Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]#[N:8])[N:3]=[CH:2]1.CN[C@@H]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[NH:17][CH3:18].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:25][N:26]([CH:28]=[O:29])[CH3:27]>>[CH:12]1([N:17]2[C:18]3[N:3]=[C:2]([N:1]4[CH:5]=[C:4]([CH2:6][C:7]#[N:8])[N:3]=[CH:2]4)[N:1]=[CH:5][C:25]=3[N:26]([CH3:27])[C:28](=[O:29])[C@H:4]2[CH2:6][CH3:7])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: N#CCc1c[nH]cn1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(CC#N)c3)nc2N1C1CCCC1
Temperature: 110 °C

Procedure:
A mixture of intermediate B (150 mg, 0.509 mmol), 2-(1H-imidazol-4-yl)acetonitrile (1.01 mmol, 2 equivalents, 108 mg), Cut (0.1 equivalents, 0.0509 mmol, 10 mg), trans-1,2 bis(methylamino)cyclohexane (14 mg, 0.102 mmol) and Cs2CO3 (1.01 mmol, 331 mg) in DMF (1 mL) was purged with nitrogen and was subsequently heated in a sealed vial at 110° C. for 18 h. The reaction was diluted with ethyl acetate, filtered through Celite and evaporated. The residue was purified by reverse phase preparative HPLC and lyophilized to give the title compound (185 mg). 1H NMR (CDCl3) δ: 8.66 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 4.31-4.37 (m, 2H), 3.91 (s, 2H), 3.38 (s, 3H), 1.70-2.13 (m, 10H), and 0.93 ppm (t, J=7.4 Hz, 3H); LCMS: 366.1 m/z (M+H)+; ret. Time: 3.444 min (Analytical Method A).
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](=O)([O:13][CH3:14])[O:11]C>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.S1(CCCC1)(=O)=O>[C:10]([O:13][CH3:14])(=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)OC
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1ccccc1
Temperature: 150 °C
Reaction time: 22 h
Yield: 92.6 %

Procedure:
A mixture of 7.03 g (0.05 g mole) of benzoyl chloride, 4.5 g (0.05 g mole) of dimethyl carbonate, and 0.85 g (0.0025 g mole) of tetra-n-butyl phosphonium bromide (TBPB) in 25 ml of sulfolane was heated at 150° C. in a reaction flask equipped with reflux condenser. After 22 hours, the condenser was replaced by a distillation head and 6.3 g (93 percent yield) of methyl benzoate distilled at 83° C.-85° C./17 mm.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH2:6][C:5](C(OCC)=O)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][O:3]1.[Cl-].[Na+].O.C(O)C>CS(C)=O>[CH3:1][C:2]1([CH3:18])[O:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][O:7]1
Reactant: CCOC(=O)C1(C(=O)OCC)COC(C)(C)OC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)C1COC(C)(C)OC1
Temperature: 180 °C
Yield: 53.2 %

Procedure:
To a solution of the product of Example 2 (65 g) in dimethyl sulfoxide (65 g) is added sodium chloride (1 g). The mixture is stirred while warming at about 180° C., and water is added in small portions while maintaining the temperature between 170° and 180° . Ethanol and water are evolved and are removed by distillation until about 60 ml of liquid has been collected. The mixture is cooled, ether (200 ml) added, and the mixture partitioned with 3 portions of water (50 ml). The organic phase is dried over sodium sulfate and evaporated to a residue. Distillation of the residue gives the title product (25 g) (57%) B.P. 38° (0.01 mm) nD26 1.4400.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1>ClCCl>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([C:18]([N:20]3[CH2:21][CH2:22][N:23]([C:42]([NH:41][C:38]4[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:40][CH:39]=4)=[O:43])[CH2:24][CH2:25]3)=[O:19])[CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCN(C(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reaction time: 8 h

Procedure:
tert-Butyl (2R)-4-cyclobutyl-2-(piperazin-1-ylcarbonyl)piperazine-1-carboxylate (350 mg) was stirred at room temperature in dichloromethane (15 ml). Triethylamine (0.14 ml) was added followed by 4-(trifluoromethyl)phenyl isocyanate (0.14 ml) and the solution stirred overnight. The solvent was removed in vacuo and the residue adsorbed onto silica for purification by chromatography eluting with 0-7.5% methanol/dichloromethane. This gave tert-butyl (2R)-4-cyclobutyl-2-{[4-({[4-(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]carbonyl}piperazine-1-carboxylate as a white glass (370 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:11](O)[CH2:12][CH3:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[SH:15][CH2:16][C:17]([OH:19])=[O:18].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1[C:3]([CH:11]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH3:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=C(O)CS
Reactant: CCC(O)c1cc2c(cc1C)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCC(SCC(=O)O)c1cc2c(cc1C)OCO2
Yield: 90.2 %

Procedure:
2.27 g of 1-(6-methyl-1,3-benzodioxol-5-yl)-1-propanol, 0.1 g of p-toluenesulfonic acid and 1.52 g of mercaptoacetic acid were dissolved in 80 ml of benzene. The solution was heated under reflux for 12 h while water was removed. The reaction mixture was poured into water. The aqueous layer was made alkaline and washed with ether. The aqueous layer was then acidified and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain a faint yellow solid. It was purified according to silica gel column chromatography (ethyl acetate/ hexane=2:8) to obtain 2.83 g of the intended compound in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]#[N:13].[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([C:12]#[N:13])=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=1
Reactant: CC(=O)Nc1ccc(Cl)c(C#N)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1cc(C#N)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 28.7 %

Procedure:
N-(4-Chloro-3-cyano-phenyl)-acetamide (3.00 g, 15.4 mmol) was dissolved in conc. sulfuric acid (15 mL) and cooled to 0° C. A solution of potassium nitrate (3.12 g, 30.8 mmol) in conc. sulfuric acid (15 mL) was added drop-wise with stirring. The reaction mixture was kept at 0° C. for 3.5 h, then slowly added to stirred ice/water. The resulting precipitate was collected, dissolved in EtOAc, dried, filtered, and concentrated. The residue was purified (FCC) (10-80% EtOAc/hexanes) to yield the titled compound (1.06 g, 29% yield). This compound did not yield MS data. 1H NMR (400 MHz, CDCl3): 10.60 (s, 1H), 9.18 (s, 1H), 8.58 (s, 1H), 2.36 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][C:19]([C:25]#[N:26])=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=1>O1CCCC1>[Br:34][C:30]1[CH:29]=[C:28]([NH:27][C:18]2[C:17]3[C:22](=[CH:23][CH:24]=[C:15]([NH:14][C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[CH:16]=3)[N:21]=[CH:20][C:19]=2[C:25]#[N:26])[CH:33]=[CH:32][CH:31]=1
Reactant: CCCC(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
Triethylamine (0.359 g, 3.55 mmol) and butyryl chloride (0.380 g, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed, and the residue was slurried with water and collected. The residue was washed with boiling methanol and dried in vacuo to give 0.773 g of brown powder; mp 276-277 ° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[NH:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([Cl:25])=[O:24].C(O)C>CO.C(OCC)(=O)C>[ClH:25].[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:23]([C:19]1[NH:18][CH:22]=[CH:21][CH:20]=1)=[O:24]
Reactant: O=C(Cl)c1ccc[nH]1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: Cl
Product: O=C(Nc1ccccc1C(=O)NCCc1ncc[nH]1)c1ccc[nH]1
Yield: 70.9 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 11 using 1.50 g (0.00651 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)-ethyl]benzamide, prepared as in Example 6A, and 1.36 g (0.0105 mol) of pyrrole-2-carboxylic acid chloride with the exception that after reducing the initial reaction solution to dryness the resultant residue was dissolved in methanol. The resulting solution was refluxed for approximately an hour and then reduced to dryness under reduced pressure to provide a solid. This solid was dissolved in an ethyl acetate/aqueous sodium bicarbonate mixture containing a small amount of ethanol. The resultant layers were separated and the organic layer was washed with a saturated sodium chloride solution, with anhydrous sodium sulfate and then reduced to dryness under reduced pressure. The resultant solid was dissolved in methanol containing diethyl ether and hydrochloric acid. After removing the methanol under reduced pressure, the final product was purified by crystallization from an ethanol/ethyl acetate solution, followed by recrystallization from a methanol/ethyl acetate solution, to provide 1.66 g of the desired titled compound (m.p. 237°-239° C.).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[CH3:14][C:15](=[N:19]O)[C:16](=O)[CH3:17].[ClH:21].C(OCC)(=O)C>>[Cl:21][CH2:14][C:15]1[N:19]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])[O:2][C:16]=1[CH3:17]
Reactant: COC(=O)c1cc(C=O)ccc1C
Reactant: Cl
Reactant: CC(=O)C(C)=NO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2nc(CCl)c(C)o2)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 41 %

Procedure:
A mixture of methyl 5-formyl-2-methylbenzoate (2.10 g), 2,3-butanedione-2-oxime (1.19 g) and 4N hydrogenchloride-ethyl acetate (50 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated, diethyl ether was added to the residue to allow precipitation of crystals, and crystals were collected by filtration. A mixture of the obtained crystal, tetrahydrofuran (50 mL) and thionyl chloride (2.11 g) was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 5-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)-2-methylbenzoate as colorless crystals (1.34 g, yield 41%) from a fraction eluted with ethyl acetate-hexane (1:9, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 89-90° C.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:14]([C:26]#[N:27])=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[Cl:37][C:38]1[CH:39]=[N:40][C:41](I)=[N:42][CH:43]=1.CCOC(C)=O>CN1C(=O)CCC1>[Cl:37][C:38]1[CH:39]=[N:40][C:41]([N:23]2[CH2:24][CH2:25][CH:20]([O:19][C:15]3[C:14]([C:26]#[N:27])=[N:13][N:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:11][CH:10]=4)[C:17](=[O:18])[CH:16]=3)[CH2:21][CH2:22]2)=[N:42][CH:43]=1
Reactant: Clc1cnc(I)nc1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-n2nc(C#N)c(OC3CCN(c4ncc(Cl)cn4)CC3)cc2=O)cc1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
To a stirring solution of 1-(4-(methylsulfonyl)phenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl (124 mg, 0.33 mmol) in NMP (3 mL) at room temperature under argon was added DIPEA (128 mg, 0.99 mmol) and 5-chloro-2-iodopyrimidine (159 mg, 0.66 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜3 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 121 mg (75%) of 4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile was obtained as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.75-2.27 (m, 4H) 3.08 (s, 3H) 3.66-3.97 (m, 2H) 3.97-4.24 (m, 2H) 4.54-4.95 (m, 1H) 6.34 (s, 1H) 7.84 (d, J=8.79 Hz, 2H) 8.07 (d, J=8.79 Hz, 2H) 8.24 (s, 2H). MS (ESI) 487 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11](O)=[O:12])[C:7](=[O:20])[CH:6]=1.[CH3:25][C:26]1([CH3:38])[O:30][C@H:29]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]2)[CH2:28][O:27]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:25][C:26]1([CH3:38])[O:30][C@H:29]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([NH:37][C:11](=[O:12])[CH:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=4[Cl:1])=[CH:6][C:7]3=[O:20])[CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[N:33]2)[CH2:28][O:27]1
Reactant: O=C(O)C(CCC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CCC(F)(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-pentanoic acid (182 mg, 0.50 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 118 mg, 0.60 mmol) in N,N-dimethylformamide (4 mL). This mixture was treated with N,N-diisopropyethylamine (250 μL, 1.5 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (330 mg, 0.75 mmol) and stirred overnight at 25° C. After this time, the reaction was diluted with ethyl acetate (25 mL) and washed with a saturated aqueous solution of ammonium chloride (25 mL), saturated aqueous solution of sodium bicarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL), dried over sodium sulfate and concentrated with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 80% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (216 mg, 79%) as a white foam: HR-ES-MS m/z calculated for C24H26N4O5ClF3 [M+H]+ 543.1617, observed 543.1619.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C@@H:27]([CH3:30])[CH2:28][OH:29])=[N:24][CH:25]=1>>[OH:29][CH2:28][C@@H:27]([NH:26][C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1)[CH3:30]
Reactant: C[C@@H](CO)Nc1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: C[C@@H](CO)Nc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-2-(5-amino-pyridin-2-ylamino)-propan-1-ol. LCMS calcd for C19H17F3N4O3 (m/e) 406, obsd 407 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:4].[CH2:24](O)[CH2:25][CH2:26]C>>[CH2:1]([O:2][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:4])[CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCCCO
Product: CCCCOC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Yield: 87 %

Procedure:
5 g of adenosine-5'-carboxylic acid methyl ester are dissolved in 200 ml of n-butanol and, together with 3 g of D-benzedrine, boiled under reflux for 3 hours. The reaction mixture is filtered and the filtrate evaporated in a vacuum. The evaporation residue is triturated with ether, filtered off with suction, again washed with ether and dried. There are thus obtained 5.6 g of adenosine-5'-carboxylic acid n-butyl ester, which has a melting point of 166°-167° C. The yield is 87% of theory. The crude product obtained can be recrystallized from water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:32]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:32][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[F:1])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(C)cc1F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(C(=O)CBr)c(F)c1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a chloroform (7.5 mL) solution of 1-(2-fluoro-4-methylphenyl)ethanone (0.50 g), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (0.65 mL) and trimethylsilyl trifluoromethanesulfonate (0.71 mL) were added, and the resultant was stirred for 30 minutes. Then, N-bromosuccinimide (0.64 g) was added thereto, and the resultant was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, and the resultant was stirred for 10 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=99/1→95/5) to obtain the title compound (0.72 g) as a white solid.
Reaction SMILES: [K].[CH2:2]([O:4][C:5](=[O:18])/[C:6](/[O-:17])=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:3].[K+].[C:20]([O:23][C@@H:24]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@@H:29]([O:35][C:36](=[O:38])[CH3:37])[C@@H:28]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[O:27][C@@H:25]1O)(=[O:22])[CH3:21]>CN(C=O)C>[C:36]([O:35][C@H:29]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:24]([O:23][C:20](=[O:22])[CH3:21])[C@@H:25]([O:17]/[C:6](/[C:5]([O:4][CH2:2][CH3:3])=[O:18])=[CH:7]\[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[O:27][C@H:28]1[CH2:39][O:40][C:41](=[O:43])[CH3:42])(=[O:38])[CH3:37]
Reactant: CCOC(=O)/C([O-])=C/c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/c1ccccc1[N+](=O)[O-])O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
The solution of potassium salt of 2-nitrophenylpyruvate B2 (100 mg, 0.36 mmol) in dry DMF (3 mL) was added dropwise over a period of 15 min, to a pre-cooled stirred solution of 2,3,4,6-tetra-O-acetyl-α-D-galactose (149 mg, 0.36 mmol) in dry DMF (2 mL) at 0° C. under nitrogen atmosphere. The temperature was gradually raised to room temperature. Reaction mixture was allowed to stir for 15 h, and the reaction was quenched with chilled, saturated aq. NaCl (25 mL). Extraction with ethyl acetate (3×30 mL), drying (MgSO4), concentration under reduced pressure, and purification by flash chromatography (SiO2, hexane-benzene-acetone-methanol, 5:4:5:1) to isolate the pure resultant compound C3 in 50% yield.
Reaction SMILES: N[C@@H:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].Cl.N([O-])=O.[Na+]>O>[O:4]=[C:3]1[O:5][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:2]1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CC[C@@H](C(=O)O)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.3 %

Procedure:
To a solution of (S)-2-aminopentanedioic acid (100 g, 680 mmol) in H2O (500 mL) was added HCl (140 mL, 1.6 mol) and then NaNO2 (70.4 g, 1.02 mol) in H2O (100 mL) was added slowly at −5° C.-0° C., and the reaction mixture was stirred at room temperature for 24 hours. The solvent was concentrated in vacuo below 50° C. The residue was suspended in EtOAc (500 mL) and filtered. The filtrate was dried over Na2SO4 and concentrated in vacuo to afford 56 g crude product of (2S)-5-oxotetrahydrofuran-2-carboxylic acid (compound 28a) as yellow oil, which was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[K+].Cl>CS(C)=O.O1CCCC1.O>[CH2:23]([O:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][OH:7])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCCCCCCCCCCCCCBr
Reactant: COC(CO)CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCOCC(CO)OC
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
In a mixture of 30 ml of dimethyl sulfoxide (DMSO) and 30 ml of tetrahydrofuran (THF) were dissolved 10.9 g of 2-methylglycerol and 10 g of 1-bromopentadecane, and 7.7 g of powdered KOH was added at room temperature. The mixture was stirred vigorously for 30 minutes, refluxed for 3.5 hours, poured into 400 ml of water, neutralized with concentrated hydrochloric acid with ice-cooling, and extracted three times with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The oily residue (10 g) was purified by silica gel column chromatography [silica gel: 110 g; eluent: n-hexane-chloroform (2:3)] to give 4.6 g of the above-identified alcohol compound.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH3:6][NH:7][C:8](=[O:21])[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1CO)=[N:10][O:11][CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:6][NH:7][C:8](=[O:21])[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:1][Br:5])=[N:10][O:11][CH3:12]
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1CBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
Carbon tetrabromide (0.33 g) was added to a solution of N-methyl-2-(2-hydroxymethylphenyl)-2-methoxyiminoacetamide (0.11 g) and triphenylphosphine (0.26 g) in tetrahydrofuran (10 ml) at 0° C. The reaction mixture was stirred at 0° C. for 11/2 hours and then at room temperature for 1 hour. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The combined extracts were washed with brine and dried over magnesium sulphate. The solution was then concentrated under reduced pressure to leave a gum. Column chromatography (eluting with diethyl ether on silica gel) gave the N-methyl-2-(2-bromomethylphenyl)-2-methoxyiminoacetamide as a gum (80 mg, 57%). 1H NMR (CDCl3) δ 2.95(d,3H), 4.0(s,3H), 4.35(s,2H), 6.8(brs,1H), 7.1-7.5(m,4H) ppm.