reaction SMILES: C[Si](C)(C)[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[Cl:10][Si:11]([Cl:14])(Cl)Cl.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:10][Si:11]([Cl:14])([O:3][Si:4]([CH3:5])([CH3:6])[CH3:7])[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Si](C)(C)O[Si](C)(C)C
Reactant: Cl[Si](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: C[Si](C)(C)O[Si](Cl)(Cl)O[Si](C)(C)C
Yield: 19.8 %

Procedure:
About 1.9 ml of a 25% solution of phosphonitrile chloride in methylene chloride are added at room temperature with stirring to a mixture containing 486 g (3.0 mol) of hexamethyldisiloxane and 170 g (1.0 mol) of tetrachlorosilane. After the mixture has been stirred at room temperature for 8 hours, the catalyst is deactivated by adding 2.2 ml of tri-n-butylamine. Distillation of the reaction mixture at 18° to 34° C. and at 2 mbar gives 55 g of 3,3-dichlorohexamethyltrisiloxane, but no 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane. Likewise the desired 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane is neither found in the distillation residue (12 g) nor in the cold trap (583 g of a mixture of trimethylchlorosilane and 1,1,1-trichloro-3,3,3-trimethyldisiloxane).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:21]>C(Cl)(Cl)Cl>[O:21]1[C:2]2([CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH2:3]2)[CH2:1]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1CN(C(=O)OCc2ccccc2)C1
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CC2(CO2)C1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
To a solution of phenylmethyl 3-methylideneazetidine-1-carboxylate (2.46 g, 0.0121 mol) in chloroform (100 mL) was added 3-chloroperoxybenzoic acid (12.5 g, 0.0726 mol) at 0° C. The reaction mixture was allowed to warm up to room temperature over a period of 12 hours then quenched with 1 M sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1). The layers were separated and the organic layer was dried over anhydrous magnesium sulfate then concentrated. The residue was purified by flash chromatography (5-15% ethyl acetate in hexanes) to afford phenylmethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (2.2 g, 83% yield) as clear and colorless oil. 1H NMR (400 MHz, CDCl3): 7.37-7.29 (m, 5H), 5.12 (s, 2H), 4.35-4.26 (m, 4H), 2.85 (s, 2H). MS (EI) for C12H13NO3: 220 (MH+).