Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][OH:4].N1C=CC=CC=1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)([O:4][CH2:3][C:2]([F:9])([F:1])[C:5]([F:8])([F:7])[F:6])(=[O:18])=[O:17]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 2,2,3,3,3-pentafluoropropanol (5.0 mL, 50 mmol) and pyridine (8.1 mL, 100 mmol) in chloroform (100 mL), cooled at 0° C. and under argon, tosyl chloride (14.29 g, 75 mmol) was slowly added. The resulting mixture was allowed to warm up to room temperature and was stirred at this temperature overnight. Then, 10% aqueous K2CO3 solution was added and the mixture was vigorously stirred for 30 min. The layers were separated, and the organic layer was treated again with K2CO3. After that, it was washed with 2 N HCl, dried over Na2SO4 and the solvent was removed, yielding 12.72 g of the desired compound (84% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([NH:9][C:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:11])[C:6](=O)[CH3:7].C(OC(=O)C)(=O)C.OS(O)(=O)=O>O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[N:9]=[C:10]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[O:11][C:6]=1[CH3:7]
Reactant: COC(=O)CC(NC(=O)c1ccc(C)s1)C(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Cc1nc(-c2ccc(C)s2)oc1C
Temperature: 90 °C
Yield: 30.4 %

Procedure:
In a 100 mL flask, 3-[(5-methyl-thiophene-2-carbonyl)-amino]-4-oxo-pentanoic acid methyl ester (12 g, 45 mmol), and acetic anhydride (30 mL) were combined. Following addition of concentrated H2SO4 (1 mL), the solution was heated to 90° C. for 30 min and then cooled to ambient temperature. The reaction was slowly diluted with DI water (30 mL, potential exotherm). The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was washed with DI water and brine (150 mL), and then dried over MgSO4 and concentrated to obtain a brown oil. The residue was purified by column chromatography (700 mL SiO2, 30% EtOAc/hexanes) to provide the desired product (3.44 g) as a pale yellow oil. Rf=0.39 (50% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=3.6 Hz, 1H), 6.73 (dd, J=3.6, 0.8 Hz, 1H), 3.71 (s, 3H), 3.55 (s, 2H), 2.51 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[C:22]1([C:28]#[C:29][C:30]2[CH:31]=[N:32][CH:33]=[C:34]([CH:38]=2)[C:35](O)=[O:36])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[CH3:40][NH:41][O:42][CH3:43]>O1CCCC1>[CH3:43][O:42][N:41]([CH3:40])[C:35](=[O:36])[C:34]1[CH:38]=[C:30]([C:29]#[C:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:31]=[N:32][CH:33]=1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Add 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (3.86 g, 20.2 mmol) and diisopropylethylamine (7.0 mL, 40.3 mmol) to a suspension of 5-phenylethynylnicotinic acid (3.0 g, 13.4 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.97 g, 20.2 mmol) in tetrahydrofuran (100 mL) and stir at room temperature overnight. Concentrate the reaction mixture, dissolve the residue in ethyl acetate and wash sequentially with an aqueous solution of phosphate buffer (pH=7) and a saturated aqueous solution of sodium chloride. Dry the organic layer over magnesium sulfate, filter and concentrate. Purify the residue by silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes, to give the title compound as a pale yellow solid (2.4 g, 67%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:21]C(=O)OC(C)(C)C)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:21]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC(=O)OC(C)(C)C)c(C)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(C)ccc32)cc1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl (5-methyl-1-tosyl-1H-indol-4-yl)carbamate (10.5 g, 26.2 mmol) in DCM (197 mL) was added TFA (65.5 mL), and the mixture was stirred at room temperature. After 20 minutes the reaction was concentrated, dissolved in EtOAc, washed with sat. aq. NaHCO3, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-70% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 301.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].[CH:36]1([C:42]([O:44][CH:45](I)[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.CCOCC.[ClH:55]>CC(N(C)C)=O>[ClH:55].[ClH:55].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O:32][CH:45]([O:44][C:42]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[O:43])[CH:46]([CH3:48])[CH3:47])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)C(I)OC(=O)C1CCCCC1
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CC(C)C(OC(=O)C1=C(CSc2nnnn2CCN(C)C)CS[C@@H]2[C@H](NC(=O)Cc3csc(N)n3)C(=O)N12)OC(=O)C1CCCCC1
Temperature: 0 °C

Procedure:
In 120 ml of dimethylacetamide is dissolved 6.0 g of potassium 7β[2-(2-aminothiazol-4-yl) acetamido]-3-[[[1-(2-dimethylaminoethyl) -1H-tetrazol-5-yl]thio]-methyl]ceph-3-em-4-carboxylate and the solution is cooled to 0° C. With stirring, 9.0 g of 1-iodo-2-methylpropyl cyclohexanecarboxylate is added at one stroke to the solution, followed by stirring for further 10 minutes. To the reaction mixture is added 70 ml of 2 N HCl-ether, followed by addition of 300 ml of ether. The ether layer is discarded and the residue is dissolved in 50 ml of 1 N hydrochloric acid and subjected to column chromatography on XAD-II ®resin (Rohm & Haas Co. U.S.A.), elution being carried out with water-acetonitrile (3:1). The fractions containing the desired product are combined, evaporated under reduced pressure to remove the solvent and lyophilized to give 2.5 g of the title compound as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([O:22]CC)=O.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([NH:29][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Reactant: CC(C)CN
Product: CC(C)CNC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and isobutylamine employing methods similar to those described in Example 2 and was obtained as a white solid; 1H NMR (d6-DMSO) δ 10.82 (1H, br), 8.22 (1H, s), 7.35-7.22 (6H, m), 4.03 (2H, s), 3.11 (2H, br), 1.77 (1H, m), 0.92 (6H, d, J=6.5 Hz); HRMS calcd for C20H21N3O3+H+: 352.1661. Found: 352.1645.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:16])[C:3]=1[NH2:17].[Cl:18][CH2:19][C:20](Cl)=[O:21]>CC1C=CC=CC=1>[Cl:18][CH2:19][C:20]([NH:17][C:3]1[C:4]([CH3:16])=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:2]=1[CH3:1])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1N
Solvent: Cc1ccccc1
Product: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CCl
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of 20 parts of 2,6-dimethyl-4-(phenylmethoxy)benzenamine and 270 parts of methylbenzene were added portionwise 10.9 parts of 2-chloroacetyl chloride (exothermic reaction, the temperature rose to 30° C.). Upon complete addition, the reaction mixture was stirred for 1 hour at reflux temperature. After cooling, the precipitated product was filtered off and dried, yielding 23.8 parts (89%) of 2-chloro-N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]acetamide; mp. 165.3° C. (int. 71).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C(C(C)=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCl
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 92.2 %

Procedure:
6.6 g (30 millimols) of 4-(4'-chlorophenoxy)phenol, 4.14 g (30 millimols) of potassium carbonate, 60 ml. of methyl ethyl ketone and 5.0 g (45 millimols) of methyl chloroacetate were treated in the same way as in Referential Example 2 to afford 8.1 g of oily methyl 4-(4'-chlorophenoxy)phenoxyacetate in a yield of 92%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:7]=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1)(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([N:27]=[C:28]=[O:29])=[C:20]([CH:30]([CH3:32])[CH3:31])[CH:19]=1.[H-].[Na+]>O1CCCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:30]([CH3:32])[CH3:31])[C:21]([NH:27][C:28]([NH:16][S:13]([C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=2)(=[O:14])=[O:15])=[O:29])=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1
Reactant: CC(=O)c1cc(C(C)=O)cc(S(N)(=O)=O)c1
Reactant: CC(C)c1cc(Cl)cc(C(C)C)c1N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(C)=O)cc(S(=O)(=O)NC(=O)Nc2c(C(C)C)cc(Cl)cc2C(C)C)c1
Yield: 40.3 %

Procedure:
The title compound was prepared as described in method A from 3,5-diacetylbenzenesulfonamide (0.35 grams). 4-chloro-2,6-diisopropylphenylisocyanate (0.37 grams), sodium hydride (0.06 grams of a 60% dispersion in mineral oil), in tetrahydrofuran (4 mL). This afforded 0.28 grams of the title compound, m.p. 201.9-203.4° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:19][CH:18]([OH:20])[CH2:17]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(O)(C)C.[N+:25]([O-])([OH:27])=[O:26]>C(OCC)(=O)C>[N+:25]([O:20][CH:18]1[CH2:19][N:16]([CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[S:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)[CH2:17]1)([O-:27])=[O:26]
Reactant: OC1CN(CCCOCCc2ccc3sccc3c2)C1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=[N+]([O-])OC1CN(CCCOCCc2ccc3sccc3c2)C1
Reaction time: 1 h

Procedure:
In 20 mL of ethyl acetate was dissolved 10.0 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol, and 20 mL of isopropanol was added thereto, after which 2.60 mL of concentrated nitric acid (61%) was added dropwise thereto at room temperature. To the reaction mixture was added dropwise 60 mL of ethyl acetate, and the resulting mixture was stirred at the same temperature for 1 hour and then at 5° C. for 1 hour. The crystals precipitated were collected by filtration to obtain 11.3 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol nitrate as colorless crystals.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[F:13][C:14]([F:45])([F:44])[C:15]1[CH:16]=[C:17]([C:25]([CH3:43])([CH3:42])[C:26]([N:28]([C@H:30]2[C@H:34]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH2:33][NH:32][CH2:31]2)[CH3:29])=[O:27])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[F:45][C:14]([F:13])([F:44])[C:15]1[CH:16]=[C:17]([C:25]([CH3:42])([CH3:43])[C:26]([N:28]([CH3:29])[C@H:30]2[C@H:34]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[CH2:33][N:32]([C:7]([Cl:10])=[O:6])[CH2:31]2)=[O:27])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)Cl)C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (31 mg, 0.10 mmol) in CH2Cl2 (5 ml) at 0° C., was added a solution of rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-N-methyl-isobutyramide (Intermediate VII-4), (100 mg, 0.21 mmol) and pyridine (0.02 ml, 0.22 mmol) in CH2Cl2 (2 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued for 2 hours. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 25 mg (22%) of the title compound as_colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[CH:19]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([O:25][CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: OCc1cccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2cccnc2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 3-pyridinemethanol and DBU in DME. EI-MS m/e (%): 293 (M+, 100), 92 (60), 65 (29), 39 (24).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1C=[CH:32][C:6]([CH2:7][N:8]2[CH2:15][CH2:14][C:11]3([CH2:13][CH2:12]3)[CH2:10][CH:9]2[C:16]([NH:18][C:19]2([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[CH2:21][CH2:20]2)=[O:17])=[CH:5][CH:4]=1.ClCC1C=[N:40]C(C(F)(F)F)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:35][C:2]([F:1])([F:34])[C:3]1[N:40]=[CH:32][C:6]([CH2:7][N:8]2[CH2:15][CH2:14][C:11]3([CH2:13][CH2:12]3)[CH2:10][CH:9]2[C:16]([NH:18][C:19]2([C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[CH2:20][CH2:21]2)=[O:17])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3Cc3ccc(C(F)(F)F)cc3)CC4)CC2)cc1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3Cc3ccc(C(F)(F)F)nc3)CC4)CC2)cc1
Yield: 93.8 %

Procedure:
The title compound (D124) (47 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (D90) (50 mg) and 3-chloromethyl-6-(trifluoromethyl)piridine (38 mg). (Cs2CO3: 1.3 eq; reaction time: 18 hrs; RT)
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>ClCCl.C(#N)C>[Br:1][C:12]1[CH:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: BrBr
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: Oc1ccc(-c2ccc(F)cc2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 117.9 %

Procedure:
A solution of bromine (4.57 g, 28.59 mmol) in dichloromethane (20 mL) was added dropwise to a solution of 4-fluoro-4′-hydroxybiphenyl [purchased from TCI] (5.38 g, 28.59 mmol) in dichloromethane (100 mL) and acetonitrile (20 mL) and the reaction mixture stirred at room temperature under nitrogen for 18 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution (200 mL) containing 10% aqueous sodium thiosulfate solution (20 mL), water (200 mL) and saturated brine (200 mL), dried (MgSO4), filtered and concentrated in vacuo to give crude 3-bromo-4′-fluoro-[1,1′-biphenyl]-4-ol (9.0 g) as a tan solid.
Reaction SMILES: FC(F)(F)C([O-])=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH3+:51])[C:18](=[O:50])[NH:19][C@H:20]2[CH2:41][O:40][C:39](=[O:42])[C@H:38]3[N:34]([CH2:35][CH2:36][CH2:37]3)[C:33](=[O:43])[C@H:32]([CH3:44])[NH:31][C:30](=[O:45])[C@H:29]([CH3:46])[N:28]([CH3:47])[C:27](=[O:48])[C@H:26]3[N:22]([CH2:23][CH2:24][CH2:25]3)[C:21]2=[O:49])[CH:12]=[C:13]([F:15])[CH:14]=1.[C:52](O)(=[O:59])/[CH:53]=[CH:54]/[CH2:55][CH2:56][CH2:57][CH3:58].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl>[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:51][C:52](=[O:59])/[CH:53]=[CH:54]/[CH2:55][CH2:56][CH2:57][CH3:58])[C:18](=[O:50])[NH:19][C@H:20]2[CH2:41][O:40][C:39](=[O:42])[C@H:38]3[N:34]([CH2:35][CH2:36][CH2:37]3)[C:33](=[O:43])[C@H:32]([CH3:44])[NH:31][C:30](=[O:45])[C@H:29]([CH3:46])[N:28]([CH3:47])[C:27](=[O:48])[C@H:26]3[N:22]([CH2:23][CH2:24][CH2:25]3)[C:21]2=[O:49])[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: CCCC/C=C/C(=O)O
Reactant: C[C@@H]1NC(=O)[C@H](C)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](NC(=O)[C@@H]([NH3+])Cc2cc(F)cc(F)c2)COC(=O)[C@@H]2CCCN2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC/C=C/C(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)N[C@H]1COC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)N(C)C(=O)[C@@H]2CCCN2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.89 g (2.75 mmol) of the compound from example 13A and 458.8 mg (3.58 mmol) of trans-2-heptenoic acid are introduced into dichloromethane (20 ml), cooled to 0° C., then treated with 2.09 g (5.51 mmol) of HATU and 462.7 mg (3.58 mmol) of ethyldiisopropylamine. The solution is stirred at 0° C. for 30 min, then a further 925.3 mg (7.16 mmol) of ethyldiisopropylamine are added, and it is stirred at room temperature for 18 h. The reaction solution is evaporated, and the residue is taken up using ethyl acetate and washed with aq. citric acid, aq. sodium hydrogencarbonate solution and sat. aq. sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The residue is chromatographed on silica gel using ethyl acetate/cyclohexane 1/2. 1.51 g (56% of th.) of the product are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1COCC1>[CH2:17]([O:16][C:14]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([CH2:4][OH:3])[CH:15]=1)[CH3:18]
Reactant: CCOC(=O)c1cc(OCC)c2[nH]c(=O)oc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOc1cc(CO)cc2oc(=O)[nH]c12
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 4-ethoxy-2-oxo-2,3-dihydro-benzooxazole-6-carboxylic acid ethyl ester (1.1 g, 4.38 mmol, 1.0 equiv; prepared as described in I. Kompis, A. Wick Helv. Chim. Acta 1977, 60, 3025-3034) in a mixture of dichloromethane (20 mL) and THF (10 mL) at −78° C. under Ar was slowly added diisobutylaluminium hydride (14.0 mL, 14.02 mmol, 3.2 equiv, 1 M solution in dichloromethane) over a time period of 15 min, the cooling bath removed on completion of addition and the reaction allowed to reach 0° C. After 1 h, the excess hydride was quenched by cautious addition of a sat. solution of potassium sodium tartrate (10 mL). The solidified mixture was extracted with hot THF, the combined organic phases concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (1:2) providing 0.69 g (75%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.37 (t, J=7.0 Hz, 3H), 4.15 (q, J=7.0 Hz, 2H), 4.49 (d, J=5.6 Hz, 2H), 5.21 (t, J=5.6 Hz, 1H), 6.82 (s, 1H), 6.85 (s, 1H), 11.64 (br s, 1H). 13C NMR (75 MHz, DMSO): δ 14.61, 62.89, 64.26, 100.74, 106.46, 117.80, 137.50, 142.74, 144.05, 154.54. MS (ISP): 209.8 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:15]1[C:20]2[CH:21]=[C:22]([C:26]([O:28][CH2:29]C)=[O:27])[CH:23]=[C:24](I)[C:19]=2[O:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:11]([N:15]1[C:20]2[CH:21]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[C:24]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)[C:19]=2[O:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14]
Reactant: c1cocn1
Reactant: CCCCN1CCOc2c(I)cc(C(=O)OCC)cc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN1CCOc2c(-c3ncco3)cc(C(=O)OC)cc21
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a −70° C. solution of oxazole (227 mg) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 2 mL). After stirred at −70° C. for 30 min, zinc chloride (1 M in ethyl ether, 13 mL) was added. The mixture was warmed to 0° C. for 1 h. To this mixture was then added ethyl 4-butyl-8-iodo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (600 mg, 1.6 mmol) in THF (5 mL) followed by tetrakis triphenylphosphine palladium (0) (115 mg). The mixture was heated at reflux for 3 h, diluted with ethyl acetate (300 mL) and washed with water followed by brine. The organic solution was dried (sodium sulfate) and concentrated under reduced pressure. Purification by silica gel plug (1:1 acetate/hexanes) provided 363 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.96, 7.73, 7.40, 7.28, 4.44, 3.90, 3.43, 3.34, 1.61, 1.41, 0.98.
Reaction SMILES: [Cl:1][C:2]1[CH:49]=[CH:48][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([C:40](=[O:47])[NH:41][CH2:42]CN(C)C)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.CN>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([C:40](=[O:47])[NH:41][CH3:42])=[CH:8][CH:7]=2)=[CH:48][CH:49]=1
Reactant: CN(C)CCNC(=O)c1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: CN
Product: CNC(=O)c1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1

Procedure:
The title compound was synthesized as described for Compound 491, except methyl amine was used instead of N1,N1-dimethyl-ethane-1,2-diamine.
Reaction SMILES: [F:1][C:2](=[C:12]([F:14])[F:13])[CH2:3][CH2:4][S:5][CH:6]1[NH:10][C:9](=[O:11])[CH2:8][O:7]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>O1CCCC1>[CH3:22][S:23]([O:11][C:9]1[N:10]=[C:6]([S:5][CH2:4][CH2:3][C:2]([F:1])=[C:12]([F:13])[F:14])[O:7][CH:8]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1COC(SCCC(F)=C(F)F)N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1coc(SCCC(F)=C(F)F)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
1 g of 2-(3,4,4-trifluoro-3-butenylthio)oxazolidin-4-one and 0.9 g of triethylamine were dissloved in 30 ml of tetrahydrofuran, to which 0.56 g of methanesulfonic chloride was added dropwise under ice cooling and stirred at 50° C. for 8 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in ether. After washing with 1N hydrochloric acid and water, it was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: hexane:dichloromethane=1:1) to obtain 0.25 g of 4-methylsulfonyloxy-2-(3,4,4-trifluoro-3-butenylthio)oxazole (yield 19%). n20D=1.4830.