Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C>O1CCOCC1.O>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: CC(C)[C@@H](N)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To 0.117 g of D-valine in 2.5 mL dioxane and 2.5 mL of water, cooled in an ice bath, was added 0.31 g of 4′-nitro-1,1′-biphenyl-4-sulfonyl chloride, followed by 0.4 mL of triethylamine, The reaction was then stirred at room temperature overnight. After concentrating the reaction mixture in vacuo, the residue was extracted with ethyl acetate and 1N HCl. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.35 g of N-[(4′-nitro-1,1′-biphenyl-4-yl)sulfonyl]-D-valine as a solid. Yield 74.5%. m.p. 165-167° C.; MS: 377.0 (M−H)−.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[CH2:13]([N:20]1[CH2:25][CH2:24][O:23][CH:22]([C:26]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][O:27]2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1.[Cu](I)I>[CH2:13]([N:20]1[CH2:25][CH2:24][O:23][CH:22]([C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([OH:27])[CH2:28][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]([F:12])([F:11])[F:10])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCOC(C3(c4ccccc4)CO3)C2)cc1
Reactant: FC(F)(F)c1ccccc1Br
Agent: I[Cu]I
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OC(Cc1ccccc1C(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Temperature: -78 °C
Yield: 11.8 %

Procedure:
To a suspension of magnesium turnings in tetrahydrofuran (2 mL) at room temperature under nitrogen atmosphere was added a solution of 1-bromo-2-trifluoromethyl-benzene (7.6 g, 5 equiv., available from Acros) in tetrahydrofuran (32 mL) and the mixture was stirred for an hour. The solution was cooled to −78° C. and copper iodide (646 mg) was added followed by dropwise addition of a solution of 4-Benzyl-2-(2-phenyl-oxiranyl)-morpholine (2 g, 1 equiv.) in tetrahydrofuran (10 mL). The resulting mixture was warmed to room temperature over 2 hours and then treated with water (10 mL). The solution was extracted with diethyl ether, the organic phase dried with MgSO4, and evaporated in vacuo. The crude material was purified using a column chromatography on silica gel eluting with a mixture of ethyl acetate/heptane (10/90) to give 352 mg of the title compound as a colourless oil (12%). LCMS (6 minutes method) [M+H]+=442 @ Rt 3.05 min. major peak.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11].[O:14]=[C:15]1[NH:24][CH:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[C:22]2[C:21](=[O:33])[CH2:20][CH2:19][CH2:18][C:17]=2[N:16]1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1>CN(C)C=O>[CH3:13][S:10]([CH2:9][CH2:8][N:24]1[CH:23]([C:25]2[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=2)[C:22]2[C:21](=[O:33])[CH2:20][CH2:19][CH2:18][C:17]=2[N:16]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=2)[C:15]1=[O:14])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)CCBr
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
Potassium carbonate (67 mg, 0.486 mmol) and 1-bromo-2-(methylsulfonyl)ethane (68 mg, 0.365 mmol) are added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 100 mg, 0.243 mmol) in N,N-dimethylformamide (3 mL). The mixture is heated at 50° C. for 3 d and then purified by reversed phase HPLC (first purification: Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3; second purification: Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 22 mg; ESI mass spectrum [M+H]+=518; Retention time HPLC: 0.86 min (Z011_S03).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:17][C:14]1[CH:15]=[CH:16][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:19]([F:22])([F:21])[F:20])[CH:4]=2)=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cc(CCl)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
To the solution of 2-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}-5-(hydroxymethyl)benzonitrile (700 mg, 2.249 mmol) in DCM (40 mL), was added thionyl chloride (2.462 mL, 33.7 mmol) dropwise. The mixture was stirred at room temperature for 1.5 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice, dried over Na2SO4, and concentrated in vacuo to afford the title compound (665 mg, 90% yield) as a light yellow solid. LCMS: rt=3.71 min
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.3 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(4-fluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.37 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) yielded the title compound as a light yellow solid (0.17 g, 35%). MS (ISP) 480.0 [(M+H)+]; mp 228.5° C.
Reaction SMILES: C([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH:14][C:15]1[N:20]=[CH:19][C:18]([N:21]([CH3:41])[C:22](=[O:40])[C:23]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)([CH3:25])[CH3:24])=[C:17]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[Cl:48])[CH:16]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl>ClCCl>[F:39][C:36]([F:37])([F:38])[C:28]1[CH:27]=[C:26]([C:23]([CH3:25])([CH3:24])[C:22]([N:21]([C:18]2[CH:19]=[N:20][C:15]([NH:14][C@@H:10]3[CH2:11][CH2:12][CH2:13][C@H:9]3[OH:8])=[CH:16][C:17]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[Cl:48])[CH3:41])=[O:40])[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N[C@@H]2CCC[C@H]2OCc2ccccc2)cc1-c1ccccc1Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N[C@@H]2CCC[C@H]2O)cc1-c1ccccc1Cl
Yield: 45.5 %

Procedure:
To a solution of 0.15 g (0.22 mmol) (1R,2R)—N-[6-(2-benzyloxy-cyclopentylamino)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 2 ml dichloromethane were added 0.87 ml (0.87 mmol) of a 1 M boron trichloride solution in dichloromethane at room temperature. After 2 h the reaction was quenched by addition of 2 ml of a 1 M aqueous hydrochloric acid solution. Neutralisation with 1 M aqueous NaOH solution was followed by extraction with 3 portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 60 mg (46%) of the title compound as an off-white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[C:17]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17]([O:23][CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]2)[CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C=O)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 101 %

Procedure:
To a solution of oxalyl chloride (0.30 mL, 3.46 mmol) in dichloromethane (5 mL) stirring at −78° C. under nitrogen atmosphere, dimethylsulfoxide was added dropwise (0.49 mL, 6.93 mmol). After 10 min, a solution of the crude 4-(tert-butyl)-2-(1-Boc-piperidine-4-yloxy)benzyl alcohol (0.42 g, 1.15 mmol) in dichloromethane (6 mL) was added slowly via cannula. After the addition was complete, the reaction mixture was stirred at −78° C. for 1 h. The reaction was then treated with triethylamine (1.6 mL, 11.5 mmol) and allowed to warm up to room temperature overnight. The reaction mixture was partitioned between brine and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to a brown residue which was purified on a silica gel chromatotron plate. Elution with ethyl acetate-hexanes (1:5) afforded the title compound (0.42 g, 100%) as a clear oil which foamed up under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:18][CH3:19])[CH:17]=[C:13]2[N:12]=[C:11]([CH3:20])[N:10]=1.[N+:21]([O-])([OH:23])=[O:22].CCOC(C)=O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:18][CH3:19])[C:17]([N+:21]([O-:23])=[O:22])=[C:13]2[N:12]=[C:11]([CH3:20])[N:10]=1
Reactant: O=[N+]([O-])O
Reactant: CCc1cc2nc(C)nc(-c3ccc(Cl)cc3Cl)n2n1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)nc(C)nc2c1[N+](=O)[O-]
Temperature: -7.5 °C
Yield: 21.4 %

Procedure:
A solution of 4-(2,4-dichlorophenyl)-7-ethyl-2-methyl-pyrazolo[1,5-a]-1,3,5-triazine (653 mg, 2.2 mmol) in acetic anhydride (4 mL) was cooled with stirring to −5 to −10° C. A solution of fuming nitric acid (160 mg, 2.55 mmol) in acetic anhydride (2 mL) was added dropwise over 15 min. The reaction mixture was stirred at the same temperature for 3 h, then it was partitioned between water and ether three times. The combined organic layers were washed with a saturated NaHCO3 solution, dried over MgSO4 and filtered. Solvent was removed in vacuo to provide a solid. Column chromatography (EtOAc:hexanes::1:9 to 1:4) provided a solid (166 mg, 21% yield) after removal of solvent in vacuo: NMR (CDCl3, 300 MHz): δ 7.64 (d, 1H, J=8), 7.63 (d, 1H, J=2), 7.50 (dd, 1H J=8, 2), 3.19 (q, 2H, J=7), 2.94 (s, 3H), 1.32 (t, 3H, J=7).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N+:7]([O-:11])=[CH:6][C:5]=1[Cl:12].[N+](C1C=CC([O:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([O:43][CH3:44])=[C:29]3[O:33][C:32]([CH:34]([O:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[CH3:35])=[CH:31][C:30]=23)=O)=CC=1)([O-])=O>CN(C)C=O>[Cl:12][C:5]1[CH2:6][N:7]([OH:11])[CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:23]([C:25]1[CH:26]=[CH:27][C:28]([O:43][CH3:44])=[C:29]2[O:33][C:32]([CH:34]([O:36][CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[CH3:35])=[CH:31][C:30]=12)=[O:22]
Reactant: Nc1c(Cl)c[n+]([O-])cc1Cl
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(C)OC3CCNCC3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NC2=C(Cl)CN(O)C=C2Cl)c2cc(C(C)OC3CCNCC3)oc12
Yield: 24.9 %

Procedure:
Prepared from sodium hydride (115 mg of a 60% dispersion in oil), 4-amino-3,5-dichloropyridine-N-oxide (474 mg), 7-methoxy-2-(1-methyl-piperidin-4-yloxymethyl)-benzofuran-4-carboxylic acid 4-nitrophenyl ester (389 mg) in N,N-dimethylformamide. Purification by column chromatography eluting with 20% methanol in dichloromethane afforded the desired product as a light brown solid (106 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5](I)=[CH:4][N:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(CC)C(C)C)(C)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(I)cnc(Cl)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(C#C[Si](C)(C)C)cnc(Cl)c1F
Temperature: 60 °C
Yield: 0.1 %

Procedure:
A mixture of 2-chloro-3-fluoro-5-iodo-4-methyl-pyridine (2960 mg, 10.9 mmol), ethynyltrimethylsilane (1.89 mL, 13.1 mmol), N,N-diisopropylethylamine (3.80 mL, 21.8 mmol), dichlorobis(triphenylphosphine)palladium(II) (390 mg, 0.545 mmol), and cuprous iodide (104 mg, 0.55 mmol) in dioxane (40 mL) was heated at 60° C. for 2 hours. The reaction mixture was filtered through a short plug of silica, rinsed with 50 mL of ethyl acetate/heptane (1:1), and the filtrate was evaporated in vacuo to provide an orange oil that was purified by flash chromatography (12 g, Silica, 0-20% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a pale yellow oil, (2.35 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 2.40 (d, J=1.9 Hz, 3H), 0.28 (s, 11H).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[B-](F)(F)(F)[CH:36]=[CH2:37].[K+].Br[C:43]1[CH:44]=[N:45][C:46]([C:49]([F:52])([F:51])[CH3:50])=[N:47][CH:48]=1>O.C1COCC1>[F:51][C:49]([C:46]1[N:47]=[CH:48][C:43]([CH:36]=[CH2:37])=[CH:44][N:45]=1)([F:52])[CH3:50]
Reactant: C=C[B-](F)(F)F
Reactant: CC(F)(F)c1ncc(Br)cn1
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cnc(C(C)(F)F)nc1
Temperature: 100 °C
Yield: 60.9 %

Procedure:
PdOAc2 (22 mg, 0.1 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (53 mg, 0.13 mmol) (DavePhos), cesium carbonate (880 mg, 2.70 mmol) and potassium trifluoro(vinyl)borate (145 mg, 1.1 mmol) were mixed. THF (10 ml), water (3 ml) and 5-bromo-2-(1,1-difluoroethyl)pyrimidine (200 mg, 0,897 mmol) was added. Degassed for 20 minutes, with argon. The resulting mixture was capped and heated to 100° C., for 30 min in microwave oven. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (10 mL). The aq. layer extracted with EtOAc (2×10 mL) and the combined organic layers washed with brine (10 mL), dried (Na2SO4) and concentrated. The reaction was purified by column chromatography on silica gel (petroleum ether: EtOAc=1:0 to 0:1) to afford 2-(1,1-difluoroethyl)-5-vinylpyrimidine (114 mg, 75% yield). 1H NMR (CDCl3 500 MHz): δ 8.88 (s, 2H), 6.73 (m, 1H), 6.02 (d, 1H), 5.61 (d, 1H), 2.10 (t, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]2[C@H:29]([CH3:30])[C@H:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:27][C:26]2=[O:37])[CH:7]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:46][CH3:47]>CC#N>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:46][CH3:47])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]2[C@H:29]([CH3:30])[C@H:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:27][C:26]2=[O:37])[CH:7]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)Cc1ccc(O)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OCC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To {4-hydroxy-3-[2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid ethyl ester (0.060 g, 0.12 mmol) in MeCN (2 mL) was added cesium carbonate (0.086 g, 0.26 mmol) and iodoethane (0.02 mL, 0.26 mmol), and the reaction was stirred at room temperature overnight. After work-up with EtOAc and 10% aqueous HCl, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][Si:28]([CH:31](Br)[C:32]#[CH:33])([CH3:30])[CH3:29]>O1CCCC1>[CH2:19]([C:20]([CH3:26])([CH2:33][C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C)Cc1ccccc1
Reactant: C#CC(Br)[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(CC#C[Si](C)(C)C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.2 ml (1.58 gm) of diisopropylamine in 20 ml of dry tetrahydrofuran, was added dropwise a solution of n-butyllithium (9.7 ml, 1.6M) at 0° C. The solution was stirred at 0° C. for 30 min, then cooled to -78° C. A solution of 2.5 gm of ethyl 3-phenyl-2-methylpropionate in 10 ml of dry tetrahydrofuran was added. After 30 min., 3 gm of trimethylsilylpropargyl bromide in 10 ml dry tetrahydrofuran was added. The mixture was warmed up to 0° C. slowly and maintained at 0° C. for 1.75 hours. The reaction mixture was quenched with 5% hydrochloric acid and partitioned between ether and 5% hydrochloric acid. The ethereal layer, washed with brine solution and water was dried and evaporated in an oil. The oil was chromatographed on silica gel (5% ethyl acetate; petroleum ether). This procedure yielded the title compound, IR: 2170, 1738 cm-1.
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:19][F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=O)C1C=CC=CC=1.[ClH:21].O>FC(F)(F)C(O)=O>[ClH:21].[NH2:11][C@H:12]([CH2:19][F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)/C=C/[C@@H](CF)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)/C=C/[C@H](N)CF
Temperature: 25 °C
Reaction time: 3 h

Procedure:
690 ml of 26B was stirred in 25 ml of trifluoroacetic acid at room temperature for 10 minutes. Then 5 ml of concentrated hydrochloric acid was added drop-by-drop. The resulting solution was stirred at room temperature for three hours, then 16 ml of water was added, and the resulting solution was stirred at room temperature for 16 hours. Then the solvent was evaporated, the residue was dissolved in 30 ml of 2N hydrochloric acid and the resulting solution was extracted with ether, and the solvent was evaporated at a temperature below 40° C. to give methyl (S)-(E)-4-amino-5-fluoro-2-pentenoate hydrochloride (26C), as a pale yellow paste.
Reaction SMILES: B([O-])=O.[Na+:4].[B].[B:6]([OH:9])([OH:8])[OH:7]>>[B:6]([O-:9])([O-:8])[O-:7].[B:6]([O-:9])([O-:8])[O-:7].[B:6]([O-:9])([O-:8])[O-:7].[B:6]([O-:9])([O-:8])[O-:7].[Na+:4].[Na+:4].[Na+:4].[Na+:4].[Na+:4].[Na+:4].[Na+:4].[Na+:4].[Na+:4].[Na+:4].[Na+:4].[Na+:4]
Reactant: OB(O)O
Agent: O=B[O-]
Agent: [B]
Agent: [Na+]
Product: [O-]B([O-])[O-]

Procedure:
FIG. 1 is a schematic drawing depicting a portion of the flow of materials in the process of the present invention, showing the production of a sodium metaborate intermediate from a boron-containing solution, and reaction of the sodium metaborate intermediate with a boric acid intermediate to produce sodium tetraborate.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:20]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)=[O:17])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])O.[Na+]>>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:20]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)Nc2onc(-c3ccc(F)cc3)c2-c2ccncn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CC(=O)Nc2onc(-c3ccc(F)cc3)c2-c2ccncn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
To 59 mg of 5-[(4-t-butoxycarbonylaminophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole, 1 mL of TFA was added under cooling with ice, and the temperature was raised to room temperature, followed by 20 minutes' stirring. The reaction solution was neutralized with saturated aqueous sodium hydrogencarbonate solution under cooling with ice, and extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and removed of the solvent by distillation under reduced pressure. The residue was washed with diethylether-hexane to provide 24 mg (yield: 51%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[C:7]([CH3:17])=[N:6]1.[OH-].[K+:24]>C(O)C>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O-:16])=[O:15])[CH:12]=2)[C:7]([CH3:17])=[N:6]1.[K+:24]
Reactant: Cc1cccc(C)c1Cn1nc(C)c2ccc(C(=O)O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1Cn1nc(C)c2ccc(C(=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound [117] (568 mg) in ethanol (20 mL) was added an aqueous solution of 1N-potassium hydroxide (1.93 mL) at room temperature, and then the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the titled compound (636 mg) as a white solid.
Reaction SMILES: C(OC([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O)C.C(Br)C1C=CC=CC=1.C(OC(=O)CCC1N=C(N)SC=1)C>>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: CCOC(=O)c1c[nH]c2ccccc12
Agent: BrCc1ccccc1
Agent: CCOC(=O)CCc1csc(N)n1
Product: c1ccc2[nH]ccc2c1

Procedure:
Indole-3-carboxylic acid ethyl ester, R5X=benzyl bromide, NH2A=3-(2-amino-thiazol-4-yl)-propionic acid ethyl ester