Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22]C(=O)CC1C=CC=CC=1.[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43]([OH:45])=O)[CH:38]=[C:39]([F:41])[CH:40]=1>>[F:41][C:39]1[CH:38]=[C:37]([CH2:42][C:43]([N:19]([C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C@@H:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20](=[O:33])[C@H:21]([CH2:32][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:7]=2)[NH2:22])=[O:45])[CH:36]=[C:35]([F:34])[CH:40]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1
Product: N[C@@H](Cc1ccccc1)C(=O)N(C(=O)Cc1cc(F)cc(F)c1)[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (97) was used except that N-[(2,3-cis)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-L-phenylalaninamide (105a) was used as the amine component and 3,5-difluorophenylacetic acid was used as the acid component to afford the title compound as a 1:1 mixture with the 2S,3S diastereomer (58 mg), white solid, m.p.115-120° C. 1H NMR (300 MHz, d6-DMSO) δ 4.45 (m, 1H), 4.75 (m, 1H), 5.10 (m, 1H), 6.70 (m, 2H), 6.95-7.90 (m, 16H), 8.25 (two d, 1H, J=8 Hz),10.5 (m 1H). MS APCI, m/z=572 (M+1). LC/MS: 2.68 min.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[I:8][C:7]1[C:2]([O:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)=[CH:21][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: Clc1ncccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Ic1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 80 °C

Procedure:
To a 250-mL round-bottomed flask was added 2-chloro-3-iodopyridine (5.32 g, 22.22 mmol), 4-(pyridin-2-ylamino)phenol (4.96 g, 26.6 mmol) and cesium carbonate (11.27 g, 34.6 mmol) in DMSO (100 mL) and the reaction was heated at 80° C. overnight. The reaction was cooled to rt and poured into water (400 mL). The solution was extracted with EtOAc (4×100 mL) and the combined organic layers were washed with brine and dried over Na2SO4. The solution was filtered, evaporated onto silica gel and purified by flash chromatography (Isco, (330 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→1:19). The material was dissolved in MeOH, evaporated onto silica gel and further purified by flash chromatography (Isco (330 gram)) eluting with EtOAc:hexanes (0:1→3:1) to give a white amorphous solid. MS (ESI, pos. ion) m/z: 389.9. IC50 (uM)=0.2284.
Reaction SMILES: [OH-].[Na+].O.C([O:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C:17]2=[O:27])[CH2:9]1)(=O)C>CO>[OH:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C:17]2=[O:27])[CH2:9]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 98.5 %

Procedure:
A solution of 7.6 parts of sodium hydroxide in 25 parts of water is added to a solution of 42.5 parts of 3β-acetoxy-5β-androstan-17-one in 140 parts of methanol with stirring. The resultant mixture is heated to reflux for 2 hours whereupon distillation is initiated and 109 parts of methanol are removed. The remaining methanol is removed by evaporation and the resulting crystalline solid is diluted with water and stirred. The crystals are collected by filtration, washed with water until the washings are about pH 6 and air-dried to afford, in 98.5% yield, 3β-hydroxy-5β-androstan-17-one. This compound melts at about 152°-155° C. and exhibits infrared absorption maxima in chloroform at 3620, 2940, 1735 cm-1 and is represented by the following structural formula. ##STR5##
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:13]([OH:19])=[C:12]([I:20])[CH:11]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Cl)[C:28]#[CH:29]>CN(C)C=O>[I:20][C:12]1[C:13]([O:19][CH2:29][C:28]#[CH:27])=[CH:14][C:15]([CH:16]([CH3:18])[CH3:17])=[C:10]([CH:11]=1)[O:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: C#CCCl
Reactant: CC(C)c1cc(O)c(I)cc1Oc1cnc(N)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To 4-(2,4-Diamino-pyrimidin-5-yloxy)-2-iodo-5-isopropyl-phenol (200 mg, 0.43 mmol) dissolved in anhydrous N,N-dimethylformamide (2 mL) was added anhydrous potassium carbonate (414 mg, 3.00 mmol) and propargyl chloride (0.03 mL, 0.43 mmol). After stirring at room temperature overnight, the reaction was extracted with dichloromethane, water and brine. The dichloromethane layer was dried using anhydrous magnesium sulfate, concentrated, and purified via silica gel column chromatography (95/5/0.1 dichloromethane/methanol/ammonium hydroxide) to yield 5-(5-iodo-2-isopropyl-4-prop-2-ynyloxy-phenoxy)-pyrimidine-2,4-diamine as white solid (131 mg, 71%), MS (M+H)=425.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[CH3:15])([O-])=O.C.[OH:17][S:18]([OH:21])(=[O:20])=[O:19]>CC(O)C.[Pd]>[S:18]([OH:21])([OH:20])(=[O:19])=[O:17].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:6][C:5]=1[CH3:15]
Reactant: Cc1cc(N2CCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: Cc1cc(N2CCCC2)ccc1N

Procedure:
20.25 g (0.098 mole) 1-(4-nitro-3-methylphenyl)pyrrolidine were combined with 2 g Darco KB carbon, 200 ml 2-propanol and 5% Pd/C. The mixture was hydrogenated at 60 psi on a Parr apparatus. When reduction was complete, the mixture was filtered through filter aid and stirred with external cooling in an ice/acetone bath. A cold solution of 10.72 g (0.105 mole) concentrated H2SO4 in 20 ml 2-propanol was added dropwise and stirred for 1 hour. The mixture was filtered, washed 2 times with 2-propanol, and dried in vacuo at 50° C. The final yield was 22.3 g (83%) of off-white solid. MS (solid probe): m/e 176 (free base).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[C:49]([C:57]([OH:59])=O)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[O:56]=[C:49]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:57]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:59]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)C(=O)c2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with benzoylformic acid, mp 106°-109° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:6]2[O:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>C(O)(=O)C>[C:25]([NH:2][C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:6]2[O:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(N)cc2c1C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(NC(=O)c2c(Cl)cccc2Cl)c2oc(C)c(C)c2c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
A mixture of 5-amino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan hydrochloride (116 mg) and acetic anhydride (74 mg) in acetic acid (1 ml) was stirred at 80° C. for 1.5 hours. The reaction mixture was cooled and to the mixture was added water. The separated solid was collected, washed with water and dried to give 5-acetylamino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan (97 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][OH:16].[CH3:17][S:18](Cl)(=[O:20])=[O:19].CNC1C=CC=C(NC)N=1.CCN(CC)CC>[Cl-].[Na+].O.O.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][O:16][S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1C1CCCCC1CO
Agent: CNc1cccc(NC)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1C1CCCCC1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
Combine [2-(2-methoxy-phenyl)-cyclohexyl]-methanol (0.725 g, 3.29 mmol), methanesulfonyl chloride (0.415 g, 3.62 mmol), 2,6-dimethylaminopyridine (80.0 mg, 0.66 mmol), Et3N (1.0 mL, 7.24 mmol), and dichloromethane (30.0 mL) at 0° C. After 20 min stir at room temperature under nitrogen. Reaction stirred for 18 hours then add water and brine. Separate layers and dry over anhydrous sodium sulfate. Concentrate and flash chromatography using 5 to 30% ethyl acetate/hexanes to yield the titled compound (0.810 g, 83%). TLC Rf=0.25 in 30% ethyl acetate/hexanes. 1H NMR (CDCl3): 7.2 (m, 1H), 7.1 (m, 1H), 6.9 (m, 2H), 4.3 (t, 1H, J=10.0 Hz), 3.9 (m, 4H), 3.3 (m, 1H), 2.8 (s, 3H), 2.6 (m, 1H), 1.8 (m, 6H), 1.5 (m, 2H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]3)O1.CC1(C)C(C)(C)OB(C2C=CC=C3C=2CN(C(OC(C)(C)C)=O)CC3)O1.Br[C:54]1[CH:55]=[N:56][C:57]([CH:60]2[CH2:62][CH2:61]2)=[N:58][CH:59]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CCO.C1(C)C=CC=CC=1>[CH:60]1([C:57]2[N:58]=[CH:59][C:54]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[CH2:15][N:14]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:13][CH2:12]4)=[CH:55][N:56]=2)[CH2:62][CH2:61]1
Reactant: Brc1cnc(C2CC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)OC(=O)N1CCc2cccc(B3OC(C)(C)C(C)(C)O3)c2C1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3cnc(C4CC4)nc3)ccc2C1
Temperature: 81 °C
Yield: 35.8 %

Procedure:
A 4:1 mixture (0.097 g, 0.27 mmol) of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, 5-bromo-2-cyclopropylpyrimidine (0.054 g, 0.27 mmol), PdCl2×dppf (0.0045 g), 2M sodium carbonate (1.0 mL), toluene (4.0 mL) and EtOH (1.0 mL) was purged with dry argon for ten minutes, then heated in a sealed vial at 81° C. for 6 h. The black solution was filtered through glass-wool, taken up in water-brine and washed twice with EtOAc. The combined organic phases were dried, filtered and concentrated with silica (5 g). Column chromatography with EtOAc-heptanes (1:5 through 1:2) gave 0.034 g (36%) of the title product as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(OCC)C>O1CCCC1>[CH3:12][O:11][C:10]1[C:2]2[NH:1][C:14](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(C(=O)O)c1N
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Yield: 226.5 %

Procedure:
To 2-amino-3-methoxybenzoic acid (5 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was added triphosgene (3.55 g, 12 mmol). This mixture was heated to reflux under a nitrogen atmosphere for 3 hours. It was cooled to ambient temperature, and diethyl ether (50 mL) was added. The mixture was filtered to yield 8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (5.25 g, 91%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=3)[NH2:21])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31](Cl)=[O:32].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:21][C:31](=[O:32])[CH2:30][C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To the solution of 3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]aniline (0.28 g) in THF (15 mL) was added 2-thienylacetyl chloride (0.16 g). The reaction was kept stirring at RT for 0.5 h and worked up with sat. NaHCO3 solution (8 mL). After extraction with EtOAc (2×10 mL), drying with Na2SO4, and concentration, the crude mixture was purified through silica gel column chromatography to afford N-{3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide as a yellow solid (0.36 g, 95%). ES-LC/MS m/z=464 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:19]([O:21]C)=[O:20].[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1c(C)n(C(C)c2ccccc2)c2ncccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)c2cccnc2n1C(C)c1ccccc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
To a solution of methyl 2-methyl-1-(1-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (500 mg, 1.70 mmol) in tetrahydrofuran (10 mL), methanol (20 mL) and water (4 mL) was added lithium hydroxide (163 mg, 6.80 mmol). The resultant reaction mixture was stirred at 60° C. for 48 hours. The mixture was concentrated in vacuo. Then the residue was diluted with water (40 mL) and slowly acidified with 1N hydrogen chloride to pH=4-5. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give 2-methyl-1-(1-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid as a white solid (400 mg, 84.0%).
Reaction SMILES: [CH3:1][N:2]([CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:14][C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[N:22]3)=[CH:19][CH:20]=2)[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O.CC#N>O>[CH3:1][N:2]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:14][C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[N:22]3)=[CH:19][CH:20]=2)[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1
Reactant: CCCC(Nc1ccc(-n2cc(-c3ccccc3)cn2)nc1)c1ccc(C(=O)N(C)CCC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CCCC(Nc1ccc(-n2cc(-c3ccccc3)cn2)nc1)c1ccc(C(=O)N(C)CCC(=O)O)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Step C of Example 1, using (+/−)-tert-butyl 3-(N-methyl-4-(1-(6-(4-phenyl-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoate. Column: Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95% H20/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, Hold at 5% H2O/95% MeCN to 5.0 min. Flow: 2.0 mL/min. Retention time: 3.27 min. MS (M+1): 498.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]([CH2:11][C:12]3[CH:13]=[C:14]([C:18]4[CH:22]=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:20][C:19]=4[S:27]([NH:30]C(C)(C)C)(=[O:29])=[O:28])[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:9][N:10]=2)=[CH:2]1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47]>C(Cl)Cl.O>[CH2:49]([O:48][C:46]([NH:30][S:27]([C:19]1[S:20][C:21]([CH2:23][CH:24]([CH3:25])[CH3:26])=[CH:22][C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:13]=1)(=[O:29])=[O:28])=[O:47])[CH2:50][CH2:51][CH3:52]
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccsc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 3-[3-(2-thiophen-3-yl-imidazol-1-ylmethyl)-phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (38.2 mg, 0.0744 mmol; see step (a)) in CH2Cl2 (1 mL) was added BCl3 (0.2 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (35.5 mg, 0.335 mmol), water (2 mL) and butyl chloroformate (11.4 μL, 0.0893 mmol) and the reaction mixture was stirred for 5 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the title compound as a white solid in 67% yield, over two steps, (28 mg, 0.050 mmol).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](=O)[CH3:26]>>[CH2:1]([N:8]([CH2:25][CH3:26])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: NC(=O)OCc1cc(-c2ccc(NCc3ccccc3)cc2)no1
Product: CCN(Cc1ccccc1)c1ccc(-c2cc(COC(N)=O)on2)cc1

Procedure:
An experiment was performed using carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester in Example 74 as a starting material and acetaldehyde in the same manner as in Example 74.4 to obtain carbamic acid 3-[4-(benzyl-ethyl-amino)-phenyl]-isoxazol-5-ylmethyl ester.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[C:14]([S-:16])[O:15][C:11]=2[CH:10]=1.[K].[CH3:20]I>CN(C=O)C>[CH3:1][CH:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[C:14]([S:16][CH3:20])[O:15][C:11]=3[CH:10]=2)=[N:4][NH:5][C:6](=[O:8])[CH2:7]1
Reactant: CC1CC(=O)NN=C1c1ccc2nc([S-])oc2c1
Reactant: CI
Agent: [K]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(C3=NNC(=O)CC3C)cc2o1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
85 g (0.284 mol) 6-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-benzoxazol-2-thiolate as potassium salt, 34.3 ml (0.55 mol) methyl iodide and 200 ml DMF are combined and the mixture is stirred for 1 h at 50° C., then the reaction mixture is poured onto ice water. The precipitated solid is suction filtered and washed with water, isopropanol and diethyl ether.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([OH:22])=[O:21]>C(O)C>[C:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH:2]=[C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5][CH:4]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:25][CH:24]=1)([OH:22])=[O:21]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C1C(=CO)C(c2ccccc2)Oc2ccccc21
Solvent: CCO
Product: O=C(O)c1ccc(CNC=C2C(=O)c3ccccc3OC2c2ccccc2)cc1

Procedure:
A mixture of 5 g 3-hydroxymethylidene-flavanone and 9 g 4-carboxybenzylamine in 50 ml dry ethanol is stirred under nitrogen and reflux for 30 minutes. After filtration and washing of the solid with warm ethanol, the filtrate is cooled with an ice bath. A yellow precipitate forms which is filtered, dried and recrystallized in toluene. Pure yellow crystalline 3-[N-(4-carboxybenzyl)amino]methylidene-flavanone is obtained; m.p. 195°-200° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[OH:16])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:16])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(O)c2ccccc2)cc1OC1CCCC1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccccc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
The alcohol (prepared above) (13.4 g, 44.8 mmol) was dissolved in CH2Cl2 (150 ml) and treated with MnO2 (22 g). The reaction mixture was vigorously stirred at RT for 18 h then treated with a further portion of MnO2 (20 g). More MnO2 (20 g) was added after 10 h and the mixture stirred for 18 h then filtered through Celite® and concentrated in vacuo. The residue was recrystallised from EtOH to afford the title compound (11.27 g; two crops) as a white crystalline solid m.p. 59°-75° C.; δH (CDCl3) 1.5-2.1 (8H, br, m, (CH2)4), 3.88 (3H, s, OMe), 4.80 (1H, br m, OCHCH2), 6.83 (1H, d, J 8.5 Hz, ArH ortho to OMe), and 7.25-7.8 (7H, m, 2×ArH meta to OMe+C6H5); m/z 296 (M+ 11%), 229 (17), 228 (95), 152 (12), 151 (100), 105 (30), 77 (21), and 41 (10).
Reaction SMILES: C([O:8][C:9](=[O:45])[CH2:10][NH:11][C:12](=[O:44])[C@@H:13]1[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][N:14]1[C:20](=[O:43])[C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26]([O:28][CH2:29][CH:30]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])C1C=CC=CC=1.C(Cl)Cl.CO.CCO>CO.[Pd]>[CH:32]1[C:31]2[CH:30]([CH2:29][O:28][C:26]([N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[C:20]([N:14]3[CH2:15][C@H:16]([O:18][CH3:19])[CH2:17][C@H:13]3[C:12]([NH:11][CH2:10][C:9]([OH:45])=[O:8])=[O:44])=[O:43])=[O:27])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1
Reactant: CO[C@@H]1C[C@@H](C(=O)NCC(=O)OCc2ccccc2)N(C(=O)[C@@H]2CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CO[C@@H]1C[C@@H](C(=O)NCC(=O)O)N(C(=O)[C@@H]2CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A suspension of Fmoc-Pro-Mop-Gly-OBn (0.74 g, 1.21 mmol) and Pd/C (0.07 g) in MeOH (25 mL) was stirred under an atmosphere of H2 (g) for 2 h. The mixture was filtered through a pad of Celite® and evaporated leaving a white solid. The product was isolated by flash chromatography (9:1 CH2Cl2/MeOH-EtOH) affording Fmoc-Pro-Mop-Gly-OH (0.54 g, 86%) as a white solid. 1H NMR (500 MHz, DMSO-d6, ˜1:1 ratio of 2 rotamers): δ7.91-7.82 (m, 2 H), 7.65 (t, J=7.4 Hz, 1 H), 7.58 (d, J=7.4 Hz, 0.5 H), 7.55 (d, J=7.5 Hz, 0.5 H), 7.44-7.28 (m, 5 H), 4.60 (dd, J=8.6, 3.1 Hz, 0.5 H), 4.52 (dd, J=8.6, 2.7 Hz, 0.5 H), 4.45-4.40 (m, 0.5 H), 4.34 (app t, J=7.4 Hz, 0.5 H), 4.27-4.10 (m, 3 H), 4.04-3.97 (m, 1 H), 3.76-3.70 (m, 0.5 H), 3.67-3.57 (m, 1.5 H), 3.42-3.29 (signals under H2O peak), 3.22 (s, 1.5 H), 3.11 (s, 1.5 H), 2.32-2.29 (m, 0.5 H), 2.28-2.18 (m, 0.5 H), 2.17-2.06 (m, 1.5 H), 2.02-1.73 (m, 4.5H); 13C NMR (125 MHz, DMSO-d6, ˜1:1 ratio of 2 rotamers): δ171.7, 171.0, 170.3, 170.2, 153.8, 143.9 (3 signals), 143.8, 140.7, 140.6, 127.7 (2 signals), 127.2, 127.1, 125.3, 125.1, 120.1, 120.0 (2 signals), 78.6, 78.4, 66.8, 66.5, 58.3 (2 signals), 57.9, 57.6, 56.1, 56.0, 55.9, 51.3, 51.2, 47.0, 46.7, 46.6, 46.3, 42.0, 34.3, 29.6, 28.6, 23.7, 22.6;