Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC4CCOCC4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OC3CCOCC3)cc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-[{[4-({cyclohexyl[3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (1.8 g) optically resolved in the above-mentioned (1) was dissolved in ethanol (20 mL), 1N aqueous sodium hydroxide solution (5 mL) was added at room temperature, and the mixture was stirred at 50° C. for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (5 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from acetone to give the title object compound (1.5 g, 88%, 99.9% ee) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A mixture of methyl 4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}benzoate obtained in Example 33 (608 mg), 1 M sodium hydroxide solution (5 mL), methanol (20 mL), and tetrahydrofuran (5 mL) was stirred at 50° C. for 4 h. 1 M hydrochloric acid solution was added to the reaction solution, and the solvent was evaporated under reduced pressure to afford crystals. Crystals were washed with water, diethyl ether and dried under reduced pressure to provide the title compound (580 mg, 99%) as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:7][C:8]([C:10]1[C@:11]2([CH2:27][CH2:26][C@H:25]3[C@@H:16]([CH2:17][CH2:18][C:19]4[CH:20]=[C:21]([OH:28])[CH:22]=[CH:23][C:24]=43)[C@@H:13]2[CH2:14][CH:15]=1)[CH3:12])=[O:9])[CH2:4][CH2:5][CH3:6].Cl[S:30]([NH2:33])(=[O:32])=[O:31].C(=O)(O)[O-].[Na+]>CN(C=O)C>[S:30](=[O:32])(=[O:31])([O:28][C:21]1[CH:22]=[CH:23][C:24]2[C@@H:25]3[C@H:16]([C@H:13]4[C@@:11]([CH2:27][CH2:26]3)([CH3:12])[C:10]([C:8](=[O:9])[NH:7][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:15][CH2:14]4)[CH2:17][CH2:18][C:19]=2[CH:20]=1)[NH2:33]
Reactant: CCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Reactant: NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Reaction time: 0.42 h
Yield: 95.2 %

Procedure:
Sodium hydride (20 mg) was added to a solution comprising 73 mg of compound 10a in 2 ml of anhydrous DMF at 0° C. The solution was stirred for 25 minutes and 126 mg of chlorosulfonamide was added in one portion. The solution was then stirred at room temperature for 2 hours. Ice and saturated sodium bicarbonate solution was added to the reaction mixture. The precipitate formed was filtered and washed with water. The residue was purified by chromatography on silica gel (CHCl3:methanol, 50:1), yielding compound 11a (85 mg, 96%). FAB-MS m/z 433 (M+H)+; 1H NMR (270 MHz, DMSO-d6) δ 0.88 (t, 3H, J=7.5 Hz, CH2CH3), 0.91 (s, 3H, CH3), 3.08 (dt, 2H, J=5.6, 6.6 Hz, NHCH2), 6.34 (s, 1H, 16-CH), 6.97 (s, 1H, ArH), 7.01 (dd, 1H, J=2.6, 8.6 Hz, ArH), 7.33 (d, 1H, J=8.6 Hz, ArH), 7.71 (t, 1H, J=5.6 Hz, NHCH2), 7.88 (s, 2H, NH2).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([Br:15])[CH:12]=[C:13]([F:14])[C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].O>C1COCC1>[Br:15][C:11]1[CH:12]=[C:13]([F:14])[C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1cc2c(F)cc(Br)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(F)cc(Br)cc2s1
Yield: 88 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 25 for the preparation of I-25b above, 6-bromo-4-fluoro-benzo[b]thiophene-2-carboxylic acid methyl ester (I-26b: 2.3 g, 7.85 mmol) in THF (25 mL) was hydrolyzed with LiOH (1.65 g, 39.38 mmol) and water (20 mL) to afford 1.9 g of the product (83% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.[CH3:13][O:14][CH:15]([O:19][CH3:20])[CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:13][O:14][CH:15]([O:19][CH3:20])[CH2:16][CH2:17][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:7]=1
Reactant: Oc1cccc(-c2ccsc2)c1
Reactant: COC(CCBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCOc1cccc(-c2ccsc2)c1)OC
Temperature: 90 °C
Reaction time: 6 h

Procedure:
1.3 g of 3-(3-thienyl)phenol, 1.09 ml of 3-bromopropanal dimethylacetal and 1.1 g of potassium carbonate were dissolved in 10 ml of dimethylformamide, and the mixture was heated at 90° C. with stirring for 6 hours. Ethyl acetate and Water were added, and the organic layer separated was worked up in a customary manner, then the product was purified by silica gel column chromatography [hexane/ethyl acetate=30/1→20/1] to give 1.0 g of 3-[3-(3-thienyl)phenoxy]propanal dimethylacetal as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1)[CH3:5].C(Cl)(Cl)Cl.[CH3:24][NH:25][C:26]([NH2:28])=[S:27].C(=O)(O)[O-].[Na+]>CO.[Na+].[Cl-]>[CH3:24][NH:25][C:26]1[S:27][CH:2]=[C:3]([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:8]([F:18])[CH:7]=2)[CH3:5])[N:28]=1
Reactant: CNC(N)=S
Reactant: CC(C(=O)CCl)c1ccc(-c2ccccc2)c(F)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Yield: 70 %

Procedure:
A mixture of (+)-1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (27.7 mg, 0.1 mmol; [α]D25 ° C.+180° (c=0.744, CHCl3), N-methylthiourea (9 mg, 0.1 mmol) and sodium bicarbonate (9.2 mg, 0.11 mmol) in methanol (1 ml) was stirred at room temperature for 28 hr and the mixture was diluted with NaCl aq., then extracted with ethyl acetate. The extracts were dried with magnesium sulfate and evaporated under reduced pressure to a residue, which was chromatographed to afford (+)-2-methylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (21.9 mg, 70% yield): [α]D25 ° C.+10.7° (c=0.15, CHCl3); 70% ee.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18].[OH-].[K+].[CH2:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24](Cl)=[O:25])[CH3:22]>C1C=CC=CC=1.C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.CCOCC>[CH2:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([O:18][C:10]1[CH2:11][C:12]([CH3:16])([CH3:17])[CH2:13][C:14](=[O:15])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])=[O:25])[CH3:22]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: Cc1ccc(C)c(C2C(=O)CC(C)(C)CC2=O)c1
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCC(CC)C(=O)OC1=C(c2cc(C)ccc2C)C(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A suspension of 1.50 g (6.14 mmol) of 2-(2',5'-dimethylphenyl)-5,5-dimethyl-1,3-cyclohexanedione in 15 ml of dry benzene was prepared and 0.49 g (7.37 mmol) of 85% powered potassium hydroxide was added, followed by 1 drop of dicyclohexyl-18-crown-6-ether. After stirring for 30 minutes, 1.20 (7.37 mmol) of 2-ethylhexanoyl chloride was added, and the reaction mixture refluxed for 12 hrs. The reaction mixture was cooled to room temperature, taken up in 150 ml ether and 50 ml of water, washed three times with 0.25N NaOH, two times with water, two times with 6N HCl, and one more with water. The ether solution was dried and stripped to leave 2.10 g (92% yield) of 3-(2-ethylhexanoyloxy)-5,5-dimethyl-2-(2',5'-dimethylphenyl)-2-cyclohexenone as a clear, colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5]C)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11](C2N=C(C3C=CC=CC=3)NC=2)=[CH:10][C:9]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][C:3]([C:11]1[CH:12]=[CH:13][C:8]([F:7])=[C:9]([CH3:25])[CH:10]=1)=[O:5]
Reactant: COC(=O)CBr
Reactant: Cc1cc(-c2c[nH]c(-c3ccccc3)n2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)CBr)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.41 mL methyl bromoacetate was added to 1 g 4-(4-fluoro-3-methyl-phenyl)-2-phenyl-1H-imidazole and 1.66 g potassium carbonate in 10 mL DMF. The reaction was stirred 3 h at RT. Then 0.41 mL methyl bromoacetate was added and the reaction was stirred over night at RT. The reaction mixture was added to ice water and extracted with DCM. The organic layer was dried and evaporated to give 1 g desired product. Rt: 0.94 min (method B), (M+H)+: 325
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:9](=[O:23])[C:7]=2[N:8]=1.C[O-].[Na+].[C:27](O)(=[O:29])C>CO>[CH3:27][O:29][C:3]1[N:4]=[N:5][C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:9](=[O:23])[C:7]=2[N:8]=1
Reactant: CC(=O)O
Reactant: CCCOc1ccccc1-c1nc2nnc(SC)nc2c(=O)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1ccccc1-c1nc2nnc(OC)nc2c(=O)[nH]1

Procedure:
A stirred mixture of 5,6-dihydro-3-methylthio-5-oxo-7-(2-propoxyphenyl)pyrimido[5,4-e][1,2,4]triazine (0.80 g) and sodium methoxide (prepared from sodium, 0.28 g and methanol) in methanol (50 ml) was heated under reflux for 1.5 hours. The cooled reaction mixture was neutralized by th e addition of glacial acetic acid (0.7 ml) to afford a yellow precipitate (0.63 g) which was recrystallized from methanol to afford the title compound, 0.47 g, m.p. 221-222° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]2[N:14]=[C:15]([Cl:19])[N:16]=[C:17](Cl)[C:12]=2[N:11]=[C:10]([Cl:20])[N:9]=1.O>C1COCC1>[Cl:20][C:10]1[N:9]=[C:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]2[N:14]=[C:15]([Cl:19])[N:16]=[C:17]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:12]=2[N:11]=1
Reactant: Clc1nc(Cl)c2nc(Cl)nc(Cl)c2n1
Reactant: C1CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc(N2CCCCC2)c2nc(Cl)nc(N3CCCCC3)c2n1
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
Piperidine (0.8 ml, 8 mmol) was added to tetrachloropyrimidopyrimidine (0.54 g, 2 mmol) in THF (15 ml) and the resulting solution was stirred for 10 minutes until a yellow precipitate formed. Water (75 ml) was added and the mixture stirred for a further 10 minutes. The precipitate was filtered under suction, washed with water and dried in vacuo (P2O5) yielding the title compound as a yellow powder (0.62 g, 75%), m.p. 240-241° C., δH (CDCl3, 200 MHz) 1.81 (12H, s, 2×(CH2)3), 4.15 (8H, s br, 2×N(CH2)2); m/z (El) 366 (M+−1), 198.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:39]=[CH:40][CH:41]=[CH:42][C:21]=3[N:20]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:19]2=[O:49])=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:39]=[CH:40][CH:41]=[CH:42][C:21]=3[N:20]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:19]2=[O:49])=[N:9]1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 6 h
Yield: 70.8 %

Procedure:
400 mg of 2-[3-(1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl-acetamide, prepared as in Intermediate 68, is dissolved in 10 mL of CHCl3 and 5 mL of TFA is added. The reaction mixture is stirred for 6 h and the solvents were removed in vacuo and the residue is purified by flash column chromatography on silica gel (MeOH 1%:CHCl3 99%) to afford 240 mg of the title compound: 1H NMR (400 MHz, CDCl3) δ7.93 (d, 1H, J=8.4), 7.51-7.19 (m, 16H), 6.99 (m, 1H), 5.03 (m,1H, J=6.8), 4.29 (d, 1, J=16.4), 4.26 (d, 1H, J=16.4), 4.14 (m, 1H), 3.89 (dd, 1H, J=16.5, 6.4), 3.82 (dd 1H,J=16.5, 6.4,), 1.08 (t, 6H, J=6.8); LOW RESOLUTION MS (FAB) m/e 558 (MH+); Tr =9.90 min. (HPLC Column: Dynamax C-8 2 mL/min., 50-90% Acetonitrile in aqueous TFA (0.1% v/v) over 15 min.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-])=O)[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl-].[NH4+]>CO.O.[Zn]>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([NH2:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(N)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 108.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methyl ester (1.50 g, 4.22 mmol) in methanol (30 mL) was treated with a solution of ammonium chloride (474 mg, 8.86 mmol) in water (3 mL). The reaction mixture was stirred at 25° C. for 5 min and then treated with zinc dust (2.70 g, 41.36 mmol). The reaction mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool to 25° C. and then filtered through a pad of celite. The filtrate was concentrated in vacuo. The resulting orange oil was dissolved in ethyl acetate, dried over magnesium sulfate, filtrated, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.49 g, 98%) as a white solid: mp 98-100° C.; EI-HRMS m/e calcd for C16H23NO4S (M+) 325.1348, found 325.1358.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][C:7]1[C:12]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:11][N:10]=[C:9]([NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[NH:23][C@H:22]([CH2:32][CH3:33])[CH2:21]2)[N:8]=1.[Cl:43][CH2:44][CH2:45][N:46]=[C:47]=[O:48].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:43][CH2:44][CH2:45][NH:46][C:47]([N:23]1[C:24]2[C:29](=[N:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C@@H:20]([NH:19][C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=3)[C:12]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:11][N:10]=2)[CH2:21][C@H:22]1[CH2:32][CH3:33])=[O:48]
Reactant: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c2nc(OC)ccc2N1
Reactant: O=C=NCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c2nc(OC)ccc2N1C(=O)NCCCl
Temperature: 60 °C
Reaction time: 9 h
Yield: 90.6 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-[1,5]naphthyridine (150 mg) is dissolved in toluene (2.0 ml), and thereto is added 2-chloroethyl isocyanate (40 mg). The mixture is stirred at 60° C. for 9 hours under nitrogen flow. To the reaction mixture is added a saturated aqueous sodium hydrogen carbonate solution, the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=2:1→1:9) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)-benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid (2-chloroethyl)amide (160 mg). MS (m/z): 702/704 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C[N:16]([CH:18]=O)C>>[CH3:5][CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:2]2[CH:7]=[CH:6][C:5]([S:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[C:4]([C:18]#[N:16])[C:3]=2[C:18]#[N:16])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCC(C)C
Product: Cc1ccc(Sc2ccc(Sc3ccc(C)cc3)c(C#N)c2C#N)cc1
Yield: 52 %

Procedure:
4-Methylthiophenol (3.41 g, 27.5 mmol), potassium carbonate (3.80 g, 27.5 mmol) and ditosylated dicyanohydroquinone (i.e. product A) (5.00 g, 10.7 mmol) in DMF (40 mL) were reacted as described above. The mixture was isolated as described above to give a yellow solid. The solid was purified by flash column chromatography (gradient elution: 5%-10%-30% ethyl acetate:isohexane, finally dichloromethane) to give the title compound as a yellow solid (2.07 g, 52%). [Found: C, 69.9%; H, 4.4%; N, 7.3%; S, 16.9%; C22H16N2S2 requires C, 70.9%, H, 4.3%, N, 7.5%, S, 17.2%]; MS (EI+) 372 (M+, 100%), 357 (M-CH3, 5%), 123 (CH3C6H4S, 15), 91 (CH3C6H4, 15).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].[NH2:37][CH2:38][C:39]([CH3:42])([OH:41])[CH3:40].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:35])([F:36])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:37][CH2:38][C:39]([OH:41])([CH3:42])[CH3:40])=[O:9])=[O:4]
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(O)CNC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 37.1 %

Procedure:
3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 4, 35 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 1-amino-2-methylpropan-2-ol (12.42 mg, 0.139 mmol), 4-methylmorpholine (0.046 mL, 0.418 mmol), and BOP (61.6 mg, 0.139 mmol). This was stirred for 1 h and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention time=33.2 min) to give single enantiomer 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-(2-hydroxy-2-methylpropyl)propanamide (15.3 mg, 0.026 mmol, 36.8% yield): LC/MS=574.3 [M+H)+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.69 (4 H, d, J=8.14 Hz), 7.52-7.65 (3 H, m), 5.11 (1 H, s), 3.52 (2 H, t, J=6.71 Hz), 3.31 (3 H, dt, J=3.25, 1.57 Hz), 2.48 (2 H, t, J=6.71 Hz), 1.16 (6 H, d, J=1.76 Hz). HPLC Peak RT=9.0 min (Analytical Method D).
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].C(N(CC)CC)C.[S:14](Cl)([CH3:17])(=[O:16])=[O:15].C(=O)(O)[O-].[Na+]>C1COCC1.C(Cl)Cl>[CH3:17][S:14]([O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])(=[O:16])=[O:15]
Reactant: [N-]=[N+]=NCCO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of compound 2-azidoethanol (1.00 g, 11.49 mmol) in THF (25 mL) and triethylamine (Et3N) (2.418 mL, 17.24 mmol) was added mesyl chloride (1.328 mL, 17.24 mmol) at 0° C., and the mixture was allowed to warm to room temperature. Stirring continued for 3 h, during which TLC revealed a quantitative conversion into a higher Rf product. CH2Cl2 (70 mL) and saturated sodium bicarbonate (50 mL) were added, and the two layers were separated. The organic layer was washed with sodium bicarbonate (2×50 mL), saturated brine (45 mL) and dried over Na2SO4. Solvent was evaporated off to give crude compound 156a (1.70 g) as a colorless oil, which was used for next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:50])[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[S:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]([S:38]([C:41]1[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:42]=1[CH3:49])(=[O:40])=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][S:26]([C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=1[CH3:37])(=[O:28])=[O:27])(=[O:13])=[O:12].IC.[CH3:53][CH2:54]CCCC.[CH3:59]COC(C)=O>CN(C=O)C>[C:5]1([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH3:50])[C:4]=1[S:11]([N:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([S:38]([C:41]1[C:42]([CH3:49])=[CH:43][C:44]([CH3:48])=[CH:45][C:46]=1[CH3:47])(=[O:39])=[O:40])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([S:26]([C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=1[CH3:37])(=[O:27])=[O:28])[CH2:53][CH3:54])[CH3:59])(=[O:13])=[O:12]
Reactant: Cc1cc(C)c(S(=O)(=O)NCCCCCN(CCCCNS(=O)(=O)c2c(C)cc(C)cc2C)S(=O)(=O)c2c(C)cc(C)cc2C)c(C)c1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCN(CCCCCN(CCCCN(C)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C
Yield: 85 %

Procedure:
NaH (60%, 0.28 g, 6.9 mmol), 33 (2.16 g, 3.0 mmol), and iodomethane (6.1 mL, 9.8 mmol) in DMF (30 mL) were combined and worked up by the method of 43. Column chromatography (7:3 hexane/EtOAc) gave 1.90 g (85%) of 53 as an oil: NMR δ 1.08-1.16 (m, 2 H), 1.38-1.50 (m, 8 H ), 2.28-2.29 (2 s, 9 H), 2.57-2.58 (2 s, 18 H), 2.63 (s, 3 H), 2.65 (s, 3 H), 3.02-3.14 (m, 8 H), 6.95 (s, 6 H); HRMS calcd. for C38H58N3O6S3 748.3487 (M+H), found. 748.3483 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([OH:18])[C:10](=[CH:16][CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4].[I-:19].[Na+]>CC(C)=O>[I:19][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([OH:18])[C:10](=[CH:16][CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4]
Reactant: CCOC(=O)c1ccc(CNC(=O)CCl)cc1O
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(CNC(=O)CI)cc1O
Temperature: 25 °C
Yield: 130.8 %

Procedure:
Ethyl N-chloroacetyl-4-aminomethylsalicylate (0.11 g, 0.40 mmoles) was dissolved in acetone (5 mL) and sodium iodide (0.06 g, 0.40 mmoles) was added. The solution was refluxed for 2.5 hours, then cooled to room temperature and filtered. The filtrate was evaporated to dryness to afford a white solid of ethyl N-iodoacetyl-4-aminomethylsalicylate (0.19 g, 100% yield) (m.p. 105°-108° C.).