Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:14]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])[NH:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:12]([N:14]1[C:18]([O:19][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:17][C:16]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])=[N:15]1)[CH3:13]
Reactant: CCn1[nH]c(-c2cccc(C#N)c2)cc1=O
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(F)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
1,4-difluoro-2-nitrobenzene (2.06 g, 9.85 mmol, 3 equiv) was added to a stirring mixture of 3-(1-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (0.70 g, 3.28 mmol, 1 equiv) and potassium carbonate (1.36 g, 9.85 mmol, 3 equiv) in DMSO (6.57 mL). The reaction mixture was stirred at 80° C. for 20 minutes then cooled to 22° C. and diluted with water. The mixture was extracted with ethyl acetate, and then the organic layer was washed sequentially with water (two times) and saturated aqueous sodium chloride. The washed solution was dried over anhydrous magnesium sulfate. The drying agent was filtered, and the filtrate was concentrated in vacuo to give the 3-[1-ethyl-5-(4-fluoro-2-nitrophenoxy)-1H-pyrazol-3-yl]benzonitrile. The crude reaction product was taken into the next step without further purification. Calcd (M+1)+: 353.1. Found: 353.2.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[O:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[O:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][NH:27][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[CH:5][CH:4]=2)[CH2:21][CH2:20]1
Reactant: NCCC1CCOCC1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(Oc2ccc(CNCCC3CCOCC3)cc2)cn1
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Place 5-(4-formylphenoxy)pyrazine-2-carboxamide (Example 437, Part B) (0.150 g, 0.617 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.0797 g, 0.617 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.1 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO®10 column with 2.0 M NH3 in methanol and ethyl acetate. After concentrating, take the product up in dichloromethane (25 mL) and wash with 1.0 N NaOH solution (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.0819 g, 37.2%): MS ES+ 357.1 (M+H)+, base peak 228.0 (M-C7H14NO)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=7.4 min, 100% purity.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]3[CH2:23][CH2:22][CH2:21][C@:20]([CH2:30][C:31]([CH3:33])=[CH2:32])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:19][C:18]3=[O:34])[CH3:16])=[CH:11][CH:10]=2)=[CH:3]1.C1([SiH3])C=CC=CC=1.C([OH:45])(C)C.C(Cl)Cl>[Co]>[OH:45][C:31]([CH3:33])([CH3:32])[CH2:30][C@:20]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH2:22][CH2:23][N:17]([C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=3)=[CH:14][CH:13]=2)[CH3:16])[C:18](=[O:34])[NH:19]1
Reactant: CC(C)O
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)N1
Agent: [Co]
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of (S)-1-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-4-(2-methylallyl)-4-phenyl-1,3-diazepan-2-one (4 mg, 0.0088 mmol) in 2:1 i-Propanol/CH2Cl2 (2 mL) was added the cobalt catalyst A (c.a. 1 mg, cat. amount) and phenylsilane (100 μL, excess). The mixture was stirred vigorously in open air for 1 h. LC-MS found the reaction completed. The mixture was quenched by 1% aq HCl, concentrated and purified by prep HPLC to afford (S)-4-(2-hydroxy-2-methylpropyl)-1-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-4-phenyl-1,3-diazepan-2-one (1.4 mg, 34%). LC-MS Method 1 tR=1.56 min., m/z 473 (M+1); 1H NMR (CD3OD) δ 7.93 (s, 1H), 7.83 (dd, 1H), 7.56 (d, 2H), 7.40-7.34 (m, 4H), 7.27 (t, 1H), 7.16 (d, 2H), 6.62 (d, 1H), 5.46 (q, 1H), 3.63 (s, 3H), 2.93 (m, 1H), 2.76 (m, 1H), 2.39 (d, 1H), 1.52 (d, 3H), 1.17 (s, 3H), 0.59 (s, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:22]=[C:21]([C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][C:25]=2[OH:36])[CH:20]=[CH:19][C:7]=1[O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)([OH:3])=[O:2].Cl.[CH2:39](O)[CH3:40]>C(Cl)Cl>[CH:31]1([O:30][C:27]2[CH:28]=[CH:29][C:24]([C:23]([C:21]3[CH:20]=[CH:19][C:7]([O:8][CH2:9][C:10]4[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=4)=[C:6]([CH2:5][CH2:4][C:1]([O:3][CH2:39][CH3:40])=[O:2])[CH:22]=3)=[O:37])=[C:25]([OH:36])[CH:26]=2)[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCO
Reactant: O=C(O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
3.32 g of 4-({2-(2-carboxyethyl)-4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}-methyl)benzoic acid was suspended in 3.3 mL of methylene chloride, to which 3.3 mL of 4M hydrogen chloride-ethanol was added, and this mixture was stirred for 7 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and then the resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=10:1] to yield 1.76 g of 4-{[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-ethoxy-3-oxopropyl)phenoxy]methyl} benzoic acid as white solid.
Reaction SMILES: S(Cl)(Cl)=O.O[CH:6]([C:12]1[N:16]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][CH3:30])=[CH:24][CH:23]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8].C(S([O-])=O)O.[Na+]>C(Cl)Cl>[CH3:11][N:9]([CH3:10])[C:7](=[O:8])[CH2:6][C:12]1[N:16]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][CH3:30])=[CH:24][CH:23]=1
Reactant: COCc1ccc(-c2nc3ccc(C)cn3c2C(O)C(=O)N(C)C)cc1
Agent: O=S([O-])CO
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCc1ccc(-c2nc3ccc(C)cn3c2CC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
8.5 ml of thionyl chloride are added dropwise to 1.5 g (4.2×10-3 mol) of α-hydroxy-N,N-dimethyl-6-methyl-2-[4-(methoxymethyl)phenyl]imidazo[1,2-a]pyridine-3-acetamide (IX) dissolved in 85 ml of dry methylene chloride. The mixture is left stirred for 15 h at room temperature and evaporated to dryness, the residue is taken up with pentane, crystallized and dried under vacuum. A white solid is obtained which is dissolved in 120 ml of methylene chloride, 1.9 g (1.2×10-2 mol, 3 eq) of Rongalite are added and the mixture is left stirred for 4 h at room temperature. The mixture is then filtered and the filtrate washed with bicarbonate water and then with water to neutral pH, dried and evaporated. The product is purified by chromatography and crystallized in ether.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10])#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][O:20][N:45]1[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]2[C:49]1=[O:50])(=[O:11])=[O:10])#[N:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C#N)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCCCON2C(=O)c3ccccc3C2=O)cc(OS(=O)(=O)c2ccccc2C#N)c1
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of 3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propanol (1.04 g, 3.0 mmol), as prepared in the preceding step, triphenylphosphine (1.05 g, 4.0 mmol), and N-hydroxyphthalimide (490 mg, 3.0 mmol) at 0° C. in tetrahydrofuran (20 mL) was added diethyl azodicarboxylate (700 mg, 4.0 mmol). The reaction mixture was stirred overnight. Water (50 mL) was added, the reaction mixture was extracted into ethyl acetate (3×50 mL). The ethyl acetate solution was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent, the residue was purified by flash column chromatography (2:1 dichloromethane/hexane to dichloromethane) to give the title compound as a colorless foam (1.12 g, 76%). 1H-NMR (300 MHz, CDCl3) δ8.09 (m, 1H), 7.97 (m, 1H), 7.84 (m, 2H), 7.78 (m, 4H), 6.67 (s, 1H), 6.60 (s, 1H), 6.50 (s, 1H), 4.37 (t, J=6.1 Hz, 2H), 4.13 (t, J=6.1 Hz, 2H), 2.27 (s, 3H), 2.19 (m, 2H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)O)[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.O>[N:21]([CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)[CH:3]([CH2:19][CH3:20])[CH2:1][CH3:2])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(CC)C(O)c1ncnn1Cc1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)C(N=[N+]=[N-])c1ncnn1Cc1ccc(F)cc1
Yield: 67 %

Procedure:
To a stirred solution of 2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butan-1-ol (0.459 g, 1.42 mmol) in DMF (10 mL) was added sodium azide (0.277 g, 4.26 mmol) and the mixture was heated to reflux for 3 h. After cooling, the reaction mixture was diluted with H2O and extracted with EtOAc twice. The organic extracts were dried (MgSO4), filtered, concentrated in vacuo and purified by column chromatography (SiO2, EtOAc/hexane, 1:9) to yield a clear oil in 67% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:11][S:12]([O:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3][C:2]([CH3:10])([CH3:9])[CH3:1])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C#CCCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)C#CCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 mg of the resulting alcohol compound was dissolved in 1 ml of ethyl acetate, and 60 μl of methanesulfonyl chloride and 200 μl of triethylamine were added. The mixture was stirred at room temperature for 1 hour, and then the precipitate of triethylamine hydrochloride was removed by filtration. The filtrate was diluted with ethyl acetate, and washed succesively with a saturated aqueous solution of sodium bicarbonate, 1N hydrochloric acid and a saturated aqueous slution of sodium chloride, then worked up in a customary manner to give 150 mg of the captioned compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][C@H:19]1[CH2:21][O:20]1.Cl.[CH:23]12[O:30][CH:27]([CH2:28][CH2:29]1)[CH2:26][NH:25][CH2:24]2>CN(C=O)C>[OH:20][C@H:19]([CH2:21][N:25]1[CH2:24][CH:23]2[O:30][CH:27]([CH2:28][CH2:29]2)[CH2:26]1)[CH2:18][O:17][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:14][CH2:15][N:16]=3)[C:10]([NH2:13])=[N:11][C:12]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CN(C)C=O
Product: COc1c(OC[C@H](O)CN2CC3CCC(C2)O3)ccc2c1N=C(N)N1CCN=C21
Yield: 271.1 %

Procedure:
A solution of 7-methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Intermediate F, 0.195 g, 0.68 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.506 g, 3.38 mmol, 10 equiv.) in DMF (4.5 mL) was heated in a microwave reactor for 45 min. at 140° C. The resulting mixture was concentrated under reduced pressure. The residue was treated with a 4:1 CH2Cl2/isopropanol solution (25 mL), washed with a saturated sodium bicarbonate solution (25 mL), dried (anh. sodium sulfate) and concentrated under reduced pressure. The resulting residue was purified using MPLC to give N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-ylamine (0.74 g, 16%): HPLC ret. time 0.70 min.; mass spectrum m/z 402 ((M+1)+, 7%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][CH2:12][CH:13]([OH:19])[CH2:14][NH:15][CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=1)[CH:2]=[CH2:3].[CH2:22]([Zn]CC)C.ICI.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:18][CH:16]([NH:15][CH2:14][CH:13]([OH:19])[CH2:12][O:11][C:10]1[CH:20]=[CH:21][C:7]([CH2:6][CH2:5][O:4][CH2:1][CH:2]2[CH2:22][CH2:3]2)=[CH:8][CH:9]=1)[CH3:17]
Reactant: CC[Zn]CC
Reactant: C=CCOCCc1ccc(OCC(O)CNC(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ICI
Product: CC(C)NCC(O)COc1ccc(CCOCC2CC2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound of formula (1) (1 g, 0.003 mol) in dry toluene (5 ml), diethylzinc (1.1 M solution in toluene, 14 ml, 0.017 mol) was added at 0° C. under nitrogen atmosphere followed by diiodomethane (1.38 ml, 0.017 mol). The reaction was stirred for 16 h at 0° C. and poured over cold aqueous solution of ammonium chloride. The organic layer was separated and the aqueous layer extracted repeatedly with toluene. The combined organic layer was washed with a solution of sodium thiosulphate, dried over anhydrous sodium sulphate, filtered and concentrated to yield racemic betaxolol of formula (2) 1.6 g (84%) mp 70 –72° C. as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:20]#[N:21])[CH2:16][C:17]([OH:19])=[O:18])=[C:11]([O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]S(O)(=O)=O>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:20]#[N:21])[CH2:16][C:17]([O:19][CH3:24])=[O:18])=[C:11]([O:22][CH3:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)O
Reactant: COc1cc(OCc2ccccc2)ccc1C(C#N)CC(=O)O
Solvent: CO
Product: COC(=O)CC(C#N)c1ccc(OCc2ccccc2)cc1OC
Temperature: 65 °C
Yield: 100 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with methanol (10 mL). To the stirred solvent was added 3-[4-(benzyloxy)-2-methoxyphenyl]-3-cyanopropanoic acid (0.62 g, 2.56 mmol) and methane sulfonic acid (1 mL), it was heated at 65° C. for 2 h. The RM was concentrated, extracted with ethyl acetate (50 mL×2). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.65 g, yield: 100.0%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].CC(C)([O-])C.[K+]>C1COCC1>[CH2:13]([CH:12]([NH:11][C:6]1[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([O:27][C:20]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=2[CH3:18])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a mixture of (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine (80 mg, 0.31 mmol) and 2,4,6-trimethylphenol (43 mg, 0.31 mmol) in 2ml of dry THF was added potassium tert-butoxide (35 mg, 0.31 mmol) and the resulting mixture was stirred at rt overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using 6:4 ratio of chloroform:hexane as eluent to give 91 mg (83%) of the title compound as yellow solid, mp 16-162° C. 1H NMR (CDCl3) δ7.62 (d, 1H), 6.87 (s, 2H), 6.18 (s, 1H), 3.40 (m, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 2.10 (s, 6H), 1.5-1.8 (m, 4H), 0.99 (t, 6H) ppm.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([NH:18][CH2:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)=[O:17])=O)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-].[C].[H][H]>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([CH2:19][NH:18][C:16]([C@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:17])[CH2:21]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNC(=O)[C@H]2CCCN2)C1
Reaction time: 5 h
Yield: 102.3 %

Procedure:
To a solution of 2.49 g of (2R)-1-benzyloxycarbonyl-N-({(3R)-1-(tert-butoxycarbonyl)-3-piperidyl}methyl)pyrrolidine-2-carboxamide in 20 ml of methanol, 15 mg of 20% palladium hydroxide-carbon catalyst was added, followed by 5 hours' stirring in hydrogen atmosphere. After filtering the catalyst off, the solvent was distilled off under reduced pressure to provide 1.78 g of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15]O)[C:11](=[O:17])[O:10]2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][Cl:20])[C:11](=[O:17])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1cccc(-n2oc(=O)n(CO)c2=O)c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CSc1cccc(-n2oc(=O)n(CCl)c2=O)c1

Procedure:
2-(3-Methylthiophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(3-methylthiophenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Br:10][C:11]([Br:26])([F:25])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1)O.CCOC(C)=O>C(Cl)Cl>[Br:10][C:11]([Br:26])([F:25])[CH:12]([F:7])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: COc1ccc(C(O)C(F)(Br)Br)cc1[N+](=O)[O-]
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(F)C(F)(Br)Br)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
(DAST 730 μL (5.58 mmol; 1.8 eq) in 5 mL CH2Cl2 was added to a solution of 1.146 g (3.1 mmol) of the alcohol (7) in 7 mL CH2Cl2 at −78° C. The reaction mixture was allowed to warm up to 0° C. over a period of 2 h, quenched with 15 mL of NaHCO3 saturated solution and diluted with 20 mL of diethyl ether. The organic phase was dried over anhydrous sodium sulfate and purified by chromatography on SiO2 using Hexane/Ethyl Acetate 7:3 to give 960 mg (2.6 mmol; 84%) of a yellow oil. Rf=0.493 (Hex./AcOEt 7:3)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12].[H][H]>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: OCCCC#Cc1ccccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCCCCCc1ccccn1
Yield: 93.1 %

Procedure:
5-(2-Pyridinyl)-4-pentyn-1-ol (8.8 g) was hydrogenated over 1.0 g of 10% Pd/C in 125 mL of ethanol at room temperature and atmospheric pressure. After the uptake of hydrogen had stopped, the catalyst was removed by filtration and the solvent was removed under reduced pressure. The residual oil was distilled on a Kugelrohr apparatus (115°-120° C./0.1 mm) to yield 8.4 g of 2-pyridinepentanol.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][C:6]=1[N+:21]([O-:23])=[O:22])[CH:2]([CH3:4])[CH3:3].[NH2:24][C:25]1[C:30]([O:31][CH3:32])=[N:29][C:28]([CH3:33])=[CH:27][N:26]=1>N1C=CC=CC=1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([S:17]([NH:24][C:25]3[C:30]([O:31][CH3:32])=[N:29][C:28]([CH3:33])=[CH:27][N:26]=3)(=[O:19])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][C:6]=1[N+:21]([O-:23])=[O:22])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1[N+](=O)[O-]
Reactant: COc1nc(C)cnc1N
Solvent: c1ccncc1
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1-c1ccc(CC(C)C)c([N+](=O)[O-])c1
Temperature: 75 °C
Yield: 39.5 %

Procedure:
4'-Isobutyl-3'-nitro-2-biphenylsulphonyl chloride (0.353 g) was added to a solution of 2-amino-3-methoxy-5-methylpyrazine (0.139 g) in pyridine (10 ml) at 0° C. The solution w?as heated at 75° C. for 18 hours and then volatile material was removed by evaporation. The residue was purified by elution with dichloromethane through a silica gel Mega Bond Elut column and the resulting foam was triturated with ether/hexane (1:1 v/v) to give 4'-isobutyl-N-(3-methoxy-5-methyl-2-pyrazinyl)-3'-nitro-2-biphenylsulphonamide (0.18 g), m.p. 114-115° C.; mass spectrum (+ve CI): 457 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33]>CN(C=O)C.C(OCC)(=O)C>[CH2:32]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[F:1])[CH3:33]
Reactant: CCI
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc3ccc(OC[C@H](C)NC(C)=O)cc3o2)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
A suspension of N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (200 mg), potassium carbonate (161 mg) and ethyl iodide (181 mg) in DMF (5 mL) was stirred at 60° C. for 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. The obtained solid was recrystallized from hexane/ethyl acetate to give the title compound (167 mg).
Reaction SMILES: [O-]CC.[K+:4].[CH:5]([O:7][CH2:8][CH3:9])=[O:6].C([O:12][C:13](=O)[CH2:14][N:15]=[C:16]([O:18][CH2:19][CH3:20])[CH3:17])C>C(OCC)C.CCO>[CH2:8]([O:7][C:5]([C:14]([N:15]=[C:16]([O:18][CH2:19][CH3:20])[CH3:17])=[CH:13][O-:12])=[O:6])[CH3:9].[K+:4]
Reactant: CCOC=O
Reactant: CCOC(=O)CN=C(C)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=C[O-])N=C(C)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a stirred suspension of 3.222 g (36 mmol, 1.05 eq) of potassium ethoxide in 30 mL diethyl ether and 5 mL EtOH at 0° C., a solution of 3.849 g (52 mmol, 1.5 eq) ethyl formate and 6 g (35 mmol) (1-ethoxy-ethylideneamino)-acetic acid ethyl ester in 30 mL diethyl ether and 5 mL EtOH is then slowly added. The reaction mixture is stirred for one hour at 0° C. After addition of 40 mL diethyl ether, the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the obtained solid was washed with diethyl ether and dried under vaccum to yielded 5 g (60%) of potassium 2-ethoxycarbonyl-2-(1-ethoxy-ethylideneamino)-ethenolate as an orange solids.