Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[C:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:41]4[CH2:42][CH2:43][N:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:39][CH2:40]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ccccc2)CC1

Procedure:
(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-phenylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=591.97 (M+H+); retention time=0.97 minutes.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH:9]2[O:13][C:12](=[O:14])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[CH:15]#[C:16][CH:17]([OH:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(N(CC)CC)C.O1CCCC1.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>[OH:26][CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16]#[C:15][C:2]1[N:7]=[C:6]([CH2:8][CH:9]2[O:13][C:12](=[O:14])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(O)CCCCCCCC
Reactant: O=C1CCC(Cc2cccc(Br)n2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)C#Cc1cccc(CC2CCC(=O)O2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.8 %

Procedure:
A solution of 500 mg of 5-[(6-bromo-2-pyridyl)-methyl]-tetrahydrofuran-2-one in 13 ml of triethylamine and 2 ml of tetrahydrofuran is mixed with 350 mg of (3RS)-1-undecin-3-ol, 37 mg of bis-(triphenylphosphine)-palladium(II) chloride and 5 mg of copper(I) iodide and the mixture is stirred for 3 days at room temperature. The reaction mixture is evaporated to dryness, distributed between water and ethyl acetate, dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-35% ethyl acetate. 294 mg of 5-{6-[(3RS)-3-hydroxy-1-undecinyl]-2-pyridyl-methyl}-tetrahydrofuran-2-one is obtained as oil.
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12]([O:14]C)=O)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]1[C:22]1[S:26][CH:25]=[N:24][CH:23]=1.O.[NH2:28][NH2:29]>CO>[C:16]1([CH:4]2[NH:5][C:6]3[C:11]4[C:2](=[N:28][NH:29][C:12](=[O:14])[C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH:3]2[C:22]2[S:26][CH:25]=[N:24][CH:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cncs1)C(c1ccccc1)N2
Solvent: CO
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1cncs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
Methyl 4-oxo-2-phenyl-3-(thiazol-5-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (110 mg, 0.29 mmol) and hydrazine monohydrate (2 mL) were added to methanol (10 mL) and the mixture was stirred room temperature for 4 h. The resulting mixture was evaporated under reduced pressure to 10 mL and then filtered; the filtrate was concentrated to give 8-phenyl-9-(thiazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (13 mg, yield 13%) as a white solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 4.67 (d, 1H), 4.78 (d, 1H), 7.10-7.19 (m, 4H), 7.24 (t, 2H), 7.45-7.56 (m, 2H), 8.76 (s, 1H); LC-MS (ESI) m/z: 347 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH2:9]>>[C:1]([NH2:2])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O
Reactant: N#Cc1cccnc1
Product: NC(=O)c1cccnc1
Reaction time: 1 h

Procedure:
The strain M33 was grown as in Example 1. A biomass containing M33 cells up to a concentration of 0.5 mg/ml and 3-cyanopyridine up to a concentration of 8% was added into a I00-ml flask containing 40 ml of distilled water (pH 7.6). The flask was incubated at 30° C. under stirring conditions. After 60 minutes, a I0%-nicotinamide solution was obtained. Nicotinic acid and 3-cyanopyridine were not present in the reaction mixture.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:15]COCCOC)=[CH:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:22]O>>[CH3:22][O:12][C:10](=[O:11])[C:9]1[CH:13]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[CH:7][C:8]=1[CH3:14]
Reactant: CO
Reactant: COCCOCOc1cc(C)c(C(=O)O)cc1C(C)(C)C
Product: COC(=O)c1cc(C(C)(C)C)c(O)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-tert-butyl-4-(2-methoxy-ethoxymethoxy)-2-methyl benzoic acid from Example AAA (20.9 g, 70.5 mmol), MeOH (150 mL), and H2 SO4 (10 mL) was refluxed for 5 hours and stirred overnight at room temperature. The mixture was concentrated by half, diluted with H2O, and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.36 (s, 9 H), 2.48 (s, 3 H), 3.82 (s, 3 H), 6.48 (s, 1 H), 7.87 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:29](/[CH:30]=[CH:31]/[CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:11]3[CH:12]=[C:13]([C:16]([N:18]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:29]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:11]3[CH:12]=[C:13]([C:16]([N:18]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(-c3cccc(Cl)c3)c(/C=C/CN3CCCCC3)c2c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(-c3cccc(Cl)c3)c(CCCN3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
In a 15 mL sealed tube were added compound of Example 72i.e. (E)-2-(3-chlorophenyl)-N,N-diisopentyl-3-(3-(piperidin-1-yl)prop-1-en-1-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (160 mg, 0.299 mmol), trifluoroacetic acid (0.069 ml, 0.896 mmol), and triethylsilane (0.143 ml, 0.896 mmol) in chloroform (5 ml) and the mixture was heated to 80-100° C. overnight, cooled down to room temperature and assayed for conversion by HPLC/LCMS. LC indicated homogenous peak but LCMS indicated the presence of both olefin and saturated compounds. Then 140 μL of TFA and 280 μL of triethylsilane were added and the mixture was heated to 100° C. for 5 days and cool down to room temperature. Saturated sodium bicarbonate was slowly added and the separated organic layer was washed with brine and dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude material was dissolved in DMF and purified on a reverse-phase Zorbax SB-C18 column 21.2×100 mm and was eluted with MeOH-water-0.1% TFA. Isocratic 30% for 3 minutes then Gradient: 30% to 100% MeOH over 14 minutes. LCMS m/z 537.3 (M+H)+, ret. time=2.55 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].O.[NH2:13][NH2:14]>C(O)(=O)C.O>[CH2:6]([C:5]1[NH:14][N:13]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=1)[CH3:7]
Reactant: CCC(=O)CC(=O)C(F)(F)F
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(C(F)(F)F)n[nH]1
Yield: 59.2 %

Procedure:
A solution of 1,1,1-trifluoro-2,4-hexane-dione (2.4 g, 14.3 mmol), hydrazine hydrate (1.0 g, 19.0 mmol) and acetic acid (1 drop) in water (10 mL) was heated to reflux for 1 h. The reaction mixture was then cooled in an ice bath to form a white precipitate. The precipitate was then filtered, dissolved in chloroform and dried over MgSO4. The resulting solution was concentrated under reduced pressure to provide 1.39 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([OH:13])=O)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH2:14]([NH2:16])[CH3:15].P(=O)(O)(O)O>O>[Br:8][C:6]1[N:7]=[C:2]2[N:16]([CH2:14][CH3:15])[C:11](=[O:13])[CH2:10][NH:9][C:3]2=[N:4][CH:5]=1
Reactant: O=C(O)CNc1ncc(Br)nc1Br
Reactant: CCN
Agent: O=P(O)(O)O
Solvent: O
Product: CCN1C(=O)CNc2ncc(Br)nc21
Temperature: 90 °C

Procedure:
The 2-((3,5-dibromopyrazin-2-yl)amino)acetic acid and ethylamine (4 equiv, 70 wt % solution) were combined in water and the mixture was stirred at 90° C. The reaction mixture was cooled to 80° C. and treated with phosphoric acid (4 equiv), and the mixture was cooled to room temperature and the solids were collected by filtration. The product was dried to obtain 7-bromo-1-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one as a solid. MS (ESI) m/z 256.9
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].C(N(CC)CC)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>C(Cl)Cl>[S:29]([O:21][CH2:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4])(=[O:31])(=[O:30])[CH3:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOS(C)(=O)=O
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
Phytanol (20.0 g, 66.7 mmol), triethylamine (18.6 mL, 133 mmol) and a stir bar were added to a 1000 mL round bottom flask. The flask was sealed and flushed with nitrogen Anhydrous DCM (250 mL) was added, and the mixture cooled to −15° C. (Ice and NaCl). Mesyl Chloride (10.4 mL, 133 mmol) was added slowly via syringe over a 30 minute period, and the reaction stirred at −15° C. for a further 1.5 hours. At this point TLC showed that the starting material had been used up. The solution was diluted with DCM (250 mL) and washed with saturated NaHCO3 (2×200 mL). The organic phase was then dried (MgSO4), filtered and concentrated (rotovap). The crude product was purified by column chromatography. Yield 21.5 g, 85.7%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29]>C1COCC1>[CH2:29]([O:14][C@H:13]1[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1)[CH:28]=[CH2:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of benzyl rel-(3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate (1 g, 2.97 mmol) in dry THF (10 mL) at 0° C. was added NaH (475 mg, 11.88 mmol). The reaction mixture was stirred at 0° C. for 1 h. Allyl bromide (1.08 g, 8.92 mmol) was added to the reaction mixture dropwise. The reaction mixture was stirred at 0° C. for 2 h and room temperature for 1 h. The reaction was quenched by adding MeOH (5 mL) and was concentrated under reduced pressure to remove most of the solvent. Then water (15 mL) was added to the reaction mixture. EtOAc (15 mL×3) was added to extract the product. The organic phases were combined, dried over MgSO4, filtered, concentrated and subjected to column chromatography (EtOAc:hexanes, 1:3 to 1:1) as the eluent to give benzyl rel-(3R,4R)-3-(allyloxy)-4-[(tert-butoxycarbonyl)amino]pyrrolidine-1-carboxylate (806.2 mg, 72%).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:30])(=[O:29])[CH3:28].[K+]>CC(C)=O.O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:30][C:27](=[O:29])[CH3:28])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(C)=O
Yield: 35.1 %

Procedure:
A mixture of 2.1 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 1.0 g of potassium acetate is stirred in a mixture of 50 ml of acetone and 3 ml of water for 20 hours. The acetone is distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 700 ml of diisopropyl ether-n-hexane (1:1), elution is carried out with 600 ml of a 3:2 mixture and 300 ml of a 5:1 mixture of the same solvents. The eluates are combined and evaporated under reduced pressure to remove the solvent, giving 0.7 g of the above-identified compound as colorless crystals.
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.P(Cl)(Cl)Cl.[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>N1C=CC=CC=1>[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:25]([C:27]([N:14]2[CH2:15][CH2:16][N:11]([CH2:1][C:2]3[CH:10]=[CH:9][C:8]4[O:7][CH2:6][O:5][C:4]=4[CH:3]=3)[CH2:12][CH2:13]2)=[O:28])[N:26]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: Nc1nc(C(=O)O)c(-c2ccncc2)s1
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: Nc1nc(C(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
To a mixture of 1-piperonylpiperazine (2.72 g) and phosphorous trichloride (0.49 ml) in pyridine (20 ml) was added 2-amino-5-(4-pyridyl)-4-thiazolecarboxylic acid (1.24 g) and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The resultant mixture was adjusted to pH 8.0 with saturated aqueous potassium carbonate. The organic extract was dried over magnesium sulfate. The solvent was evaporated in vacuo to give a crystalline residue, which was recrystallized from ethyl acetate to afford 2-amino-5-(4-pyridyl)-4-[(4-piperonyl-1-piperazinyl)carbonyl]thiazole (0.45 g). mp 216°-217° C.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].N1C(C)=CC(C)=CC=1C.[OH:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]1[CH2:28][S:27][C:26](=[O:29])[NH:25]1)=[O:23]>C(#N)C>[N+:7]([O:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]1[CH2:28][S:27][C:26](=[O:29])[NH:25]1)=[O:23])([O-:8])=[O:6]
Reactant: O=[N+]=O
Reactant: O=C1N[C@H](C(=O)NCCO)CS1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: Cc1cc(C)nc(C)c1
Product: O=C1N[C@H](C(=O)NCCO[N+](=O)[O-])CS1
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
0.44 g of nitronium tetrafluoroborate and a solution of 0.41 g of 2,4,6-collidine in 20 ml of acetonitrile were added at a temperature of from -10° C. to 0° C. to 30 ml of acetonitrile, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, 0.50 g of (4R)-N-(2-hydroxyethyl)-2-oxothiazolidine-4-carboxamide was added to the mixture, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then freed from the solvent by distillation under reduced pressure. The residue was mixed with ethyl acetate and insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent. The pale yellow crystals thus obtained were recrystallized from ethyl acetate, to give 86 mg of the title compound as colorless crystals. The melting point and nuclear magnetic resonance spectrum of the product were identical with those of the compound produced as described in Example 1.
Reaction SMILES: Br[CH:2]([C:5]1[C:6]([F:20])=[C:7]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:8]([Cl:11])=[CH:9][CH:10]=1)[CH2:3][CH3:4].[CH3:21][C:22]([NH2:26])([CH3:25])[CH2:23][OH:24]>CN(C=O)C>[C:12]([C:7]1[C:6]([F:20])=[C:5]([CH:2]([NH:26][C:22]([CH3:25])([CH3:21])[CH2:23][OH:24])[CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[Cl:11])(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(N)CO
Reactant: CCC(Br)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Solvent: CN(C)C=O
Product: CCC(NC(C)(C)CO)c1ccc(Cl)c(C(=O)c2ccccc2)c1F

Procedure:
Step 3 A solution of [3-(1-bromo-propyl)-6-chloro-2-fluoro-phenyl]-phenyl-methanone (50 mg; 0.14 mmol) and 2-methyl-2-aminopropanol (30 μl; 2 equiv.) in DMF (1 ml) was stirred at room temperature for 72 hours then partitioned between Et2O and brine. The Et2O later was separated, dried (Na2SO4), filtered and evaporated. The crude material was purified by flash column chromatography using gradient elution from 0-10% MeOH/DCM. Product containing fractions were combined, treated with saturated HCl/EtOAc then evaporated. The residue was triturated with Et2O, the solid collected by filtration, washed with Et2O and sucked dry to give 55 mg of 2-{[1-(3-benzoyl-4-chloro-2-fluorophenyl)-propyl]amino}-2-methylpropan-1-ol as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[CH3:21][C:22]1[S:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:27]([C:25]2[S:26][C:22]([CH3:21])=[CH:23][CH:24]=2)=[O:28])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Product: Cc1ccc(C(=O)NCC(=O)NC(c2cccc(F)c2)c2cccc(F)c2)s1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and 5-methyl-thiophene-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[NH:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][N:8]=2)[C:4](=[O:21])[CH2:3]1.[C:23]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:23][N:6]1[C:2]([CH3:22])([CH3:1])[CH2:3][C:4](=[O:21])[N:5]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][N:8]=1
Reactant: CC1(C)CC(=O)N(c2ccc(C#Cc3ccccc3)cn2)N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN1N(c2ccc(C#Cc3ccccc3)cn2)C(=O)CC1(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
(35 mg, 120 μmol) 5,5-Dimethyl-2-(5-phenylethynyl-pyridin-2-yl)-pyrazolidin-3-one (Example 1, step 4) was dissolved in ACN (2 ml). K2CO3 (33 mg, 240 μmol, 2 equiv.) and iodomethane (22 mg, 156 μmol, 1.3 equiv.) were added and the mixture was stirred for 16 hours at 80° C. The reaction mixture was evaporated and extracted with water and two times with ethyl acetate. The organic layers were extracted with brine, dried with sodium sulfate and evaporated to dryness. The crude product was purified by reverse phase column chromatography. The desired 1,5,5-trimethyl-2-(5-phenylethynyl-pyridin-2-yl)-pyrazolidin-3-one (18 mg, 49% yield) was obtained as a colorless oil, MS: m/e=306.2 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1)(=[O:33])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Solvent: ClCCl
Product: O=C(CCc1cccnc1)NCCCCC1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 0 °C

Procedure:
3.5 g (12 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide and 6.7 ml (48.1 mmol) TEA are placed in 100 ml absolute dichloromethane and cooled to ca. 0° C. under moisture exclusion. 3.0 g (13.2 mmol) naphthalin-2-sulfonic acid chloride are dissolved in 40 ml absolute dichloromethane and added dropwise. The mixture is stirred without further cooling at RT overnight. Subsequently, the batch is washed twice, each with 80 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (97/3) and crystallized from acetic acid ethyl ester after drawing off the solvent. Colorless crystals with an MP of 103-105° C.; yield 2.87 g (50%).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[H-].[Na+].C1(C)C(C([O:21][C@@H:22]2[C@@H:26]([CH2:27][O:28]C(C3C(C)=CC=CC=3)=O)[O:25][C@H:24](Cl)[CH2:23]2)=O)=CC=CC=1.O>CN(C)C=O>[O:10]([C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[C@@H:24]1[O:25][C@H:26]([CH2:27][OH:28])[C@@H:22]([OH:21])[CH2:23]1
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@H](Cl)C[C@@H]1OC(=O)c1ccccc1C
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(O[C@H]2C[C@H](O)[C@@H](CO)O2)cc1
Reaction time: 3 h
Yield: 69.6 %

Procedure:
p-Nitrophenol (178 mg, 1.28 mmol) and sodium hydride (64 mg of a 60% dispersion in mineral oil, 1.6 mmol) were stirred together in dry dimethylformamide (4 ml) at room temperature for 30 minutes then the chloride (416 mg, 1.07 mmol) from Example 16 was added. The mixture was stirred for a further 3 hours, then water (100 ml) was added and the mixture was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 20% ethyl acetate in hexanes) to give a pale yellow oil which crystallized from a mixture of chloroform and hexanes to give the title compound as a colourless solid (190 mg, 36%).
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:38][CH2:39][CH3:40])[C:26](NC(C4C=CC=CC=4)CO)=[O:27])=[CH:20][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:42].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH:11]1[C:12]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@@H:25]([O:38][CH2:39][CH3:40])[C:26]([OH:42])=[O:27])=[CH:20][CH:19]=3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: CCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)NC(CO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCO[C@H](Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)O
Temperature: 100 °C
Yield: 57 %

Procedure:
A solution of [2R diastereomer, N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide (0.45 g, 0.84 mmol) obtained in example 21a in mixture of 1M sulphuric acid (17 mL) and dioxane/water (1:1, 39 mL) was heated in an oil bath at 100° C. for 60-68 h. The pH of the mixture was adjusted to 3.0 by addition of an aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate (2×25 mL) and the organic extract was washed with water (50 mL), brine (25 mL), dried (Na2SO4) and evaporated. The residue was chromatographed over silica gel using a gradient of 50-75% ethyl acetate in pet. ether to afford the title compound (0.2 g, 57%) as a white solid. mp: 77-78° C.