Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[NH2:11][C:5]1[C:6]([C:8](=[O:10])[CH3:9])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)ncc1N
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of 1-(2-chloro-5-nitropyridin-4-yl)ethanone (1.0 equiv.) in acetic acid (0.3 M) was added iron (6.0 equiv.). The solution was vigorously stirred for 4 hours, at which time it was filtered through a celite pad (9 cm×3 inches) eluting with MeOH and then ethyl acetate. The volatiles were removed in vacuo, and the crude material was partitioned between ethyl acetate and Na2CO3(sat.). The organic layer was washed further with Na2CO3(sat.) (3×), with NaCl(sat.), dried over MgSO4, filtered and concentrated yielding 1-(5-amino-2-chloropyridin-4-yl)ethanone (87%). LCMS (m/z): 171.0 (MH+); LC Rt=2.20 min. 1H NMR (CDCl3): δ 9.18 (s, 1H), 7.36 (s, 1H), 2.60 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:28]=[C:13]3[CH:14]=[C:15]([C:18]4[C:19]([F:27])=[C:20]([C:23]([F:26])=[CH:24][CH:25]=4)[CH:21]=[O:22])[CH:16]=[CH:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1.CO.[Cl-].[NH4+]>ClCCl.O.O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:28]=[C:13]3[CH:14]=[C:15]([C:18]4[C:19]([F:27])=[C:20]([CH2:21][OH:22])[C:23]([F:26])=[CH:24][CH:25]=4)[CH:16]=[CH:17][N:12]3[N:11]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1c(F)ccc(-c2ccn3nc(-c4ccc(Cl)cc4)cc3c2)c1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCc1c(F)ccc(-c2ccn3nc(-c4ccc(Cl)cc4)cc3c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
0.040 g (1.06 mmol) of sodium borohydride is added portionwise to a solution, cooled to approximately 5° C., of 0.135 g (0.37 mmol) of 3-[2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-2,6-difluorobenzaldehyde in 10 ml of a mixture of methanol and tetrahydrofuran (1/1). The medium is stirred at ambient temperature for 1 hour, then cooled to 5° C. and then hydrolysed by dropwise addition of 10 ml of a saturated aqueous ammonium chloride solution and 10 ml of water. The mixture is concentrated under reduced pressure and the residue obtained is taken up in 50 ml of dichloromethane and 50 ml of water. The medium is subsequently filtered through a hydrophobic cartridge (70 ml liquid/liquid extraction column, Radleys®) and the organic phase is recovered and concentrated under reduced pressure after having added 1 g of silica. The residue is purified by chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2). 0.065 g (48%) of the expected product is obtained in the form of a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].[C:15]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1)(=[O:17])[CH3:16].[OH-].[Na+]>CO>[C:15]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][S:14][C:3]3[N:2]([CH3:1])[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][C:9]=4[CH3:13])[N:4]=3)=[CH:34][CH:35]=2)=[O:27])=[CH:24][CH:23]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OCCOc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)OCCOc1ccc(C(=O)c2ccc(CSc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Yield: 56.5 %

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.888 g), 4-(4-acetoxyethoxybenzoyl)benzyl bromide (3.895 g) and 1N-aqueous sodium hydroxide solution (14.3 ml) in methanol (30 ml) was stirred at room temperature for 30 minutes. This reaction mixture was concentrated and extracted with chloroform. The extract was washed with water, dried, and concentrated, and the residue was recrystallized from ethyl acetate to provide the title compound as colorless solid (2.597 g).
Reaction SMILES: [C:1]1([C:7]([C:9]2[N:14]=[C:13]3[S:15][C:16]([C:18]([O:20]CC)=[O:19])=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:24]>C1COCC1>[C:1]1([C:7]([C:9]2[N:14]=[C:13]3[S:15][C:16]([C:18]([O-:20])=[O:19])=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:24]
Reactant: C=C(c1ccccc1)c1ccc2nc(C(=O)OCC)sc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1ccc2nc(C(=O)[O-])sc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of ethyl 5-(1-phenylvinyl)thiazolo[5,4-b]pyridine-2-carboxylate (1.04 g, 3.35 mmol) in THF (12.9 mL) was added sodium hydroxide (1.0N, aq.) (3.35 mL, 3.35 mmol), and the resulting suspension was stirred at 25° C. for 5 min. The reaction solution was subsequently concentrated in vacuo at 25° C. to provide sodium 5-(1-phenylvinyl)thiazolo[5,4-b]pyridine-2-carboxylate as a light-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][N:19]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:9]=1[F:16])=O.C(N(C(C)C)CC)(C)C.O(Cl)Cl.[P+5]>O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:17]=[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]2[C:5]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:9]=1[F:16])=[O:24]
Reactant: COC(=O)C(Cc1ccncn1)C(=O)Nc1ccc(SC)cc1F
Agent: ClOCl
Agent: [P+5]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2ccncn2c1Nc1ccc(SC)cc1F
Temperature: 0 °C
Yield: 42.2 %

Procedure:
To a solution of N-(2-fluoro-4-methylsulfanyl-phenyl)-2-pyrimidin-4-ylmethyl-malonamic acid methyl ester (2 g, 5.72 mmol) and diisopropylethyl amine (2.9 mL, 17.2 mmol) in dioxane (30 mL) was added phosphorous (V) oxychloride (2.7 mL, 28.6 mmol) and the reaction mixture heated at reflux for 1 hour. The reaction mixture was cooled to 0° C. and quenched with water (10 mL). The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 10-20% ethylacetate in cyclohexane) to yield the title compound as a light brown solid (0.80 g, 42%). LCMS (Method B): RT=3.70 min, M+H+=332.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10](N)[C:11]([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(O)CCC>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=1
Reactant: CC(C)(C)CN
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)Cc1cc(Cl)nc(N)n1

Procedure:
A solution of 2-amino-4,6-dichloropyrimidine (1 mmol), neopentylamine (1.05 mmol), and triethylamine (2 mmol) in n-butanol was stirred at 110° C. for 12 h. Extraction and chromatography gave 2-amino-4-chloro-6-neopentylpyrimidine as a yellow solid. TLC: Rf=0.2, 30% EtOAc-hexane.
Reaction SMILES: [CH:1]([C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1)=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O-:25])=[O:24])C=CC=CC=1.[Na+].O.S(=O)(=O)(O)O>CS(C)=O>[C:23]([CH2:22][CH2:21][CH2:20][CH:19]=[CH:1][C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1)([OH:25])=[O:24]
Reactant: O=C([O-])CCCC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc2cncn12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCCC=Cc1cccc2cncn12

Procedure:
A solution of 5-formylimidazo[1,5-a]pyridine (1.46 g) in 15 ml of dry dimethylsulfoxide is added to a solution of sodium 5-(triphenylphosphoranyl)valerate (4.4 g) in 50 ml of dry dimethylsulfoxide at room temperature (Helv. Chem. Acta 63 1430 (1980)). The reaction is stirred for 3 hours, hydrolyzed with water and neutralized with dilute sulfuric acid. Extraction with ethyl acetate and chromatography or silica gel yields 5-(5-carboxypent-1-enyl)-imidazo[1,5-a]pyridine.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2]1.[NH:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O>[OH:1][CH:3]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][N:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26]
Reactant: CCCCCCCCCCCCCCCCCCSCC1CO1
Reactant: Nc1cc[nH]c(=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCSCC(O)Cn1ccc(N)nc1=O
Temperature: 25 °C

Procedure:
rac-1,2-Epoxy-3-octadecylthiopropane (2.0 g, 5.83 mmol) is added to a mixture of cytosine (1.0 g, 9.0 mmol) and anhydrous potassium carbonate (40 mg) in dimethyl formamide (25 mL) over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 80°-90° C. (oil bath temperature) for 48 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to leave a residue. The residue is stirred with chloroform (50 mL). The undissolved material is filtered in vacuo, and the filtrate concentrated in vacuo, purified by chromatography and dried in vacuo to afford 1-[2'-hydroxy-3'-octadecylthiopropyl]-cytosine.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[N:7]=[C:6]([C:18]3[N:23]=[C:22]([NH2:24])[C:21]([O:25][CH3:26])=[CH:20][N:19]=3)[C:5]=2[CH3:27])[CH2:3][CH2:2]1.Cl.Br[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[N:7]=[C:6]([C:18]3[N:23]=[C:22]([NH:24][C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[C:21]([O:25][CH3:26])=[CH:20][N:19]=3)[C:5]=2[CH3:27])[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(-c3ncc(OC)c(N)n3)c(C)c2C2CC2)cc1
Reactant: Brc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c(C)c2C2CC2)cc1
Temperature: 105 °C
Reaction time: 2 h

Procedure:
1.03 g of 2-[5-cyclopropyl-1-(4-methoxybenzyl)-4-methyl-1H-pyrazol-3-yl]-5-methoxypyrimidin-4-amine (2.82 mmol, 1.00 eq.), 603 mg of 4-bromopyridine hydrochloride (1:1) (3.10 mmol, 1.10 eq.), 245 mg of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.423 mmol, 0.15 eq.), 2.76 g of cesium carbonate (8.46 mmol, 3.00 eq.) and 63 mg of palladium diacetate (0.282 mmol, 0.1 eq.) were suspended in 10.8 mL of dry DMF and stirred under nitrogen atmosphere at 105° C. bath temperature for two hours. The reaction mixture was diluted with water and the crude product was extracted with DCM. The combined organic layers were dried over a silicon filter and concentrated in vacuo. The residue was purified by flash chromatography yielding 930 mg (1.95 mmol, 69%) of analytically pure target compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:12]([O-])=O.N1CCC[CH2:16]1.COC(OC)N(C)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[CH:1]=[CH:16][NH:12]2
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Reactant: C1CCNC1
Agent: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc2[nH]ccc12
Temperature: 60 °C
Yield: 57.2 %

Procedure:
A solution of 2-methyl-1-nitro-3-(trifluoromethyl)benzene (10.00 g, 48.8 mmol), pyrrolidine (4.44 mL, 53.7 mmol) and dimethylformamide dimethylacetal (19.8 mL, 146 mmol) in DMF (100 mL) was heated at 100° C. for 4 h, cooled and concentrated in vacuo. The residue was partitioned between Et2O/H2O, the layers were separated and the aqueous layer was extracted with Et2O (×3). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in THF/MeOH (1:1, 200 mL), and transferred to a 3-necked flask equipped with an overhead stirrer, reflux condenser, and dropping addition funnel. Raney-Ni (Raney® 2800 slurry in water, 10 g) was added in one portion and the entire apparatus was thoroughly flushed with N2. The mixture was heated to 60° C., under N2, and a solution of hydrazine monohydrate (8 mL) in THF/MeOH (1:1, 20 mL) was added dropwise over 1 h. The mixture was heated at 60° C. for 1 h, cooled, and filtered through a pad of Celite®. The filtrate was concentrated in vacuo, the residue was partitioned between Et2O/H2O, the layers were separated and the aqueous layer was extracted with Et2O (×3). Combined organics were washed (10% HCl, H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 5.17 g of the title compound as a light brown liquid: 1H NMR (300 MHz, methanol-d4) δ 7.61 (d, J=8.2 Hz, 1H), 7.39 (d, J=3.2 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.19 (partially resolved dd, J 8.4, 7.5 Hz, 1H), 6.59 (br. s, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:20]1>CCCCCC.CS(C)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:33][CH:32]=1
Reactant: COc1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (88 mg, 2.2 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (10 ml). The obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (0.40 g, 2 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-(4-methoxyphenethyl)homopiperidine (0.59 g, 2.2 mmol) in dimethyl sulfoxide (5 ml) was added dropwise into the obtained solution, and they were stirred at 50° C. for 2 hours. The reaction liquid was distributed in saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (6:1) and then with hexane and ethyl acetate (3:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(4-methoxyphenethyl) piperidine-2-ylmethyl] dibenzo[b,e][1,4]oxazepine in the form of a light yellow solid (0.63 g, 73%).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cccc(F)c1
Agent: N
Product: Fc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.43-7.51 (m, J=8.5, 8.5, 2.6, 1.0 Hz, 1H), 7.61-7.72 (m, 2H), 7.98 (ddd, J=9.1, 2.6, 1.4 Hz, 1H), 8.08 (ddd, J=8.0, 1.3, 1.0 Hz, 1H), 8.56 (dt, J=8.0, 1.9 Hz, 1H), 8.74 (dd, J=5.2, 1.6 Hz, 1H), 9.30 (dd, J=2.0, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 242 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[CH2:6][CH:7]=[CH:8][CH2:9][PH:10](=[O:14])[O:11][CH2:12][CH3:13]>CCO.[Pd]>[NH2:18][C:17]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][CH2:8][CH2:9][PH:10](=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCO[PH](=O)CC=CCc1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCO[PH](=O)CCCCc1ccc(N)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl (3-methoxy-4-nitrobenzyl)prop-2-en-1-ylphosphinate (Compound 37E, 1.075 g, 3.59 mmol) in EtOH (20.0 mL) was charged with Palladium 10% wt on activated carbon (0.365 mg, 0.34 mmol). The reaction mixture was evacuated and purged with hydrogen gas (3×). The reaction mixture was allowed to stir under hydrogen at rt for 16 h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to a light purple oil, (0.97 g, 99%). This material was used in successive reactions without further purification. 1H NMR (CDCl3, 400 MHz): δ=6.79 (t, J=1.8 Hz, 1H), 6.70-6.75 (m, 1H), 6.64-6.69 (m, 1H), 3.93-4.09 (m, 2H), 3.86 (s, 3H), 3.04 (d, J=16.2 Hz, 2H), 1.60 (dt, J=2.5, 4.9 Hz, 4H), 1.29 (t, J=7.1 Hz, 3H), 0.98 (dt, J=1.3, 7.1 Hz, 3H). MS (ESI): m/z 272.13 [M+H]+. UPLC: tR=0.98 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=[O:26])[CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[C:9](=[O:27])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>O1CCCC1.[C].[Pd]>[C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=[O:26])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[C:9](=[O:27])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1ccc2c(c1)OCO2)C1C(=O)CC(c2ccccc2)CC1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCc1ccc2c(c1)OCO2)C1C(=O)CC(c2ccccc2)CC1=O

Procedure:
In 200 ml of tetrahydrofuran was dissolved 10.8 g of 5-phenyl-2-[3-(3,4-methylenedioxyphenyl)-propenoyl]cyclohexane-1,3-dione prepared in step (1) above, and 2 g of a 5% palladium-carbon catalyst was added to the solution and catalytic reduction was carried out for 7 hours with hydrogen under atmospheric pressure. The catalyst was removed by filtration and tetrahydrofuran was removed by distillation. Recrystallization from isopropyl alcohol have 7.5 g (the yield being 70%) of the desired 5-phenyl-2-[3-(3,4-methylenedioxyphenyl)propionyl]-cyclohexane-1,3-dione.
Reaction SMILES: CN(C)C1N=CC([C:9]2[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]3[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:19]3)=[N:13][C:14]=2[CH2:15][CH3:16])=C(C)C=1.[Cl:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:42]=1B(O)O>>[Cl:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:42]=1[C:9]1[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of benzyl (3R,4S)-3-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethylpyrazin-2-yl}amino)-4-ethoxypyrrolidine-1-carboxylate but substituting 2,4-dichloro phenyl boronic acid and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.40–7.25, 5.20–5.13, 4.76, 4.11, 3.98, 3.73–3.60, 3.51–3.31, 2.70, 2.47, 1.31–1.24, 1.15; IR (liq.) 2972, 2342 (w), 1948 (w), 1709 (s), 1567, 1552, 1498 (s), 1470 (s), 1449 (s), 1420 (s), 1397 (s), 1350, 1126, 1100 (s), 1080, cm−1
Reaction SMILES: N.[Na].[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C:12]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][N:21]3CC2C=CC=CC=2)([OH:16])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+]>O1CCCC1.O>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C:12]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)([OH:16])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC1(c2cccc3c2ccn3Cc2ccccc2)CCCN(Cc2ccccc2)C1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2cccc3[nH]ccc23)CCCN(Cc2ccccc2)C1
Yield: 104.9 %

Procedure:
500 ml of ammonia and then 1.5 g of sodium were progressively added at -40° C. to a solution of 14.8 g of 1-benzyl-3-[1-benzyl-1H-indol-4-yl]-3-piperidinol in 250 ml of tetrahydrofuran and after the addition was complete, ammonium chloride was added to the mixture until the faint blue coloration disappeared. The residue was taken up in water and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness to obtain 12 g of 1-benzyl-3-(1H-indol-4-yl)-3-piperidinol.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].Cl.[NH2:8][CH2:9][CH:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[C:18]([F:29])[CH:17]=2)[CH2:11]1.N1C=CC=CC=1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[F:29][C:18]1[CH:17]=[C:16]([N:12]2[CH2:11][CH:10]([CH2:9][NH:8][C:3](=[O:4])[CH:2]([F:6])[F:1])[O:14][C:13]2=[O:15])[CH:21]=[CH:20][C:19]=1[N:22]1[CH:23]=[CH:24][C:25](=[O:28])[CH2:26][CH2:27]1
Reactant: O=C(O)C(F)F
Reactant: NCC1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C1C=CN(c2ccc(N3CC(CNC(=O)C(F)F)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Difluoroacetic acid (0.031 mL, 0.48 mmol) is added to a solution of 1-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-2,3-dihydro-1H-pyridin-4-one hydrochloride (0.150 g, 0.44 mmol) in DMF (1.5 mL) with pyridine (0.071 mL, 0.88 mmol), followed by addition of diisopropylcarbodiimide (0.076 mL, 0.48 mmol). The mixture is stirred at r.t. for 1 h. Most of the solvent is removed under high vacuum, and the product is purified by silica gel column chromatography (eluent: 2% MeOH in DCM). The chromatography is repeated (eluent: 1% MeOH in DCM) to afford N-{3-[3-Fluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl} difluoroacetamide as a white solid. Yield 0.065 g (39%). MS (m/z): 384 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.36 (t, J=5.5 Hz, 1H), 7.82–7.49 (m, 4H), 6.44 (t, J=53.6 Hz, 1H), 5.18 (d, J=7.7 Hz, 1H), 5.03–4.98 (m, 1H), 4.38–4.32 (m, 1H), 4.07 (t, J=7.4 Hz, 2H), 3.97 (dd, J=6.3 and 9.3 Hz, 1H), 3.72 (t, J=5.5 Hz, 1H), 3.51–3.49 (m, 2H), 2.69–2.64 (m, 2H).