Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](I)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH2:12]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:11][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(C=Cc2ccncc2)c1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
A mixture of 3.0 g (20 mmol) of 3-nitroiodobenzene, 3.5 mL (25 mmol) of TEA, 0.045 g (0.20 mmol) of palladium(II) acetate and 2.77 g (25.0 mmol) of 4-vinylpyridine was suspended in 4 mL of dry acetonitrile in a pyrex sealed tube and heated to 100 ° C. for 48 h. The mixture was cooled to rt and was quenched with 200 mL of 10% hydrochloric acid. The resulting yellow solid was isolated by filtration and partitioned between 250 mL of EtOAc and 250 mL of 1 N aqueous sodium hydroxide. The organic phase was dried over MgSO4 and concentrated to give 3.0 g (66%) of 4-[2-(3-nitrophenyl)ethenyl]-pyridine as a yellow solid: 1H NMR (DMSO-d6): δ3.0-4.6 (brs, 1H), 7.71-7.78 (m, 2H), 8.07 (d, J=15.8 Hz, 1H), 8.13-8.16 (m, 3H), 8.24 (d, J=8.0 Hz, 1H), 8.56 (s, 1H), 8,84 (d, J=5.7 Hz, 2H); ESI−MS m/z 227 (M+1)+. A portion (1.3 g, 7.1 mmol) of this solid was dissolved in 100 mL of EtOAc, and 0.5 g of 10% palladium on charcoal was added. The mixture was hydrogenated on a Parr apparatus at 40 psi for 1.5 h. Another 0.5 g batch of 10% palladium on charcoal was added and the mixture was subjected to further hydrogenation for 1 h. The palladium catalyst was removed by filtration through a pad of celite, and the filtrate was concentrated to give 1.13 g (100%) of 3-(4-pyridinyl)ethylaniline: 1H NMR (DMSO-d6): δ2.69 (m, 2H), 2.80 (m, 2H), 4.9 (bs, 2H), 6.33 (d, J=7.7 Hz, 2H), 6.38 (s, 1H), 6.86 (t, J=7.7 Hz, 1H), 7.20 (d, J=5.8 Hz, 2H), 8.41 (d, J=5.8 Hz, 2H). Conversion of 3-[2-(4-pyridinyl)ethyl]-aniline to 4-(2-pyridin-4-yl-ethyl)-1H-indole-2,3-dione was accomplished according to Procedure A in 24% overall yield: 1H NMR (DMSO-d6): δ2.80 (m, 2H), 3.10 (m, 2H), 6.70 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 7.24 (m, 2H), 7.40 (t, J=8.0 Hz, 1H), 8.42 (bs, 2H), 11.00 (s, 1H). Conversion of 4-(2-pyridin-4-yl-ethyl)-1H-indole-2,3-dione to the title compound was accomplished according to Procedure G in 40% overall yield: 1H NMR (DMSO-d6): δ2.98 (t, J=7.9 Hz, 2H), 3.30 (m, 2H, underneath water peak), 6.78 (d, J=7.7 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.25 (s, 2H), 7.29 (d, J=6.0 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 8.47 (d, J=6.0 Hz, 2H), 11.13 (s, 1H), 12.98 (s, 1H); APCI−MS m/z 420 (M−1)−. Anal. Calcd for C21H19N5O3S.0.15HCl: C, 55.93, H, 4.43; N, 15.53; S, 7.11. Found C, 56.05, H, 4.36; N, 15.38; S, 7.18.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1
Yield: 6 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[4-(methylsulfonyl)phenyl]pyridazin-4(1H)-one (crude 615 mg, 1.77 mmol) in 20 mL of methanol was added phenylhydrazine (765 mg, 7.08 mmol). The mixture was, refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-[4-(methylsulfonyl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (42 mg, 6% for two steps) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[C:37]([C:39]([O:41]C)=[O:40])[CH:38]=1)[CH2:8][CH:9]([CH2:13][CH2:14][CH2:15][S:16]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].C([SiH](C(C)C)C(C)C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:39]([C:37]1[CH:36]=[C:7]([CH2:8][CH:9]([CH2:13][CH2:14][CH2:15][SH:16])[C:10]([OH:12])=[O:11])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:38]=1)([OH:41])=[O:40]
Reactant: COC(=O)c1cc(CC(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cc(C(C)(C)C)c1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(CC(CCCS)C(=O)O)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.6 %

Procedure:
To a solution of 2-(3-tert-butyl-5-methoxycarbonyl-benzyl)-5-[(triphenylmethyl)thio]pentanoic acid XII (5.5 g, 9.7 mmol) in dichloromethane (30 mL) were added triisopropylsilane (2.4 mL, 11.6 mmol) and trifluoroacetic acid (10 mL), and the mixture was stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography (1% AcOH in Hexanes/EtOAc, 4:1) to afford 3-carboxy-5-(1,1-dimethylethyl)-alpha-(3-mercaptopropyl)-benzenepropanoic acid (1.7 g, 5.3 mmol, 55%) as a white solid: 1H NMR (CD3OD) δ1.3 (s, 9H), 1.5-1.8 (m, 4H), 2.4 (m, 2H), 2.6-2.7 (m, 1H), 2.8-2.9 (m, 1H), 2.9-3.0 (m, 1H), 7.5 (s, 1H), 7.7 (s, 1H), 7.8 (s, 1H); 13C NMR (CD3OD) δ24.8, 31.7 (3C), 31.9, 32.9, 35.6, 39.5, 48.6, 125.7, 128.5, 131.6, 132.0, 140.9, 152.8, 170.3, 179.0. Elemental analysis calculated for C17H24O4S: C, 62.93; H, 7.46; S, 9.88. Found: C, 63.02; H, 7.36; S, 9.82.
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.[CH2:15]([C:19]1[N:20]=[C:21]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=2[O:44][CH3:45])[C:22]2[NH:27][N:26]=[C:25]([C:28]#[C:29][CH2:30][CH2:31][CH2:32]Cl)[C:23]=2[N:24]=1)[CH2:16][CH2:17][CH3:18]>CN(C)C=O.ClCCl>[CH2:15]([C:19]1[N:20]=[C:21]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=2[O:44][CH3:45])[C:22]2[NH:27][N:26]=[C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:12]3[CH2:13][CH2:14][C@H:10]([F:9])[CH2:11]3)[C:23]=2[N:24]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCl)c2n1
Reactant: F[C@H]1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(CCCCCN3CC[C@H](F)C3)c2n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 50.6 %

Procedure:
Triethylamine (0.860 mL, 6.20 mmol) was added to a mixture of (S)-3-fluoropyrrolidine hydrochloride (390 mg, 3.10 mmol) and 5-butyl-3-(5-chloropent-1-yn-1-yl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (457 mg, 1.034 mmol) in N,N-dimethylformamide (7 mL). The mixture was heated to 80° C. and stirred for 18 hours. An additional portion of (S)-3-fluoropyrrolidine hydrochloride (195 mg, 1.55 mmol) and triethylamine (0.430 mL, 3.10 mol) were added to the reaction mixture. The reaction was stirred at 80° C. for a further 6 hours. N,N-Dimethylformamide (3 mL) was added and the reaction mixture was stirred at 80° C. for a further 18 hours and then allowed to cool to room temperature. The mixture was evaporated in-vacuo to yield a brown oil. The resulting oil was partitioned between dichloromethane (50 mL) and water/brine (20 mL). The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a brown oil. The oil was dissolved in the minimum volume of dichloromethane, loaded onto a 50 g aminopropyl functionalised silica cartridge and purified using a 0-10% methanol in dichloromethane gradient over 40 minutes. (detection wavelength=230 nm). Appropriate fractions were combined and evaporated in-vacuo to yield a brown oil (261 mg). A mixture of the oil and 10% palladium on carbon (50 mg) in ethanol (20 mL) was stirred under a hydrogen atmosphere for 3 hours. Additional 10% palladium on carbon (50 mg) was added to the reaction and the mixture was stirred under a hydrogen atmosphere for 18 hours. A further portion of 10% palladium on carbon (50 mg) was added to the reaction and the mixture was stirred under a hydrogen atmosphere for 5 hours. The reaction was filtered through a celite cartridge (10 g) and evaporated in-vacuo to yield a brown oil. The oil was dissolved in the minimum volume of dichloromethane, loaded onto a 50 g aminopropyl functionalised silica cartridge and purified using a 0-10% methanol in dichloromethane gradient over 40 mins. (detection wavelength=230 nm). Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a brown oil (175 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([C:8]2[N:13]=[C:12]([CH3:14])[NH:11][C:10](=O)[CH:9]=2)[CH:7]=1.CN(C)C=O.C(Cl)(=O)C([Cl:26])=O>ClCCl.O1CCOCC1>[Cl:26][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:16][CH3:17])[N:13]=[C:12]([CH3:14])[N:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Cl)cc1-c1cc(=O)[nH]c(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1-c1cc(Cl)nc(C)n1
Reaction time: 1 h
Yield: 94 %

Procedure:
To a suspension of 6-(5-chloro-2-methoxy-phenyl)-2-methyl-3H-pyrimidin-4-one (520 mg, 2.1 mmol) in dichloromethane (20 ml) and 1,4-dioxane (20 ml) was added N,N-dimethylformamide (0.2 ml) followed by a solution of oxalyl chloride in dichloromethane (2 M, 4.2 ml). After stirring for 1 hour, the mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (60 ml). The organic phase was dried over magnesium sulfate and concentrated under vacuum to give 4-chloro-6-(5-chloro-2-methoxy-phenyl)-2-methyl-pyrimidine (530 mg, 94% yield) as a white powder. 1H NMR (DMSO-d6) δ 2.67 (s, 3H, CH3), 3.91 (s, 3H, CH3), 7.26 (d, 1H, J=9.2 Hz, Ar), 7.59 (dd, 1H, J=8.8 Hz, J=2.6 Hz, Ar), 7.95 (s, 1H, Ar), 7.96 (d, 1H, J=2.9 Hz, Ar).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:16](OCC)(=[O:18])[CH3:17].O>C1C=CC=CC=1>[C:16]([CH:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][C:10]1=[O:13])(=[O:18])[CH3:17]
Reactant: CCOC(C)=O
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)C1CC(c2ccccc2)CCC1=O
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 4-phenylcyclohexanone (10 mmol, Lancaster) in benzene (5 ml) is added dropwise to a suspension of NaH (20 mmol) in absolute ethyl acetate (20 mmol) and the reaction mixture is stirred after complete evolution of the gas for 3 h at 40° C. Then it is mixed with water, the reaction mixture is extracted three times with ether, the combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and the solvent is removed in a vacuum. After column chromatography purification on silica gel with hexane/EtOAc 15:1 a clean product is obtained. tR 2.14; MS (pos. Ion.) m/z 217.26 [M+H]+. (J. Med. Chem. 1989, 32(2), 351-357).
Reaction SMILES: N1C=CC=CC=1.C(Cl)Cl.[CH2:10]([C:12]1[N:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH3:11].[NH2:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][C:27]=2[Br:33]>O>[Br:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[N:25]=[CH:24][C:23]([NH:22][S:18]([C:15]1[CH:16]=[N:17][C:12]([CH2:10][CH3:11])=[CH:13][CH:14]=1)(=[O:20])=[O:19])=[CH:32]2
Reactant: Nc1cnc2c(Br)cccc2c1
Reactant: CCc1ccc(S(=O)(=O)Cl)cn1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(S(=O)(=O)Nc2cnc3c(Br)cccc3c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine (0.5 ml) and a methylenechloride (0.5 ml) solution containing 6-ethyl-3-pyridinesulfonyl chloride (30 ml) were added to 3-amino-8-bromoquinoline (18 mg, Production Example 5b) at 0° C. After stirring at room temperature for 30 minutes, water was added thereto and the mixture was extracted with ethyl acetate. The extract was purified by preparative TLC (hexane-ethyl acetate=1:1), to give the title compound (20 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:10]([Br:13])[C:11]#[CH:12]>>[Br-:13].[CH2:12]([N+:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1)[C:11]#[CH:10]
Reactant: c1ccc2scnc2c1
Reactant: C#CCBr
Product: C#CC[n+]1csc2ccccc21
Product: [Br-]
Temperature: 25 °C
Yield: 82.7 %

Procedure:
13.5 g of benzothiazole was mixed with 13.1 g of propargyl bromide. The mixture was heated at 80° to 100° C for one hour on a hot water bath to solidify it. After cooling to room temperature (about 20°- 30° C), the solid was washed with acetone to give 21 g of 3-propargylbenzothiazolium bromide, m.p. 209°- 210° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:17]2[CH:16]=[N:15][C:14]([O:13][CH2:9][CH2:10][CH2:11][CH2:12][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:19][CH:18]=2)=[N:7][CH:6]=1
Reactant: Brc1cnc(Br)nc1
Reactant: CCCCOc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
Yield: 75.9 %

Procedure:
A reaction of 115 mmol of 2,5-dibromopyrimidine, 115 mmol of 2-butoxypyrdine-5-boronic acid, 230 mmol of sodium carbonate and 1.2 mmol of tetrakis(triphenylphosphine)palladium(0) in 280 ml of toluene, 140 ml of ethanol and 140 ml of water is carried out analogously to the procedure indicated for precursor 3. Corresponding purification gives 15.9 g (38%) of a colorless solid, m.p. 99-101 ° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25].C(O)(C(F)(F)F)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)c1nc2cc(N)ccc2n1CC1CCC(F)(F)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-amine (440 mg, 1.37 mmol) and DMAP (165 mg, 1.37 mmol) were dissolved in 50 mL of DCM. Ethanesulfonyl chloride (0.170 mL, 1.78 mmol) was added dropwise and the solution was stirred at rt for 2.5 h. The solution washed with saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was purified by silica gel flash chromatography using EtOAc as eluent. The fractions were concentrated and the residue was dissolved in 25 mL of MeOH. TFA (0.155 mL, 2.06 mmol) was added dropwise and the solution was stirred at rt for 30 min. The solvent was evaporated and the product was precipitated in ether affording the title compound as its corresponding TFA salt. Yield: 565 mg (78%). 1H NMR (400 MHz, METHANOL-D4) δ 1.29 (t, J=7.42 Hz, 3H), 1.48-1.60 (m, 2H), 1.64 (s, 9H), 1.66-1.72 (m, 2H), 1.73-1.82 (m, 2H), 1.99-2.09 (m, 2H), 2.18-2.28 (m, 1H), 3.11 (m, 2H), 4.50 (d, J=7.62 Hz, 2H), 7.38 (dd, J=9.08, 2.05 Hz, 1H), 7.72 (d, J=2.15 Hz, 1H), 7.85 (d, J=8.98 Hz, 1H); MS (ESI) (M+H)+ 414.0.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].CC1C=C(C)[N:32]([C:36](=[N:38][N+:39]([O-:41])=[O:40])N)N=1>CO>[F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[N:17]=[C:18]([CH2:21][O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:19][CH:20]=3)=[CH:14][CH:15]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:36]([NH2:32])=[N:38][N+:39]([O-:41])=[O:40]
Reactant: Cc1cc(C)n(C(N)=N[N+](=O)[O-])n1
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F
Solvent: CO
Product: NC(=N[N+](=O)[O-])Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F

Procedure:
In a sealed glass tube suitable for microwave heating, 2-fluoro-4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.6 g, 1.6 mmol) and 3,5-dimethyl-N′-nitro-1H-pyrazole-1-carboximidamide (0.296 g, 1.6 mmol) in 5 ml of methanol are heated at 150° C. in a microwave oven (Biotage, Emrys Optimiser) for 2700 seconds. The reaction medium is evaporated to dryness. After passing the residue obtained through a silica column (eluent dichloromethane/ethanol 98/2), a solid is obtained in the form of white powder.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:49]1[CH:53]=[N:52][S:51][N:50]=1>C1COCC1>[S:51]1[N:52]=[CH:53][C:49]([O:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:18]2)=[N:50]1
Reactant: O=C1O[C@@H](CO)CN1c1ccccc1
Reactant: Oc1cnsn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2cnsn2)CN1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisopropylazodicarboxylate (4.45 g, 22 mmol) was added dropwise to a stirred solution of 5(R)-hydroxymethyl-3-phenyloxazolidin-2-one (Gregory et al. J. Med, Chem, 32, 1673 (1989); 4.25 g,22 mmol), triphenyl phosphine (5.76 g, 22 mmol) and 3-hydroxy-1,2,5-thiadiazole (Weinstock et al, J.Org. Chem, 32, 2823 (1967)) (2.04 g, 20 mmol) in 30 ml THF, in an ice-bath. After stirring at ambient temperature for two hours and evaporating in vacuo, the resulting oil was purified by chromatography (Merck 9385 silica. Gradient elution from isohexane to ca. 50% EtOAc/isohexane to give a white solid. Further purification by flash chromatography on silica using 1% MeOH/dichloromethane was necessary to remove remaining diisopropylcarboxyhydrazine yielding the title product as a white crystalline solid (4.7 g, 83%). MS: ESP+ (M+H)+=278.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5])#[N:2].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19](Cl)=[O:20]>[OH-].[Na+]>[C:1]([CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH:5][C:19]([C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1)=[O:20])#[N:2]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: N#CC[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: N#CC[C@H](NC(=O)c1ccc2ccccc2c1)C(=O)O
Yield: 18.3 %

Procedure:
0.114 g of 3-cyano-L-alanine was dissolved in 5 ml of 1N sodium hydroxide solution and treated with 0.285 g of 2-naphthoyl chloride at 0° C. After acidification with 2M hydrochloric acid and flash chromatography on silica gel using 25% methanol in dichloromethane for the elution there was obtained 0.049 g of 3-cyano-N-(2-naphthoyl)-L-alanine of melting point 95°-100° C.
Reaction SMILES: [NH2:1][C:2](=[C:7]1C(=O)O[C:10](C)([CH3:14])[O:9][C:8]1=[O:16])[CH2:3][CH:4]1[CH2:6][CH2:5]1.[Na]>C(O)C.ClCCl>[CH2:10]([O:9][C:8](=[O:16])[CH:7]=[C:2]([NH2:1])[CH2:3][CH:4]1[CH2:5][CH2:6]1)[CH3:14]
Reactant: CC1(C)OC(=O)C(=C(N)CC2CC2)C(=O)O1
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C=C(N)CC1CC1
Yield: 70 %

Procedure:
397 mg (2 mmol) 5-(1-Amino-2-cyclopropyl-ethylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione were added to a solution of 45 mg (2 mmol) sodium in 3 ml ethanol. The reaction mixture was heated under reflux for 14 h, diluted with dichloromethane and poured onto ice water/brine 1/1. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure to give 231 mg (1.4 mmol, 77%) of the title compound as orange oil.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:8]=[C:7]2I.C([Mg]Cl)(C)C.[CH2:26]([Sn:30]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:32][CH2:33][CH2:34][CH3:35])Cl)[CH2:27][CH2:28][CH3:29]>C1COCC1>[F:1][CH:2]([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:8]=[C:7]2[Sn:30]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CN(C)CCCn1nc(I)c2cc(OC(F)F)ccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(CCCN(C)C)c2ccc(OC(F)F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a solution of 3-(5-(difluoromethoxy)-3-iodo-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (1.2 g, 2.78 mmol) in dry THF (25 mL) was added isopropylmagnesium chloride (1.5 mL, 2M in THF, 3 mmol) drop-wise at −16° C. under nitrogen atmosphere, stirred for 30 minutes, tributylchlorostannane (3.3 mL, 3.6 mmol) was added drop-wise at −16° C. under nitrogen, then the reaction mixture was warmed to room temperature slowly and stirred for 2 hours. Then the reaction mixture was quenched with a saturated solution of NH4Cl (40 mL) and extracted with EtOAc (3×30 mL), the combined organic layer were dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine, (1.1 g, 71%) as an oil, used into the next step without purification.
Reaction SMILES: CSC.B.[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:14][C@H:13]1[C:28](O)=[O:29])=[O:11])([CH3:8])([CH3:7])[CH3:6].O>C1COCC1>[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:14][C@H:13]1[CH2:28][OH:29])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1C(=O)O
Agent: B
Solvent: O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1CO
Temperature: 0 °C
Yield: 102.3 %

Procedure:
Borane-dimethyl sulfide (0.63 ml, 6.3 mmol) was added to a solution of (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylic acid (1.12 g, 3.13 mmol) in THF (30 ml) under stirring at 0° C. The reaction mixture was stirred at 50° C. for 1.5 hours. After the reaction mixture was cooled to 0° C., water (20 ml) was added thereto. The mixture was then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from chloroform/methanol (50/1) eluate fractions, the title compound (1.10 g, 100%) was obtained as a pale yellow oil.