Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@@H:3]([OH:5])[CH3:4].N1C=CN=C1.CN(C)C=O.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>ClCCl>[Si:17]([O:6][CH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: C[C@H](O)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](O)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 0° C. solution of (S)—(+)-1,3-butanediol (2.1 g, 23.3 mmol), imidazole (1.74 g, 25.6 mmol), and N,N-dimethylformamide (1.0 mL) in dichloromethane (40 mL) was treated with tert-butyl-dimethylsilyl chloride (3.68 g, 23.3 mmol). The reaction mixture was warmed to room temperature, stirred overnight, quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The combined dichloromethane layers were dried (MgSO4), filtered and concentrated to afford of the desired product of sufficient purity for subsequent use without further purification in near quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][N:18](S(C4C=CC(C)=CC=4)(=O)=O)[C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.[OH-].[K+].C(O)(=O)C>CN(C)C=O.CO>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)=[O:6]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(Cl)c(N)c(C(=O)O)c3)cc12
Reactant: C1COCCN1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(Cl)c(N)c(C(=O)N4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
25.0 mg (0.046 mmol) of 2-amino-3-chloro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid was combined with 18.5 mg (0.114 mmol) of N,N′-carbonyldiimidazole in 1.0 mL dimethylformamide. The solution was stirred at room temperature for 2 hours whereupon 9.9 μL (0.114 mmol) of morpholine was added and the solution was stirred at room temperature for 16 hours. The crude reaction mixture was then diluted with 1.0 mL methanol and 100 μL of 50% w/v potassium hydroxide aqueous solution was added. The mixture was stirred at room temperature for 2 hours and then neutralized with acetic acid. The material was filtered through a 0.45 μm syringe filter and purified by mass-triggered reverse phase HPLC in a gradient of acetonitrile and water (containing 0.1% formic acid). The clean fractions were lyophilized to afford 6.9 mg (0.015 mmol, 32% yield) of {2-amino-3-chloro-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-morpholin-4-yl-methanone as a fluffy white powder. 1H NMR (500 MHz, MeOD) δ 8.39 (d, 1H), 8.15 (d, 1H), 7.65 (s, 1H), 7.64 (d, 1H), 7.58 (dd, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.13 (d, 1H), 7.06 (t, 1H), 3.86 (s, 3H), 3.72 (s, br., 8H); MS: m/z 463.0 (M+H+).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][O:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1)=[O:6])[CH3:3].[CH3:35][C:36]([CH3:55])([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]2[CH:54]=[CH:53][C:50]([CH:51]=O)=[CH:49][CH:48]=2)[CH2:43][CH2:42]1)=[O:40])[CH3:37]>C1COCC1>[CH3:37][C:36]([CH3:55])([O:38][C:39]([N:41]1[CH2:42][CH2:43][N:44]([C:47]2[CH:48]=[CH:49][C:50]([CH:51]=[CH:13][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:34][CH:33]=3)=[CH:53][CH:54]=2)[CH2:45][CH2:46]1)=[O:40])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: CCOC(=O)COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C=Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 0 °C
Yield: 103.5 %

Procedure:
To an oven dried 100 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(ethoxycarbonylmethoxy)benzyltriphenyl-phosphonium bromide (1.106 g, 2.07 mmol) and dry THF (50 mL). To this well stirred mixture was added a solution of lithium hexamethyldisilylazide (2.20 mL of a 1M solution in THF). The deep red solution was stirred 1 h at ambient temperature then cooled in an ice bath to 0° C. To this mixture was added a solution of 4-(4-(1,1-dimethylethoxycarbonyl)piperazinyl)benzaldehyde (0.60 g, 2.07 mmol) in 10 mL of THF. The ice bath was removed and the solution was stirred at ambient temperature for 3 h. The reaction mixture was diluted with EtOAc and washed with water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave 1 g of an oil. This material was chromatographed on 80 g of silica gel using 25% EtOAc-hexane as eluant. There was obtained (E)-ethyl 4-(2-(4-(4-(1,1-dimethylethoxycarbonyl)piperazinyl)phenyl)ethenyl)phenoxyacetate 35-7 as an oil. 1H NMR (CDCl3): δ 1.26 (t, j=7 Hz, 3H), 1.49 (s, 9H), 3.16 (m, 4H), 3.57 (m, 4H), 4.27 (q, j=7 Hz, 2H), 4.60 (s, 2H), 6.90 (m, 6H), 7.40 (m, 4H), and 175 mg of a mixture of E,Z isomers.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:34][C:35]1[C:39]([Cl:40])=[C:38]([CH2:41][OH:42])[S:37][N:36]=1.[C:43](O)(=[S:45])[CH3:44]>C(OCC)(=O)C.C1COCC1>[C:43]([O:42][CH2:41][C:38]1[S:37][N:36]=[C:35]([Cl:34])[C:39]=1[Cl:40])(=[S:45])[CH3:44]
Reactant: CC(O)=S
Reactant: OCc1snc(Cl)c1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=S)OCc1snc(Cl)c1Cl
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a THF (50 ml) solution of 2.85 g (10.9 mmol) of triphenylphosphine was added, under ice-cooling, 2.2 g (10.9 mmol) of diisopropyl azodicarboxylate, followed by stirring for 30 minutes. To the solution was added a THF (5 ml) solution of 1.0 g (5.43 mmol) of (3,4-dichloroisothiazol-5-yl)methanol and 0.83 g (10.9 mmol) of thioacetic acid, followed by stirring at room temperature for 5 hours, to give rise to a reaction. After the completion of the reaction, ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 0.42 g (yield: 32%) of (3,4-dichloroisothiazol-5-yl)methyl thioacetate as a light red oily substance (refractive index: 1.5855).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)[CH:5]=[CH:4][C:3]1=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:51][C:52]1[CH:63]=[CH:62][C:55]2[NH:56][C:57]([C@@H:59]([NH2:61])[CH3:60])=[N:58][C:54]=2[CH:53]=1.[Cl:64]Cl>O1CCCC1.C(OCC)(=O)C>[Cl:64][C:19]1[CH:18]=[C:14]([CH:13]=[CH:12][C:11]=1[N:6]1[C:7]2[CH2:8][CH2:9][CH2:10][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5]1)[C:15]([NH:61][C@H:59]([C:57]1[NH:56][C:55]2[CH:62]=[CH:63][C:52]([Cl:51])=[CH:53][C:54]=2[N:58]=1)[CH3:60])=[O:17]
Reactant: ClCl
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(-n2ccc3c2CCCC3=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)c1ccc(-n2ccc3c2CCCC3=O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 54 %

Procedure:
Prepared analogously to Example 1g from 4-(4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 54%; Rf value: 0.41 (silica gel: ethyl acetate); C24H20Cl2N4O2 (467.354); mass spectrum: (M+H)+=467/469/471 (chlorine isotope).
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[N:14]=1)([CH3:6])([CH3:5])[CH3:4].COC([O:25][CH3:26])OC.[C:27]([O-])([O-])=O.[Na+].[Na+]>C(O)CO>[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[S:11][CH:12]=[C:13]([C:15]2([CH3:16])[O:25][CH2:26][CH2:27][O:17]2)[N:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: COC(OC)OC
Reactant: CC(=O)c1csc(C(C)(C)O[SiH2]C(C)(C)C)n1
Agent: N#N
Agent: [Na+]
Solvent: OCCO
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(C2(C)OCCO2)cs1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[2-(tert-butyl-dimethyl-silanyloxymethyl)-thiazol-4-yl]-ethanone (1.77 g, 6.52 mmol) in ethylene glycol (7 mL) was treated with trimethylorthoformate (1.46 mL, 13.29 mmol) followed by LiBF4 (125 mg, 1.30 mmol). The reaction mixture was heated at 95° C. for 4 h. Sat. aq. Na2CO3 (5 mL) was added and the mixture was extracted with Et2O (2×20 mL). The org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1->3:1 hept-EA) gave the title compound as a brown oil. TLC:rf (1:1 hept-EA)=0.56. LC-MS-conditions 02: tR=1.11 min; [M+H]+=316.36.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH:3]([C:28]1[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=1)/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:8][CH:7]=1.O.NN>CCO>[F:38][C:2]([F:1])([F:37])[CH:3]([C:28]1[CH:29]=[C:30]([Cl:36])[C:31]([Cl:35])=[C:32]([Cl:34])[CH:33]=1)/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH2:17])=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Temperature: 80 °C

Procedure:
To a stirred solution of (E)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione (0.4 g, 0.7 mmol) in EtOH was added hydrazine hydrate (0.18 g, 3.5 mmol), and the resultant reaction mixture was heated at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, and the solution was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The title compound was isolated as a gummy liquid (150 mg, 50%). The product obtained in this reaction was carried on to the next step without further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH3:16][N:17]([C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33])[C@H:18]([C:20]([C@:22]([CH3:31])([OH:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:21])[CH3:19].O>C(Cl)Cl>[CH3:16][N:17]([C:32]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:33])[C@H:18]([C:20]([C@:22]([CH3:31])([OH:30])[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[O:21])[CH3:19]
Reactant: C1COCCN1
Reactant: C[C@@H](C(=O)[C@](C)(O)C(=O)OC(C)(C)C)N(C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C[C@@H](C(=O)[C@](C)(O)C(=O)OC(C)(C)C)N(C)C(=O)N1CCOCC1

Procedure:
0.65 g (5.0 mmol) of N,N-diisopropylethylamine (“Hünig's base”) and 0.45 g (5.0 mmol) of morpholine are added at room temperature to a solution of 2.0 g (5.0 mmol) of tert-butyl N-methyl-N-(4-nitro-phenoxy)carbonyl-L-alanyl-D-lactate in 40 ml of methylene chloride, and the mixture is stirred at reflux temperature for 18 hours. During the course of this a strong yellow colouration of the reaction mixture occurs. The reaction solution is shaken twice with water, and the organic phase is separated off and concentrated in vacuo after drying over sodium sulphate. The residual crude product is chroratographed on a silica gel column (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane:ethyl acetate (1:1).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([CH2:21][CH3:22])[C:5]([C:6](NC2C=CC=C3C=2N=CC=C3)=[O:7])=[C:4]([CH2:23][CH3:24])[CH:3]=1.S(=O)(=O)(O)[OH:26]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:23][CH3:24])[C:5]([C:6]([OH:7])=[O:26])=[C:19]([CH2:21][CH3:22])[CH:20]=1
Reactant: CCc1cc(Br)cc(CC)c1C(=O)Nc1cccc2cccnc12
Reactant: O=S(=O)(O)O
Product: CCc1cc(Br)cc(CC)c1C(=O)O
Temperature: 120 °C
Yield: 56 %

Procedure:
A mixture of 4-bromo-2,6-diethyl-N-quinolin-8-yl-benzamide (2.9 g, 7.6 mmol) in 40% sulphuric acid (15 ml) is heated at 120° C. for 16 h. After completion, the reaction mixture is extracted with ether (2×100 ml) and the combined organic layers are dried over sodium sulfate and concentrated to obtain 4-bromo-2,6-diethyl-benzoic acid (1.1 g, 4.28 mmol, 56%).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6](OCC)=O.[CH3:15][C:16](=O)[CH2:17][CH3:18].C(O)(=O)C.O.[NH2:25][NH2:26]>C(O)C>[CH2:17]([C:16]1[CH:15]=[C:6]([C:5]([O:12][CH2:13][CH3:14])=[O:11])[NH:26][N:25]=1)[CH3:18]
Reactant: CCC(C)=O
Reactant: NN
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)n[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
Ethanolic sodium ethoxide solution (21% w/w; 143 ml, 0.39 mol) was added dropwise to a stirred, ice-cooled solution of diethyl oxalate (59.8 ml, 0.44 mol) in absolute ethanol (200 ml) under nitrogen and the resulting solution stirred for 15 minutes. Butan-2-one (39 ml, 0.44 mol) was then added dropwise, the cooling bath removed, the reaction mixture stirred for 18 hours at room temperature and then for 6 hours at 40° C., then the cooling bath reintroduced. Next, glacial acetic acid (25 ml, 0.44 mol) was added dropwise, the resulting solution stirred for 30 minutes at 0° C., hydrazine hydrate (20 ml, 0.44 mol) added dropwise, then the reaction mixture allowed to warm to room temperature and maintained there over a period of 18 hours, before being evaporated under reduced pressure. The residue was partitioned between dichloromethane (300 ml) and water (100 ml), then the organic phase separated, washed with water (2×100 ml), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (66.0 g). δ (CDCl3): 1.04 (3H, t), 1.16 (3H, t), 2.70 (2H, q), 4.36 (2H, q), 6.60 (1H, s). LRMS: m/z 169 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[C:13]([Br:29])[N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Yield: 71.2 %

Procedure:
A mixture of 1-cyclopentylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (147 mg, 0.39 mmol) and N-bromosuccinimide (76 mg, 0.43 mmol) in CH2Cl2 (1.5 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-15% EtOAc/hexanes+1% AcOH) to give 127 mg of the title compound as a yellow solid. MS: (−) m/z 455.21, 457.17 (M−1, 79/81Br).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH:2]1[C:9]([O:11][CH3:12])=[O:10]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:1]1[CH2:6][CH2:5][S:4](=[O:7])(=[O:8])[CH2:3][CH:2]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1CS(=O)(=O)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CS(=O)(=O)CCN1
Temperature: 0 °C
Yield: 94.7 %

Procedure:
To a solution of 4-(1,1-dimethylethyl) 3-methyl 3,4-thiomorpholinedicarboxylate 1,1-dioxide (D15; 1.73 g, 5.9 mmol) in 17 ml of anhydrous methylene chloride, trifluoroacetic acid (4.2 ml) was added dropwise while stirring at 0° C. under nitrogen atmosphere. The solution was stirred for 3 h, while allowing it to reach room temperature. The solvent was removed under reduced pressure and the residue was loaded on a SCX cartridge, washed with methanol and eluted with 0.5M methanolic ammonia. The basic fractions were collected and the solvent removed leaving 1.08 g of the target product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][CH:29]1[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][CH:29]3[CH2:30][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Yield: 86 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole with tert-butyl 3-amino-1-azetidinecarboxylate gave tert-butyl 3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-azetidinecarboxylate in 86% yield: mp (CH2Cl2/hexanes) 201-203° C.; 1H NMR (DMSO-d6) (rotamers) δ8.50 and 8.45 (2d, J=6.3, 6.5 Hz, 1H), 8.01 and 7.93 (2d, J=8.2, 8.3 Hz, 1H), 7.83 and 7.44 (2t, JHF=53.1, 52.9 Hz, 1H), 7.44-7.37 (m, 1H), 6.96 and 6.95 (2d, J=8.1, 8.0 Hz, 1H), 4.73-4.58 (m, 1H), 4.78 (t, J=7.8 Hz, 2H), 3.97 (s, 3H), 3.87-3.82 (m, 2H), 3.78 (m, 4H), 3.69, (m, 4H), 1 40 and 1.39 (2s, 9H); Anal. Calcd. for C24H30F2N8O4: C, 54.1; H, 5.7; N, 21.0. Found: C, 54.0; 5.8; N, 21.0%.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:26]=[CH:25][C:18](/[CH:19]=[CH:20]/[S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[ClH:14].[Cl:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:19]=[CH:20]/[S:21]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cl
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)N1CCNCC1

Procedure:
In the same manner as in Referential Example 1, a reaction was conducted using tert-butyl 1-piperazinecarboxylate and (E)-4-chlorostyrylsulfonyl chloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:35])=[C:5]([C:26]([O:33]C)=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:30][O:29][C:28]1[C:3](=[O:2])[C:4]([CH3:35])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])[C:26](=[O:33])[C:27]=1[O:31][CH3:32]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OCC(=O)OC(C)(C)C
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(CC2=C(C)C(=O)C(OC)=C(OC)C2=O)ccc1OCC(=O)OC(C)(C)C
Yield: 68 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(tert-butoxycarbonylmethyloxy)benzoate (1.25 g, 2.56 mmol) was dissolved in a mixed solution of acetonitrile (30 ml) and water (10 ml) and after adding thereto CAN (3.50 g, 6.39 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (0.800 g, 1.74 mmol, 68%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:13])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12].CCN(CC)CC.[CH3:21][O:22][C:23](=[O:26])[C:24]#[CH:25]>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:26])[CH:24]=[CH:25][O:1][NH:2][C:3](=[NH:13])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12]
Reactant: COCCOCCOCC(=N)NO
Reactant: C#CC(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCCOCC(=N)NOC=CC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a vigorously stirred mixture of crude N-hydroxy-2-[2-(2-methoxy-ethoxy)-ethoxy]-acetamidine (3.02 g) and NEt3 (2.30 mL) in DCM (40 mL) was added propynoic acid methyl ester (1.43 mL) dropwise. The mixture was stirred for 30 min at RT, washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue, crude 3-({2-[2-(2-Methoxy-ethoxy)-ethoxy]-acetimidoyl}-aminooxy)-acrylic acid methyl ester (4.50 g) was directly used in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:20])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(cnn2CC)c1Cl

Procedure:
A mixture of 23.5 g. 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine- 5-carboxylic acid ethyl ester (0.1 mol.) and 150 ml. of phosphorous oxychloride is refluxed for 4 hours. Subsequently, the excess phosphorous oxychloride is removed by means of vacuum distillation. As soon as the phosphorous oxychloride has been removed, the oily residue solidifies on cooling. It is treated with water and filtered under suction (24.5 g., m.p. 55°-60°). The 4-chloro compound is recrystallized from N-hexane (22.5 g. (87%), m.p. 62°).
Reaction SMILES: CN(C)N=[C:4]([CH3:6])[CH3:5].[Li+].CCC[CH2-].[F:13][C:14]([F:34])([F:33])[C:15]1[CH:32]=[CH:31][C:18]([O:19][C:20]2[CH:30]=[CH:29][C:23]([O:24][CH:25]([CH3:28])[CH:26]=[O:27])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.C(O)(=[O:37])C>O1CCCC1>[OH:27][CH:26]([CH:25]([O:24][C:23]1[CH:29]=[CH:30][C:20]([O:19][C:18]2[CH:31]=[CH:32][C:15]([C:14]([F:33])([F:34])[F:13])=[CH:16][CH:17]=2)=[CH:21][CH:22]=1)[CH3:28])[CH2:5][C:4](=[O:37])[CH3:6]
Reactant: CC(=O)O
Reactant: CC(C=O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)=NN(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of acetone N,N-dimethylhydrazone (0.32 g, 3.23 mmol) in tetrahydrofuran (THF; 5 ml) is added N-butyllithium (0.21 g, 3.23 mmol) at -65°, and the mixture is stirred for 30 minutes. To this is added dropwise 2-[4-(4-trifluoromethylphenoxy)phenoxy]propanal (1.0 g, 3.23 mmol) in 5 ml of THF, keeping the temperature at or below -60°. After 3 hours at -65°, the reaction mixture is allowed to warm to 0°, and is poured onto 20 g ice made slightly acidic with 10% acetic acid. It is extracted into ether, and the organic extract is washed with water and with NaCl and is dried over sodium sulfate. Solvent is removed, and the residue is purified by prep. TLC (silica gel, 20% ethyl acetate/hexane) to give 4-hydroxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone (C'; Q1 is CH, Y is hydrogen, Z is trifluoromethyl, R 1 is methyl and R2 is methyl). ##STR21##