Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]#[N:8].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20](OCC)=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:20](=[O:21])[CH2:6][C:7]#[N:8])[CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC#N
Reactant: CCOC(=O)c1cccc(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
n-BuLi (1.6 M in hexanes, 146 mL, 234 mmol) was added dropwise at −78° C. to a solution of CH3CN (10.39 mL, 199 mmol) in THF (600 mL) and the reaction mixture was stirred for 30 min. A solution of ester (2) (30.0 g, 117 mmol) in THF (50 mL) was added and the mixture was further stirred for 30 min at −78° C. The reaction mixture was quenched at −78° C. by addition of aqueous NH4Cl (200 mL), diluted with EtOAc (500 mL), the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 3-(3-(benzyloxy)phenyl)-3-oxopropanenitrile (3) as a pale yellow solid. Yield (25.0 g, 85%); 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.48-7.36 (m, 6H), 7.35-7.33 (m, 1H), 7.27-7.26 (m, 1H), 5.12 (s, 2H), 4.05 (s, 2H).
Reaction SMILES: C1(=O)[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].NN>C(O)(C)C>[CH2:16]([O:15][C:13]([NH:12][C@H:9]1[CH2:10][CH2:2][C@H:3]([CH2:4][NH2:5])[CH2:7][CH2:8]1)=[O:14])[C:17]1[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=1
Reactant: CCOC(N)=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: NN
Solvent: CC(C)O
Product: NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Reaction time: 4 h

Procedure:
The above urethane phthalimide was treated with 1 equiv anhydrous hydrazine in isopropanol for 18 h at room temperature followed by 4 h reflux. The mixture was concentrated, diluted with cold aqueous acetic acid and filtered to remove phthalazinedione. The aqueous layer was basified with NaOH followed by extraction with ethyl acetate, drying, and evaporation to afford the desired product as a solid. mp 118-121.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O/[N:29]=[C:30](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:31]([O:33][CH2:34][CH3:35])=[O:32].N(C(OC)=O)=NC(OC)=O>C1C=CC=CC=1>[CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([O:8]/[N:29]=[C:30](/[C:36]2[N:37]=[C:38]([NH:41][C:42]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[S:39][CH:40]=2)\[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:4][CH2:3]1
Reactant: C=C1CCC(O)CC1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C=C1CCC(O/N=C(\C(=O)OCC)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CC1
Reaction time: 65 h
Yield: 10.5 %

Procedure:
4-Methylenecyclohexanol (412 mg), triphenylphosphine (860 mg), and ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate (1.37 g) were dissolved together in anhydrous benzene (9 ml). Dimethyl azodicarboxylate (0.40 ml) was added slowly with stirring and the resulting orange solution was stored at room temperature for 65 h with exclusion of moisture. Workup and chromatography as in example 4a, method 3 afforded the title compound (174 mg), δH (CDCl3) 1.33 (3H, t, J 7 Hz), 1.82, 2.08 and 2.31 (8H, 3m), 4.35 (2H, q, J 7 Hz), 4.51 (1H, m), 4.63 (2H, s), 6.48 (1H, s), 6.96 (1H, br s, D2O exch.), and 7.30 (15H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=2)[C:18]([O:20]C(C)(C)C)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:25]=[C:26]([C:28]([F:30])([F:31])[F:29])[N:27]=2)[C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)c1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(=O)O)cc(C(F)(F)F)n2)CC1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
tert-Butyl 2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}-6-(trifluoromethyl)isonicotinate (3.4 g, 7.6 mmol, from Step 1) was treated with potassium hydroxide (3.4 g, 61 mmol) in tetrahydrofuran (50. mL). After 2 hours, the mixture was acidified to pH 2-3 by the addition of 1.0 N HCl. Brine (50 mL) was also added and the product was extracted with three 50 mL portions of chloroform. The extracts were dried over sodium sulfate, filtered and concentrated to afford product as a light yellow powder (2.8 g, 94%). LCMS (M+Na)+: 412.0.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=2)[CH2:16][CH2:15]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1C[C@@H]1C1CCN(c2ccc(CO)cn2)CC1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COCc1ccc(N2CCC([C@H]3C[C@H]3CCO[Si](C)(C)C(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the (6-{4-[(1R,2S)-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyridin-3-yl)methanol (0.3 g, 0.768 mmol) in THF (1.920 ml) was cooled at ice-bath temperature. A solution of NaHMDS (0.922 ml, 0.922 mmol) was added followed by addition of methyl iodide (0.067 ml, 1.075 mmol). The bath was removed and the resulting mixture stirred at room temperature for 2 hours. The mixture was diluted with 1N NaOH (50 ml), extracted with EtOAc (3×30 ml), the organic fractions combined, washed with brine, dried over sodium sulfate, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel, Biotage 25 g, using a gradient eluant of 0-30% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 405 (M+H)+.
Reaction SMILES: [CH3:1][S:2]CCl.[CH2:5]([S:8][C:9]1[NH:10][C:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)C=C>>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:11]2[N:10]=[C:9]([S:8][CH2:5][S:2][CH3:1])[NH:13][C:12]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:27][CH:26]=1
Reactant: C=CCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Reactant: CSCCl
Product: COc1ccc(-c2nc(SCSC)[nH]c2-c2ccc(OC)cc2)cc1

Procedure:
By substituting chloromethyl methyl sulfide for the allyl bromide of Example 11 one obtains as product 4,5-bis-(4-methoxyphenyl)-2-(methylthiomethylthio)imidazole, m.p. 171°-172°.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].S(=O)(=O)(O)O.[Cl-].[Na+].N([O-])=O.[Na+].[Na+].[I-:24]>O>[I:24][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(I)cc1[N+](=O)[O-]
Temperature: 2 °C
Reaction time: 0.75 h
Yield: 81.7 %

Procedure:
To a suspension of 4-methyl-3-nitroaniline (4.30 g, 28.26 mmol) in water (40 mL) cooled in ice-water bath, 98% sulfuric acid (1.89 mL) was added cautiously (Herm et al., 2002, which is incorporated herein by reference). Sodium chloride was added into the ice-water bath to lower the temperature to minus 2° C., and a solution of NaNO2 (2.15 g, 31.10 mmol) in water (10 mL) was added at a rate that the reaction temperature did not exceed 0° C. Upon completion of the addition, the mixture was stirred at minus 2° C. for 45 minutes. This solution of the diazo compound was then carefully added (in small portions) to a boiling solution of NaI (12.89 g, 86 mmol) (CAUTION: vigorous gas evolution). Upon completion of the addition, the reaction mixture was cooled down to room temperature and extracted with methylene chloride (50 mL) four times. The combined organic phase was washed with saturated NaHCO3 (40 mL) and water (40 mL), dried over Na2SO4, concentrated in vacuo. The residue was purified by silica gel chromatography to yield 4-iodo-2-nitrotoluene (6.07 g, 82%). 1H NMR (400 MHz, CDCl3): δ 8.28 (d, 1H, J=1.8 Hz, Ph-H), 7.81 (dd, 1H, J=2.2 and 8.1 Hz, Ph-H), 7.09 (d, 1H, J=8.1 Hz, Ph-H), 2.55 (s, 3H, CH3).
Reaction SMILES: [OH-].[Li+].[OH:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C@H:13]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[C:30]4[C:25](=[N:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=4)[N:24](S(C4C=CC(C)=CC=4)(=O)=O)[CH:23]=3)[C:19]([C:45]#[N:46])=[CH:18][N:17]=2)[CH3:14])[CH2:9][CH2:8]1)=[O:6]>O1CCCC1>[OH:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C@H:13]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[C:30]4[C:25](=[N:26][CH:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=4)[NH:24][CH:23]=3)[C:19]([C:45]#[N:46])=[CH:18][N:17]=2)[CH3:14])[CH2:9][CH2:8]1)=[O:6]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCN(C(=O)CO)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](Nc1ncc(C#N)c(-c2c[nH]c3ncc(C(F)(F)F)cc23)n1)C1CCN(C(=O)CO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
1M solution of lithium hydroxide (382.5 μl, 0.38 mmol) was added to a solution of 2-((R)-1-(1-(2-hydroxyacetyl)piperidin-4-yl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (80 mg, 0.128 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The crude mixture was concentrated to dryness and redissolved in ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion|) to afford the title compound as a white solid (30 mg, 50% yield).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])=[O:4].[O-:45][C:46]#[N:47].[K+].C(OCC)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[O:45]=[C:46]1[NH:47][CH2:2][C:3](=[O:4])[N:5]1[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33]
Reactant: O=C(CCl)NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: N#C[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1CNC(=O)N1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 81.2 %

Procedure:
A solution of (2S,4S)-2-(chloroacetylamino)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (1.0 g), potassium cyanate (1.3 g) and tetra-n-butylammonium iodide (0.2 g) in acetonitrile (50 ml) was stirred at 60°-80° C. for 8 hours To a reaction mixture was added ethyl acetate (150 ml) and the organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (50 g) eluting with a mixture of chloroform and acetone (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-(2,5-dioxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (0.82 g).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc([N+](=O)[O-])cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, yellow solid (69 mg, 80%), MS (ISP) m/z=347.5 [(M+H)+], mp 193.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-nitro-phenylboronic acid (54.3 mg, 0.325 mmol).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]=[O:11].S(OC)(O[CH3:16])(=O)=O.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:16][O:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: COc1c(C=O)cccc1C=O
Temperature: 75 °C
Yield: 54 %

Procedure:
2-Hydroxy-1,3-benzenedicarboxaldehyde (1.05 g, 7 mmol), dimethyl sulfate (1.06 g, 8.4 mmol), and 55 mL of acetonitrile were charged into a 1-necked flask equipped with a mechanical stirrer. 1.45 g (10.5 mmol) of potassium carbonate was added at room temperature under nitrogen. The mixture was stirred at 75° C. until GC-MS indicated that the reaction was complete. The reaction mixture was cooled to ambient temperature, diluted with diethyl ether, washed with NaCl/H2O, and dried over MgSO4. The ether was evaporated off. The crude product was recrystallized from diethyl ether. Pale yellow solid (0.62 g, 54% yield) was obtained. 1H NMR in CDCl3 was consistent with the proposed structure. 1H NMR (CDCl3): δ 10.4 (2H), 8.1 (2H), 7.4 (1H), 4.1 (3H).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].C(=O)([O-])O.[Na+].[CH2:26](O)[CH3:27]>>[CH2:26]([O:10][C:9]([C:8]1[CH:12]=[C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:15][C:7]=1[OH:6])=[O:11])[CH3:27]
Reactant: CCO
Reactant: COCCOc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc(OCCOC)ccc1O

Procedure:
Concentrated sulphuric acid (0.5 ml) was added to a stirred solution of 2-hydroxy-5-(2-methoxyethoxy)benzoic acid (2 g) in ethanol (50 ml). The mixture was heated at reflux for 12 hours. The reaction mixture was added to sodium hydrogen carbonate solution (5% by weight in water, 200 ml) and the aqueous mixture was extracted with ethyl acetate (4×50 ml). The organic extracts were combined, washed with water (50 ml), brine, (50 ml), dried (MgSO4) and evaporated to give 2-ethoxycarbonyl-4-(2-methoxyethoxy)phenol (1.85 g) as an oil; NMR: 1.35(3H,t), 3.31(3H,s), 3.6(2H,m), 4.0(2H,m), 4.3(2H,q), 6.9(1H,d), 7.18(1H d of d), 7.2(1H,d); m/z 241(MH). This was converted into the trifluoromethane sulphonate ester using an analogous procedure to that described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxy)propionate. There was thus obtained after chromatography on silica gel (Varian bond elut S1 silica gel) using a gradient of 5 to 25% ethyl acetate in hexane as eluent as an oil; NMR(6): 1.3(3H,t), 3.3(3H,s), 3.62(2H,m), 4.2(2H,m), 4.34(2H,q), 7.35(1H, d of d), 7.49(2H,m); m/z 373(M+H).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:25](O)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.O[N:30]=[C:31]([CH:33]1[CH2:35][CH2:34]1)[NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:33]1([C:31]2[N:32]=[C:25]([CH:12]3[CH2:11][CH:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:28])=[CH:5][CH:6]=4)[CH2:15][N:14]([C:16]([N:18]4[CH2:19][CH2:20][S:21](=[O:24])[CH2:22][CH2:23]4)=[O:17])[CH2:13]3)[O:26][N:30]=2)[CH2:35][CH2:34]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)CC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N1CCS(=O)CC1)N1CC(c2ccc(OC(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
200 mg (0.48 mmol) of the compound from Example 39A and 96 mg (0.96 mmol) of N′-hydroxycyclopropanecarboximidamide were initially charged in 1.8 ml of DMF and reacted with 274 mg (0.72 mmol) of HATU and 0.25 ml (186 mg, 1.44 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at RT for 15 minutes and then partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in 2.0 ml of DMF and converted in a microwave at 180° C. for 2 minutes. The reaction mixture was purified by means of preparative HPLC. Yield: 25 mg (10% of theory)
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][O:4][N:3]=1.[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CCC.C(OC)(C)(C)C>[N:7]1([C:2]2[CH2:6][CH2:5][O:4][N:3]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCNC1
Reactant: BrC1=NOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCCCO
Product: C1CCN(C2=NOCC2)C1
Temperature: 120 °C

Procedure:
3-(Pyrrolidin-1-yl)-4,5-dihydroisoxazole III-59 was prepared in 1 step according to the following procedure: 3-bromo-4,5-dihydroisoxazole III-18 (1.0 equiv) was dissolved in n-butanol (0.64 M) followed by the addition of pyrollidine (1.2 equiv) and sodium carbonate (2.5 equiv). The reaction is the sealed and heated in an oil bath to 120° C. for 18 h after which it allowed to cool and then transferred to a separatory funnel with excess water and tert-butylmethyl ether. The aqueous layer was washed with tert-butylmethyl ether (2×) and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrate to provide a orange solid that was purified using flash silica gel chromatography (gradient ethyl acetate/hexanes) to provide III-59 as a white solid. [M+H]+=345.4 m/z. Activity: C
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH:18]=O)[CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][NH:31][CH:28]2[CH2:30][CH2:29]2)[CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CN(CCc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCc1ccc(Cl)c(CNC2CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A mixture of [2-(4-chloro-3-formyl-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (325 mg, 1.09 mmol), Et3N (0.228 mL, 1.64 mmol) and cyclopropylamine (0.115 mL, 1.64 mmol) in MeOH (3.66 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (103 mg, 2.73 mmol) was added. The mixture was stirred for 1 h at rt, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc several times. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC yielded the title compound (186 mg, 50%). LC-MS: tR=0.79 min; ES+: 339.39.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([CH2:20][OH:21])[NH:17]2)=[CH:13][CH:12]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([CH:20]=[O:21])[NH:17]2)=[CH:13][CH:12]=1
Reactant: OCc1cc2ccc(Oc3nc4ncccc4s3)cc2[nH]1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2ccc(Oc3nc4ncccc4s3)cc2[nH]1
Temperature: 80 °C
Yield: 15.7 %

Procedure:
To a solution of [6-(thiazolo[4,5-b]pyridin-2-yloxy)-1H-indol-2-yl]-methanol (0.89 g, 3.0 mmol) in CHCl3 (30 mL) was added MnO2 (2.6 g, 30 mmol) and the reaction mixture was heated (80° C., 3 h). The reaction mixture was cooled (rt), filtered (Celite®) and washed with isopropanol:DCM (15%, 300 mL). The filtrate was dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to provide the title compound as a colorless solid (139 mg, 16%). MS (ESI): mass calcd. for C16H9N3O2S, 295.0; m/z found, 296.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.94 (s, 1H), 8.59 (dd, J=4.8, 1.7, 1H), 8.46 (dd, J=8.0, 1.7, 1H), 7.95 (t, J=18.7, 1H), 7.61 (d, J=2.2, 1H), 7.55 (s, 1H), 7.40 (dd, J=8.0, 4.8, 1H), 7.34-7.15 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]([OH:16])=O)[CH:8]=[CH:9][C:2]1=2.[C:17](Cl)(=O)C(Cl)=O.[Na].C(OC(C)(C)C)(=O)CC(OC(C)(C)C)=O.[H-].[Na+].Cl>C(Cl)Cl.C(OCC)(=O)C.O.O1CCCC1.CN(C)C=O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]([CH3:17])=[O:16])[CH:8]=[CH:9][C:2]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COCCc1ccc2sccc2c1
Agent: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)COCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 50 mL of methylene chloride is dissolved 5.00 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-acetic acid. At an ice-cooled temperature, 2.2 mL of oxalyl chloride and 0.1 mL of N,N-dimethylformamide are added to the solution obtained above, and the mixture thus formed is stirred at ambient temperature for 30 minutes. The solvent is distilled off under reduced pressure, the residue is dissolved in 5 mL of tetrahydrofuran, and the solution thus obtained is dropwise added to a tetrahydrofuran solution of sodium salt of di-tert-butyl malonate, prepared from 1.01 g of sodium hydride and 5.70 mL of di-tert-butyl malonate, at an ice-cooled temperature. The mixture thus obtained was stirred at the same temperature as above for 30 minutes. The reaction mixture is introduced into a mixture of ice water and ethyl acetate, pH is adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is heated under reflux together with 20 mL of methylene chloride and 10 ml of trifluoroacetic acid, the solvent is distilled off under reduced pressure, and the residue is heated to make progress a de-carbonization reaction. Water and ethyl acetate are added to the reaction mixture, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: n-hexane:ethyl acetate=7:1 to 5:1) to obtain 3.67 g of 1-(2-benzo[b]thiophen-5-ylethoxy)-acetone.