Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][CH2:6][N:7](C)[CH3:8])[CH2:3][CH2:2]1.CN>C1C=CC=CC=1>[CH:1]1([C:4](=[O:10])[CH2:5][CH2:6][NH:7][CH3:8])[CH2:3][CH2:2]1
Reactant: CN(C)CCC(=O)C1CC1
Agent: CN
Solvent: c1ccccc1
Product: CNCCC(=O)C1CC1

Procedure:
A solution of 42.5 g. (0.3 mole) of 1-cyclopropyl-3-dimethylamino-1-propanone in 200 ml. of benzene was refluxed while methylamine was bubbled through the solution for eight hours. The nuclear magnetic resonance spectrum indicated a 90% conversion to 1-cyclopropyl-3-methylamino-1-propanone.
Reaction SMILES: N1C=CC=CC=1.S(Cl)(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:23]1[C:24]([O:29][CH3:30])=[N:25][CH:26]=[CH:27][CH:28]=1)O.[Cl-:31].[NH4+]>ClCCl>[Cl:31][C:15]1([C:23]2[C:24]([O:29][CH3:30])=[N:25][CH:26]=[CH:27][CH:28]=2)[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([Cl:11])[CH:13]=2)[NH:17][C:16]1=[O:21]
Reactant: [Cl-]
Reactant: COc1ncccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ncccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyridine (0.33 ml) and thionyl chloride (0.30 ml) were added successively to an ice-cold solution of the intermediate from Step A (1.1 g, 3.44 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude intermediate was rapidly employed without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22](O)=[O:23])=[N:20][CH:21]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:58]1[CH2:63][CH2:62][NH:61][CH2:60][C:59]1=[O:64]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:61]4[CH2:62][CH2:63][NH:58][C:59](=[O:64])[CH2:60]4)=[O:23])=[N:20][CH:21]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C1CNCCN1
Reactant: COc1ccc(-c2cnc(Nc3ccc(C(=O)O)nc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cnc(Nc3ccc(C(=O)N4CCNC(=O)C4)nc3)nc2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-pyridine-2-carboxylic acid 5 (0.05 mmol) in DMF (1 mL) is added HATU (0.06 mmol) and DIEA (0.14 mmol) at rt. The resulting mixture is stirred for 2 min and then piperazine-2-one (0.05 mmol) is added. The reaction mixture is stirred at it for 12 h and then directly purified by preparative LCMS to give 4-{5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]pyridine-2-carbonyl}-piperazin-2-one A2 as a white solid. 1H NMR (400 MHz, d4-CH3OH) δ 8.98 (d, J=4.0 Hz, 1H), 8.77 (s, 1H), 8.53-8.52 (m, 2H), 7.74-7.73 (m, 2H), 7.58-7.56 (m, 2H), 7.07-7.05 (m, 2H), 3.94 (bs, 2H), 3.81 (s, 3H), 3.46 (bs, 2H), 3.45 (bs, 2H). MS (m/z) (M+1)+: 405.2.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[N+:10]([C:3]1[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[CH:9][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
4-Bromo-3-nitrobenzaldehyde (2.0 g) was suspended in N,N-dimethylformamide (30 mL), phenylboronic acid (1.3 g), sodium carbonate (1.8 g), water (6 mL) and tetrakis-(triphenylphosphine)palladium(0) (1.0 g) were added, and the resulting mixture was stirred at 90° C. for 17 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed successively with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (1.6 g).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])/[CH:1]=[CH:2]/[CH:3]([OH:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(O)CCCCCCCC
Product: CCCCCCCCC(O)/C=C/[Sn](CCCC)(CCCC)CCCC
Temperature: 120 °C

Procedure:
To 0.07g (0.42 mmol) of the titled product of Example 7 is added 0.15g (0.5 mmol) of tri-n-butyltin hydride and 20mg of azoisobutyronitrile (AIBN). The reaction mixture was heated to 120°C. for 2 hours. Afterwards, it was cooled to room temperature and pumped at high vacuum overnight. The crude reaction mixture was then heated to 90°C. and maintained at high vacuum for 2 additional hours. Upon cooling to room temperature, the crude product was used as is.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C:10]1[CH:11]=[C:12]([C:21]([O:23]CC)=[O:22])[C:13]([C:16]([O:18]CC)=[O:17])=[N:14][CH:15]=1)[CH3:9].[OH-].[Na+]>O>[CH2:8]([C:10]1[CH:11]=[C:12]([C:21]([OH:23])=[O:22])[C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1)[CH3:9]
Reactant: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cnc(C(=O)O)c(C(=O)O)c1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Toluene 50 ml, 5-ethyl-2,3-diethoxycarbonylpyridine 10.3 g (0.041 mol), and water 29 ml were mixed in a 200 ml four neck distillation flask with a reflux condenser, and 48% aqueous sodium hydroxide solution 21.9 g was added thereto under vigorous stirring in nitrogen atmosphere and refluxed for 3.5 hours. The reaction mixture was allowed to cool to room temperature and stand still to separate into water layer and toluene layer. The water layer was acidified at 45° to 55° C. with 28.3 g of 50% sulfuric acid, and slowly cooled to 20° C. The resultant white crystals were filtered and washed with 10 ml of cold water. Dried under reduced pressure at 50° to 60° C., 5.9 g of 5-ethylpyridine-2,3-dicarboxylic acid was obtained. The melting point of the obtained crystals was 154° to 156° C. (decomposed). The 5-ethylpyridine-2,3-dicarboxylic acid obtained was recrystallized from a mixed solvent of acetone and n-hexane and gave a melting point of 156.5° C. to 157.5° C. (decomposed).
Reaction SMILES: [Cl-].C([NH+](CC)CC)C.[C:9]1([CH3:19])[CH:14]=CC(S([O-])(=O)=O)=C[CH:10]=1.[NH+]1C=CC=CC=1.S(=O)(=O)(O)[O-].[NH4+].S(=O)(=O)(O)[O-].[K+].[CH:38]([O:45][CH2:46]C)([O:42][CH2:43]C)OCC.CC(C)=CC=O>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)C>[CH3:46][O:45][CH:38]([O:42][CH3:43])[CH:10]=[C:9]([CH3:19])[CH3:14]
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CC(C)=CC=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[NH+](CC)CC
Solvent: CCO
Product: COC(C=C(C)C)OC
Temperature: 2 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Various acidic catalysts were tested in J. Org. Chem. 1995, 60, 1995, 3397-3400. Use of p-toluenesulfonic acid resulted in polymerization of the 3-methyl-2-butenal. Triethylammonium chloride, pyridinium p-toluenesulfonate, tetrabutylammonium bisulfate and ammonium bisulfate likewise gave unsatisfactory results. Potassium bisulfate proved to be more suitable. The reaction conditions are likewise described in the Patent Application EP 0629619. Triethyl orthoformate and 3-methyl-2-butenal are added to abs. ethanol at 4° C. The clear solution is cooled to 2° C., and potassium bisulfate is added. The heterogeneous reaction mixture warms to 10° C. owing to the exothermic reaction. The mixture is then allowed to warm to 21° C. over the course of 45 minutes and is then stirred at this temperature for 15 minutes. The catalyst is then filtered off and washed with ethanol. The filtrate is mixed with potassium carbonate and stirred at room temperature for one hour. The potassium carbonate is then likewise filtered off and washed with ethanol. Distillation affords 3-methyl-2-butenal dimethyl acetal in a yield of 85%. The disadvantages of this process are that elaborate temperature control is required and the alternating cooling and warming steps require increased energy consumption and elaborate apparatus.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:12]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:12]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:11]([C:37]3[CH2:38][CH2:39][O:34][CH2:35][CH:36]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CCOC(=O)c1c(C2CCOCC2)nc2c(c1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C2CCOCC2)nc2c(c1C1=CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-ethyl 5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-(tetrahydro-2H-pyran-4-yl)-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]([N:13]=[C:14]=[O:15])([CH3:12])[CH2:10]I)[CH:3]=1.C([OH:20])(C)(C)C>CN(C)C=O.F[B-](F)(F)F.[Ag+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]2([CH3:12])[CH2:10][O:20][C:14](=[O:15])[NH:13]2)[CH:3]=1
Reactant: CC(C)(C)O
Reactant: CC(CI)(N=C=O)c1cc(Br)ccc1F
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1(c2cc(Br)ccc2F)COC(=O)N1
Temperature: 80 °C

Procedure:
A solution of the crude (RS)-4-bromo-1-fluoro-2-(2-iodo-1-isocyanato-1-methyl-ethyl)-benzene (20.0 g, 52 mmol) in N,N-dimethylformamide (180 ml) and tert-butanol (7.7 ml, 104 mmol) was treated with silver tetrafluoroborate (11.15 g, 57 mmol). The yellow suspension was heated at 80° C. for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure. After chromatography on silica gel using a using a gradient of heptane and ethyl acetate=100/0 to 40/60 as the eluent, the (RS)-4-(5-bromo-2-fluoro-phenyl) -4-methyl-oxazolidin-2-one (intermediate C4A) was obtained as a white solid (28.49 g, 53.5% of theory).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=[C:13]([O:1][CH2:2][CH2:3][C:4]3[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=3)[C:7]#[N:8])[CH:23]=[C:17]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cccc(CCO)c1
Product: CN1CCCn2c1cc(OCCc1cccc(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from of 3-(2-hydroxyethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[Br:14]Br.O>C(O)(=O)C>[Br:14][CH:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(=O)[nH]1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(Br)c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a solution of 2-ethyl-3H-quinazolin-4-one (3.0 g, 17.22 mmol) in glacial acetic acid (50 ml) cooled in an ice bath was added dropwise a solution of bromine (2.75 g, 17.22 mmol) in glacial acetic acid (5 ml). After addition was complete, the reaction was heated to reflux for 18 hours. At which time it was allowed to cool to room temperature. Water was then added to the solution and the mixture was extracted with dichloromethane. The organic layer was then washed with 10% sodium bisulfite solution, and then washed with saturated brine (2×30 ml). The combined organic phase was collected and dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a brown crude product. The resulting residue was purified by silica gel chromatography with 50% dichloromethane in hexane. The product was collected and was dried under reduced pressure to give 2-(1-Bromo-ethyl)-3H-quinazolin-4-one (Yield 3.02 g, 69.74%). 1H NMR (400 MHz, DMSO-d6): δ 2.22 (d, 3H, J=6.57 Hz), 5.09 (q, 1H, J=14.40, 6.57 Hz), 7.57 (m, 1H), 7.69 (d, 1H, J=8.08 Hz), 7.87-7.80 (m, 1H), 8.12 (d, 1H, J=6.82 Hz), 12.42 (s, 1H). MS m/z calc. 251.99, found (ESI); 253.0 (M+1)+. Retention time 2.60 minutes.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=O)=[C:7]([CH:9]=1)[NH2:8])[CH3:2].[N:13]#[C:14][NH2:15].[CH]Cl.[OH-].[Na+]>O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N+:10]([O-:12])=[N:13][C:14]([NH2:15])=[N:8][C:7]=2[CH:9]=1)[CH3:2]
Reactant: N#CN
Reactant: CCc1ccc([N+](=O)[O-])c(N)c1
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc2c(c1)nc(N)n[n+]2[O-]
Temperature: 50 °C
Reaction time: 3 h
Yield: 43.3 %

Procedure:
A mixture of 5-ethyl-2-nitroaniline (21) (1.38 g, 8.3 mmol) and cyanamide (1.40 g, 33.2 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (15 mL) added carefully and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (100 mL), filtered, washed with water (3×20 mL), washed with ether (3×5 mL) and dried. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 22 (684 mg, 43%) as a yellow powder, mp (MeOH) 259-262° C.; 1H NMR [(CD3)2SO] δ 8.03 (d, J=8.8 Hz, 1 H, H-8), 7.31 (d, J=1.7 Hz, 1 H, H-5), 7.20-7.25 (m, 3 H, H-7, NH2), 2.72 (q, J=7.6 Hz, 2 H, CH2), 1.23 (t, J=7.6 Hz, 3 H, CH3); 13C NMR [(CD3)2SO] δ 160.3, 152.4, 149.0, 128.2, 125.6, 123.2, 119.6, 28.2, 14.5. Anal. calcd for C9H10N4O: C, 56.8; H, 5.3; N, 29.5. Found: C, 56.7; H, 5.1; N, 29.2%.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][C:5]1[NH:9][CH:8]=[N:7][C:6]=1[CH2:10][S:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:25]=NC=[CH:28][CH:29]=2)=[CH:18][N:17]=1.[N:30]1C=CC=C(CC2C(=O)NC(SC)=NC=2)[CH:31]=1>>[ClH:1].[ClH:1].[ClH:1].[CH3:4][C:5]1[NH:9][CH:8]=[N:7][C:6]=1[CH2:10][S:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:30]=[CH:31][CH:25]=2)=[CH:18][N:17]=1
Reactant: Cc1[nH]cnc1CSCCCNc1ncc(Cc2cccnc2)c(=O)[nH]1
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Agent: Cl
Product: Cc1[nH]cnc1CSCCCNc1ncc(Cc2ccncc2)c(=O)[nH]1

Procedure:
In a similar manner 2-[3-(5-methyl-4-imidazolylmethylthio)propylamino]-5-(3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p. 184°-189° was prepared from 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[O:33]1[C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=[N:34]1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:38]([C:37]3[O:33][N:34]=[CH:35][CH:36]=3)=[O:39])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: O=C(Cl)c1ccno1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)c3ccno3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (2 ml). At room temperature, isoxazol-5-carbonyl chloride (26 mg, 197 μmol, 3 eq.) was added, and the mixture was stirred overnight. Once HPLC showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (5 mg, 15% of theory).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[C:12](=[N:14][OH:15])[CH3:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:17][NH:18][C:19]([NH2:21])=[S:20].C(O)(=O)C>CO.O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:17][NH:18][C:19]([NH2:21])=[S:20])[C:12](=[N:14][OH:15])[CH3:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: NNC(N)=S
Reactant: CC(=O)Nc1ccc(C(=O)C(C)=NO)cc1
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C(=NNC(N)=S)C(C)=NO)cc1
Yield: 68.2 %

Procedure:
4'-Acetamido-2-hydroxyiminopropiophenone (1.87 g) was added to a suspension of thiosemicarbazide (1 g) and acetic acid (0.1 ml) in a mixture of methanol (15 ml) and water (3 ml) and then heated at 100° for 39 hours with stirring. After cooling, the resultant precipitates were collected by filtration, washed with methanol, and then dried to give 1.7 g of 4'-acetamido-2-hydroxyiminopropiophenone thiosemicarbazone.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:49][C@@H:50]([CH2:64][C:65]1[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=1)[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1>CN(C=O)C.C(Cl)(Cl)Cl>[F:71][C:69]1[CH:70]=[C:65]([CH:66]=[C:67]([F:72])[CH:68]=1)[CH2:64][C@H:50]([NH:49][C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:7])[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To methyl hydrogen isophthalate (1.0 g, 5.6 mmol) in DMF/chloroform (1:2, 15 mL) is added diisopropylethylamine (3.9 mL, 22 mmol), HATU (2.5 g, 6.7 mmol), then (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (2.5 g, 6.1 mmol). The reaction is stirred 1 h at room temperature. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) gives the title compound. ESI MS m/z 497.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24]CC3C=CC=CC=3)[C:19]=2[O:32]CC2C=CC=CC=2)=[CH:7][CH:6]=1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:40])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:19]=2[OH:32])=[CH:9][CH:10]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OCCCCCCc2cccc(O)c2O)cc1
Yield: 85 %

Procedure:
A solution of 2.3 g of 4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid ethyl ester in 50 mL of ethyl acetate and 0.3 g of 10% palladium on carbon was stirred in a hydrogen atmosphere for 22 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to a solid. Recrystallization from ethyl acetate-hexane gave 1.3 g, mp 45°-47°, (85% yield) to 4-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid ethyl ester.
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:13](OCCC(C)C)=O.[C:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[C:27]([CH3:35])[C:26]=1[F:36])(=[O:23])[CH3:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:21]([O:24][C:25]1[C:26]([F:36])=[C:27]2[C:28](=[CH:29][CH:30]=1)[N:31]([C:32](=[O:34])[CH3:33])[N:13]=[CH:35]2)(=[O:23])[CH3:22]
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1ccc(OC(C)=O)c(F)c1C
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc2c(cnn2C(C)=O)c1F
Reaction time: 11 h
Yield: 42.4 %

Procedure:
Acetic anhydride (2.83 ml, 30.0 mmol), tetrabutylammonium bromide (161 mg, 0.500 mmol), potassium acetate (1.96 g, 20.0 mmol) and isoamyl nitrite (1.75 ml, 13.0 mmol) were added in that order to a solution of 4-(acetylamino)-2-fluoro-3-methylphenyl acetate (2.25 g, 9.99 mmol) in ethyl acetate (30 ml) at room temperature. The resulting mixture was slowly heated until heating under reflux was caused. Then, the mixture was stirred for 11 hours while maintaining the temperature. After cooling, the mixture was partitioned and extracted with water and ethyl acetate, and the organic phase was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-acetyl-4-fluoro-1H-indazol-5-yl acetate (1.00 g, 38%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([C@@H:9]1[NH:12][C:11](=[O:13])[C@H:10]1[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[N:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:8].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:6][C:7]([C@@H:9]1[N:12]([C:1](=[O:3])[CH3:2])[C:11](=[O:13])[C@H:10]1[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[N:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])=[O:8]
Reactant: COC(=O)[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Yield: 32.5 %

Procedure:
Acetyl chloride (9.5 g, 0.12 mol) was added to a -10° C. methylene chloride (50 mL) solution of compound 7 (2.0 g, 4.0 mmol). Triethylamine (12.3 g, 0.12 mol) was added dropwise with vigorous stirring of the reaction mixture. After the addition was complete, the resultant suspension was stirred for an additional 2 h at room temperature and then washed with H2O. The organic phase was separated, washed with saturated aqueous NaHCO3 solution, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 :MeOH/99.5:0.5) to afford 700 mg (36%) of the title product.