Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:16]=[C:15]([O:30][CH3:31])[N:14]=2)[CH:8]=1)[CH3:4].O.[NH2:35]N>C(O)(=O)C>[CH3:31][O:30][C:15]1[N:16]=[C:17]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH:18]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:6]3[NH:35][N:2]=[C:3]([CH3:4])[N:5]=3)[CH:8]=2)[N:14]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(C(=O)N=C(C)N(C)C)c3)nc(OC)n2)cc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cccc(-c4nc(C)n[nH]4)c3)nc(OC)n2)cc1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of N-(1-dimethylamino-ethylidene)-3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzamide [0.132 mmol, Intermediate (46)] and hydrazine hydrate (15 μL, 0.48 mmol) in acetic acid (1 mL) is heated to 90° C. After stirring for 30 minutes removed from heat, quenched with saturated sodium bicarbonate solution (20 mL) and extracted twice with EtOAc (20 mL). The organic extracts are dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The resulting oil is subjected to flash column chromatography on silica gel eluting with 40% EtOAc in heptane gradient to afford {2-methoxy-6-[3-(5-methyl-2H-[1,2,4]triazol-3-yl)-phenyl]-pyrimidin-4-yl}-[2-(4-methoxy-phenyl)-ethyl]-amine [38 mg, 69%, Example 37]. LCMS: RT=2.59 minutes MS: 417 (M+H). IC50=3.7 nM
Reaction SMILES: COC([C:5]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O.COC(C(S(C)(=O)=O)(CC#CC1(OC(=O)C)CCCCC1)CCCCCCC(OC)=O)=O>>[CH3:32][S:29]([CH:5]([CH2:16][C:17]#[C:18][C:19]1([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:30])=[O:31]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: COC(=O)CCCCCCC(CC#CC1(OC(C)=O)CCCCC1)(C(=O)OC)S(C)(=O)=O
Product: COC(=O)CCCCCCC(CC#CC1(OC(C)=O)CCCCC1)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out by the procedure of Example 3, Step D, except that methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxyheptadecanoate is replaced by an equivalent quantity of methyl 8-methoxycarbonyl-8-methylsulfonyl-11-(1-acetoxycyclohexyl)-10-undecynoate.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]([CH2:28]C)[C:17]2=[O:30].[CH3:31][N:32]([CH3:37])[CH2:33][C:34](O)=[O:35].C(N(CC)CC)C>ClCCl>[CH3:31][N:32]([CH3:37])[CH2:33][C:34]([NH:13][C:14]1[CH:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]([CH3:28])[C:17]2=[O:30])=[O:35]
Reactant: CCn1c(=O)c2cc(N)ccc2c2ccccc21
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)Nc1ccc2c(c1)c(=O)n(C)c1ccccc21
Yield: 33.5 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (63 mg, 0.33 mmol) was added in one portion to a solution of 8-amino-5-ethyl-5H-phenanthridin-6-one I-16c (65 mg, 0.27 mmol), N,N-dimethylglycine (34 mg, 0.33 mmol) 4-dimethylaminopyridine (7 mg, 0.054 mmol), and triethylamine (0.076 ml, 0.55 mmol) in dichloromethane (5 ml). The resultant solution was stirred at 23° C. for 16 hours and diluted with 1:1 ethyl acetate/hexanes (20 ml). The reaction mixture was washed with water (25 ml) and saturated aqueous ammonium chloride (25 ml) and dried over anhydrous magnesium sulfate and concentrated. The residue was purified by rotary chromatography on silica gel (dichloromethane grading to 5% methanol/dichloromethane) to provide 2-dimethylamino-N-(5-methyl-6-oxo-5,6-di hydro-phenanthridin-8-yl)-acetamide 16A (28 mg, 33%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][OH:15])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
1-(tert-Butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (Bionet Co., 1.0 g) was dissolved in tetrahydrofuran (10 ml) and triethylamine (0.55 ml), and the mixture was cooled to 0° C. Under ice-cooling, ethyl chloroformate (0.34 ml) was added to the mixture, and the mixture was stirred for 30 min. Sodium borohydride (250 mg) was added and the mixture was stirred for 30 min. The mixture was warmed to room temperature and stirred for 2 hr. After completion of the reaction, 1N sodium hydroxide was added, and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-(hydroxymethyl)-4-phenyl-1-piperidinecarboxylic acid tert-butyl ester (1.0 g, yield 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[CH:15][S:16][C:12]=3[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.Cl>CN(C)C=O.C(OCC)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3[CH:14]=[CH:15][S:16][C:12]=3[CH2:11][CH2:10][N:9]2[CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2NCCc3sccc32)cc1
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: COc1ccc(CN2CCc3sccc3C2c2ccc(Cl)cc2)cc1
Reaction time: 72 h
Yield: 67.3 %

Procedure:
4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (0.10 g, 0.38 mmol) was dissolved in N,N-dimethylformamide (0.5 ml) and triethylamine (110 μl, 0.76 mmol) and 4-methoxybenzyl chloride (51 μl, 0.38 mmol) were added and the resulting mixture was shaken at 1000 rpm for 3 days. Water (2 ml) was added and the mixture was extracted with ethyl acetate (2×1 ml). The combined organic extracts were concentrated in vacuo. The residue was purified by preparative thin layer chromatography eluting with a mixture of ethyl acetate and heptane (1:4) to afford the free base. This was dissolved in diethyl ether and 1N HCl in diethyl ether was added drop wise to complete precipitation to afford 52 mg (34%) of the title compound.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([S:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([S:18]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)=[O:1])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCNC(=O)Nc1ccc(Sc2ccc(OC)c(-c3cccc(Cl)c3)c2)cc1
Reactant: OO
Solvent: CC(=O)O
Product: CCNC(=O)Nc1ccc(S(=O)c2ccc(OC)c(-c3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of 10% v/v 30% aqueous hydrogen peroxide (w/w) (1 mL) in glacial acetic acid (9 mL) was made. To a slurry of the above compound (P-448) (41.3 mg, 0.100 mmol) in acetic acid (300 uL) was added the hydrogen peroxide solution (96.7 uL, 0.100 mmol hydrogen peroxide). The solution was stirred for 1 hour at room temperature. The solvent was removed under vacuum, and the residue purified by silica gel thin layer chromatography (eluting with 10% acetone in dichloromethane), triturated with diethyl ether (5 mL), filtered, and dried to give the product (P-449) (29.3 mg, 68% yield) as a brown gum. 1H NMR (400 MHz, DMSO-d6) 7.55-7.44 (m, 5H), 7.36-7.32 (m, 5H), 7.20 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.27 (m, 1H), 3.84 (s, 3H), 3.29-3.22 (m, 2H), 1.12 (t, J=7.4 Hz, 1H) ppm. LCMS=97.6% purity. MS (APCI+)=429.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC.[F-].[Cs+]>O1CCOCC1.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>[CH:10]1([CH2:9][O:8][C:5]2[N:4]=[CH:3][C:2]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])=[CH:7][N:6]=2)[CH2:12][CH2:11]1
Reactant: Brc1cnc(OCC2CC2)nc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: C=C(OCC)c1cnc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
760 mg (3.32 mmol) of 5-bromo-2-cyclopropylmethoxypyrimidine in 15 mL of dioxane, 1.36 mL (3.82 mmol) of tributyl(1-ethoxyvinyl)tin, 58.22 mg (0.08 mmol) of bis(triphenylphosphine)palladium(II) chloride, 1.12 g (7.30 mmol) of cesium fluoride. This mixture is subjected to microwave irradiation at 110° C. for 1 hour. The reaction mixture is evaporated to dryness and the residue is taken up in 100 mL of ethyl ether. A solution of 2.80 g of cesium fluoride in 10 mL of water is added. After stirring for 1 hour at room temperature, the mixture is filtered through Celite. The filtrate is washed with aqueous NaHCO3 solution and then with saturated NaCl solution. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 10/90 EtOAc/heptane) to give 480 mg of 2-cyclopropylmethoxy-5-(1-ethoxyvinyl)pyrimidine, the characteristics of which are as follows:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:18][C:19]1[C:20]([C:44]2[CH:49]=[CH:48][C:47]([N:50]3[N:54]=[CH:53][CH:52]=[N:51]3)=[CH:46][CH:45]=2)=[CH:21][C:22](=[O:43])[N:23]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31]C2CCCCO2)=[O:29])[CH:24]=1>C(O)C>[F:18][C:19]1[C:20]([C:44]2[CH:45]=[CH:46][C:47]([N:50]3[N:54]=[CH:53][CH:52]=[N:51]3)=[CH:48][CH:49]=2)=[CH:21][C:22](=[O:43])[N:23]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][OH:31])=[O:29])[CH:24]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@](CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
Pyridinium p-toluenesulfonate (360 mg, 0.50 mmol) was added to a solution of (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (1.53 g, 2.87 mmol) in ethanol (60 mL). The solution was heated to 70° C. and was stirred at this temperature for 3 h. The reaction was allowed to cool and was stirred at rt for three days. The solid was collected via filtration, washed with ethanol (20 mL) and hexanes (20 mL). The solid was dried under vacuum to afford the title compound as a white solid (1.05 g, 81.5%). MS (LCMS) m/z 450.0 (M+1), 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3 H) 2.08-2.27 (m, 0 H) 2.38-2.59 (m, 1 H) 3.12 (s, 3 H) 3.72-3.90 (m, 1 H) 4.00-4.17 (m, 1 H) 6.62 (d, J=7.61 Hz, 1 H) 7.70-7.88 (m, 2 H) 8.08 (d, J=6.63 Hz, 1 H) 8.12-8.18 (m, 2 H) 8.19 (s, 2 H) 9.25 (d, J=1.95 Hz, 1 H) 11.09 (d, J=1.76 Hz, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc2nonc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc2nonc2c1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
5-(2-Hydroxyethyl)benzofurazan (1.48 g, 9 mmol) was dissolved in dichloromethane (45 ml) and triethylamine (1.88 ml, 1.37 g, 13.5 mmol) was added. The mixture was cooled to -30° C. and methanesulfonyl chloride (0.84 ml, 1.24 g, 10.8 mmol) was added dropwise over 5 minutes. The mixture was stirred at -30° C. for 15 minutes and dichloromethane (100 ml) was added. The mixture was washed with water (100 ml), dried (Na2SO4) and evaporated under reduced pressure to give the benzofurazan as a yellow solid (2.10 g, 96%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22]CC)=[O:21])[O:14][N:13]=1.O>O1CCOCC1>[F:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([OH:22])=[O:21])[O:14][N:13]=1
Reactant: CCOC(=O)[C@@](C)(CCc1cc(-c2cccc(OC)c2F)no1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2cc(CC[C@](C)(C(=O)O)S(C)(=O)=O)on2)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
Sodium hydroxide (1.0 M aqueous solution, 4.7 mL, 4.7 mmol, 4.0 equiv) was added to solution of ethyl(2R)-4-[3-(2-fluoro-3-methoxyphenyl)isoxazol-5-yl]-2-methyl-2-(methylsulfonyl)butanoate (0.47 g, 1.2 mmol, 1.0 equiv) in 1,4-dioxane (10 mL), and the reaction was allowed to stir overnight (18 h) at room temperature. Water (5 mL) was added, and the mixture was extracted with diethyl ether (25 mL). The aqueous phase was acidified to pH=3 with 1.0 M hydrochloric acid and then extracted with ethyl acetate (2×50 mL). The combined ethyl acetate phases were dried over potassium carbonate, filtered and concentrated under reduced pressure to provide a light tan solid (0.42 g, 96%). MS (LCMS) m/z 372.1 (M+1). 1H NMR (400 MHz, METHONAL-d4) δ1.68 (s, 3H) 2.26-2.41 (m, 1H) 2.61-2.74 (m, 1H) 2.85-3.00 (m, 1H) 3.04-3.15 (m, 1H) 3.16 (s, 3H) 3.92 (s, 3H) 6.65 (d, J=3.12 Hz, 1H) 7.18-7.24 (m, 2H) 7.36-7.44 (m, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:33]/[C:34](=[N:37]/[H])/[NH:35]O.[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:35]=[C:34]([CH2:33][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=3[Cl:25])[N:37]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: [H]/N=C(/Cc1cccc(Cl)c1Cl)NO
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(Cc3cccc(Cl)c3Cl)no2)c(=O)c2[nH]c(Cl)nc21
Yield: 54.8 %

Procedure:
Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (53 mg, 0.15 mmol) and (1Z)-2-(2,3-dichlorophenyl)-N-hydroxyethanimidamide (36 mg, 0.165 mmol; Entry 3, Table 7) and 21% ethanolic sodium ethoxide (0.083 ml, 0.22 mmol) were heated together in EtOH (0.75 ml) in the microwave reactor at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl, the organic phase separated, evaporated and the product purified by MDAP to give the title compound as a solid (42.1 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH:12]([CH3:16])[CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:15][O:14][CH2:13][CH:12]([CH3:16])[O:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: COCC(C)Oc1cc(Cl)cnc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)Oc1cc(Oc2ccccc2)cnc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 22 %

Procedure:
5-Chloro-3-(2-methoxy-1-methyl-ethoxy)-2-nitro-pyridine (2 mmol) is dissolved in DMF (15 ml), phenol (3 eq.) and K2CO3 (4 eq.) is added. The reaction is heated to 100° C. in the microwave for 45 min. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxy-1-methyl-ethoxy)-2-nitro-5-phenoxy-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow oil in a yield of 22%. HPLC (method C): 2.03 min; LC-MS (method A): 1.99 min, 305.15 (MH+).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CS(C)(=O)=O
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(=CN(C)C)S(C)(=O)=O
Temperature: 85 °C

Procedure:
6.65 g (40 mmol) of ethyl methanesulphonylacetate and 5.72 g (48 mmol) of N,N-dimethylformamide dimethyl acetal are admixed and heated at 85° C. overnight. The solution is concentrated using a rotary evaporator, and the solid is comminuted with cyclohexane and filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([NH:20][CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[CH:17]=[CH:16][N:15]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:33][CH:34]([Cl:38])[C:35](Cl)=[O:36]>ClCCl>[Cl:33][CH:34]([Cl:38])[C:35]([N:20]([C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH:19]=1)[CH2:21][O:22][CH:23]([CH3:25])[CH3:24])=[O:36]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)OCNc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-(2,6-Dichlorophenyl)isoxazol-5-yl)-N-(isopropoxymethyl)pyridin-4-amine (269 mg, 0.58 mmol) was dissolved in anhydrous dichloromethane with triethylamine (100 μL, 0.70 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (70 μL, 0.70 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 99:1 dichloromethane:methanol to yield 2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)-N-(isopropoxymethyl)acetamide (Cpd. No. 4). 1H NMR (CDCl3): 8.81 (d, 1H), 8.02 (s, 1H), 7.51-7.32 (m, 3H), 7.12 (s, 1H), 6.23 (s, 1H), 5.21 (s, 2H), 6.00 (s, 1H), 3.90 (m, 1H), 3.10 ppm (m, 6H). MW=489 confirmed by LC-MS, tr=14.57 min (Method Y) MH+=487-491.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[NH:23]1[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[N:24]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][N:23]2[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[N:24]2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
A mixture of 4-(4-chloromethylphenoxy)methyl-5-methyl-2-phenyloxazole (3.55 g), ethyl 1H-pyrazol-4-carboxylate (1.50 g), potassium carbonate (2.76 g), and N,N-dimethylformamide (25 ml) was stirred at room temperature for 24 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration, and ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carboxylate (3.79 g, yield: 91%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 108–109° C.
Reaction SMILES: C[Si](C[Mg]Cl)(C)C.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]1[S:18][C:19]2[C:24]([N:25]=1)=[CH:23][CH:22]=[C:21]([C:26]1([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27]1)[N:20]=2)[CH:12]=O.[CH3:35]C(C)([O-])C.[K+].Cl>C1COCC1>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH2:35])[CH:14]=[CH:15][C:16]=1[C:17]1[S:18][C:19]2[C:24]([N:25]=1)=[CH:23][CH:22]=[C:21]([C:26]1([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]1)[N:20]=2
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CC(C)(C)[O-]
Agent: C[Si](C)(C)C[Mg]Cl
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trimethylsilylmethylmagnesium chloride, 1.1 M solution in THF (15 mL) was added dropwise to a solution at 0° C. of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde (4.00 g, 11 mmol) in THF (80 mL) and the reaction mixture was stirred for 30 min at 0° C. The reaction mixture was quenched with 1 N aq. HCl and extracted with EtOAc twice, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in THF (100 mL), and cooled to 0° C. in ice bath. The slurry of potassium t-butoxide (2.4 g, 21 mmol) in THF (12 mL) was added slowly. At the end of the addition the reaction mixture was allowed to stir for 30 min at 0° C. At this time 1 N HCl was added and the mixture was extracted with EtOAc and the organic layer was dried over MgSO4. The residue was concentrated in vacuo and purified by silica gel chromatography to afford 2-(2-fluoro-4-vinylphenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine. MS (ESI) m/z: calculated: 372.1; Observed: 373.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:45][N:46]2[CH:50]=[N:49][CH:48]=[N:47]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][N:36]([CH:39]([CH3:43])[CH:40]([OH:42])[CH3:41])[C:35]5=[O:44])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.[Cl:51][CH2:52][C:53](Cl)=[O:54].N1C=CC=CC=1>C(Cl)Cl>[Cl:51][CH2:52][C:53]([O:42][CH:40]([CH3:41])[CH:39]([N:36]1[C:35](=[O:44])[N:34]([C:31]2[CH:30]=[CH:29][C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:12]5[CH2:11][O:10][C:9]([C:3]6[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=6[F:1])([CH2:45][N:46]6[CH:50]=[N:49][CH:48]=[N:47]6)[O:13]5)=[CH:17][CH:18]=4)[CH2:27][CH2:26]3)=[CH:33][CH:32]=2)[CH:38]=[N:37]1)[CH3:43])=[O:54]
Reactant: CC(O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(OC(=O)CCl)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Temperature: 25 °C

Procedure:
A mixture of intermediate 2a (0.01 mol) and chloroacetyl chloride (0.0115 mol) in CH2Cl2 (200 ml) was stirred at room temperature. Pyridine (0.02 mol) was added and the mixture was stirred for 2 hours, washed with water, dried, filtered and the solvent was evaporated. The residue was crystallized from MIK/DIPE. The precipitate was filtered off and dried, yielding 6.7 g (87%) [2S-[2α,4α[(R*,R*)]]]-2-[4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]-1-methylpropyl chloroacetate. (interm.3)