Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H](OC)[CH2:4][C@@H:3]1[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:12]=1.[ClH:27].CO.CC(C)=O>CO>[ClH:27].[OH:1][C@@H:2]1[CH2:6][O:7][CH2:4][C@H:3]1[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[N:12]=1
Reactant: CO[C@@H]1C[C@H](Oc2nc(N3CCNCC3)nc3ccccc23)[C@@H](O)[C@H]1O
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: O[C@@H]1COC[C@H]1Oc1nc(N2CCNCC2)nc2ccccc12

Procedure:
4-[(3R,4R)-(4-Hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl)quinazoline 1/2 hydrochloride (cf. Example 21) (178 mg) is dissolved in methanol (3 ml) with heating, and thereto is added 2N HCl-methanol (0.32 ml) and acetone (10 ml), and the mixture is allowed to stand at room temperature. The precipitated crystals are separated by filtration to give 4-[(3R,4R)-(4-hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl)quinazoline monohydrochloride (124 mg) as crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:30][CH2:31][N:32]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:33][CH2:34]2)[S:27][CH:28]=1
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)c(F)c1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccc(F)cc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 59.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (211 mg, 0.782 mmol), 1-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 169 mg (59.4%) of the desired product as a solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C@@H:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])[C:8](=O)[CH2:9][C@H:5]12)[CH3:3].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:34]2[N:35]=[CH:36][N:37]3[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][C:38]=23)=[O:33])[CH:27]=1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:8]([C:40]3[S:39][C:38]4=[C:34]([C:32]([C:28]5[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=5)=[O:33])[N:35]=[CH:36][N:37]4[CH:41]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cccnc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)C[C@H]12
Yield: 73 %

Procedure:
4-Nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (469 mg) was prepared in the same manner as in step a) of Example 1, except that 400 mg of 4-nitrobenzyl (3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and 700 mg of 7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3]1>[Ni].CO>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3]1
Reactant: CCOC(=O)C=C1CC(C)CC(C)C1
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)CC1CC(C)CC(C)C1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a 1 liter autoclave which is fitted with heating means, cooling means and a stirrer are added 54 g of ethyl 3,5-dimethyl-cyclohexylideneacetate, 200 ml of absolute methanol and 3 g of Raney-nickel, which has been washed three times with absolute methanol. The mixture is hydrogenated at 100° C. under a hydrogen pressure of 40 atmospheres. The hydrogen uptake stops after 8 hours. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled. There are obtained 52.3 g of ethyl 3,5-dimethyl-cyclohexylacetate.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([NH:12][NH:13][C:14]1[C:15](=[O:29])[N:16](O)[C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)(=O)C>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[N:23]2[C:22]3[C:17]([NH:16][C:15](=[O:29])[C:14]2=[N:13][N:12]=1)=[CH:18][C:19]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:21]=3)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(=O)NNc1nc2ccc(C(F)(F)F)cc2n(O)c1=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCOP(=O)(Cc1nnc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12)OCC
Yield: 39.8 %

Procedure:
A solution of 3-[2-[(diethoxyphosphoryl)acetyl]hydrazino]-1-hydroxy-7-trifluoromethylquinoxalin-2(1H)-one (438 mg, 1 mmol) and triphenylphosphine (525 mg, 2 mmol) in 25 ml of glacial acetic acid was heated under reflux overnight (ca. 15 h). The mixture was evaporated to dryness, and the residue was flash chromatographed (SiO2) with dichloromethane to remove excess triphenylphosphine, then with ethyl acetate to remove triphenylphosphine oxide, and finally with 5% acetic acid in ethyl acetate to give 161 mg (40%) of the title compound. M.p. 224°-226° C., dec. (ethanol).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[S:33]>>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[NH:31][C:32]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1)=[S:33]
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(Cl)c4Cl)CC3)nc21

Procedure:
Pipemidic acid (51 mg, 0.168 mmol) and 2,3-dichlorophenyl isothiocyanate (20 μL, 0.141 mmol) were used. Purification on silica yielded compound 15 in table 1, below (15.5 mg, 22%). 1H NMR (300 MHz, DMSO) δ 9.03 (s, 1H), 8.78 (s, 1H), 7.53 (d, J=7.43 Hz, 1H), 7.41-7.26 (m, 2H), 4.51-3.90 (m, 10H), 1.43-1.27 (m, 3H) ppm.
Reaction SMILES: [CH:1]12[CH2:8][CH:4]([CH2:5][C:6]1=O)[C:3]1[CH:9]=CC=C[C:2]2=1.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15]C1>>[CH:4]12[CH2:8][CH:1]([CH2:6][CH2:5]1)[CH2:2][CH:3]2[CH:9]1[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:13]1
Reactant: O=C1CC2CC1c1ccccc12
Reactant: c1ccc2c(c1)OCO2
Product: c1ccc2c(c1)OC(C1CC3CCC1C3)O2

Procedure:
benzobicyclo[2.2.1]heptan-2-one is converted to 2-(benzobicyclo[2.2.1]hept-2-yl)-1,3-benzodioxole in 93.5% yield.
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:10]([C:21]3[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].[C:35](Cl)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[C:1]([C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:10]([C:21]3[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:35])=[O:18])[C:11]([F:12])([F:13])[F:14])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)COC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2[nH]ccc12)C(F)(F)F
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2[nH]ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(+) or (−)-Methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate (tr=3.5 min—from Example 35-B) (54 mg, 0.114 mmol) was dissolved in ethanol (2.0 mL). This solution was added to a mixture of acetyl chloride (1.0 mL) in ethanol (20.0 mL) at 0° C. This mixture was gradually warmed to room temperature and stirred for 16 hr. The reaction solution was basified with saturated sodium bicarbonate solution and the majority of the ethanol was removed in vacuo. The resulting reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. This material was purified using FCC eluting with ethyl acetate/heptane (0-60%) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.89 (br.s., 1H) 11.09 (br. s., 1H) 8.26 (s, 1H) 7.83-8.06 (m, 1H) 7.49-7.73 (m, 1H) 7.38 (t, J=2.78 Hz, 1H) 6.91-6.96 (m, 1H) 6.74 (s, 1H) 3.98-4.36 (m, 2H) 3.73-3.97 (m, 2H) 3.04-3.06 (s, 3H) 2.47-2.50 (s, 3H) 0.97-1.08 (m, 3H) HRMS calcd. for C24H21F3N4O4 (M+H)+ 487.1548. found 487.1576.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][CH:48]1[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]1=[O:62].Br[C:64]1[CH:65]=[C:66]([O:70][CH3:71])[CH:67]=[CH:68][CH:69]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:71][O:70][C:66]1[CH:65]=[C:64]([C:48]2([CH3:47])[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]2=[O:62])[CH:69]=[CH:68][CH:67]=1
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Reactant: COc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc(C2(C)CCC(=CN(C)c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 87.1 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with tris(dibenzylideneacetone)dipalladium (0) (23 mg, 0.025 mmol, 10 mol % Pd), (S)-BINAP (46.7 mg, 0.075 mmol, 15 mol %) and 2-methyl-5-(N-methyl-anilinomethylene) cyclopentanone (108 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. 3-Bromoanisole (187 mg, 1.0 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added to the tube. The tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL), and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 140 mg (87%) of the title compound. The ee was determined to be 85% by chiral HPLC analysis.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[NH:7][CH2:6][CH:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C2CCC(=O)NC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCC(c2ccc(C(=O)O)cc2)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Ethyl 4-(6-oxo-piperidin-3-yl)-benzoate (320 mg, 1.30 mmol, reference example 66) is dissolved in MeOH (8 mL). To this solution is added 1 N NaOH (1.43 mL, 1.43 mmol) and the resulting solution stirred at room temperature for 1 hour. An additional portion of 1 N NaOH (2 mL) is added and the mixture allowed to stir at room temperature overnight (16 hours). 1 N HCl is added until pH 2-3 is reached. A precipitate formed and is filtered, washed with water and placed in a vacuum oven to dry overnight to afford the title compound (250 mg, 88%) as small white crystals (needles). 1H NMR (300 MHz, DMSO) δ 1.94 (m, 2H), 2.23 (m, 2H), 3.06 (m, 1H), 3.23 (m, 2H), 7.42 (d, J=8.3, 2H), 7.57 (bs, 1H), 7.87 (d, J=8.1, 2H); MS (Ion spray) m/z 220 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C@@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:12])[NH:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][C@H:39]4[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 51 %

Procedure:
A solution of 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea from Example 95B (50 mg, 0.111 mmol), (R)-3-hydroxy-1-tert-butoxycarbonylpyrrolidine (31 mg, 0.167 mmol), triphenylphosphine (44 mg, 0.167 mmol) and diisopropylazodicarboxylate (34 mg, 0.167 mmol) in dry tetrahydrofuran (1 mL) was stirred at room temperature for 15 h. The reaction mixture was partitioned between aqueous 1M sodium hydroxide solution (20 mL) and 10% methanol in dichloromethane (50 mL) and the organic layer was separated and washed with brine (50 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 100% dichloromethane to 10% methanol in dichloromethane to afford (S)-tert-butyl 3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylate as a colorless oil (35 mg, 51%). 1H NMR (300 MHz, CDCl3) δ 9.30 (brs, 1H), 8.62 (s, 1H), 8.30 (brs, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.26-7.39 (m, 2H), 7.00 (m, 1H), 5.95 (s, 1H), 5.12 (s, 1H), 4.02 (s, 3H), 3.50-3.80 (m, 5H), 2.20-2.40 (m, 2H), 1.50 (s, 9H), 1.30 (s, 9H); LC-MS (ESI) m/z 619 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[C:11]2[CH:12]=[N:13][C:14]([NH:16][C:17]([NH:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])=[O:18])=[CH:15][C:10]=2[NH:9][N:8]=1)C(=O)C)[CH3:2].[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC(N(C)C)=O.CO>[CH2:1]([NH:3][C:7]1[C:11]2[CH:12]=[N:13][C:14]([NH:16][C:17]([NH:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])=[O:18])=[C:15]([F:29])[C:10]=2[NH:9][N:8]=1)[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCN(C(C)=O)c1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CCNc1n[nH]c2c(F)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)—N-Ethyl-N-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide (154 mg, 0.420 mmol) was dissolved in DMA (1 mL) and methanol (1 mL), charged with powdered Selectfluor® (164 mg, 0.462 mmol), and stirred at room temperature overnight. The reaction was then to heated to 55° C. for 8 h. The resulting crude residue was purified by mass-triggered reverse phase HPLC. Fractions containing pure compound were filtered through a PS-HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)-1-(3-(ethylamino)-7-fluoro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C19H21FN6O2 [M+1]+ 385. found 385.
Reaction SMILES: [CH3:1][C:2]1([C:10]([OH:12])=O)[CH2:5][C:4]([F:7])([F:6])[C:3]1([F:9])[Cl:8].S(Cl)([Cl:15])=O>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:1][C:2]1([C:10]([Cl:15])=[O:12])[CH2:5][C:4]([F:7])([F:6])[C:3]1([Cl:8])[F:9]
Reactant: CC1(C(=O)O)CC(F)(F)C1(F)Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC1(C(=O)Cl)CC(F)(F)C1(F)Cl
Yield: 75.4 %

Procedure:
One drop of dimethylformamide is added to a mixture of 91.2 g (0.45 mol) of 1-methyl-2,3,3-trifluoro-2-chlorocyclobutane-1-carboxylic acid and 450 ml of chloroform. After this, 80.3 g (0.675 mol) of thionyl chloride are added dropwise at 25°-30° C. with stirring, and the stirred mixture is heated to the boil. After 6 hours the mixture is cooled, the solvent is stripped off, and the residue is subjected to fractional distillation under reduced pressure. 75 g (75% of theory) of 1-methyl-2-chloro-2,3,3-trifluoro-cyclobutane-1-carbonyl chloride are obtained in form of a liquid of boiling point 65°-70° C. at 20 mbar. ##STR60##
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:42])[N:16]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5])[CH3:3].[C:43]([NH:53][CH2:54][C:55](O)=[O:56])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>>[C:43]([NH:53][CH2:54][C:55]([NH:1][C@@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:42])[N:16]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5])[CH3:3])=[O:56])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]
Reactant: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](C)N
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](C)NC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-D-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-dodecyl-dodecanamide and N-carbobenzoxy-glycine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:26]([CH3:28])[CH3:27])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=2)=[O:17])[N:13]=1.Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:26]([CH3:28])[CH3:27])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:20]([CH3:25])[CH:19]=2)=[O:17])[N:13]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cc(C(=O)CCc2nc(-c3ccc(Cl)cc3O)oc2C(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)CCc2nc(-c3ccc(Cl)cc3O)oc2C(C)C)cc1C
Yield: 42.5 %

Procedure:
In methyl ethyl ketone (10 mL), 3-[2-(2-hydroxy-4-chlorophenyl)-5-isopropyl-4-oxazolyl]-1-(3-methyl-4-hydroxyphenyl)propan-1-one (150 mg, 0.38 mmol), ethyl 2-bromo-2-methylpropionate (146 mg, 0.75 mmol) and potassium carbonate (103 mg, 0.75 mmol) were suspended. The suspension was refluxed for 20 hours, and allowed to room temperature. After insoluble was filtered off, the mixture was washed with methyl ethyl ketone to removed the solvent. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (8/1) to give the desired compound (83 mg) as colorless oil (yield 43%).
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=[C:9]([F:30])[CH:8]=1.[CH3:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=[C:34]([O:47][CH2:48][C:49]2([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:52][CH2:51][CH2:50]2)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[F:30][C:9]1[CH:8]=[C:7]([C:37]2[C:32]([CH3:31])=[CH:33][C:34]([O:47][CH2:48][C:49]3([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:52][CH2:51][CH2:50]3)=[N:35][CH:36]=2)[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1
Reactant: CCOC(=O)C1(COc2cc(C)c(B3OC(C)(C)C(C)(C)O3)cn2)CCC1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2cc(C)c(-c3ccc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)c(F)c3)cn2)CCC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
N,N-dimethylformamide (5 mL) was added to 2-(4-bromo-2-fluorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (293 mg), ethyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}methyl)-cyclobutanecarboxylate (250 mg) and palladium chloride (dppf) methylene chloride complex (28 mg), and after adding 2N aqueous sodium carbonate solution (1 mL) to the mixture, the atmosphere was replaced with nitrogen and the mixture was stirred at 65° C. for 3 hours. To the reaction mixture were added ethyl acetate and water to extract the objective compound. The organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 80:20) to obtain ethyl 1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate (316 mg).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:14]2[NH:15][NH:16][C:17]3[N:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11]>C(O)(=O)C>[ClH:1].[CH3:13][O:12][C:8]1[CH:7]=[C:6]([C:14]2[N:15]([C:8](=[O:12])[CH3:7])[N:16]([C:4](=[O:3])[CH3:9])[C:17]3[N:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:5]=[C:4]([O:3][CH3:2])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(C2=Nc3cccnc3NN2)cc(OC)c1OC
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(C2=Nc3cccnc3N(C(C)=O)N2C(C)=O)cc(OC)c1OC

Procedure:
12.0 g (0.032 mole) of 3-(3',4',5'-trimethoxyphenyl)-1,2-dihydropyrido[3,2-e]-as-triazine hydrochloride are boiled in 40 ml of glacial acetic acid for a short time. The reaction mixture is cooled and the separated product is filtered off.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[N:3]=1.[N:22]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:6]([C:7]([N:30]2[CH2:31][CH2:32][CH:27]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:28][CH2:29]2)=[O:8])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(OC(F)(F)F)cc2)c(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1nn(-c2ccc(OC(F)(F)F)cc2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 95 %

Procedure:
In analogy to the procedure described in Example 18], 3,5-dimethyl-1-(4-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 95% yield as light brown solid. MS: 437.2 (MH+).