Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:31])[NH:23][C:24]2[S:25][CH:26]=[C:27](SC)[N:28]=2)=[CH:18][CH:17]=1)(=[O:14])[CH3:13].[S:32]([O-:36])([O-])(=[O:34])=S.[Na+].[Na+]>ClCCl.O>[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:31])[NH:23][C:24]2[S:25][CH:26]=[C:27]([S:32]([CH3:2])(=[O:36])=[O:34])[N:28]=2)=[CH:18][CH:17]=1)(=[O:14])[CH3:13]
Reactant: O=S([O-])([O-])=S
Reactant: CSc1csc(NC(=O)c2ccc(OC(C)=O)cc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)Nc2nc(S(C)(=O)=O)cs2)cc1
Reaction time: 1.25 h
Yield: 30 %

Procedure:
A solution of m-chloroperbenzoic acid (1.0 g, 6.0 mmol, maximum 77%) dissolved in dichloromethane (30 mL) was added to a suspension of 82 (0.63 g, 2.0 mmol) in dichloromethane (60 mL). The reaction became homogeneous and the dark brown solution became lighter with time. After 1.25 hours, saturated aqueous sodium thiosulfate was added to the reaction and the reaction mixture was stirred vigorously for 20 minutes. The yellow mixture was diluted with water and the resulting layers separated. The organic layer was washed twice with saturated aqueous sodium bicarbonate, once with brine, dried with anhydrous sodium sulfate and concentrated in vacuo to give a beige solid. The crude product was recrystallized from 50% ethyl acetate/hexane (220 mL). After 4 days the suspension was filtered, the filter pad was washed with hexanes and then diethyl ether, and dried in vacuo at 55° C. overnight to give 83 (0.20 g, 30%) as a light orange solid. Concentration of the filtrate in vacuo followed by triturating the resulting residue with diethyl ether and filtering off the resulting solid yielded an additional 45 mg of 83 as a tan solid.
Reaction SMILES: [Cl:1]C1C(C(N[C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=O)=CC=CN=1.NC1C=C2C(C=NN2)=CC=1.C[N:31]1[C:35](=[O:36])CCC1>C(Cl)Cl>[ClH:1].[CH3:19][CH:17]([C:14]1[CH:13]=[CH:12][C:11]([C:35]([NH2:31])=[O:36])=[CH:16][CH:15]=1)[CH3:18]
Reactant: CC(C)c1ccc(NC(=O)c2cccnc2Cl)cc1
Reactant: CN1CCCC1=O
Agent: Nc1ccc2cn[nH]c2c1
Solvent: ClCCl
Product: CC(C)c1ccc(C(N)=O)cc1
Product: Cl

Procedure:
A mixture of (2-chloro(3-pyridyl))-N-(4-isopropylphenyl)carboxamide (1.5 g, Step A) and 6-aminoindazole (880 mg) was heated at 160° C. in NMP for 3 h. The reaction was cooled and diluted with CH2Cl2 and washed with water twice, followed by brine. The organic layer was dried with Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography with 35% EtOAc/Hexane and further mixed with MeOH and 1 N HCl/Et2O (3 ml). The solution was evaporated to furnish the titled compound. MS (ES+): 372 (M+H)+; (ES−): 371 (M−H). Calc'd. for C22H21N5O—371.2.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:7])[CH2:4][CH2:5][CH3:6].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][C:17]=1[Cl:30].Cl>O1CCCC1>[Cl:30][C:17]1[CH:18]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]#[N:29])[CH:20]=[CH:21][C:16]=1[CH2:15][CH:8]([C:3](=[O:7])[CH2:4][CH2:5][CH3:6])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(Cl)c1
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1Cl)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (0.40 g) in tetrahydrofuran (20 mL) was added dropwise a solution of ethyl butyrylacetate (2.13 g) in tetrahydrofuran (10 mL). After stirring for 30 min, 4′-(bromomethyl)-3′-chlorobiphenyl-2-carbonitrile (2.06 g) was added. The mixture was stirred at room temperature for 15 hr, and 1 M hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give ethyl 2-[(3-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate. Then, a solution of the obtained ethyl 2-[(3-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate, ethanimidamide hydrochloride (2.55 g), 28% sodium methoxide (7.80 g) in methanol (50 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and saturated aqueous ammonium chloride solution was added to the residue. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (0.64 g, 73%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)(=[O:13])[CH3:12]>C1COCC1.O>[OH:13][C:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:16][CH2:15]1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: c1cscn1
Reactant: CC(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(c1nccs1)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazole (740 mg, 8.72 mmol) in THF (87 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 3.84 mL, 9.59 mmol) and the solution was stirred for 30 minutes at −78° C. A solution of benzyl (trans-4-acetylcyclohexyl)carbamate (1.20 g, 4.36 mmol) in THF (5 mL) was added and the reaction was stirred for one hour at −78° C. The reaction was diluted with water and warmed to room temperature. The mixture was extracted with ethyl acetate and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography on silica gel (0-10% methanol gradient in dichloromethane) afforded benzyl {trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexyl}carbamate MS ESI calc'd. for C19H25N2O3S [M+H]+ 361. found 361. 1H NMR (500 MHz, DMSO-d6) δ 7.67 (d, J=3.2, 1H), 7.51 (d, J=3.2, 1H), 7.40-7.20 (m, 4H), 7.12 (d, J=8.0, 1H), 5.70 (s, 1H), 4.95 (s, 2H), 3.19-2.98 (m, 1H), 1.88-1.66 (m, 3H), 1.65-1.49 (m, 1H), 1.47-1.33 (m, 4H), 1.28-1.14 (m, 1H), 1.14-0.89 (m, 3H).
Reaction SMILES: [C:1](=[O:65])([O:51][CH:52]([CH2:59][O:60][P:61]([OH:64])([OH:63])=[O:62])[CH2:53][O:54][P:55]([OH:58])([OH:57])=[O:56])[O:2][C@H:3]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=1)[C@@H:4]([N:6](C(OC(C)(C)C)=O)[CH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([F:27])=[CH:20][C:19]=1[O:28][CH3:29])[CH3:5].[ClH:66]>>[Cl-:66].[F:50][C:47]([F:48])([F:49])[C:39]1[CH:38]=[C:37]([C@H:3]([C@@H:4]([NH2+:6][CH2:7][C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[C:22]([CH:24]([CH3:25])[CH3:26])[C:21]([F:27])=[CH:20][C:19]=2[O:28][CH3:29])[CH3:5])[O:2][C:1](=[O:65])[O:51][CH:52]([CH2:59][O:60][P:61]([OH:63])([OH:64])=[O:62])[CH2:53][O:54][P:55](=[O:56])([OH:58])[OH:57])[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=1
Reactant: Cl
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@@H](C)[C@H](OC(=O)OC(COP(=O)(O)O)COP(=O)(O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C[NH2+][C@@H](C)[C@H](OC(=O)OC(COP(=O)(O)O)COP(=O)(O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: [Cl-]

Procedure:
A solution of (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[4′-fluoro-5′- isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propyl 2-(phosphonooxy)-1-[(phosphonooxy)methyl]ethyl carbonate (46.7 mg, 0.047 mmol) in HCl saturated EtOAc (3 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo to afford (8R,9S)-8-[3,5-bis(trifluoromethyl)phenyl]-N-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,1-dihydroxy-6-oxo-4-[(phosphonooxy)methyl]-2,5,7-trioxa-1λ5-phosphadecan-9-aminium1-oxide chloride, as a colorless glass/solid. LCMS calc.=890.16; found=890.00 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=2)=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4].[CH3:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1.C1(C)C=CC=CC=1.N1C=CC=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=2)=[CH:8][C:9]=1[N:10]([C:35]([C@H:32]1[CH2:33][CH2:34][C@H:29]([CH3:28])[CH2:30][CH2:31]1)=[O:36])[CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1NC1CCC(n2cncn2)CC1
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(n2cncn2)CC1
Temperature: 25 °C

Procedure:
5-cyclohex-1-enyl-3-(4-[1,2,4]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester (555 mg, 1.436 mmol) was treated with a 1M solution of trans-4-methylcyclohexanecarbonyl chloride in toluene (2.87 mL, 2.87 mmol). Pyridine (128 μl, 1.58 mmol) was added and the mixture was stirred at reflux overnight under nitrogen. It was cooled to room temperature and dilute with EtOAc. The resulting mixture was washed twice with a saturated aqueous sodium bicarbonate and once with brine, dried over Na2SO4 and concentrated. The crude was purified by silica gel column chromatography using a gradient from 50% EtOAc:hexanes to 100% EtOAc as eluent to afford 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-[1,2,4]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (494 mg, 67%) as a yellow mixture of cis and trans isomers.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:37]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]3[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6][CH2:7]3)[CH:12]=2)=[O:29])=[CH:21][C:22]=1[O:27][CH3:28])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
N-[3-(4-tert-Butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide (100 mg) obtained in Example 20, triethylamine (94 mg) and 4-dimethylaminopyridine (5 mg) are dissolved in methylene chloride (5 ml), and thereto is added dropwise acetyl chloride (40 mg) under ice-cooling. The mixture is stirred at 25° C. for 18 hours, and the reaction solution is washed with water. The organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (90 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]2[N:24]([C:27]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][C:28]=3[O:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[N:25]=[CH:26][C:19]=12>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[N:23]=[CH:22][N:21]=[C:20]3[N:24]([C:27]4[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:35][C:28]=4[O:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[N:25]=[CH:26][C:19]=23)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CN(C)CCOc1cc(S(C)(=O)=O)ccc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1cc(S(C)(=O)=O)ccc1-n1ncc2c(OC3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a reaction vial was place a stir bar, NaH (60% in oil, 110 mg), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (70 mg) and THF (3 mL). The mixture was stirred at room temperature for 15 min under N2. {2-[2-(4-Chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methanesulfonyl-phenoxy]-ethyl}-dimethyl-amine was then added. The mixture was stirred at 80° C. for 30 min. After cooled down to room temperature, the reaction was quenched with H2O and product was extracted with CH2Cl2. The organic extracts were concentrated under vacuum. The residue was purified by silica column chromatography using 20% MeOH/CH2Cl2 as eluent to give 4-{1-[2-(2-dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester. 1HNMR (CDCl3,400 MHz) δ 1.49 (s, 9H), 1.88 (m, 2H), 2.10 (m, 2H), 2.20 (s, 6H), 2.67 (t, 2H), 3.10 (s, 3H), 3.32 (m, 2H), 3.87 (m, 2H), 4.28 (t, 2H), 5.59 (m, 1H), 7.70 (m, 3H), 8.25 (s, 1H), 8.54 (s, 1H). Exact mass calculated for C26H36N6O6S 560.24, found 561.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH2:14])[CH:8]=1)[CH3:2].[CH:24](OCC)(OCC)OCC.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.O>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:23])[C@@H:5]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH:24]=[N:14][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(N)c1)NC(=O)OC(C)(C)C
Reactant: CCOC(OCC)OCC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc2ocnc2c1)NC(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a solution of crude 3-(3-amino-4-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid ethyl ester (0.89 g, 2.74 mmol) in toluene (20 mL) was added triethyl orthoformate (0.57 mL, 3.36 mmol) and the mixture was heated to 75° C. under an atmosphere of argon for 3 hours at which time all starting material had been consumed. The reaction mixture was concentrated in vacuo to a black waxy solid which was dissolved in acetonitrile (25 mL) and di-tert-butyldicarbonate (0.80 g, 3.67 mmol) added. The mixture was stired at ambient temperature under an atmosphere of argon for 16 hours then poured into water (100 mL), diluted with brine (50 mL) and extracted with ethyl acetae (3×50 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to a black viscous oil. Purification by chromatography over silica gel eluted with 35% ethyl acetate/65% hexanes gave (S)-3-benzooxazol-5-yl-2-tert-butoxycarbonylamino-propionic acid ethyl ester as a colorless solid (0.54 g, 59%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:11]=2[C:12]#[N:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCO.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>O.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: O
Solvent: CCO
Product: CC(C)N1CCN(c2ccc(N)cc2C#N)CC1
Reaction time: 2 h
Yield: 95 %

Procedure:
A round-bottom flask was charged with 2-(4-isopropylpiperazin-1-yl)-5-nitrobenzonitrile (1.76 g, 6.42 mmol), EtOH (65 mL), and 10% Pd/C (50% in water, Degussa type E101; 355 mg, 20 wt % by weight of the starting nitro compound). The flask was sealed with a rubber septum, degassed, and back-filled with H2 (×3) from a balloon filled with H2. The reaction was stirred for 2 h using a H2 filled balloon. The reaction mixture was filtered through a pad of celite, and the pad of celite was rinsed with MeOH. The filtrate was evaporated to dryness, and the product dried in vacuo to provide 5-amino-2-(4-isopropylpiperazin-1-yl)benzonitrile (1.49 g, 95% yield) as a yellow solid that was used without further purification.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N+]([CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-])=O.C(O)(=O)C(CC(O)=O)O>CCOC(C)=O>[CH2:11]([N:18]1[C:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6]=2[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: CC(C)N1CCC(=O)CC1
Agent: O=C(O)CC(O)C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)N1CCc2c(c(-c3ccccc3)cn2Cc2ccccc2)C1

Procedure:
The title compound (111.0 mg) was prepared from 372 μL of 1-isopropyl-piperidin-4-one, 270 μL of benzylamine, and 0.38 g of (2-nitro-vinyl)-benzene as in Example 41. The product was diluted with EtOAc and malic acid (39.0 mg) was added. The solids that formed were collected by filtration to give the title compound as a maleate salt. MS (ESI): exact mass calculated for C23H26N2, 330.21. found, m/z 331.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38-7.33 (m, 6H), 7.30-7.27 (m, 1H), 7.23-7.19 (m, 3H), 7.14 (s, 1H), 6.25 (s, 2H), 5.15 (s, 2H), 3.74-3.66 (m, 1H), 2.96-2.91 (br m, 2H), 1.41 (d, J=6.6 Hz, 6H).
Reaction SMILES: N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1)=O)CC1C2C(=CC=CC=2)NC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:62][C@H:63]([C:71](O)=O)[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.[NH2:74][N:75]1[CH2:81][C:79](=[O:80])[NH:78][C:76]1=[O:77]>CN(C)C=O>[NH2:62][CH:63]([CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)[CH:71]=[N:74][N:75]1[CH2:81][C:79](=[O:80])[NH:78][C:76]1=[O:77]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NN1CC(=O)NC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Solvent: CN(C)C=O
Product: NC(C=NN1CC(=O)NC1=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Z-Trp-Trp-OH (0.1 mmol), 1-Hydroxybenzotriazolhydrate (0.1 mmol), and TBTU (0.1 mmol) were dissolved in dry dimethylformamide and stirred at r.t. After a few minutes Phe-Aminohydantoin (0.11 mmol) solved in dimethylformamide was added in portions and the reaction was allowed to reach room temperature over 18 hours. The solvent was removed and the residue was redissolved in ethyl acetate. The solution was washed with 1 mol/l HCl, and with 10% Na2CO3 and then dried over MgSO4. The reaction was filtered and the solvent was removed in vaccuo. The compound was purified by preparative HPLC.
Reaction SMILES: OCCN[N:5]1[NH:9][CH:8]=[C:7]([C:10]2[N:11]([CH3:18])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=2)[S:6]1.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH2:24])[CH3:20].O1CCOCC1>O>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH:24][N:5]1[NH:9][CH:8]=[C:7]([C:10]2[N:11]([CH3:18])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=2)[S:6]1)[CH3:20]
Reactant: CCOC(CN)OCC
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(NCCO)S1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(CNN1NC=C(c2ncc([N+](=O)[O-])n2C)S1)OCC

Procedure:
A mixture composed of 9.8 g. of 2-(2-chloro-5-thiadiazole)-1-methyl-5-nitroimidazole, (Example 16), 11.0 g. of 2,2-diethoxyethylamine, and 250 ml. of dioxane is stirred and heated on the steam bath for 12 hours. It is then diluted with 500 ml. of cold water, cooled, and the precipitated yellow solid collected and dried. Recrystallization from 50% aqueous ethanol gives the pure compound melting at 154°-155° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:11][C:12](=[O:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[F:16][C:17]1[CH:22]=[C:21]([CH:23]=[CH2:24])[CH:20]=[CH:19][C:18]=1[C:25]1[S:26][C:27]2[C:32]([N:33]=1)=[CH:31][CH:30]=[C:29]([C:34]1([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:36][CH2:35]1)[N:28]=2>CS(C)=O>[C:12]([NH:11][C:5]([CH2:24][CH2:23][C:21]1[CH:20]=[CH:19][C:18]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]2([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:35][CH2:36]2)[N:28]=3)=[C:17]([F:16])[CH:22]=1)([C:4]([O:3][CH2:1][CH3:2])=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:14])[CH3:13]
Reactant: C=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Solvent: CS(C)=O
Product: CCOC(=O)C(CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)(NC(C)=O)C(=O)OCC
Temperature: 35 °C
Reaction time: 2 h

Procedure:
A slurry of CsCO3 (0.420 g, 1.29 mmol) and acetamidomalonic acid diethyl ester (0.560 g, 2.58 mmol) in 6 mL DMSO under argon was allowed to stir for 2 h. 2-(2-Fluoro-4-vinylphenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (0.400 g, 1.07 mmol) was added as a solid and the reaction mixture sealed and heated to 35° C. for 3 h. The clear, red reaction mixture was quenched with ice and 1N aq. HCl until acidic, and partitioned between water and EA. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and passed through a Redi-Sep® pre-packed silica gel column (40 g) using 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford diethyl 2-acetamido-2-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)malonate as a white solid. MS (ESI) m/z: calculated: 589.2; Observed: 590.1 (M++1).
Reaction SMILES: [OH-].[Na+].Cl.[NH:4]1[CH2:7][CH2:6][CH:5]1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][OH:16].[Cl:17][C:18]([Cl:25])([Cl:24])[CH2:19][O:20][C:21](Cl)=[O:22].Cl>O1CCOCC1.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH:5]2[CH2:6][CH2:7][N:4]2[C:21]([O:20][CH2:19][C:18]([Cl:25])([Cl:24])[Cl:17])=[O:22])=[C:9]([CH2:15][OH:16])[CH:10]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: OCc1cc(Cl)ccc1C1CCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC1c1ccc(Cl)cc1CO
Temperature: 25 °C

Procedure:
Aqueous sodium hydroxide (1 M, 2.67 mL) was added to a stirred solution of (2-azetidin-2-yl-5-chlorophenyl)methanol hydrochloride (0.312 g, 1.33 mmol) and trichloroethoxycarbonyl chloride (0.184 mL, 1.33 mmol) in dioxane (8 mL) and water (0.4 mL) at 0° C. The reaction was warmed to ambient temperature and after 1 h was acidified with 1 M HCl solution, extracted into ether, dried (Na2SO4) and evaporated in vacuo to an oil. The crude product was purified by flash column chromatography on silica (eluting with 5% methylene chloride/10-50% ethyl acetate/hexanes gradient) to give 2,2,2-trichloroethyl 2-[4-chloro-2-(hydroxymethyl)phenyl]azetidine-1-carboxylate (283 mg a colorless gum: 1H NMR (CDCl3, 400 MHz) δ 2.24 (br m, 1H), 2.78 (m, 1H), 4.20 (br s, 2H), 4.61 (br m, 2H), 4.68 (br m, 2H), 5.66 (dd, J=8.6, 6.4 Hz, 1H), 7.34 (m, 2H), 7.56 (d, J=8.1 Hz, 1H).