Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:25][CH3:26])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:27])=[CH:10][CH:11]=3)[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:34][C:35]([F:50])([C:46]([F:49])([F:48])[F:47])[C:36]([F:45])([F:44])[C:37]([F:43])([F:42])[S:38](F)(=[O:40])=[O:39]>CN(C=O)C>[F:43][C:37]([F:42])([S:38]([O:27][C:9]1[CH:8]=[C:7]2[C@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:25][CH3:26])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1)(=[O:40])=[O:39])[C:36]([F:44])([F:45])[C:35]([F:50])([F:34])[C:46]([F:49])([F:48])[F:47]
Reactant: COC(C)(C)C#Cc1cnc2c(c1)[C@@]1(COC(N)=N1)c1cc(O)ccc1O2
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc1O2
Reaction time: 0.17 h

Procedure:
A 25-mL flask was charged with (R)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (577.53 mg, 1.581 mmol), cesium carbonate (566 mg, 1.739 mmol), and DMF (7903 μL). The resulting mixture was stirred for 10 min, then the vial was submerged in an ice-bath for 10 min. nonafluorobutanesulfonyl fluoride (306 μL, 1.739 mmol) was added dropwise over 2 minutes. Stirred for 2 hours before the mixture was quenched with saturated aqueous ammonium chloride (10 mL). The mixture was partitioned between water (15 mL) and EtOAc (15 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on an 80-g Redi-Sep column, eluting with 0-50% of a 90:10 mixture of DCM/MeOH in DCM to give (R)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:6]([CH:9]=[CH:10][S:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][S:8][C@H:3]12.[C:36]([O:55]/[N:56]=[C:57](/[C:61]1[N:62]=[C:63]([NH:66][C:67]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[S:64][CH:65]=1)\[C:58](O)=[O:59])([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C=O>[C:36]([O:55][N:56]=[C:57]([C:61]1[N:62]=[C:63]([NH:66][C:67]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[S:64][CH:65]=1)[C:58]([NH:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:19])=[C:6]([CH:9]=[CH:10][S:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][S:8][C@H:3]12)=[O:59])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3ccncc3)CS[C@H]12
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3ccncc3)CS[C@H]12)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
To a solution of benzhydryl 7-amino-3-[2-(4-pyridyl)thiovinyl]-3-cephem-4-carboxylate (a mixture of cis- and trans-isomers) (1.0 g) in a mixture of methylene chloride (10 ml) and dimethylformamide (1.0 ml) were added (Z)-2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (1.46 g) and DCC (dicyclohexylcarbodiimide) (450 mg) and the resultant mixture was stirred at room temperature for 2 hours. After completion of the reaction, the dicyclohexylurea was filtered off and the filtrate was diluted with ethyl acetate (50 ml), washed with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure to give a crude product (2.65 g). This crude product was chromatographed on a column of silica gel and eluted with benzene-ethyl acetate to provide benzhydryl 7-[2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[2-(4-pyridyl)thiovinyl]-3-cephem-4-carboxylate (1.6 g).
Reaction SMILES: [CH3:1][O:2][N:3]([C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:4]1[NH:5][C:6](=[O:24])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@:14]3([C:22]#[CH:23])[F:21])[C:11]=2[N:12]=1.[Si:44](Cl)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][N:3]([C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:4]1[NH:5][C:6](=[O:24])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:18][C@H:17]([CH2:19][O:20][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C@@H:15]([OH:16])[C@@:14]3([C:22]#[CH:23])[F:21])[C:11]=2[N:12]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#C[C@@]1(F)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 12 (2.29 mmol) in pyridine (5 ml) at 0° C., was added tert-butyldimethylsilyl chloride (2.75 mmol). The reaction mixture was stirred at room temperature for 24 hours. It was then diluted in DCM and washed twice with H2O. The organic phase was extracted, dried over Na2SO4, filtered and evaporated. The crude material was purified by silica gel chromatography (DCM/MeOH) to yield the title compound. Yellowish oil. Molecular Formula C38H44FN5O5Si. Scan ES+ 696 (M+H)+, λmax 260 nm. Scan ES− 694 (M+H)−, UV λmax 260 nm
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:37])[NH:14][CH2:15][C:16]2[CH:20]=[CH:19][N:18]([C:21]3[CH:30]=[C:29]4[C:24]([NH:25][C:26](=[O:32])[C:27](=[O:31])[NH:28]4)=[CH:23][C:22]=3[C:33]([F:36])([F:35])[F:34])[CH:17]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Li+]>O>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:37])[NH:14][CH2:15][C:16]2[CH:20]=[CH:19][N:18]([C:21]3[CH:30]=[C:29]4[C:24]([NH:25][C:26](=[O:32])[C:27](=[O:31])[NH:28]4)=[CH:23][C:22]=3[C:33]([F:36])([F:35])[F:34])[CH:17]=2)=[CH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(NC(=O)NCc2ccn(-c3cc4[nH]c(=O)c(=O)[nH]c4cc3C(F)(F)F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(NCc1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2C(F)(F)F)c1)Nc1ccc(C(=O)O)cc1
Yield: 72.8 %

Procedure:
1.6 g (3.1 mmol) of the compound from Example 1 and 0.3 g (12.4 mmol) of lithium hydroxide were stirred in 40 ml of water at room temperature for 2 h. The mixture was then filtered, and the filtrate was neutralized with 1 M hydrochloric acid. The resulting precipitate was filtered off with suction. 1.1 g (74%) of the product were obtained.
Reaction SMILES: [CH2:1]([CH:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.[CH3:23][Sn:24](Cl)([CH3:26])[CH3:25]>C1COCC1.CCCCCC>[CH2:1]([CH:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][C:7]1[S:8][C:9]([Sn:24]([CH3:26])([CH3:25])[CH3:23])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCC(CCCC)Cc1cccs1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCC(CCCC)Cc1ccc([Sn](C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(2-butyloctyl)thiophene (1.52 g, 6.02 mmol) in dry THF (30 mL) was cooled to −78° C., and a solution of n-BuLi (2.5 M, 3.6 mL, 9.0 mmol) was then added slowly. This mixture was stirred at −78° C. for additional 10 minutes, and allowed to warm to room temperature and stirred at room temperature for 30 minutes, before it was cooled back to −78° C. again. A solution of trimethylstannyl chloride (1.0 M, 9 mL, 9.0 mmol) was added slowly. This mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature, and stirred at room temperature overnight. The reaction was quenched by water. The resulting reaction mixture was diluted with hexane, washed with water, dried over Na2SO4, and concentrated on a rotary evaporator, leading to a slightly yellow oil (2.48 g, 99.2%), which was directly used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:11]2[C:12]3[CH:3]([CH2:4][C:5](=[O:13])[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[C:2]1=[O:14].[H-].[Na+].Br[CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>CN(C=O)C>[O:29]=[C:20]1[C:21]2[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:24])[N:19]1[CH2:18][C:3]12[C:2](=[O:14])[NH:1][C:11]3[C:12]1=[C:7]([CH:8]=[CH:9][CH:10]=3)[NH:6][C:5](=[O:13])[CH2:4]2
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: O=C1CC2C(=O)Nc3cccc(c32)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC2(CN3C(=O)c4ccccc4C3=O)C(=O)Nc3cccc(c32)N1
Reaction time: 0.17 h

Procedure:
To a stirred solution of (±)-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione (2.00 g, 10.6 mmol, described in Intermediate 18) in degassed DMF (30 mL) at 0° C. was added sodium hydride (468 mg of a 60% dispersion in mineral oil, 11.7 mmol). The mixture was stirred for 10 min, then N-(bromomethyl)phthalimide (2.55 g, 10.6 mmol) was added and stirring was continued for 2 h. An additional portion of N-(bromomethyl)phthalimide (500 mg) was added and stirring was continued for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to give the title compound. MS: m/z=348 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]2[CH2:17][CH2:16][CH:15]2[C:18](OC)=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C>CCOCC>[C:7]1([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]2[CH2:17][CH2:16][CH:15]2[CH2:18][OH:19])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C1CCN1C(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCC1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
To a suspension of 0.57 g of lithium aluminium hydride in 30 ml of dry ether is dropwise added a solution of 6 g (0.021 mole) of 1-diphenylmethyl-2-methoxycarbonylazetidine [prepared in the manner described in J. Heterocyclic Chem., 6, 435 (1969) by R. M. Rodebaugh and N. H. Cromwell] in 30 ml of dry ether in a period of 15 minutes, and the mixture is stirred at room temperature for 15 minutes. The excess amount of lithium aluminium hydride is decomposed with ethyl acetate. The insoluble materials are filtered off and washed with dry ether. The combined filtrate and washings are evaporated to dryness under reduced pressure. The residue is dissolved in ether and the resulting solution is evaporated to yield 4.7 g of crude syrupy 1-diphenylmethyl-2-hydroxymethylazetidine in 90% yield.
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[CH:16]=[N:15][S:14][N:13]=1)=[O:11])=O)(C)(C)C.Cl.O1CCOCC1>>[S:14]1[N:15]=[CH:16][C:12]([C:10]([NH:9][NH2:8])=[O:11])=[N:13]1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1cnsn1
Agent: Cl
Solvent: C1COCCO1
Product: NNC(=O)c1cnsn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Solid t-butyl-2-(1,2,5-thiadiazol-3-ylcarbonyl)hydrazinecarboxylate (I86) (265 mg, 0.890 mmol) was treated with a solution of hydrochloric acid (4 M) in dioxane (4.45 ml, 17.79 mmol) and stirred under argon at RT for 6 hr. The solvent was evaporated in vacuo and the residue dissolved in methanol (˜10 ml), added to a 10 g SCX column and eluted with Dichloromethane (˜50 ml), methanol (˜50 ml) and a solution of ammonia (2 M) in methanol (˜100 ml). The basic fractions were combined and evaporated in vacuo to afford the free base as a white solid in 95.5 mg.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[C:36](O)=[O:37])[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:35]=4[N:26]=[CH:27][CH:28]=[CH:29]5)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cccc2cccnc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5cccnc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoline-8-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]([O:9][N:10]=[C:11]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[C:12]([OH:14])=[O:13])([CH3:8])[CH3:7])=O)C.ClCCl.[NH3:23]>>[NH2:23][C:4]([C:6]([O:9][N:10]=[C:11]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[C:12]([OH:14])=[O:13])([CH3:8])[CH3:7])=[O:3]
Reactant: CCOC(=O)C(C)(C)ON=C(C(=O)O)c1ccco1
Reactant: N
Solvent: ClCCl
Product: CC(C)(ON=C(C(=O)O)c1ccco1)C(N)=O
Reaction time: 22 h
Yield: 77 %

Procedure:
2-(2-Ethoxycarbonylprop-2-yloxyimino)-2-(fur-2-yl) acetic acid (syn isomer) (2.0 g) was dissolved in concentrated aqueous ammonia (50 ml) and the solution stood at room temperature for 22 hours. Most of the ammonia was removed by evaporation and the solution was then acidified with concentrated hydrochloric acid and extracted with ether. The ether extracts were washed with brine and dried and the solvent was removed to give a white solid. Trituration with dichloromethane gave the title compound (1.37 g, 77%), m.p. 160°-162°; λ max (EtOH) 271nm (ε 15,100).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[BrH:22]>O>[Br:22][C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: OC(c1cccc(Br)c1)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 2-(3-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.1 g, 12 mmol) in HBr (48%, 24 mL) and H2O (4.8 mL) was added NaNO2 (990 mg, 14 mmol) in H2O (3 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 30 minutes and was then added to a solution of CuBr (6.9 g, 48 mmol) in HBr (48%, 24 mL) and H2O (4.8 mL) at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over MgSO4. Solvent was removed and the residue was purified by column chromatography (0-20% ethyl acetate-hexane) to yield 2-(3-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.1 g, 79%). 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.57 (t, J=0.8 Hz, 1H), 7.55 (t, J=0.9 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 3.62 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1)=[O:44]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccncc2N)C1
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1

Procedure:
Following the procedures as described in EXAMPLE 1 and starting with (R)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, the title compound was obtained as a white solid (8 mg, 7.2%). 1H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 8.21 (d, J=5.2, 1H), 7.67 (s, 2H), 7.54 (ddd, J=14.7, 8.4, 6.3, 1H), 7.29 (t, J=8.9, 2H), 7.12 (d, J=5.3, 1H), 3.12 (d, J=7.6, 2H), 3.05-2.91 (m, 2H), 1.93-1.79 (m, 1H), 1.72 (s, 2H), 1.29-1.08 (m, 1H). ESIMS m/z=431.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2].Cl.[NH2:33][OH:34].N1C=CC=CC=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[N:33][OH:34])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=NO
Temperature: 25 °C
Yield: 58.5 %

Procedure:
1-Oxo-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carboxylic acid ethyl ester (1.5 g, 3.64 mmol) obtained in Example 7 was dissolved in ethanol (100 mL), hydroxylamine hydrochloride (759 mg, 10.92 mmol) and pyridine (1.15 g, 15.56 mmol) were added thereto, refluxed for 1 hr, and cooled to RT. The resulting mixture washed with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 0.91 g of the titled compound (yield: 58%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12]Br>C(Cl)(Cl)Cl.CO>[Br:12][C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrBr
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(O)c(Br)c1
Reaction time: 2 h

Procedure:
Methyl 4-hydroxybenzoate (25.00 g) was dissolved in chloroform (225 mL) and methanol (25 mL), and a chloroform (30 mL) solution of bromine (8.5 mL) was added dropwise to the solution, and then the mixture was stirred for 2 hours. The reaction solution was diluted with chloroform, washed with water, an aqueous 10% sodium thiosulfate solution and saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (37.81 g) as a colorless crystal.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]=[CH2:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2]>C(O)C>[CH2:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH:24]=[C:9]([C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:25])[N:7]=4)[N:10]=3)[CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)[CH3:23]
Reactant: C=Cc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Solvent: CCO
Product: CCc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.7 %

Procedure:
2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-vinyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine from Example 447 (0.300 g, 0.894 mmol) was dissolved in ethanol (5 mL) and purged with N2. 10% Palladium on Carbon (0.1:0.9, Palladium:carbon black, 0.0952 g) was added. The resulting suspension was placed under vacuum followed by addition of H2 at atm pressure. This process was repeated three times to saturate the catalyst. The reaction was stirred for 18 hours at room temperature. The reaction mixture was filtered and concentrated to dryness. The crude product was purified using reverse phase chromatography to give 499 (0.189 g, 62.9% yield).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[N:16]=[C:17]([N:20]=[C:21]([NH2:23])[NH2:22])[S:18][CH:19]=2)[N:14]=1.[CH3:24][N:25]=[C:26]=[O:27]>CO>[NH2:22][C:21](=[N:20][C:17]1[S:18][CH:19]=[C:15]([C:13]2[N:14]=[C:10]([CH2:9][NH:8][C:26]([NH:25][CH3:24])=[O:27])[S:11][CH:12]=2)[N:16]=1)[NH2:23]
Reactant: CN=C=O
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.6 %

Procedure:
Triethylamine (0.7 g) was added to a suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (1.0 g) in methanol (20 ml). To the mixture was added methylisocyanate (0.21 g). The mixture was stirred at room temperature for 1.5 hours. The solvent was removed under the reduced pressure and the residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1). Recrystallization from a mixture of water and methanol afforded 2-(diaminomethyleneamino)-4-[2-(3-methylureido)methylthiazol-4-yl]thiazole (0.5 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C@H:15]([CH2:24][CH2:25][C:26](=[O:28])[NH2:27])[NH:16][C:17](OC(C)(C)C)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([O:37][C:38]1[CH:46]=[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:44]=[CH:43][C:39]=1C(O)=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C@H:15]([CH2:24][CH2:25][C:26](=[O:28])[NH2:27])[NH:16][C:17](=[O:18])[C:44]2[CH:43]=[CH:39][C:38]([O:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:46][C:45]=2[O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Product: NC(=O)CC[C@H](NC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Yield: 26.9 %

Procedure:
Condensation of 1-benzyl-4-(N-tert-butoxycarbonyl-L-glutaminyl)piperazine (1.0 g) and 2,4-dibenzyloxybenzoic acid (752 mg) was carried out in the same manner as in Example 7 (i) to obtain colorless crystalline powder 1-benzyl-4-(2,4-dibenzyloxybenzoyl-L-glutaminyl)piperazine (375 mg). Melting point: 133°-135° C.