Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:21])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[CH2:22](Br)[C:23]#[CH:24]>C1COCC1>[CH2:19]([OH:20])[CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:21][CH2:24][C:23]#[CH:22]
Reactant: C#CCBr
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCCOCCOCCOCCOCCOCCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Sodium hydride, 60% dispersion in mineral oil, (0.86 g, 21.4 mmol) was added in portions to the solution of hexaethylene glycol (5.5 g, 19.4 mmol) in anhydrous THF (40 mL) at 0° C. (FIG. 3). The reaction mixture was stirred at 0° C. for 15 minutes then propargyl bromide, 80% in toulene, (2.4 mL, 21.4 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 3 hours. The formed sodium bromide was removed by filtration and the solvent was evaporated. The crude product was purified on SiO2 column using methanol/dichloromethane gradient 0-100% to yield 3.4 g (54%) of 1 as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.45 (t, J=2.4 Hz, 1H), 2.74 (bs, 1H), 3.61-3.71 (m, 24H), 4.21 (d, J=2.4 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 58.4, 61.7, 69.1, 70.3-70.6, 72.5, 74.5, 79.7; MS ESI (m/z): [M+H]− calcd. for C15H29O7, 321.38. found 321.4.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][N:7]=[C:8]1[C:20]2[C:15](=[N:16][C:17]([C:23](=[O:25])[NH2:24])=[C:18]([C:21]#[N:22])[N:19]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)C.O[Li].O.Cl>C1COCC1.O>[C:23]([C:17]1[N:16]=[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8](=[N:7][O:6][CH2:5][C:4]([OH:26])=[O:3])[C:20]2=[N:19][C:18]=1[C:21]#[N:22])(=[O:25])[NH2:24]
Reactant: CCOC(=O)CON=C1c2ccccc2-c2nc(C(N)=O)c(C#N)nc21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NOCC(=O)O
Temperature: 25 °C
Yield: 63.4 %

Procedure:
To a solution of 37 (70 mg, 0.2 mmol) in THF/H2O (1:1, 15 ml) LiOH.H2O (41 mg, 1.0 mmol) was added and the mixture was stirred at room temperature. After 2 h 2N HCl was added up to pH=5. The solvent was removed under reduced pressure and the crude was purified by flash chromatography (CH2Cl2/MeOH/AcOH 90:10:1) affording 38 (41 mg, 63%) as yellow solid. ESI+MS: calcd for C15H9N5O4: 323.27; found: 324.3 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1>C(O)C>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]2[CH3:14])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC1CCCCN1
Reactant: CC#CCOc1ncnc(Cl)c1F
Solvent: CCO
Product: CC#CCOc1ncnc(N2CCCCC2C)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
Into 3 ml of ethanol was resolved 0.3 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine, 0.45 g of 2-methylpyperidine was added therein, and the mixture was stirred for 5 hours under reflux condition. The reaction mixture was cooled to near room temperature and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.28 g of 4-(2-butynyloxy)-5-fluoro-6-(2-methylpiperidino)pyrimidine (hereinafter, referred to as Compound (1)).
Reaction SMILES: [NH2:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[N:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1.[CH3:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]1[O:22][CH2:21]1>CO>[CH3:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[N:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1
Reactant: Cc1ccccc1OCC1CO1
Reactant: CC(C)(N)CCOc1ccc(Cl)nn1
Solvent: CO
Product: Cc1ccccc1OCC(O)CNC(C)(C)CCOc1ccc(Cl)nn1
Yield: 82.6 %

Procedure:
A mixture of 645 mg of 3-(3-amino-3-methylbutoxy)-6-chloropyridazine, 650 mg of 1-(2-methylphenoxy)-2,3-epoxypropane and 15 ml of methanol was refluxed for 5 hours, and the solvent was evaporated under reduced pressure. A solution of the residue in benzene was extracted with 1N hydrochloric acid. The aqueous layer was extracted with chloroform, and the organic layer was washed with 5% sodium carbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 938 mg of 1-(2-methylphenoxy)-3-[1,1-dimethyl-3-(chloro-6-pyridazinyloxy)propylamino]-2-propanol as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([P:8]([N:27]([CH2:31][CH2:32][Cl:33])[CH2:28][CH2:29][Cl:30])([O:10][CH2:11][CH2:12][S:13][CH2:14][C@@H:15]([C:24]([OH:26])=[O:25])[NH:16]C(OC(C)(C)C)=O)=[O:9])[CH2:5][CH2:6][Cl:7].Cl[Si](C)(C)[CH3:36].CO>ClCCl.C(OCC)(=O)C>[CH3:36][O:26][C:24](=[O:25])[C@H:15]([CH2:14][S:13][CH2:12][CH2:11][O:10][P:8]([N:27]([CH2:31][CH2:32][Cl:33])[CH2:28][CH2:29][Cl:30])([N:4]([CH2:5][CH2:6][Cl:7])[CH2:3][CH2:2][Cl:1])=[O:9])[NH2:16]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)C(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H](N)CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl
Temperature: 0 °C

Procedure:
3-[[2-[[Bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-N-tert-butoxycarbonyl-L-alanine, 5.0 g (8.4 mmol), prepared as in Synthetic Example 2, was dissolved in 35 mL dichloromethane, and 5.3 mL (42 mmol) chlorotrimethyl silane added with stirring at 0° C., followed by 80 mL methanol. With continued stirring, the mixture was allowed to warm to room temperature, then stirred overnight. The solvents were then removed under vacuum to give a light yellow oil. This was dissolved in ethyl acetate and precipitated with diethyl ether. Filtration and concentration of the filtrate gave two fractions of 3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-L-alanine methyl ester, totaling 4.87 g. Purity (96%) and identity were verified by ELSD and LC-MS (m/z 508 (M+2+H)+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:24])[C@@H:13]([NH:16]C(OC(C)(C)C)=O)[CH2:14][F:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:24])[C@@H:13]([NH2:16])[CH2:14][F:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CF)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 160 mg 4-((R)-2-tert-Butoxycarbonylamino-3-fluoro-propionyl)-piperazine-1-carboxylic acid ethyl ester in 5 ml dichloromethane was added 1.0 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 216 mg.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>CC(C)=O>[OH:1][C:2]1[C:7]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:6][C:5]([CH2:12][N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1
Reactant: OCCNCCO
Reactant: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(CN(CCO)CCO)cc(-n2nc3ccc(Cl)cc3n2)c1O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
2-(2′-Hydroxy-3′-tert-butyl-5′-methylphenyl)-5-chlorobenzotriazole (3.95 g, 0.01 mole), diethanol amine (3.14 g, 0.03 mole) were dissolved in 100 mL of acetone. The reaction mixture was refluxed with constant stirring at 80° C. for 6 h. The solvent was then removed by rotary evaporation. Crude product was purified using silica gel column chromatography. Product was identified by 1H-NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[C:4]([F:13])[C:3]=1[CH3:14].[OH-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:13])[C:3]=1[CH3:14]
Reactant: CCOC(=O)c1ccc(N)c(C)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(N)ccc(C(=O)O)c1F
Yield: 98.3 %

Procedure:
In 7 ml of ethanol was suspended 0.70 g of ethyl 4-amino-2-fluoro-3-methylbenzoate, followed by adding thereto 7 ml of lN sodium hydroxide, and the resulting mixture was stirred at 40° C. for 4 hours. To the reaction mixture was added 1.2 ml of 6N hydrochloric acid, followed by extraction with 50 ml of ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent, to obtain 0.59 g of 4-amino-2-fluoro-3-methylbenzoic acid as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]4[O:22][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].C1C=C(Cl)C=C(C(OO)=O)C=1>CC(O)=O.C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[C@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:22][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@@H]1C5
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
According to literature methods for the preparation of oxycodeinone from thebaine,[16] oripavine (1.00 g of 78% w/w, 2.62 mmol) was treated with two portions of m-CPBA (0.82 g in total of max 77% reagent, approx. 3.66 mmol) in HOAc (4.5 mL) and TFA (0.35 mL). When the reaction was complete, the mixture was poured into ice-water (20 mL). After stirring for 30 min, the solid was removed by filtration. The filtrate was extracted with CHCl3 (5 mL×2), made basic to pH 9 with conc. NH4OH, and extracted with CHCl3/i-PrOH (5:1; 20 mL×4). The latter extracts were combined, dried (Na2SO4), filtered and concentrated to give oxymorphinone (B1) as an off-white solid, 670 mg (85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[OH:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2cccc(F)c2)nc2ccccc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccc(F)c3)nc3ccccc13)C2
Yield: 24 %

Procedure:
Reaction of 2-(3-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 42 (24% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.63 and 2.90 (2t, 2H), 3.50 and 4.04 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.40 and 4.92 (2s, 2H), 6.32 and 6.77 (2d, 1H), 6.71 and 6.91 (2d, 1H), 7.44-7.46 (m, 1H), 7.61-7.82 (m, 2H), 7.89-8.00 (2d, 1H), 8.08-8.26 (m, 3H), 8.31-8.41 (m, 1H); 8.68-8.72 (2s, 1H); MS (ESI) m/z 430 ([M+H]+).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([F:19])[CH:11]=1.N12CCCN=C1CCCCC2>C(#N)C>[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:15])=[C:12]([F:19])[CH:11]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzyl bromide (0.86 g, 5.0 mmol, 1.1 eq.) was added neat to a solution of 4-bromo-2-fluorobenzoic acid. (1.0 g, 4.6 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.36 mL, 9.2 mmol, 2.0 eq.) in anhydrous acetonitrile (20 mL). The reaction was stirred at room temperature for 18 hours before removing the solvent in vacuo. The residue was diluted with ether and washed with water, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, and brine. The organic layer was dried (MgSO4) and concentrated in vacuo to provide the title compound as a pale yellow oil that crystallized into long needles upon standing (1.4 g, 99%): 1H NMR (300 MHz, CDCl3) δ 7.82 (t, 1 H), 7.42-7.31 (m, 7 H), 5.35 (s, 2 H); GC/MS m/z 308/310 (M+ and M+2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:19])([S:15]([CH3:18])(=[O:17])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:19][C:10]([S:15]([CH3:18])(=[O:17])=[O:16])([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:3][CH:4]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)C(C)(CCc1ccc(Br)cc1)S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(CCc1ccc(C#C[Si](C)(C)C)cc1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 168.1 %

Procedure:
To a stirring suspension of methyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.3, 6.36 g, 18.23 mmol), bis(triphenylphosphine)palladium(II) chloride (1.28 mg, 1.82 mmol) and copper(I) iodide (347 mg, 1.82 mmol) in triethylamine (30 mL) was added ethynyltrimethylsilane (0.92 mL, 6.49 mmol) and the reaction mixture was heated to 80° C. briefly, and then allowed to stir at room temperature for 18 hr. Volatiles were removed under reduced pressure and the resulting residue was purified by flash chromatography (silica gel/15-50% EtOAc/hexanes) to yield methyl 2-methyl-2-(methylsulfonyl)-4-(4-((trimethylsilyl)ethynyl)phenyl)butanoate (9.4, 4.0 g, 59.9% yield). MS: m/z calcd for C18H26O4SSi 366.13. found [M+H]+ 367.2.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.[Br:25][C:26]1[N:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[Cl:33]>ClCCl>[Br:25][C:26]1[N:31]=[C:30]([NH:32][C:14]([C:11]2([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]2)=[O:15])[CH:29]=[CH:28][C:27]=1[Cl:33]
Reactant: Nc1ccc(Cl)c(Br)n1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reaction time: 16 h
Yield: 69.4 %

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (0.878 g, 3.37 mmol) was placed in an oven-dried flask which was allowed to cool under nitrogen. Dichloromethane (10 mL), triethylamine (1.42 mL, 10.1 mmol) and 6-bromo-5-chloropyridin-2-amine (10.1 mmol) were added and the reaction mixture was stirred for 16 hours. The reaction mixture was then washed with a saturated aqueous solution of sodium chloride, evaporated to near dryness, and then purified on 40 g of silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield N-(6-bromo-5-chloropyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.01 g, 69%). ESI-MS m/z calc. 429.9. found; 431.3 (M+1)+ Retention time 2.33 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](Cl)=[O:7].C(N(CC)CC)C.[CH:22]1[N:23]=[CH:24][N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12>ClCCCl>[CH:22]1[N:23]=[C:24]([C:6]([C:5]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:7])[N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12
Reactant: c1ccn2cncc2c1
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)c2ncc3ccccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.5 g (0.053 mol) of 3-methoxy-4-nitrobenzoyl chloride and 7.8 ml (0.056 mol) of triethylamine are added to 3 g (0.025 mol) of imidazo[1,5-a]pyridine [described in J. Chem. Soc., (1955), 2834-2836] dissolved in 100 ml of 1,2-dichloroethane. The mixture is stirred at ambient temperature for 2 hours. The reaction medium is concentrated under reduced pressure and the residue is then taken up in dichloromethane and a saturated aqueous sodium bicarbonate solution. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in dichloromethane and purified by filtration through a bed of silica gel. After evaporation, 7.1 g of a yellow solid are collected. Melting point: 183° C.; 1H NMR (d6-DMSO): 4.01 (3H, s), 7.35-7.40 (1H, m), 7.47-7.54 (1H, m), 7.97 (1H, s), 8.06-8.11 (3H, m), 8.15 (1H, s), 9.77 (1H, d).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][CH:29]=2)[N:11]2[CH2:14][C:13](=[C:15]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:12]2)=[CH:6][CH:5]=1.O>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][OH:35])=[CH:32][CH:33]=2)[N:11]2[CH2:12][C:13](=[C:15]([C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:14]2)=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(C=O)cc2)C1)c1cc(F)cc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(CO)cc2)C1)c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 12.9 %

Procedure:
A solution of 30 mg of sodium borohydride in 2 cm3 of methanol is poured into a solution of 0.77 g of (−)-1-[(4-chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine in 20 cm3 of methanol at 0° C. under argon. After stirring for 4 hours at 0° C., water is added and the mixture is then extracted with dichloromethane. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness under reduced pressure (2.7 kpa). The white foam obtained is purified on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 17 cm) with, as eluent, a cyclohexane/ethyl acetate (60/40 by volume) mixture. 0.1 g of (+)-1-[(4-chlorophenyl)(4-hydroxymethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained, after crystallization from 1.5 cm3 of absolute ethanol, in the form of white crystals melting at 190° C., [a]20D=+4.2° (c=0.5% in methanol) [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 3.05 (3H, s, SCH3), 3.95 (2H, s, NCH2), 4.22 (2H, s, NCH2), 4.48 (2H, d, J=6 Hz, CH2O), 4.75 (1H, s, NCH), 5.15 (1H, t, J=6 Hz, OH), 7.20 (2H, m, 2CH arom.), 7.28 (2H, d, J=7 Hz, 2CH arom.), 7.40(5H, m, 5 CH arom.), 7.50 (2H, d, J=7 Hz, 2CH arom.)].
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:6][C:7]1[C:14]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O)[CH2:4][CH3:5].[BH4-].[Na+]>CO>[CH3:1][NH:2][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][C:16]([F:19])([F:18])[F:17])[C:7]=1[O:6][CH2:3][CH2:4][CH3:5]
Reactant: CN
Reactant: CCCOc1c(C=O)cccc1OC(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1c(CNC)cccc1OC(F)(F)F
Reaction time: 18 h
Yield: 73 %

Procedure:
A solution of methylamine (19 mL of a 2.0 M solution in MeOH, 38 mmol) was added to 2-propoxy-3-trifluoromethoxybenzaldehyde (1.15 g, 4.60 mmol). The mixture was stirred for 18 h. The solution was concentrated under reduced pressure. The resulting clear oil was dissolved in EtOH (19 mL) and treated with NaBH4 (0.174 g, 4.60 mmol). After stirring for 5.5 h, the reaction mixture was concentrated under reduced pressure, then dissolved in 1 N NaOH (19 mL). The mixture was extracted with Et2O (3×50 mL). The organics were collected, washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (0.89 g, 73%) as an orange oil: 1H NMR (300 MHz, DMSO-d6) δ 7.41 (dd, J=7.7, 1.6 Hz, 1H), 7.25 (dd, J=6.7, 1.3 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 3.87 (t, J=6.3 Hz, 2H), 3.68 (s, 2H), 2.27 (s, 3H), 2.07 (br s, 1H), 1.74 (q, J=6.4 Hz, 2H), 1.02 (t, J=3.1 Hz, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([OH:36])([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:14]=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:38]1([C@@H:48]([N:50]=[C:51]=[O:52])[CH3:49])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1>CN(C)C1C=CN=CC=1.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([O:36][C:51](=[O:52])[NH:50][CH:48]([C:38]4[C:47]5[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=5)[CH:41]=[CH:40][CH:39]=4)[CH3:49])([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[C:14]=3[CH2:15][C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reactant: C[C@H](N=C=O)c1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2(OC(=O)NC(C)c3cccc4ccccc34)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
To 15 mL dichloromethane was added 3-benzo[1,3] dioxol-5-yl-5-hydroxy-5-(4-methoxyphenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 1.00 g (1.98 mmol) and stirred to dissolve. To this was added (S)-1-(1-naphthyl)ethyl isocyanate 414 mg (2.1 mmol) and a catalytic amount of 4-dimethylaminopyridine 20 mg (0.164 mmol). The mixture was stirred at room temperature for 24 hours. The solution was washed with 50 mL water and 50 mL brine, and the organic phase was separated and dried over magnesium sulfate, then evaporated to dryness. The crude product was then purified by flash chromatography (150 g silica gel, 10% EtOAc/CH2Cl2). The product was isolated by evaporation of the appropriate fractions to give 840 mg (60%) as a white foam. The product was identified by 1H NMR, MS, [M+H]+ =704 Da. and microanalysis.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([C:28]2[CH:45]=[CH:44][C:31]([O:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41](O)=[O:42])=[CH:35][CH:34]=3)=[CH:30][CH:29]=2)[C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([C:28]2[CH:45]=[CH:44][C:31]([O:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41](=[O:42])[NH:1][CH2:2][C:3]([N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)=[O:4])=[CH:35][CH:34]=3)=[CH:30][CH:29]=2)[C:23]([N:24]([CH3:26])[CH3:25])=[O:27])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: COc1cc(C=C(C(=O)N(C)C)c2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)cc(OC)c1
Reactant: NCC(=O)N1CCOCC1
Product: COc1cc(C=C(C(=O)N(C)C)c2ccc(Oc3ccc(CCC(=O)NCC(=O)N4CCOCC4)cc3)cc2)cc(OC)c1

Procedure:
Following the general procedure for conversion of carboxylic acids to amides mentioned above and using 2-amino-1-morpholin-4-yl-ethanone as amine, 3-(4-{4-[2-(3,5-dimethoxyphenyl)-1-dimethylcarbamoylvinyl]-phenoxy}-phenyl)-propionic acid, 38, was converted to 63.