Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-:10].[Na+].[CH2:12]=O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([OH:9])=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[CH2:12][OH:10]
Reactant: [OH-]
Reactant: C=O
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: OCc1cc(Cl)cc(Cl)c1O

Procedure:
A mixture of 2,4-dichlorophenol (15.3 g), 10% sodium hydroxide solution (100 ml) and 40% aqueous formaldehyde solution (37.5 ml) was heated at 95°-100° C. for 4 hr, then cooled and acidified by addition of 2-normal sulphuric acid (70 ml). The precipitated oil was extracted into toluene, and the extract washed with sodium bicarbonate solution, dried and evaporated. The residue was recrystallised from boiling water to yield 3,5-dichloro-2-hydroxybenzyl alcohol (4.0 g), m.p. 81°-82° C. on drying at 56° C./20 mm. Hg=2660 Pa.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[F:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([N:15]=[C:16]=[O:17])=[O:14].C([O-])(=O)CCC([O-])=O>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:16]([NH:15][C:13](=[O:14])[C:12]1[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=1[F:10])=[O:17])[CH2:3]2
Reactant: O=C=NC(=O)c1ccccc1F
Reactant: NC1CN2CCC1CC2
Agent: O=C([O-])CCC(=O)[O-]
Product: O=C(NC(=O)c1ccccc1F)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine (0.63 g, 5 mmol) and crude 2-fluorobenzoyl isocyanate (1.3 g, ca 7 mmol). The product (1.35 g) was converted to the 1:1 succinate, mp 187°-188° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(O[N:31]1[C:36](=[O:37])[CH2:35][CH2:34][C:32]1=[O:33])=[N+](C)C)C>CN(C=O)C>[CH2:35]1[C:36](=[O:37])[N:31]([O:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)=[O:8])[C:32](=[O:33])[CH2:34]1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C(O)c1ccc(I)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To the solution of 4-iodobenzoic acid (1)(1.24 g, 5.0 mmol) and triethylamine (0.71 mL, 5.0 mmol) in DMF (30 mL) was added TSTU (1.51 g, 5.0 mmol). The solution was stirred at room temperature for 2 hours. The reaction was quenched by addition of 10% HCl (50 mL). The precipitate was collected by filtration, washed with water and dried in vacuo to yield the title compound (2) as a white powder (1.42 g, 82%); m.p. 130-132° C.; vmax/cm−1(neat) 1769 (C═O, ester), 1719 (C═O, amide); (Found C, 38.40; H, 2.41; N, 4.15. C11H8INO4 requires C, 38.28; H, 2.34; N, 4.06%.); δH (300 MHz, CDCl3) 7.92 (2H, d, J 12.0 Hz, H2/6), 7.85 (2H, d, J 12.0 Hz, H3/5), 2.92 (4H, s, CH2); δc (75 MHz, CDCl3) 169.0 (OCO), 162.0 (NCO), 138.7 (C2/6), 132.0(C3/5), 125.3 (C1), 103.3(C4), 26.0 (CH2); m/z (E.I.), 345 (M+, 5%), 231 (100%), 202 (20%), and 76 (48%); HRMS for C11H8INO4 requires 344.9493 found 344.9493.
Reaction SMILES: [CH2:1]([C:5]1([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]1[CH3:14])[CH:2]([CH3:4])[CH3:3].[CH3:19][I:20]>>[I-:20].[CH2:1]([C:5]1([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N+:7]([CH3:19])=[C:6]1[CH3:14])[CH:2]([CH3:4])[CH3:3]
Reactant: CC1=Nc2ccccc2C1(CC(C)C)CC(C)C
Reactant: CI
Product: CC1=[N+](C)c2ccccc2C1(CC(C)C)CC(C)C
Product: [I-]

Procedure:
3,3-Diisobutyl-2-methyl-(3H)-indole (2.43 g, 0.01 mole) and methyl iodide (3 g, excess) were heated in a flask with condenser on a steam bath for 30 min. The excess methyl iodide was evaporated, and the resulting syrup was dissolved in a small amount of methanol and diluted to 350 mL with ether while stirring in a beaker. After stirring for 20 min., the product was filtered, washed with ether, and dried to give 3.0 g (77.8%). The NMR was good. (MW 385.33)
Reaction SMILES: [Li]N1C(C)(C)CCCC1(C)C.[Li]CCCC.[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[Te:27][CH:28]=[CH:29][CH:30]=2)=[C:22]([F:31])[C:21]=1[F:32])[CH3:18].[CH:33](N1CCOCC1)=[O:34].Cl>C1COCC1.O>[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[Te:27][C:28]([CH:33]=[O:34])=[CH:29][CH:30]=2)=[C:22]([F:31])[C:21]=1[F:32])[CH3:18]
Reactant: CCOc1ccc(-c2ccc[te]2)c(F)c1F
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(-c2ccc(C=O)[te]2)c(F)c1F
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of LiTMP (comprising 3.9 ml (22.9 mmol) of TMP and 14.0 ml (22.3 mmol, 15% soln. in hexane) of n-BuLi) is added to 6.8 g (20.3 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)tellurophene in 70 ml of THF at 0° C. The mixture is stirred at this temperature for 1 h. The solution is cooled to −60° C., and N-formylmorpholine is added. The reaction mixture is warmed to 0° C. and stirred for 1 h. Water and 2 N hydrochloric acid are added, and the mixture is extracted with MTBE. The organic phase is washed with sodium chloride and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is recrystallised from toluene. Drying in vacuo gives 5-(4-ethoxy-2,3-difluorophenyl)tellurophene-2-carbaldehyde as a brown solid.
Reaction SMILES: Br[C:2]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C(CC(=O)C)(=O)C.[Ni].C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]([C:5]2[N:10]3[N:11]=[CH:12][N:13]=[C:9]3[N:8]=[CH:7][CH:6]=2)([CH3:4])[CH3:3])=[CH:17][CH:16]=1
Reactant: CC(C)(Br)c1ccnc2ncnn12
Reactant: Oc1ccc(Cl)cc1
Agent: [Ni]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(Oc1ccc(Cl)cc1)c1ccnc2ncnn12

Procedure:
A mixture of 7-(1-bromo-1-methylethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.95 g, prepared in a similar manner to that described above), 4-chlorophenol (1.56 g), sodium bicarbonate (1 g), nickel acetyl acetone (5 mg) and dry toluene (80 ml) was stirred and heated under reflux for 7 days. The solvent was evaporated and the crude product was purified by flash chromatography using as eluent a mixture of toluene and ethylacetate (in the ratio 5:1 respectively), followed by recrystallisation from n-hexane, to give 7-[1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 0.67 g, (mp 132°-135° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][CH2:8]1
Reactant: BrCCOCc1ccccc1
Reactant: COC(=O)CCCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCC1CCN(CCOCc2ccccc2)CC1
Yield: 37.7 %

Procedure:
A solution of 2 (2.00 g, 10.8 mmol), (2-bromoethoxymethyl)benzene (2.31 g, 10.8 mmol), and triethylamine (4.5 ml, 32.4 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. Solvent was evaporated and the residue was purified by Flash™ chromatography (BIOTAGE, Inc) (9.3:0.7 dichloromethane/methanol, v/v) to provide 3a (1.3 g, 42%) as a yellow oil. 1H NMR (300 MHz, CD3OD) δ 1.30 (m, 5H), 1.66 (m, 2H), 1.87 (d, 2H), 2.37 (m, 2H), 2.58 (m, 2H), 3.04 (m, 2H), 3.39 (m, 2H), 3.65 (s, 3H), 3.80 (m, 2H), 4.55 (s, 2H), 7.37 (m, 5H). m/z (ESI): 320 [C19H29NO3+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH3:14])[CH:5]=[C:6]([CH3:13])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11].[CH2:15](Br)[CH3:16]>C1COCC1>[CH2:15]([O:3][CH:4]([CH3:14])[CH:5]=[C:6]([CH3:13])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH3:16]
Reactant: CC(C)=CCCC(C)=CC(C)O
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(C)C=C(C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
THF (500 mL) and sodium hydride (60%, 52 g, 1.3 mol) were charged to a flame dried 2 L reaction flask equipped with a thermometer, a mechanical stirrer, a condenser, and an addition funnel. 8-Hydroxy-2,6-dimethyl-nona-2,6-diene (obtained as detailed above) was added dropwise while allowing the temperature to rise no higher than 50° C. After the addition was completed, the reaction mixture was aged for 1 hour. Ethyl bromide (142 g, 1.3 mol.) was added dropwise for over 2 hours. The reaction mixture was then heated to 60° C. and aged until the conversion rate was shown to be over 90%. The reaction mixture was cooled to lower than 30° C. and quenched by the slow addition of HCl (pH<5, 10%). The layers were split. The aqueous phase was extracted three times with toluene (100 mL). The extracts were added to the crude reaction mixture, which was then washed with saturated sodium bicarbonate followed by saturated salt solution and dried over anhydrous sodium sulphate. The crude reaction mixture was concentrated. The solvents were recovered via a rotary evaporator. Fractional distillation provided the compound 8-ethoxy-2,6-dimethyl-nona-2,6-dien with a boiling point of 125° C. at a pressure of 4.5 mmHg.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:14][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Product: c1ccc(Cn2c3ccccc3c3ccccc32)cc1

Procedure:
Carbazole (5 g; 0.03 mol) was reacted with benzyl bromide (7.11 ml; 0.06 mol) by working in a manner similar to that described in Example 1a).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13](N)[CH:14]=1)=[O:8])[CH3:5].N(OCCC(C)C)=O.[I:31]CI>>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([I:31])[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Reactant: ICI
Agent: CC(C)CCON=O
Product: COCC(C)NC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 158.8 %

Procedure:
A mixture of 5-amino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (5.3 g, 17. 8 mmol), iso-amyl nitrite (13.5 ml, 88.9 mmol) and diiodomethane (8 ml, 106.7 mmol) was stirred at room temperature for 1 hour. The mixture was then heated to 65° C. and kept for 8 hours, LC/MS indicated that reaction completed. The reaction mixture was cooled to room temperature and the separation of iodobenzene from excess diiodomethane was effected by addition of the reaction mixture at room temperature to a stirred solution of piperidin-CH3CN (V/V=90 ml/90 ml). A vigorous exothermic reaction ensued. The excess volatile reagents were removed by rotary evaporation at 80° C. The residue was diluted with ethyl acetate, washed with 10% hydrochloric acid, water and brine. The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexanes=10:1) to yield 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as a yellow solid (5.2 g, 83.8%). MS (M+H)=410.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([C:8]#[CH:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:24])[N:15]([CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:17][C:18]([CH3:20])=[CH2:19]>CCCCCC>[CH:21]([N:15]([CH:16]1[CH:17]=[C:18]([CH3:20])[CH2:19][CH:9]=[C:8]1[C:6]([C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=1)=[O:7])[C:14]([O:13][CH3:12])=[O:24])([CH3:22])[CH3:23]
Reactant: C=C(C)C=CN(C(=O)OC)C(C)C
Reactant: C#CC(=O)c1ccc(F)cc1
Solvent: CCCCCC
Product: COC(=O)N(C(C)C)C1C=C(C)CC=C1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred suspension of 67,9 g 4-fluorobenzoylacetylene in 160 ml hexane under reflux is added dropwise within 1 hour 78,8 g N-isopropyl-N-(3-methyl-1,3-butadienyl)-carbamic acid methylester in 40 ml hexane. After the addition is completed, the reaction mixture is stirred for additional 6 hours under reflux, and then cooled to room temperature, whereby the heading compound precipitates, m.p. 98°-102° C.
Reaction SMILES: I(O)(=O)(=O)=O.[F:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH:13]([F:15])[F:14])[C:8]=1[CH:16]=[O:17].C(OCC)(=[O:20])C>C(#N)C.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>[F:15][CH:13]([F:14])[C:9]1[C:8]([C:16]([OH:20])=[O:17])=[C:7]([F:6])[N:11]([CH3:12])[N:10]=1
Reactant: Cn1nc(C(F)F)c(C=O)c1F
Reactant: CCOC(C)=O
Agent: O=[Cr](=O)([O-])Cl
Agent: [O-][I+3]([O-])([O-])O
Agent: c1cc[nH+]cc1
Solvent: CC#N
Product: Cn1nc(C(F)F)c(C(=O)O)c1F
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A suspension of 79.7 g (350 mmol) of periodic acid in 640 ml of absolute acetonitrile was stirred for 30 min. At 0° C., 56.6 g (318 mmol) of 5-fluoro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde (IV-1) and 1.4 g (6 mmol) of PCC dissolved in 130 ml of dry acetonitrile were added. The reaction mixture was subsequently stirred at room temperature for 2.5 hours. After 1600 ml of ethyl acetate had been added, the reaction mixture was washed in succession with saturated sodium chloride solution/water (1:1), saturated sodium metabisulphite solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated to obtain 51.4 g (83% of theory) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid (V-1) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(O)(=O)C.[CH:16](OCC)(OCC)OCC.[N-:26]=[N+:27]=[N-:28].[Na+]>O>[N:1]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH:16]=[N:28][N:27]=[N:26]1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1cncc(N)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cncc(-n2cnnn2)c1
Temperature: 80 °C

Procedure:
A mixture of methyl 5-aminonicotinate (5.0 g, 33 mmol) in acetic acid (47 ml, 820 mmol) was treated with triethyl orthoformate (8.8 ml, 53 mmol), followed by sodium azide (3.2 g, 49 mmol). The resulting mixture was heated at 80° C. for 1 hour, after which the reaction mixture was cooled to room temperature and diluted with water. The resulting precipitate was collected and dried under high vacuum to provide methyl 5-(1H-tetrazol-1-yl)nicotinate.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])=[CH:28][NH:29]2)=[CH:25][CH:24]=1>>[OH:6][C:5]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:7])[C:4]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:28]1[NH:29][C:30]2[C:26]([C:27]=1[CH2:32][NH:33][C:34](=[O:36])[CH3:35])=[CH:25][CH:24]=[C:23]([CH3:22])[CH:31]=2
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Reactant: CC(=O)NCc1c[nH]c2cc(C)ccc12
Reactant: O=Cc1ccccc1
Product: CC(=O)NCc1c(C(C2=C(O)C(C)(c3ccccc3)C2=O)c2ccccc2)[nH]c2cc(C)ccc12

Procedure:
Using general procedure C, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with benzaldehyde and N-(6-methyl-1H-indol-3-ylmethyl)-acetamide to give N-{2-[(2-hydroxy-3-methyl-4-oxo-3-phenyl-cyclobut-1-enyl)-phenyl-methyl]-6-methyl-1H-indol-3-ylmethyl}-acetamide as a pale red solid. MS: 463.4 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]([CH3:19])=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:6]1.[F:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([NH:27][NH:28][CH:29]([CH3:31])[CH3:30])=[O:26])=[CH:23][CH:22]=1.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.CCOC(C)=O>[F:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([NH:27][N:28]([CH:29]([CH3:30])[CH3:31])[C:16](=[O:18])/[CH:15]=[CH:14]/[C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:4][CH:3]=[C:2]([CH3:1])[CH3:19])[CH:6]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: CC(C)NNC(=O)c1ccc(F)cc1
Reactant: CC(C)=CCn1cc(/C=C/C(=O)O)c2ccccc21
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
Solvent: CCOC(C)=O
Product: CC(C)=CCn1cc(/C=C/C(=O)N(NC(=O)c2ccc(F)cc2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acrylic acid (161 mg, 0.63 mmol), 4-fluoro-N′-isopropylbenzohydrazide (82.4 mg, 0.42 mmol) and HATU (239.5 mg, 0.63 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.11 ml, 0.63 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (35% EtOAc) for refinement and dried so that ivory (E)-4-fluoro-N′-isopropyl-N′-(3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acryloyl)benzohydrazide was obtained (116.0 mg, 42.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([OH:17])[CH2:14][CH:15]=[CH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:20])=[N-].N#N>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([OH:17])[CH2:14][CH:15]2[CH2:20][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: C=CCC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](C(O)CC2CC2)C1
Temperature: 25 °C

Procedure:
Add palladium (II) acetate (2.31 g; 0.298 mmol) to a stirred solution of (3S)-3-(1-hydroxy-but-3-enyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (S-mix) (14.4 g, 59.7 mmol) in dichloromethane (43.2 mL). Add slowly a freshly prepared solution of diazomethane (100 mL, about 50 mmol in diethyl ether) under nitrogen at −30 to −40° C. (Caution: vigorous N2 gas evolution). Evaporate the solvent and dissolve the crude in dichloromethane (43.2 mL). Add palladium (II) acetate (2.31 g, 0.298 mmol) followed by a freshly prepared solution of diazomethane (100 mL, about 50 mmol in diethyl ether) to the mixture kept under nitrogen at −30 to −40° C. (Caution: vigorous N2 gas evolution). Evaporate the solvent and dissolve the crude in dichloromethane (43.2 mL). Add palladium (II) acetate (2.31 g, 0.298 mmol) followed by a freshly prepared solution of diazomethane (50 mL, about 25 mmol in diethyl ether) to the mixture kept under nitrogen at −30 to −40° C. (Caution: vigorous N2 gas evolution). Evaporate the solvent, add hexanes (140 mL) to the crude residue and stir the suspension over night at room temperature. Filter the suspension over a pad of celite® and concentrate to obtain a quantitative yield (3S)-3-(2-cyclopropyl-1-hydroxyethyl)pyrrolidine-1-carboxylic acid tert butyl ester (S-mix). MS (m/z)=200.1 [M−55].
Reaction SMILES: O.O.[C:3](O)(=O)[C:4]([OH:6])=[O:5].[CH3:9][N:10]([CH3:24])[CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[O:23])[CH:20]=2)[NH:15][CH:14]=1.C(O)(=O)[C:26]([OH:28])=[O:27]>C(O)C>[CH:22]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:12][CH2:11][NH+:10]([CH3:9])[CH3:24])=[O:23].[C:26]([CH2:3][C:4]([O-:6])=[O:5])([OH:28])=[O:27]
Reactant: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Reactant: O=C(O)C(=O)O
Solvent: O
Solvent: CCO
Product: C[NH+](C)CCc1c[nH]c2ccc(C=O)cc12
Product: O=C([O-])CC(=O)O

Procedure:
A solution of oxalic acid di-hydrate (2.91 g, 23.12 mmol) in ethanol (15 ml) is added slowly to a refluxing solution of 3-(2-Dimethylamino-ethyl)-1H-indole-5-carbaldehyde (5.0 g, 23.12 mmol) in ethanol (15 ml). On addition of ca. 70% of the oxalic acid solution, crystallization of the product as a microcrystalline solid starts. The salt is filtered off, washed twice with ethanol/ether (1:1 v:v, 15 ml each portion) and ether (30 ml) and dried to give 6.45 g (91.1%) of a cream coloured very fine leaflets. The DSC shows three endothermic regions: 150° C. (broad, probably phase transition), 168.6° C. (probably melting point) and 237.7° C. (probably decomposition). 1H-NMR (DMSO, 300 MHz) δ 2.84 (s, 6H, NH(CH3)2); 3.17, 3.31 (2 m, 2H each, CH2CH2NHMe2); 7.39 (d, 1H, J=2.3 Hz, H-2); 7.52 (d, 1H, J=8.5 Hz, H-7); 7.66 (dd, 1H, J=1.9 Hz, H-6); 8.20 (v br s, 1H, NH); 8.25 (d, 1H, H-4); 9.96 (s, 1H, CHO); 11.60 (s, 1H, NHMe2). 13C-NMR (DMSO, 75 MHz) δ 20.86 (CH2); 43.01 (NH(CH3)2); 57.52 (CH2NHMe2); 112.35 (C-3); 112.97 (C-7); 121.78 (C-6); 124.72 (C-4); 126.19 (C-2); 127.30 (C-9); 129.17 (C-5); 140.33 (C-8); 165.47 (oxalate); 192.91 (CHO).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2/[NH:14][C:15]3([CH2:22][CH2:21][N:20]([C:23](=[O:37])[CH2:24][CH2:25][C:26]4[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=4)[CH2:19][CH2:18]3)[CH2:16][NH:17]/2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Cl[CH2:39][C:40]([N:42]([CH2:46][CH2:47][CH3:48])[CH2:43][CH2:44][CH3:45])=[O:41].C(=O)([O-])O.[Na+]>CN(C=O)C.O.C(Cl)Cl>[CH2:43]([N:42]([CH2:46][CH2:47][CH3:48])[C:40]([CH2:39][O:33][C:32](=[O:34])[CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][C:23]([N:20]2[CH2:21][CH2:22][C:15]3([NH:14]/[C:13](=[N:12]/[C:10]([C:3]4[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=4)=[O:11])/[NH:17][CH2:16]3)[CH2:18][CH2:19]2)=[O:37])=[CH:36][CH:35]=1)=[O:41])[CH2:44][CH3:45]
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)CCc4ccc(OCC(=O)O)cc4)CC3)N2)nc1Cl
Reactant: CCCN(CCC)C(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCCN(CCC)C(=O)COC(=O)COc1ccc(CCC(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)cc1
Temperature: 70 °C

Procedure:
A solution of [4-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid (Step 1) (811 mg, 1.53 mmol) in DMF (30 ml) was treated with 2-chloro-N,N-dipropyl-acetamide (813 mg, 4.59 mmol) and sodium hydrogen carbonate (808 mg, 8.92 mmol). The reaction mixture was heated at 70° C. for 7 days. The reaction was allowed to cool to RT and diluted with water (100 ml). A white precipitate formed which was extracted into EtOAc (2×75 ml) and DCM (2×75 ml). The organic extracts were combined, dried over MgSO4 and concentrated in vacuo to afford a brown oil. Purification by chromatography on silica eluting with a gradient of 0-20% EtOH/DCM afforded a yellow oily solid which was dissolved in DCM (˜5 ml) and filtered through a 2 μM syringe filter. The solution was concentrated in vacuo to 1 ml, and diethyl ether (10 ml) was added. The resulting white precipitate was collected by filtration and dried in vacuo at 50° C. overnight to afford the title compound; 1H NMR (400 MHz, DMSO-d6) δ 9.10-7.94 (1H br), 8.43 (1H br s), 8.36 (1H, br s), 7.15 (2H, d), 6.96-6.45 (1H, br s), 6.86 (2H, d), 6.72 (2H, br s), 4.88 (2H, s), 4.81 (2H, s), 3.62-3.37 (4H, m), 3.38 (2H, s), 3.19-3.14 (4H, m), 2.74 (2H, t), 2.59 (2H, t), 1.67-1.54 (4H, m), 1.54-1.45 (4H, m), 0.85 (3H, t), 0.80 (3H, t). LC-MS Rt 4.45 mins; 672.5 [M+H]+, Method 10minLC_v003.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:7])[CH2:5][CH3:6].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH:4]([CH2:5][CH3:6])[CH2:3][O:2][CH3:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CCC(O)COC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCC(COC)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methoxybutan-2-ol (1.10 mL) in pyridine (5 mL) was added dropwise a solution of 4-methylbenzenesulfonyl chloride (2.75 g) in pyridine (15 mL) over 30 min or more at 0° C. The reaction mixture was stirred overnight at room temperature, and poured into ice-water. The reaction mixture was stirred at 0° C. for 1 hr, and the precipitate was collected by filtration, and washed with cold water. The obtained solid was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.23 g).