Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(pyrrolidin-1-yl)quinoxaline-6-carboxylate (72 mg, 0.20 mmol) in methanol (20 mL) was added sodium hydroxide (50 mg, 1.25 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with hydrochloric acid (3N). The product formed a precipitate and was filtered to give 2-(4-fluorophenyl)-3-(pyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (41.5 mg, 60%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.[OH-].[Na+]>C(O)C.CCN(CC)CC.O>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc2nc(-c3ccnc(N4CCNCC4)n3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 60 °C

Procedure:
A vial was charged with a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (10 mg), dioxane (500 μL), H2O (200 μL), Et3N (50 μL), and piperazine (40 mg). The reaction was heated to 60° C. for 1 h. Ethanol (absolute, 500 μL) and 5 M aq NaOH (500 μL) were added. The reaction was heated to 60° C. for 30 min. The reaction was cooled to 23° C. and directly purified by reverse phase HPLC (5-100% ACN/H2O+0.1% TFA) giving the title compound. 1H NMR (400 MHz, CD3OD) δ 8.49 (d, J=5.0 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.81 (s, 1H), 7.68-7.44 (m, 3H), 7.41 (d, J=5.0 Hz, 1H), 5.08 (s, 1H), 3.92-3.69 (m, 4H), 2.85 (dd, J=18.8, 13.9 Hz, 4H), 2.66 (s, 3H), 0.91 (s, 9H). LCMS-ESI+: calc'd for C20H31ClN5O3S [M+H+]: 552.2, 554.2; Found: 552.4, 552.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[C:12](I)=[N:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1.[C:23]([Cu])#[N:24].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[C:12]([C:23]#[N:24])=[N:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccc(Br)o3)noc2c1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(-c3ccc(Br)o3)noc2c1O
Temperature: 110 °C
Yield: 34.3 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-7-hydroxy-4-iodoisoxazolo[4,5-c]pyridine-6-carboxylate (155 mg, 0.324 mmol) and CuCN (87 mg, 0.971 mmol) were added to 2.2 mL of N-methyl-2-pyrrolidone. The resulting suspension was heated in an oil bath (T=110° C.) for 1 h. The reaction mixture was cooled slightly and poured into a vigorously stirring mixture of ammonium hydroxide (5 mL, 15% aqueous solution) and EtOAc (50 mL). The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-100% EtOAc/hexanes) to afford 42 mg of the title compound. MS: (+) m/z 378.29, 380.26 (M+1, 79Br/81Br).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][N:4]=1>ClCCl.O=[Mn]=O>[C:10]([NH:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH:2]=[O:1])[CH:8]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccnc(CO)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)Nc1ccnc(C=O)c1

Procedure:
2 g of the thus obtained 2-hydroxymethyl-4-acetylaminopyridine were suspended in 400 ml of dichloromethane, mixed with 6 g of MnO2 and refluxed for 26 hours. The MnO2 was then filtered hot and the dichloromethane solution rotated in to dryness. 1.5 g of 4-acetylaminopyridine-2-aldehyde were obtained.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([C:9]1[O:13][N:12]=[C:11]([C:14](Cl)=[O:15])[CH:10]=1)[CH2:7][CH3:8].O>ClCCl>[C:1]([NH:5][C:14]([C:11]1[CH:10]=[C:9]([CH2:6][CH2:7][CH3:8])[O:13][N:12]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CCCc1cc(C(=O)Cl)no1
Solvent: ClCCl
Solvent: O
Product: CCCc1cc(C(=O)NC(C)(C)C)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
At 5° C., 9.3 g (126.8 mmol) of tert-butylamine in 20 ml of dichloromethane was dripped into 10.0 g (57.6 mmol) of 5-n-propyl-isoxazole-3-carboxylic chloride in 250 ml of anhydrous dichloromethane. The mixture was stirred for 12 hours at room temperature, 200 ml of water was added, the phases were separated, the organic phase was washed once with 150 ml of saturated sodium bicarbonate solution and once with 150 ml of saturated sodium chloride solution, followed by drying over magnesium sulfate and stripping off the solvent under reduced pressure. There was obtained 11.5 g (95%) of 5-n-propylisoxazole-3-carboxylic acid-tert-butylamide as a solid of melting point 34°-37° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]1[CH2:13][CH:12]([NH:14][C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23]/[CH:24]=[C:25](/[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])\[CH3:26])=[CH:18][CH:17]=2)[CH2:11][N:10]1[CH2:34][CH3:35])[CH3:8].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>>[CH2:34]([N:10]1[CH2:11][CH:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23]/[CH:24]=[C:25](/[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])\[CH3:26])=[CH:18][CH:17]=2)[CH2:13][N:9]1[CH2:7][CH3:8])[CH3:35]
Reactant: CCN1CC(NC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)CN1CC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Product: CCN1CC(NCc2ccc(OC/C=C(\C)CCC=C(C)C)cc2)CN1CC
Yield: 36.1 %

Procedure:
To a suspension of lithium aluminum hydride (0.27 g) in tetrahydrofuran anhydride (40 ml) was added a solution of N-(1,2-diethyl-4-pyrazolidinyl)-4-geranyloxybenzamide (0.89 g) in tetrahydrofuran anhydride (10 ml) dropwise while being cooled with ice. After being refluxed with heating for 5 hours, the reaction solution, with aqueous solution of sodium potassium tartrate added thereto, was extracted with dichloromethane. The extract was concentrated under a vacuum and thus obtained residue was purified by silica gel column chromatography (chloroform:methanol=40:1), thereby yielding 0.31 g (36%) of the aimed compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cn1ccc(CBr)n1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccn(C)n3)C2=O)cn1
Yield: 19 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-(bromomethyl)-1-methyl-1H-pyrazole. Yield 19%. MS M+H calculated 370.1; found 370. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.4 uM.
Reaction SMILES: [CH3:1]N(C)CCN(C)C.[Si:9]([O:16][CH2:17][C@@H:18]1[C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[CH2:21][N:20]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C([Li])(CC)C.CCCCCC>C(OCC)C.C(OCC)(=O)C>[CH3:1][CH:19]1[C@H:18]([CH2:17][O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[CH2:21][N:20]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2cccc(F)c2)C1
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2cccc(F)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 20.7 %

Procedure:
N,N,N′,N′-Tetramethylethylenediamine (0.268 mL, 2.4 mmol) was added to a solution of 3-(R)-((tert-butyldimethylsilyloxy)methyl)-4-(S)-(3-fluorophenyl)-1-tert-butoxycarbonylpyrrolidine (1.0 g, 2.4 mmol, from Step A) in 5 mL of diethyl ether at −78° C. under nitrogen. sec-Butyllithium (2.2 mL, 1.3M in cyclohexane, 2.8 mmol) was then added dropwise. After 45 min., (MeO)2SO2 (0.298 mL, 4.8 mmol) was added, and the reaction mixture was slowly warmed to room temperature overnight. The reaction was quenched with 5 mL of sat. aq. ammonium chloride, and the mixture was partitioned between diethyl ether and water. The aqueous layer was extracted three times with diethyl ether and the combined organic extracts were dried over Na2SO4. Flash chromatography (95:5 hexane:ethyl acetate) provided 210 mg (21% yield) of the title compound, contaminated with small amounts of the other regioisomer. ESI-MS (M+H): 424.3; HPLC A: 5.33 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC2CN(C(=O)OC(C)(C)C)C2)cc1OC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1C(=O)O
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 2-methoxy-4-(1-tert-butyloxycarbonyl-3-azetidinyloxy)benzoate from Step 4 above (200 mg, 0.647 mmol) in methanol (10 mL) was added 2N NaOH (5 mL, 10 mmol). The reaction mixture was refluxed for 30 minutes, then cooled in a ice water bath. The solution was acidified with 5% citric acid then the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (2×25 mL). The aqueous layer was made alkaline (pH=9) with DIEA, cooled, then di-tertbutyldicarbonate (275 mg, 1.26 mmol) was added to the stirring solution. After 4 hours, the aqueous solution was extracted with diethyl ether (50 mL), and then made acidic by addition of 1N HCl (25 mL). The aqueous layer was extracted with methylene chloride (3×25 mL) and the organic layers were collected, dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. 2-Methoxy-4-(1-tert-butyloxycarbonyl-3-azetidinyloxy)benzoic acid was obtained as a white solid which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9])=[C:4]([F:15])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:35]1[C:36]2[C:37]3[CH:50]=[CH:49][S:48][C:38]=3[C:39](=[O:47])[NH:40][C:41]=2[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]>>[F:15][C:4]1[CH:3]=[C:2]([C:35]2[C:36]3[C:37]4[CH:50]=[CH:49][S:48][C:38]=4[C:39](=[O:47])[NH:40][C:41]=3[CH:42]=[CH:43][C:44]=2[O:45][CH3:46])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1F
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)c(F)c1
Yield: 15.2 %

Procedure:
Following General Procedure E, 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzenesulfonamide (3.30 mg, 1.1 mmol) was reacted with bis(pinacolato)diborane (300 mg, 1.2 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (310 mg, 1.0 mmol) to afford the desired product (68 mg, 13%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.04 (t, J=5.8 Hz, 1H), 7.93 (t, J=7.8 Hz, 1H), 7.93 (d, J=5.4 Hz, 1H), 7.57 (d, J=9.1 Hz, 1H), 7.49-7.43 (m, 2H), 7.30 (dd, J=8.0, 1.5 Hz, 1H), 5.89 (d, J=5.4 Hz, 1H), 4.78 (t, J=5.6 Hz, 1H), 3.72 (s, 3H), 3.46 (q, J=6.2 Hz, 2H), 3.05 (m, 2H).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][C@@H:46]([C:54]([NH:56][CH2:57][C:58]([NH:60][C@H:61]([C:64]([NH:66][C@H:67]([C:72]([O:74]C(C)(C)C)=[O:73])[CH2:68][C:69](=[O:71])[NH2:70])=[O:65])[CH2:62][OH:63])=[O:59])=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])[CH3:11])=[O:8].FC(F)(F)C(O)=O.Cl.N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CCC(=O)O.NCC(O)=O.N[C@H](C(O)=O)C.N[C@H](C(O)=O)CC1C=CC=CC=1>O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][C@@H:46]([C:54]([NH:56][CH2:57][C:58]([NH:60][C@H:61]([C:64]([NH:66][C@H:67]([C:72]([OH:74])=[O:73])[CH2:68][C:69](=[O:71])[NH2:70])=[O:65])[CH2:62][OH:63])=[O:59])=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[O:13])[CH3:11])=[O:8]
Reactant: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](Cc1ccccc1)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Agent: C[C@H](N)C(=O)O
Agent: Cl
Agent: NCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](Cc1ccccc1)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O

Procedure:
Using 500 mg of pGlu-Ala-Lys(Boc)-Ser-Gln-(D)-Phe-Gly-Ser-Asn-OBut and 15 ml of trifluoroacetic acid, the same procedure as Example 5-(VIII) is followed to prepare the above-identified compound. Yield 280 mg; [α]D24 -51.7°(c=0.2, water), Rf4 (Avicel)=0.35; amino acid analysis (hydrolyzed with HCl); Lys, 1.00(1); Asp, 0.70(1); Ser, 2.02(2); Glu, 2.03(2); Gly, 1.02(1); Ala, 0.77(1); Phe, 1.01(1); average recovery 84.5%.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)([OH:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[CH2:26]1CCN2C(=NCCC2)CC1.CI>C(#N)C>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)([OH:11])[C:8]([O:10][CH3:26])=[O:9])=[CH:5][CH:4]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Solvent: CI
Solvent: CC#N
Product: COC(=O)C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
38.5 g (0.115 mol) of 4,4′-di(trifluoromethyl)benzilic acid, 30.5 g (0.20 mol) of DBU, and 56.8 g (0.40 mol) of methyl iodide are reacted in 400 ml acetonitrile analogously to step I.10.3. The product is purified by flash chromatography (eluant cyclohexane/ethyl acetate 95:5). Yield: 20.05 g of white crystals (46% of theory); melting point: 68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:10]([O:15][CH3:23])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(O)C(=Cc1ccc(Cl)cc1)n1cncn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C(=Cc1ccc(Cl)cc1)n1cncn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
The I'-B isomer (2 g) of 1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazole-1-yl)-pentene-3-ol (Compound No. 1) was dissolved in dimethylformamide (20 cc), and 65% sodium hydride (0.26 g) was added thereto. After stirring at room temperature for 1 hour, the reaction mixture was cooled to 10° C., and methyl iodide (1 g) was added. The reaction mixture was kept at 10° C. for 1 hour and then allowed to stand at room temperature for 16 hours. Dimethylformamide was removed under reduced pressure, and the residue was extracted with addition of ice water (100 g) and chloroform (100 cc). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (acetone:n-hexane=1:10) to obtain 1.0 g of the entitled compound as an oily product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[NH:12][C:13]1[C:14]([NH:23][S:24]([C:27]2[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=2)(=[O:26])=[O:25])=[N:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.Cl.CN(C)CCCN=C=NCC.[C:45]([NH:62][C@H:63]([C:67](O)=[O:68])[CH:64]([CH3:66])[CH3:65])([O:47][CH2:48][CH:49]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]2[C:50]1=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:46].O>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[CH:51]1[C:50]2[CH:49]([CH2:48][O:47][C:45]([NH:62][C@H:63]([C:67]([O:1][CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=3[NH:12][C:13]3[C:14]([NH:23][S:24]([C:27]4[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=4)(=[O:26])=[O:25])=[N:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:22]=3)=[O:68])[CH:64]([CH3:65])[CH3:66])=[O:46])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: COc1ccc(CCO)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cn(C)cn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCOC(=O)[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(C)C)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cn(C)cn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
To a suspension of N-(3-{[2-(2-hydroxyethyl)-5-methoxyphenyl]amino}quinoxalin-2-yl)-1-methyl-1H-imidazole-4-sulfonamide (200 mg; 0.44 mmol; 1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92.8 mg; 0.48 mmol; 1.1 eq) and N,N-dimethylpyridin-4-amine (59 mg; 0.48 mmol; 1.1 eq) in a mixture of DCM (10 mL) and DMF (1 mL) is added fmoc-l-valine (164 mg; 0.48 mmol; 1.1 eq). The reaction mixture is stirred for 18 h at room temperature. Water is added and organic phase is washed several times with 10% citric acid then dried under MgSO4. The solvent is removed under reduced pressure and residue purified by flash chromatography using EtOAc as eluent to afford 200 mg (59%) of the title compound as a yellow gum. HPLC (max plot) 98%; Rt 5.46 min. LC/MS: (ES+): 775.7, (ES−): 773.9.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:24])OC3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[OH:35][C:36]1[CH:37]=[C:38]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1>>[OH:35][C:36]1[CH:37]=[C:38]([S:42]([NH:45][C:16]([NH:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([N:6]3[C:2]([CH3:1])=[C:3]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:4]([C:25]([F:27])([F:26])[F:28])=[N:5]3)=[CH:8][CH:9]=2)=[O:24])(=[O:43])=[O:44])[CH:39]=[CH:40][CH:41]=1
Reactant: NS(=O)(=O)c1cccc(O)c1
Reactant: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccc(O)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-methyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 7 of Example 52) and 3-hydroxybenzenesulfonamide: MS (ESI) m/z 545 [M+H]+, 543 [M−H]−, 1H-NMR (CDCl3) δ 7.48-7.01 (13H, m), 6.32 ▪ 1H, br.s), 3.50 (2H, t, J=6.1 Hz), 2.85 (2H, t, J=6.1 Hz), 2.20 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][N:12]([CH3:18])[C:11]2=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CI
Reactant: O=C1NCCN1c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(p-nitrophenyl)-2-imidazolidinone (25 g) in 450 ml of dimethylformamide is stirred under nitrogen and sodium hydride (50%, 6.4 g) added in small portions. The mixture is stirred at 50° for 11/2 hours, cooled to room temperature, and then methyl iodide (25 g) is added. After stirring 2 hours, the pH of the reaction mixture is 9. Another batch of methyl iodide (4 g) is added over 6 hours until the pH of the mixture is about 8. Water (150 ml) is added, the precipitated solid is filtered off, washed with dimethylformamide/water (1:1), then with water (2×150 ml). The solid is dried to give 1-(p-nitrophenyl)-3-methyl-2-imidazolidinone, m.p. 207°-208°.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5])#[N:2].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19](Cl)=[O:20]>[OH-].[Na+]>[C:1]([CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH:5][C:19]([C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1)=[O:20])#[N:2]
Reactant: N#CC[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Product: N#CC[C@H](NC(=O)c1ccc2ccccc2c1)C(=O)O
Yield: 18.3 %

Procedure:
0.114 g of 3-cyano-L-alanine was dissolved in 5 ml of 1N sodium hydroxide solution and treated with 0.285 g of 2-naphthoyl chloride at 0° C. After acidification with 2M hydrochloric acid and flash chromatography on silica gel using 25% methanol in dichloromethane for the elution there was obtained 0.049 g of 3-cyano-N-(2-naphthoyl)-L-alanine of melting point 95°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C@H:8]([O:21]S(C)(=O)=O)[CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:4](OC(=O)C)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C(OCC)(=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[O:6][CH2:7][C@H:8]([CH2:9][N:10]3[C:14](=[O:15])[C:13]4=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]4[C:11]3=[O:20])[O:21][C:4]=2[CH:3]=1
Reactant: CC(=O)Oc1cc(Cl)ccc1OC[C@@H](CN1C(=O)c2ccccc2C1=O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1C[C@H]1COc2ccc(Cl)cc2O1
Temperature: 50 °C
Reaction time: 9 h
Yield: 69.1 %

Procedure:
To a reaction vessel were added crude (R)-1-(4-chloro-2-acetoxyphenoxy)-2-methanesulfonyloxy-3-phthalimidopropane 242 mg (0.50 mmol), sodium carbonate 58.3 mg (0.60 mmol) and methanol 2 mL, and the mixture was stirred at 50° C. for 9 hours. To the reaction mixture was added ethyl acetate and the mixture was washed with water. The solvent was evaporated and recrystallized to give (S)-7-chloro-2-(phthalimidomethyl)-1,4-benzodioxane 114 mg (yield 70%, chemical purity 98%, optical purity 98% ee) as a white solid.