Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][CH2:9][C:10](=[O:12])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:13]([NH:23][C@H:24]([C:26](Cl)=[O:27])[CH3:25])([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].CCCCCC>ClCCl.N1C=CC=CC=1.CC(C)=O>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([O:12][C:26](=[O:27])[C@H:24]([CH3:25])[NH:23][S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Reactant: O=C1CSC(c2ccccc2)=N1
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Oc2csc(-c3ccccc3)n2)cc1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
4.43 g (0.025 mole) of 2-phenyl-4(5H)-thiazolone was dissolved in a cosolvent of 150 ml of dichloromethane and 6 ml of pyridine and cooled to 5° C. The solution of N-tosyl-L-alanyl chloride (10 g) dissolved in dichloromethane cooled to below was added to the mixture. The reacting solution was stirred, followed by standing at room temperature for 3 hours. The solution was washed with 1N citric acid, water, 5% sodium bicarbonate and a saturated sodium chloride solution in that order, dried over magnesium sulfonate, filtered; and concentrated under reduced pressure. Yellowish solid residue, so formed, was dissolved in 50 ml of acetone, and 50 ml of hexane was added to the solution. After standing the solution at room temperature for 1 hour, the thick yellowish amorphous solid, so formed, was removed. 200 ml of another hexane was added to the filtrate, followed by 10 hours' standing in the refrigerator. Filtration gave pale yellowish needle crystals as a desired compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22].CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:20](=[O:23])[CH2:21][CH3:22]
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CCC(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(=O)N(C)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.25 g, 0.92 mmol), propionyl chloride (0.29 g, 3.1 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was successively washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was recrystallized from tetrahydrofuran-hexane to give the titled compound (0.15 g, 49%).
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[C:35]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:29][CH:28]=1)[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=O)=O)([O-])=O.SCC(O)=O.O.[OH-].[Li+].C(OCC)(=O)C>CN(C)C=O>[C:43]1([C:35]2[N:34]([CH2:33][C:30]3[CH:29]=[CH:28][C:27]([CH2:26][NH:13][C:14]4[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=4)=[CH:32][CH:31]=3)[C:42]3[C:37]([CH:36]=2)=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COC(=O)CCc1ccc(N(Cc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(NCc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 66 %

Procedure:
To a solution of the residue obtained in Example 9 and mercaptoacetic acid (0.209 mL, 3.00 mmol) in N,N-dimethylformamide (2 mL) was added lithium hydroxide monohydrate (0.252 g, 6.00 mmol), and the mixture was stirred at room temperature for 64 hr. Ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-25% ethyl acetate/hexane) to give the title compound (0.470 g, yield 66%, 2 steps) as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[CH:11]=O.Cl.[OH:14][NH2:15].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[CH:11]=[N:15][OH:14]
Reactant: NO
Reactant: O=C[C@H]1COC2(CCCCC2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: ON=C[C@H]1COC2(CCCCC2)O1
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
To a solution of (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (9.0 g, 59.9 mmol) in THF (120 mL and 60 mL of water) was added hydroxyl amine hydrochloride (3.73 g, 52.9 mmol) and the reaction stirred until clear (10 minutes). Sodium carbonate (2.75 g, 25.9 mmol) was added and the reaction stirred overnight at ambient temperature. The reaction was poured into ethyl acetate (500 mL) and the layers were separated. The organics were washed with water (200 mL), brine (200 mL), dried over magnesium sulfate and concentrated in vacuo to yield (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (9.08 g, 49 mmol, 92.7%).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[NH2:2].[F:12][C:13]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:14]=1[CH:15]=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:14]=1[CH:15]=[N:2][NH:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: NNc1cccc(C(=O)O)c1
Reactant: O=Cc1cc(I)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(NN=Cc2cc(I)ccc2F)c1
Yield: 97.6 %

Procedure:
3-Hydrazinylbenzoic acid (1.52 g, 10 mmol)), 2-fluoro-5-iodobenzaldehyde (2.5 g, 10 mmol) and caesium carbonate (3.26 g, 10 mmol) were stirred in DMF (10 mL) at room temp under argon atmosphere for 2.5 h. Water (40 mL) was added and the clear solution was acidified with aqueous HCl (1.7 M). The beige-orange precipitate that formed was collected by, filtration, washed with water and dried in vacuo to give the title compound (3.75 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][N:18]=[C:19]=[O:20]>N1C=CC=CC=1.C1COCC1>[CH3:11][C:9]1[CH:8]=[CH:7][C:6]([CH3:12])=[C:5]2[C:10]=1[C:2]([NH:1][C:19]([NH:18][CH3:17])=[O:20])=[C:3]([C:13]([O:15][CH3:16])=[O:14])[NH:4]2
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1N
Reactant: CN=C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CNC(=O)Nc1c(C(=O)OC)[nH]c2c(C)ccc(C)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 24 %

Procedure:
A mixture of 0.6 g (2.75 mmol) of methyl 3-amino-4,7-dimethylindole-2-carboxylate, one drop of pyridine and 15 ml of anhydrous THF was prepared and 5.0 ml of methyl isocyanate was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2.5 hours. The crystals precipitated were separated by filtration, washed with ethyl acetate and air-dried to provide 180 mg of white crystals. Yield: 24%
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]([N:22]1[CH2:28][CH:27]=[CH:26][CH2:25][CH2:24][CH:23]1[CH3:29])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20]([N:22]1[C@H:23]([CH3:29])[CH2:24][CH2:25][C@H:26]2[C@@H:27]([O:9]2)[CH2:28]1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1CCC=CCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: C[C@@H]1CC[C@@H]2O[C@H]2CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
m-Chloro-perbenzoic acid (1.10 g, 57-86% pure) was added to a solution of 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester (0.72 g, 2.94 mmol) in CH2Cl2 at 0 degrees C. The reaction mixture was stirred for half an hour, then was warmed to RT. Additional m-chloro-perbenzoic acid (0.660 g, 57-86% pure) was added and the reaction was stirred 2 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then 80 ml of 9:1 hexanes/EtOAc was added and the reaction mixture was filtered. The filtrate was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 20% EtOAc:hexanes) to give (1S,4R,7S)4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.450 g, 75%) and the title compound (0.15 g, 25% yield): 1H NMR: 7.42-7.22 (m, 5H), 5.13 (2H, s), 4.50-4.15 (m, 2H), 3.27 (1H, d), 3.12-2.95 (1H, m), 2.15-1.70 (m, 2H), 1.47 (m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=262.0.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]([N:17]1[CH2:20][CH:19](CS([O-])(=O)=O)[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CC#N>[CH:4]([N:17]1[CH2:20][CH:19]([N:2]([CH3:3])[CH3:1])[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=S(=O)([O-])CC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC#N
Product: CN(C)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C
Yield: 92 %

Procedure:
Aqueous dimethylamine (1 L, 33%) was added to a solution of (1-benzhydrylazetidin-3-yl)methanesulfonate (Intermediate 30, 260 g, 0.82 mol) in CH3CN (1 L) and the mixture was refluxed at 100° C. overnight. The mixture was then cooled and the solvent was removed in vacuo. The mixture was partitioned between water (300 mL) and CH2Cl2 (300 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×500 mL). The combined organic solutions were dried (Na2SO4) and concentrated in vacuo. Purification by FCC gave the title compound (200 g, 92%) as a brown solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:3][CH:4]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)c1ncc(-c2ccccn2)o1
Reaction time: 0.33 h
Yield: 52.9 %

Procedure:
(185) A solution of 2-(oxazol-5-yl)pyridine (102 mg, 0.70 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.77 mmol, 0.31 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.40 mmol, 2.8 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.70 mmol, 133 mg) was added, and the solution was stirred for 10 min at 0° C. Lauroyl chloride (2 equiv, 1.4 mmol, 306 mg, 0.32 mL) was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)dodecan-1-one (185) (122 mg, 0.37 mmol, 53% yield) as an off-white powder: mp 73-74° C.; 1H NMR (CDCl3, 250 MHz) d 8.65 (br d, J=4.0 Hz, 1H), 7.89-7.75 (m, 3H), 7.34-7.25 (m, 1H), 3.09 (t, J =7.7 Hz, 2H), 1.83-1.69 (m, 2H), 1.41-1.19 (m, 16H), 0.86 (br t, J=7.0 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.6, 153.2, 150.1 (2C), 146.3, 137.1, 126.8, 124.1, 120.3, 39.1, 31.9, 29.6 (2C), 29.4, 29.3, 29.2 (2C), 24.0, 22.7, 14.1; IR (KBr) umax 2929, 2857, 1704, 1609, 1415, 1378 cm−1; MALDI-FTMS (DHB) m/z 329.2214 (C20H28N2O2+H+ requires 329.2223).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH:19]([CH3:20])[C:18]2[C:13](=[N:14][C:15]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=2)[N:12]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])[C:11]1=[O:36].[OH-:37].[Na+].OO.O>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH:19]([CH3:20])[C:18]2[C:13](=[N:14][C:15]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:16][CH:17]=2)[N:12]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]([NH2:32])=[O:37])[C:11]1=[O:36]
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4ccccc4)ncc3C2C)c(F)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(N2C(=O)N(c3cccc(C(N)=O)c3)c3nc(Nc4ccccc4)ncc3C2C)c(F)c1
Reaction time: 0.75 h

Procedure:
(±)-3-[3-(2-Fluoro-4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (0.80 g; 1.67 mmol) (from Example 9b supra) was dissolved in dimethyl sulfoxide (25 mL). Most of the material went into solution. Aqueous sodium hydroxide (1.0 N; 3.34 mL; 3.34 mmol) was added followed by hydrogen peroxide (30% in water; 0.51 mL, 4.99 mmol) at room temperature. After stirring for 45 minutes, water was added and a white solid precipitated out of solution. The solid was collected, washed with water and dried. Dissolution of the solid required significant volumes of dichloromethane-methanol-acetonitrile. The solvent mixture was then distilled off until solid began to crystallize out of solution. Cooling and filtration gave (±)-3-[3-(2-fluoro-4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzamide as a white solid. (Yield 0.56 g; 67.6%).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([O:27][C:26]([F:36])([F:37])[F:25])=[CH:29][CH:30]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: Cc1nc(NCc2ccc(OC(F)(F)F)cc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [4-(trifluoromethoxy)benzyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19-1.28 (m, 3H), 1.59 (d, J=13.59 Hz, 4H), 1.67 (s, 1H), 1.86 (s, 3H), 2.23 (s, 3H), 3.79 (s, 1H), 4.56 (d, J=5.04 Hz, 2H), 7.30 (d, J=8.11 Hz, 2H), 7.40-7.45 (m, 2H), 7.57 (d, J=7.23 Hz, 1H), 8.18 (t, J=5.26 Hz, 1H), 12.85 (bs, 1H); MS (ESI) m/z 394.8 (M+1)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[O:30][CH:29]=[CH:28][C:27]3=[O:34])[CH2:20][CH2:19]1)=O.[Al].[Li].[OH-].[Na+]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[O:30][CH:29]=[CH:28][C:27]3=[O:34])[CH2:22][CH2:23]1
Reactant: COC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5occc(=O)c5c4)CC3)c2c1
Agent: [Al]
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1ccoc2ccc(N3CCN(CCCCc4c[nH]c5ccc(CO)cc45)CC3)cc12
Temperature: 25 °C

Procedure:
A solution of 3.6 g of 1-[4-(5-methoxycarbonylindol-3-yl)butyl]-4-(chromen-4-on-6-yl)piperazine in 40 ml of THF is added dropwise with stirring at room temperature to a suspension of 0.6 g of lithium aluminum hyride in 20 ml of THF. The mixture is then stirred for a further hour at 25° C., 20 ml of dilute sodium hydroxide solution are added, the mixture is filtered and the filtrate is worked up in the customary manner. 1-[4-(5-Hydroxymethylindol-3-yl)butyl]-4-(chromen-4-on-6-yl)piperazine is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[C:6]([NH:21][C@@H:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[N:5]=[CH:4][N:3]=1.O.NN>C(O)C>[NH2:10][CH2:9][CH2:8][C:7]1[C:6]([NH:21][C@@H:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)=[N:5][CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: O=C1c2ccccc2C(=O)N1CCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Temperature: 23 °C
Yield: 49.9 %

Procedure:
2-(2-{4-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-5-yl}ethyl)-1H-isoindole-1,3(2H)-dione (3.50 g, 8.32 mmol) was suspended in ethanol (102 mL) and hydrazine hydrate (1.62 mL, 33.3 mmol) was added. The mixture was heated to reflux for 1 hour. At that time, LCMS indicated complete conversion. The mixture was cooled to 23° C., crystals were filtered off, the residue was evaporated in vacuo and purified using chromatography on silica gel using gradient 0 to 20% MeOH in methylene chloride to afford the title compound (1.20 g, 50%). LC/MS: Rt=1.29 min, ES+ 289 (AA standard).
Reaction SMILES: C(O[C@@H]1O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@H]1[NH:24][C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])(=O)C.C1(C)C(S)=CC=CC=1.B(F)(F)F.CCOCC.C(O[C@H:54]1[C@@H:67]([O:68][C:69](=[O:71])[CH3:70])[C@H:66]([O:72][C:73](=[O:75])[CH3:74])[C@@H:65]([CH2:76][O:77][C:78](=[O:80])[CH3:79])[O:64][C@@H:55]1[S:56][C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=1)(=O)C>C(Cl)Cl>[C:69]([O:68][C@H:67]1[C@H:66]([O:72][C:73](=[O:75])[CH3:74])[C@@H:65]([CH2:76][O:77][C:78](=[O:80])[CH3:79])[O:64][C@@H:55]([S:56][C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)[C@@H:54]1[NH:24][C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])(=[O:71])[CH3:70]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)OC[C@H]1O[C@H](Sc2ccc(C)cc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cc1ccccc1S
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(C)cc2)[C@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 89 %

Procedure:
The tittle compound was prepared from 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxylcarbonylamino)-β-D-glucopyranose (Boullanger, P. et al Carbohydr. Res. 1990, 202, 151) (11.8 g, 22.5 mmol), thiocresol (3.07 g, 24.75 mmol) and BF3-Et2O (10 mL) in dry CH2Cl2 (60 mL) by the procedure described above (see compound 1) The crude product was crystallization from ether to give 21 (11.8 g, 89%) as white crystals: m.p. 175–176° C.; [α]D22 +3° (c, 0.5, CHCl3); 1H-NMR (400 MHz, CDCl3) δ 2.00 (s, 3H), 2.01 (s, 3H), 2.09 (s, 3H), 2.35 (s, 3H), 3.71–3.73 (m, 1H), 4.11–4.25 (m, 2H), 4.73 (d, 1H, J=12.0 Hz), 4.79 (d, 1H, J=10.8 Hz), 5.01 (t, 1H, J=9.8 Hz), 5.26 (d, 1H, J=9.8 Hz), 5.31 (d, 1H, J=9.1 Hz), 7.11 (d, 2H, J=8.0 Hz), 7.41 (d, 2H, J=8.0 Hz); 13C-NMR (400 MHz, CDCl3); δ 20.56, 20.61, 20.73, 21.15, 54.93, 62.25, 68.44, 73.14, 74.47, 75.70, 86.65, 95.36, 127.84, 129.71, 133.62, 138.70, 153.85, 169.45, 170.61; HRMS for C22H26NO9SCl3Na (M+Na) calcd 610.0266. found 610.0286. Anal. Calcd for C22H26NO9SCl3: C, 45.03; H, 4.47; N, 2.39. Found: C, 45.46; H, 4.26; N, 2.30.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:17]([NH2:19])=[O:18])=[C:9]([NH:12][C:13](=O)[CH2:14][CH3:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C[O-].[Na+].Cl>O>[CH2:14]([C:13]1[NH:19][C:17](=[O:18])[C:8]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][S:10][C:9]=2[N:12]=1)[CH3:15]
Reactant: CCC(=O)Nc1scc(-c2ccccc2)c1C(N)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1nc2scc(-c3ccccc3)c2c(=O)[nH]1
Reaction time: 18 h

Procedure:
The solid 4-phenyl-2-propionylaminothiophene-3-carboxylic amide was added to a mixture of ethanol (50 ml) and sodium methoxide (2.24 g) and the resultant mixture was heated under reflux with stirring for 18 hours. The cooled mixture was diluted with water (300 ml) and acidified with concentrated hydrochloric acid. The resulting solid was collected by filtration, washed with water followed by acetonitrile and dried in vacuo to give 2-ethyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one (2.38 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](Cl)=[O:18])=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.[NH2:22][C@@H:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[O:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([NH:22][C@@H:23]3[C:32]4[C:27](=[CH:28][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:30][CH:31]=4)[O:26][CH2:25][CH2:24]3)=[O:18])=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CCOc2cc(C(F)(F)F)ccc21
Reactant: O=C(Cl)N1CCC[C@@H]1c1ncnn1Cc1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCOc2cc(C(F)(F)F)ccc21)N1CCC[C@@H]1c1ncnn1Cc1ccc(Cl)cc1

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-5-(1-chlorocarbonylpyrrolidin-2-yl)-1H-1,2,4-triazole (60 mg), (S)-4-amino-7-trifluoromethylchroman and DIEA in dry MeCN was stirred overnight at RT. The solvent was removed and the residue was partitioned between water and EtOAc. The EtOAc layer was washed with water and evaporated after drying over Na2SO4. The residue was purified by chromatography (silica gel, hexane:EtOAc (1:1)→EtOAc) to give 40 mg of the desired product.
Reaction SMILES: C(O[CH:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([N:24]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:26]=[N:25]2)[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(OC(=O)C)(=O)C.[BrH:40]>ClCCl.CC(O)=O>[C:8]([O:7][C@@H:6]1[C@@H:11]([N:24]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:26]=[N:25]2)[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]1[Br:40])(=[O:10])[CH3:9]
Reactant: COC(=O)c1cn([C@H]2[C@@H](OC(C)=O)[C@@H](COC(C)=O)OC(OC(C)=O)[C@@H]2OC(C)=O)nn1
Reactant: Br
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cn([C@@H]2[C@@H](OC(C)=O)[C@@H](Br)O[C@H](COC(C)=O)[C@@H]2OC(C)=O)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
1,2,4,6-Tetra-O-acetyl-3-deoxy-3-[4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl]-D-galactopyranose 23 (33 mg, 0.072 mmol) was dissolved in dichloromethane (1 ml) which had been dried over 4 Å molecular sieves. Acetic anhydride (14 l, 0.20 mmol) and HBr (0.2 ml of a 33% solution in AcOH) were added, and the mixture was stirred under N2 at room temperature. After 3 h 15 min, the reaction mixture was diluted with dichloromethane (30 ml) and poured into ice-water (30 ml). The organic phase was washed with NaHCO3 (30 ml of a saturated aqueous solution), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give 24 (16 mg, 46%), which was used immediately in the synthesis of 25.