Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Si:10]([N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].Cl[CH2:24][C:25]([N:27]([C:30]1[C:31]([Cl:41])=[N:32][N:33]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:34]=1)[CH2:28][CH3:29])=[O:26]>C1COCC1>[Si:10]([N:17]1[CH2:21][CH2:20][CH:19]([CH2:24][C:25]([N:27]([C:30]2[C:31]([Cl:41])=[N:32][N:33]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH:34]=2)[CH2:28][CH3:29])=[O:26])[C:18]1=[O:22])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CCN(C(=O)CCl)c1cn(-c2cccnc2)nc1Cl
Reactant: CC(C)(C)[Si](C)(C)N1CCCC1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)CC1CCN([Si](C)(C)C(C)(C)C)C1=O)c1cn(-c2cccnc2)nc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
DIPEA (0.629 mL, 4.41 mmol) was dissolved in THF (20 mL) and cooled to about −78° C. n-Butylithium (1.77 mL, 4.41 mmol) was then added, and the reaction mixture was warmed to about 0° C. for 10 minutes, then re-cooled to about −78° C. Then, 1-(tert-butyldimethylsilyl)pyrrolidin-2-one (0.800 g, 4.01 mmol) was added, and the reaction mixture was warmed to 23° C. and stirred for 1 hour. The reaction was then re -chilled to −78° C., and 2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.600 g, 2.01 mmol) was then added dropwise as a solution in THF (3 mL). The reaction mixture was stirred cold for 30 minutes, then was allowed to slowly warm to room temperature. After 1 hour, the reaction was quenched with a NH4Cl solution and extracted with diethyl ether. The organics were washed with brine, dried over Na2SO4, and concentrated. The resulting oil was purified by flash column chromatography using 0-40% acetone/hexanes as eluent provided the intermediate 2-(1-(tert -butyldimethylsilyl)-2-oxopyrrolidin-3-yl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.604 g, 1.31 mmol). 1H NMR analysis indicated a mixture of molecules present favoring the desired product of about 5:1 over main byproduct. The mixture carried through to the deprotection step without further purification. 2-(1-(tert-Butyldimethylsilyl)-2-oxopyrrolidin-3-yl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.604 g, 1.31 mmol) was dissolved in THF (13 mL) and added was tetrabutylammonium fluoride (TBAF, 1.96 mL, 1.96 mmol). The reaction mixture was stirred for 30 minutes. The reaction product was concentrated onto CELITE® and purified by flash column chromatography using 40-100% acetone/hexanes as eluent providing the title compound (0.204 g, 30% over 2 steps).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH3:3].Cl[C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:10][C:9]1[C:4]([CH:2]([CH3:1])[CH3:3])=[CH:5][C:6]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:8]=1[CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
Propofol 5 (1.78 g, 10.0 mmol) and methyl 4-chloro-4-oxobutyrate (4.5 g, 25 mmol) were dissolved in methylene chloride (350 mL), the reaction mixture was cooled to −78° C. and titanium (IV) chloride (5.7 g, 30 mmol) was added drop-wise. The reaction mixture was stirred for 2 h at −78° C., allowed to warm up to room temperature and stirred overnight. The reaction mixture was then poured into water (300 mL), the organic phase was washed sequentially with saturated sodium bicarbonate solution, water and brine, and the solution dried over anhydrous magnesium sulfate. The product was purified by column chromatography on silica gel using hexane and hexane-ethyl acetate (4:1) step-gradient as an eluent to produce pure 6 (1.14 g, 39%) as a slightly yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.75 (s, 2H), 5.84 (s, 1H), 3.72 (s, 3H), 3.32 (t, J=6.8 Hz, 2H), 3.20 (septet, J=6.9 Hz, 2H), 2.76 (t, J=6.8 Hz, 2H), 1.28 (d, J=6.9 Hz, 12H). 13C NMR (100.61 MHz, CDCl3): δ 196.81, 173.35, 154.40, 133.27, 129.05, 123.97, 51.41, 32.59, 27.82, 26.79, 22.18. HRMS (m/z): [M+H]+ calcd. for C17H24O5 293.1747. found 293.1759.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH:34]([F:36])[F:35])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:17]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:43]([O:47][C:48](=[O:51])[CH2:49]Br)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C.O>[C:43]([O:47][C:48](=[O:51])[CH2:49][N:10]1[CH:11]=[C:12]([NH:13][C:14]([C:16]2[C:17]([NH:25][C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:33][CH:34]([F:36])[F:35])=[N:9]1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)Nc1nn2cccnc2c1C(=O)Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1cc(NC(=O)c2c(NC(=O)OC(C)(C)C)nn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.8 %

Procedure:
A solution of tert-butyl (3-((3-(5-chloro-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamate (1.0 g, 1.92 mmol) in DMF (10 mL) was treated with cesium carbonate (0.69 g, 2.12 mmol) and tert-butyl-bromoacetate (0.43 g, 2.12 mmol) and was left to stir at room temperature for 2.5 hours. The reaction mixture was diluted with water and the resultant precipitate was collected by filtration. The resultant solid was purified by flash chromatography on silica eluting with 0-70% EtOAc in cyclohexane. Appropriate fractions were combined and evaporated to afford [4-[(2-tert-butoxycarbonylamino-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-3-(5-chloro-2-difluoromethoxy-phenyl)-pyrazol-1-yl]-acetic acid tert-butyl ester as a white solid (0.91 g, 74%). LCMS (Method 3) [M+H]+=633.9, RT=4.46 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.78 (s, 1H), 9.70 (s, 1H), 8.76 (dd, 1H, J=1.8, 6.8 Hz), 8.47 (dd, 1H, J=1.8, 4.3 Hz), 8.34 (s, 1H), 7.69 (d, 1H, J=2.5 Hz), 7.41 (dd, 1H, J=2.7, 8.7 Hz), 7.28 (d, 1H, J=8.8 Hz), 6.92 (dd, 1H, J=4.4, 6.9 Hz), 6.47 (t, 1H, J=74.0 Hz), 4.85 (s, 2H), 1.56 (s, 9H), 1.49 (s, 9H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]#[C:14][CH3:15].C(N(CC)CC)C>C(OCC)C>[CH2:18]([O:17][C:12]([C:13]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=2)=[N:2][O:1][C:14]=1[CH3:15])=[O:16])[CH3:19]
Reactant: CC#CC(=O)OCC
Reactant: O/N=C(\Cl)c1ccc(F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(F)cc2)noc1C
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of (E)- and/or (Z)—N-hydroxy-4-fluoro-benzenecarboximidoyl chloride (15.4 g, 89 mmol) (11.1 g, 64 mmol) in diethylether (151 mL) was added ethyl 2-butynoate (7.2 g, 7.5 mL, 64 mmol) at 0° C. followed by the dropwise addition of triethylamine (7.8 g, 10.7 mL, 77 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (9.8 g, 44%) which was obtained as an off white solid. MS: m/e=250.1 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N:22]1([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:28])=[CH:20][CH:19]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCNCC1
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (1.163 g) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid (˜4 mL). After 30 min, additional trifluoroacetic acid (5 mL) was added, and the mixture was stirred for a further 2 h. The mixture was diluted with diluted with saturated aquoues NaHCO3 and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to yield the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:16][CH2:15][CH2:14][N:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:12])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: O=C1NCCN1c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccccc2)C1=O

Procedure:
By using 1-phenylimidazolidin-2-one obtained by the method described in literature (J. Org. Chem., 1951, 16, 1829) and t-butyldimethylsilyl 2-bromoethyl ether obtained by the method of Example 92a, 1-[2-(t-butyldimethylsilyloxy)ethyl]-3-phenylimidazolidin-2-one was obtained as crude product by similar procedures to those of Example 151a. By using the resulting product, the title compound was obtained as colorless solid by similar procedures to those of Example 92b (yield: 75%).
Reaction SMILES: C(OC([N:11]([C:23]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29])NC(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pt]=O>[NH2:11][C:23]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29]
Reactant: [H][H]
Reactant: CCOC(=O)C1(N(NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)CC(=O)NC1=O
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)C1(N)CC(=O)NC1=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 64.1 %

Procedure:
To a solution of the compound of Example 1 (496 mg) in acetic acid (15 ml) was added platinum oxide (102 mg). This mixture was stirred vigorously at 50° C. under hydrogen (atmospheric pressure) for 6 hours. During this reaction, to remove carbon dioxide generated with the progress of the reaction, the gas in the reactor was replaced with hydrogen gas several times. The reaction mixture was filtered through a Celite pad and then the Celite was washed with a small amount of acetic acid. The filtrate combined with the washers was concentrated and to the resulting residue was added toluene to remove azeotropically the residual acetic acid and then the mixture was concentrated again. To the residue was added ethyl acetate and the insoluble material was filtered off, and then the ethyl acetate solution was concentrated to give a crude product which was then purified by a flash column chromatography (chloroform:methanol=30:1) to give the desired product (126 mg, 64%) as crystal. 1H NMR (CDCl3) data of this product were consistent with those of an optical active substance described in J. Med. Chem., 1998, 41, p. 4118 to 4129.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=2[S:5](=[O:14])(=[O:13])[N:4]([CH3:15])[C:3]=1[C:16]([O:18]C)=O.[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1>C1(C)C(C)=CC=CC=1>[CH3:15][N:4]1[C:3]([C:16]([NH:20][C:21]2[S:22][C:23]([CH3:26])=[CH:24][N:25]=2)=[O:18])=[C:2]([OH:1])[C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=2[S:5]1(=[O:13])=[O:14]
Reactant: Cc1cnc(N)s1
Reactant: COC(=O)C1=C(O)c2cc(C)ccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: Cc1ccc2c(c1)C(O)=C(C(=O)Nc1ncc(C)s1)N(C)S2(=O)=O

Procedure:
4.0 gm (14 millimols) of methyl 4-hydroxy-2,6-dimethyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2.0 gm (17 millimols) of 2-amino-5-methyl-thiazole were refluxed in 200 ml of anhydrous xylene for 24 hours. After cooling, the crystals which had separated out were filtered off. After recrystallization from ethylene chloride 3.6 gm (70% of theory) of 2,6-dimethyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3carboxamide-1,1-dioxide were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:26]([CH2:28][NH2:29])[OH:27]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:29][CH2:28][CH2:26][OH:27])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.79 (1H, t, J=5.4 Hz), 10.81 (1h, br s), 10.07 (1H, br s), 8.18 (0.61H, s), 8.15 (0.39H, s), 7.35-7.23 (3H, m), 7.14-7.08 (2H, m), 4.73 (1H, br), 3.98 (2H, s), 3.51-3.41 (2H, m), 3.35-3.20 (2H, m); HRMS calcd for C18H16FN3O4+H+: 358.1203. Found 358.1194.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]2[CH2:14][C:15]3[C:20]([CH:9]12)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:21][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[O:13]=[C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]2[C:20]3[C:15]([C:14](=[O:21])[C@@H:10]2[CH2:11]1)=[CH:16][CH:17]=[CH:18][CH:19]=3
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2Cc3ccccc3C21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)C[C@H]2C(=O)c3ccccc3[C@H]21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester F1 (5.00 g, 18.2 mmol) in acetone (90 mL) and water (20 mL) was added KMnO4 (14.7 g, 93 mmol). The solution was stirred for 48 h at room temperature and filtered. The solution was concentrated to half the volume and sodium thiosulfate solution was added (2%, 50 mL). The solution was extracted with ethylacetate, washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (7/3) to give the desired product F26 (1.6 g, 30%). LCMS (method E): 0.81 min; ES+: 597 (2M+Na+).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7](Cl)=[N:6][C:5]=2[CH:4]=1.[NH:19]1[CH:23]=[CH:22][CH:21]=[N:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:19]1([CH2:2][C:3]2[S:11][C:10]3[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:8][C:7]([C:5]4[CH:4]=[CH:3][CH:2]=[C:21]5[C:22]=4[CH:23]=[N:19][NH:20]5)=[N:6][C:5]=3[CH:4]=2)[CH:23]=[CH:22][CH:21]=[N:20]1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc(-c2nc(N3CCOCC3)c3sc(Cn4cccn4)cc3n2)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 from Example 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added pyrazole (18 mg, 0.3 mmol) and K2CO3 (50 mg, 0.4 mmol). The resulting solution stirred at room temperature overnight then was concentrated in vacuo. The residue was diluted with water and filtered. The crude product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 325 after reverse phase HPLC purification (13 mg). MS (Q1) 418 (M)+
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.CC([O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=O)(C)C>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9]([NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][N:1]3[C:35](=[O:36])[CH2:34][NH:33][C:31]3=[O:30])[N:4]=2)=[O:10])=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CN3C(=O)CNC3=O)cs2)c(C(=O)C2CCCC2)c1
Yield: 22.1 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[4-(2,5-dioxo-imidazolidin-1-ylmethyl)-thiazol-2-yl]-urea (78 mg, 69%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (358 mg, 1.0 mmol) and t-Boc-glycine (90 mg, 0.80 mmol) following the general procedure U.
Reaction SMILES: C[C:2]([CH3:5])([O-])C.[K+].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][C:11]=12.O>O1CCCC1>[CH3:11][N:7]1[CH:8]=[CH:9][N:10]=[C:2]1/[CH:5]=[CH:16]/[C:13]1[CH:14]=[CH:15][N:10]2[CH:9]=[CH:8][N:7]=[C:11]2[CH:12]=1
Reactant: O=Cc1ccn2ccnc2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccnc1/C=C/c1ccn2ccnc2c1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-triphenylphosphonium-1-methyl-1H-imidazole chloride (656 mg, 1.6 mmol, 1 equiv) in tetrahydrofuran (5 ml) at room temperature was added dropwise a solution of potassium tert-butoxide in tetrahydrofuran (1M, 3.3 ml, 3.3 mmol, 2 equiv). This brightly orange mixture was stirred thus for 2 hours and then a solution of imidazo[1,2-a]pyridine-7-carbaldehyde (245 mg, 1.7 mmol, 1 equiv) in tetrahydrofuran (8 ml) was added and the lightly coloured mixture was stirred at room temperature overnight. To the reaction was added water and the mixture was extracted with ethyl acetate. The organic liquors were washed with water and brine and then dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (0-20% methanol/ethyl acetate) furnishing 7-[(E)-2-(1-methyl-1H-imidazol-2-yl)-vinyl]-imidazo[1,2-a]pyridine (87 mg). MS:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[C:16]([O:20][C:21]([N:23]([CH3:27])[CH2:24][CH:25]=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([NH:15][CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:22])[CH3:27])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(N)cc1NC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc(NCCN(C)C(=O)OC(C)(C)C)cc1NC(C)=O
Reaction time: 64 h
Yield: 85.7 %

Procedure:
To a cooled solution of methyl 2-acetylamino-4-aminobenzoate (300 mg, 1.44 mmol) and N-tert-butoxycarbonyl-N-methylglycinal (499 mg, 2.88 mmol) in 1,2-dichloroethane (30 ml), was added NaBH(OAc)3 (964 mg, 4.32 mmol) and the stirring was continued for 64 h at 0° C. The mixture was poured into sat. NaHCO3 and was extracted with CHCl3 (50 ml×3), washed with brine, and dried over MgSO4. After removal of the solvent in vacuo, the residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient of hexane-EtOAc from 9:1 to 2:1) to give methyl 2-acetylamino-4-[2-(N-tert-butoxycarbonyl-N-methylamino)ethylamino]benzoate (451 mg, 86%) as a colorless oil. 1H-NMR (CDCl3, 400 MHz) δ 1.48 (s, 9 H), 2.22 (s, 3 H), 2.90 (s, 3 H), 3.32 (m, 2 H), 3.50 (m, 2 H), 3.80 (s, 3 H), 6.20 (dd, J=2.2 Hz, 8.8 Hz, 1 H), 7.80 (m, 1 H), 7.95 (m, 1 H), 11.30 (br s, 1 H); MS (FAB) m/z 366 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][S:14]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:29][C@@H:30]([CH2:44][C:45]1[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[CH:46]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH3:42])[CH:36]=1.CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:29][C@@H:30]([CH2:44][C:45]1[CH:46]=[C:47]([F:52])[CH:48]=[C:49]([F:51])[CH:50]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH3:42])[CH:36]=1)=[O:26])[CH2:13][S:14]([CH:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])(=[O:15])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(CC)c1
Reaction time: 3 h

Procedure:
N-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alanine (LXXXIV, 4.0 g, 10 mmole) and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (1.2 g, 12 mmole) are mixed in anhydrous methylene chloride (50 ml). To the reaction mixture is added NMM (5.6 ml, 51 mmole), hydroxybenzotriazole (1.7 g, 13 mmole) and lastly 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.1 g (16 mmole). After stirring at 20–25° for 3 hours, HPLC analysis indicates complete reaction. The reaction mixture is diluted with methylene chloride and washed with saturated sodium bicarbonate solution, citric acid (0.5 M), and saline. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give N2-[(benzyloxy)carbonyl]-N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]alaninamide (LXXXV).
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([SH:6])[CH3:5].[CH3:7][C:8]1([CH3:31])[O:12][N:11]=[C:10]([S:13][CH2:14][C:15]2[C:16]([C:27]([F:30])([F:29])[F:28])=[N:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19]=2F)[CH2:9]1>CN(C)C=O>[CH3:7][C:8]1([CH3:31])[O:12][N:11]=[C:10]([S:13][CH2:14][C:15]2[C:16]([C:27]([F:30])([F:29])[F:28])=[N:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19]=2[S:6][CH2:4][CH3:5])[CH2:9]1
Reactant: CCS
Reactant: CC1(C)CC(SCc2c(C(F)(F)F)nn(-c3ccccc3)c2F)=NO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1c(CSC2=NOC(C)(C)C2)c(C(F)(F)F)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
0.2 g (4.0 mmoles) of sodium hydroxide and 1 ml of water were added to a solution of 0.25 g (4.0 mmoles) of ethanethiol dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 30 minutes. Thereto was added a solution of 0.5 g (1.4 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 5 ml of N,N-dimethylformamide. The resulting mixture was stirred for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.6 g (yield: 100%) of 5,5-dimethyl-3-(5-ethylthio-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.