Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:12].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:11]([O:13][C:14](=[O:23])[CH:15]=[C:16]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:12]
Reactant: CCOC(=O)C=Cc1cccnc1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1cccnc1)c1ccc2cc[nH]c2c1

Procedure:
3-(1H-Indol-6-yl)-3-pyridin-3-yl-acrylic acid ethyl ester CLVII was prepared from 6-bromo-1H-indole and 3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described above for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.O=O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)=C(C(=O)O)c1ccc(F)cc1
Agent: O=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)[C@H](C(=O)O)c1ccc(F)cc1

Procedure:
1.0 g (5.15 mmol) of 2-(p-fluorophenyl)-3-methylcrotonic acid and 0.52 g (5.15 mmol) of triethylamine were suspended in 6 ml of methanol in a glove box (O2 content <1 ppm) in a 30 ml autoclave at RT and a solution of 4.1 mg (0.0051 mmol) of Ru(OAc)2 ((R)-MeOPIPHEP) in 5 ml of methanol was added as the catalyst. The autoclave was sealed and the hydrogenation was carried out at 20° while stirring and under an initial pressure of 200 bar. The pressure decreased to about 190 bar during the reaction. After a reaction period of 21 hours a sample of the hydrogenation solution was evaporated at 50°/20 mbar and analyzed. There was obtained (S)-2-(p-fluorophenyl)-3-methylbutanoic acid with an ee of 93%.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].O=C1CC[N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[CH2:4]=[C:3]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:1][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of methyl triphenylphosphonium bromide (2.69 g, 7.5 mmol) in THF (20 mL) was n-butyllithium (1.8 M; 4.2 mL, 7.5 mmol) in hexane slowly added at −78° C. The mixture was stirred for 1 h. After this time, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1 g, 5.0 mmol) in THF (10 mL) was added dropwise to the mixture. The resultant mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with isohexane (×3). The combined isohexane layers were evaporated and filtrated through a silica-plug. The crude product was purified using flash chromatography with DCM as eluent yielding 0.58 g (59%) of the title compound. HPLC purity 91%, RT=2.47 min (System A; 10-97% MeCN over 3 min); 86%, RT=2.43 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H) 2.12-2.22 (m, 4H) 3.35-3.46 (m, 4H) 4.73 (s, 2H). MS (ESI+) for C11H19NO2 m/z 142 (M-C4H8)+. *Previously reported in J. Med. Chem. 2002, 45, 3143-3160.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[CH2:16]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(O)c(Cc2ccccc2)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Trifluoromethanesulfonic anhydride (10.0 mL, 60 mmol) was added over 3 min to a solution of 2-benzyl-4-methoxyphenol (10.71 g, 50 mmol; prepared according to J. Am. Chem. Soc. 1949, 71, 64) and anhydrous 2,6-lutidine (12.0 mL, 100 mmol) in anhydrous CH2Cl2 (250 mL) at -78° C. under argon. The reaction was stirred at -78° C. for 0.5 h, then was warmed to RT. After 1 h, the reaction was diluted with hexanes (250 mL) and washed sequentially with 1.0 N HCl (2×100 mL), 1.0 N NaOH (2×50 mL), H2O (100 mL) and brine (50 mL). Drying (Na2SO4), concentration, and silica gel chromatography (10% EtOAc/hexanes) gave the title compound as a light yellow solid (16.65 g, 96%): TLC Rf 0.51 (10% EtOAc/hexanes); 1H NMR (250 MHz, CDCl3) δ 7.10-7.40 (m, 6H), 6.77 (dd, J=9.0, 3.1 Hz, 1H), 6.66 (d, J=3.1Hz, 1H), 4.03 (s, 2H), 3.73 (s, 3H); FTIR (CCl4) 1492, 1423, 1405, 1249, 1216, 1161, 1144, 1039, 869 cm-1 ; MS (ES) m/e 369 (M+Na)+, 364.0 (M+NH4)+, 347.0 (M+H)+.
Reaction SMILES: I[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25](OB(O)O)=[C:24]([O:33][CH3:34])[CH:23]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O>[CH3:34][O:33][C:24]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[C:23]=1[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Reactant: COc1cc(C)cc(C)c1OB(O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(C)c1-c1cccc2c(NC(=O)OC(C)(C)C)c(SC)nn12
Temperature: 80 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
After dissolving tert-butyl N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (2.0 g) in 1,2-dimethoxyethane (60 mL) and water (30 mL), 4,6-dimethyl-2-methoxyphenylboric acid (1.33 g), tetrakis(triphenylphosphine)palladium(0) complex (865 mg) and barium hydroxide octahydrate (2.34 g) were added and the mixture was heated and stirred at 80° C. for 3 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (2.1 g) was obtained from the n-hexane:ethyl acetate (20:1) fraction as yellow amorphous.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:14]1([CH2:17][NH:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[CH:14]1([CH2:17][N:18]([CH2:19][CH2:20][CH3:21])[C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:16][CH2:15]1
Reactant: CCCNCC1CC1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzaldehyde (5.38 g) and cyclopropylmethyl-propyl-amine (4.75 g) are dissolved in toluene (50 ml), and thereto is added potassium carbonate (11.6 g) and the mixture is stirred at 120° C. for 4 hours. The reaction solution is cooled to room temperature, and thereto is added water and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (8.0 g). MS (m/z): 286 [M+H]+
Reaction SMILES: [Na].[C:2]1([CH2:8][C:9]([O:11]CC)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:17])=[O:16].Cl>O>[C:2]1([CH2:8][C:9](=[O:11])[CH2:14][C:15](=[O:16])[CH3:17])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na]
Solvent: O
Product: CC(=O)CC(=O)Cc1ccccc1
Reaction time: 1 h
Yield: 24.7 %

Procedure:
Sodium (28 g) was added in small portions to a solution of ethyl phenylacetate (600 g, 3.66 moles) and acetone (70.7 g, 1.22 moles) under nitrogen, was dissolved at 30°-40° C. with stirring for 1 hour and then the mixture was reacted at 70°-80° C. for 4.5 hours. The reaction mixture was taken up in H2O (1.2 l), neutralized with dilute hydrochloric acid and extracted with chloroform. The organic layer was washed with H2O, dried over anhydrous MgSO4 and then evaporated. The residue was distilled under reduced pressure to give 53.2 g of the desired product as a colorless oil having a boiling point of 142°-146° C./15 mmHg. [Lit.: bp. 133°-136° C./10 mmHg; K. G. Hampton, T. M. Harris, C. R. Hauser, Org. Synth., 51., 128 (1971).]
Reaction SMILES: [H-].[Na+].[CH:3]1([C:7]([O:9]CC)=O)[CH2:6][CH2:5][CH2:4]1.[C:12](#[N:14])[CH3:13]>>[CH:3]1([C:7](=[O:9])[CH2:13][C:12]#[N:14])[CH2:4][CH2:5][CH2:6]1
Reactant: CC#N
Reactant: CCOC(=O)C1CCC1
Agent: [H-]
Agent: [Na+]
Product: N#CCC(=O)C1CCC1
Temperature: 75 °C

Procedure:
A stirred suspension of sodium hydride (12 g of a 60% dispersion in mineral oil, 0.30 mol, which was washed with petroleum ether twice in dry THF) was heated to 75° C. To this was added a mixture of ethyl cyclobutanecarboxylate (25.64 g, 0.20 mol) and dry acetonitrile (12.32 g, 0.30 mol), dropwise, and the resulting colorless suspension was heated at 70° C. for 24 h. After cooling to rt the reaction mixture was concentrated under reduced pressure and the residue poured into water (100 mL) and extracted with ethyl acetate (100 mL). The aqueous layer was separated, acidified to pH 2 with aqueous 2 M HCl and extracted with diethyl ether (2×200 mL). The combined diethyl ether layers were dried over magnesium sulfate then concentrated under reduced pressure to afford 3-cyclobutyl-3-oxopropanenitrile as yellow oil which was used in the next step without further purification.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([CH3:10])([CH2:8][F:9])[C:5](=[O:7])[CH3:6].CCOCC>O>[Br:1][CH2:6][C:5](=[O:7])[C:4]([CH3:10])([CH3:3])[CH2:8][F:9]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)CF
Solvent: CCOCC
Solvent: O
Product: CC(C)(CF)C(=O)CBr
Yield: 79.8 %

Procedure:
480 g of bromine were slowly added dropwise to a mixture of 354 g (3 mols) of 3,3-dimethyl-4-fluoro-2-butanone and 2,000 ml of ether at 20° to 30° C., while cooling and stirring. The yellowish solution was subsequently stirred for a further hour at 20° C. and 500 ml of water were then carefully added. The ether phase was separated off, washed several times with water and dried over sodium sulphate. After distilling off the solvent, the residue was distilled under a waterpump vacuum. 472 g (80% of theory) of 1-bromo-3,3-dimethyl-4-fluoro-2-butanone of boiling point 80°-90° C./11 mm Hg were obtained. ##STR81##
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>CN(C=O)C.CCN(CC)CC.CCOC(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>[F:6][C:7]1[C:8]([C:4]#[C:3][C@@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@H](C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H](C)O)c21

Procedure:
Using Method C above, (S)-but-3-yn-2-ol (36 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and Cul (2 mg) in a mixture of DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-70% EtOAc in hexanes gradient and trituration with petroleum ether. (Yield 32 mg, 75%).
Reaction SMILES: [C:1]([CH2:3][C:4](O)=O)#[N:2].[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:13]=O>O1CCOCC1>[N:7]1([CH2:13][C:3](=[CH2:4])[C:1]#[N:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N#CCC(=O)O
Reactant: C=O
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: C=C(C#N)CN1CCCCC1
Reaction time: 2 h

Procedure:
Cyanoacetic acid (51 g., 6 mole) was dissolved in 150 ml. of dioxane, the solution cooled to 5° C. and piperidine (53 g., 0.6 mole) dripped in while maintaining the temperature at 10°-15° C. Then, 37% aqueous formaldehyde (109.5 g., 1.35 mole) was slowly added at 0°-10° C. After two hours, the ice bath was removed and the mixture stirred overnight at 20°-25° C. It was then stripped at 15 mm. pressure and bath temperature of 48° C. The residue was chilled, mixed with 100 ml. of ether, saturated with sodium chloride and the ether layer separated. This extract was washed with two 25 ml. portions of cold 5% aqueous potassium carbonate and finally with 10 ml. of ice water. The ether solution was dried over anhydrous magnesium sulfate, filtered, stripped and fractionated using a Vigreux column. The fraction boiling at 86°-88° C./2 mm. was of practically analytical quality, 40.8 g., Rf 0.66 on silica gel using chloroform-methyl alcohol (90:10) development. This is, however, a known compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18](=[O:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:17][C:18](=[O:20])[CH3:19]
Reactant: Oc1ccc(F)cc1Br
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
Cool a suspension of 2-bromo-4-fluoro-phenol (1 g, 4.89 mmol) and K2CO3 (1.8 g, 13.2 mmol) in DMF (10 mL) to 0° C. in an ice bath under nitrogen. Add chloroacetone (678 mg, 7.33 mmol) during a period of 30 min. Stir the mixture at RT overnight. Add water and extract with ethyl acetate. Wash the solution with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (hexane to 10% ethyl acetate in hexane) to give the title compound as a yellow oil (0.75 g, 59%). 1H NMR (400 MHz-CDCl3) δ 2.35 (s, 3H), 4.51 (s, 2H), 6.73 (dd, J=4.8, 8.8 Hz, 1H), 6.97 (m, 1H), 7.32 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCc1cc2c(OCC(=O)OC)cccc2n1Cc1ccccc1
Yield: 68.3 %

Procedure:
Using the procedure described in Example 1, Part E, 2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole (1.56 g, 6.2 mmol) was treated with 248 mg (6.2 mmol) of 60% NaH/mineral oil and then 0.6 mL (6.2 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 1.37 g (69% yield) of [[2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester, 89°-92° C.
Reaction SMILES: Cl[C:2]1[C:3]2[S:18][C:17]([NH2:19])=[N:16][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1.[NH2:20][C@@H:21]([CH2:23][OH:24])[CH3:22].C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[NH2:19][C:17]1[S:18][C:3]2[C:2]([NH:20][C@H:21]([CH3:22])[CH2:23][OH:24])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:5][C:4]=2[N:16]=1
Reactant: C[C@@H](N)CO
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 100 °C
Reaction time: 24 h
Yield: 32 %

Procedure:
The product of example 1 step c) (25.0 g), D-Alaninol (12.3 g) and diisopropylethylamine (26.0 g) were diluted in N-methylpyrrolidinone (250 ml) and stirred at 100° C. for 24 h before cooling and pouring the reaction mixture into H2O (2.5 l). The precipitate was filtered and dried in vacuo before being preabsorped onto silica gel. Chromatography using EtOAc. 4% MeOH/EtOAc as eluents afforded the desired product as a yellow solid (9.0 g. 32%).
Reaction SMILES: C[O-].[K+].C[O:5][C:6](=[O:20])[CH:7]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>CO>[C:12]([O:11][C:9](=[O:10])[CH2:8][CH:7]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:6]([OH:20])=[O:5])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)CC(C)C
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
Potassium methoxide (0.15 g, 2.04 mmol) in methanol (3 mL) was added dropwise to a stirring solution of 2 (0.49 g, 2.04 mmol) in methanol (5 mL) at 0° C. After 10 minutes, the mixture was partitioned between ether (100 mL) and water (50 mL). The ether layer was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, pentane/ether, 98:2) to give the nitro-alkene 3 (0.21 g, 57%) as a pale yellow oil; Rf(heptane/ethyl acetate, 8:2) 0.54; νmax(film)/cm−1 1643 (C═C), 1509 (NO2), 1342 (NO2); δH (400 MHz; CDCl3): 7.12 (1H, quint,J=2.0, CHNO2), 3.01 (1H, ddt, J=20.5, 8.0, 2.1), 2.90 (1H, ddt, J=20.5, 7.3, 2.1), 2.54 (1H, ddt, J=17.8, 7.1, 2.0), 2.43 (1H, ddt, J17.7, 5.6, 1.9), 2.21 (1H, m), 2.12 (1H, m), 1.60–1:24 (8H, m).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(O)(=O)C.C(O)C.[Fe]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([OH:12])=[CH:4][C:3]=1[S:2][CH3:1]
Reactant: CSc1cc(O)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CSc1cc(O)ccc1N
Temperature: 25 °C
Reaction time: 17 h
Yield: 52.9 %

Procedure:
Iron powder (1.59 g, 28.5 mmol) was added slowly to a solution of 3-(methylthio)-4-nitrophenol (1.76 g, 9.5 mmol) in acetic acid (50 mL) and ethanol (5 mL). The mixture was stirred 17 hours at room temperature.v Then iron was removed with a magnet and the slurry mixture filtered. The filtrate was diluted in water (100 mL) and neutralised with a saturated solution of Na2CO3. The mixture was extracted with DCM, and the combined organic layer dried over Na2SO4. Then, the solvent was evaporated under vacuum to provide the title compound (780 mg, 53%) as a grey powder. 1H-NMR (δ, ppm, DMSO-d6): 2.29 (s, 3H, HMe), 4.48 (bs, 2H, NH2), 6.44 (d, 1H, Harom 5, J6-5=8.5 Hz), 6.54 (d, 1H, Harom 6, J6-5=8.5 Hz), 6.61 (s, 1H, Harom 2), 8.58 (broad s, 1H, OH). GC-MS (m/z): 155.09
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:29][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A solution of 4-methyl-benzoic acid (10 g, 73.4 mmol) in benzene (133 mL) was treated with benzoyl peroxide (72 mg, 0.29 mmol). This mixture was heated at reflux until it became homogeneous. At this time, the reaction was treated with N-bromosuccinimide (13 g, 73.4 mmol) and additional benzoyl peroxide (72 mg, 0.29 mmol). This mixture was heated at reflux for 2.5 h. At this time, the reaction was cooled to 25° C. The resulting precipitate was collected by filtration and washed with hot water (50 mL). The solid was taken up in water (150 mL). This slurry was heated at 80° C. and then filtered while hot. The solid that was collected was dried in vacuo to afford 4-bromomethyl-benzoic acid (12.3, 77.9%) as a white solid: mp 224-226° C.; EI-HRMS m/e calcd for C8H7BrO2 (M+) 213.9629, found 213.9628.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.6 g, 2 mmol) stirring at room temperature under argon in DMF (150 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (0.356 g, 2 mmol), followed by PyBOP (1.14 g, 2.2 mmol), and N,N-diisopropylethylamine (1.38 mL, 8 mmol). The mixture was stirred at room temperature for 17 h. The solvent was pumped off, and the residue taken up in CH2Cl2 (300 mL), and washed with water (300 mL). The organic phase dried over anhydrous Na2SO4, filtered and concentrated. This was then CombiFlashed on a 40 gram silica column eluted with 20-100% EtOAc to afford the title compound. LC-MS m/z 465.8 (M+H)+, 1.49 min (ret time).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(C=CC(=O)O)cc(OC)c1
Temperature: 100 °C
Yield: 70.7 %

Procedure:
To a solution of 3,5-dimethoxybenzaldehyde (12.5 g) in pyridine (20 ml) was added malonic acid (8.61 g) and piperidine (1 ml). The resulting solution was heated at 100° C. for 16 hours, cooled to room temperature, poured onto ice and acidified using conc. HCl. The resulting precipitate was collected, extracted into sodium bicarbonate solution and washed with isohexane. The aqueous phase was acidified using conc. HCl to yield a white precipitate which was filtered off, washed with water and dried to afford the subtitle compound (11.07 g).