Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4]C(C)C)([CH3:3])[CH3:2].[Al:8].Cl.O.[NH:11]1[C:21](=[O:22])[C:20]2[NH:19][C:17](=[O:18])[NH:16][C:15]=2[NH:14][ClH:12]1=[O:13]>C(O)C>[CH3:2][CH:1]([CH3:3])[O-:4].[Al+3:8].[CH3:2][CH:1]([CH3:3])[O-:4].[CH3:2][CH:1]([CH3:3])[O-:4].[NH:11]1[C:21](=[O:22])[C:20]2[NH:19][C:17](=[O:18])[NH:16][C:15]=2[NH:14][ClH:12]1=[O:13]
Reactant: CC(C)OC(C)C
Reactant: [Al]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)[O-]
Product: [Al+3]

Procedure:
In this example, 3 grams of aluminum isopropyloxide is first dissolved in anhydrous ethanol. The pH is adjusted to 2 by HCl. 10 ml of a non-ionic surfactant polyglycol octyl phenyl ether is then added to the solution. 4 ml of a water solution of chlorauric acid which has a concentration of 0.04 mol/L is then added. After thorough mixing, a homogeneous, transparent light yellow colored AIP (aluminum isopropoxide), chlorauric acid and surfactant mixture is obtained. By slowly adding 15 ml 3 wt. % of ammonia water solution into above mixture, aluminum isopropoxide is hydrolyzed completely to obtain a light yellow colored, thick aluminum hydroxide gel. The reaction is allowed to continue for 3 hours. 6 ml of 0.3 mol/L of NaBH4 water solution is then added for a reduction process to obtain a homogeneous, purple colored aluminum hydroxide gel. Continuing the reaction for two more hours and aged at high temperature for 10 hours. After filtering, washing, drying and calcining, Au/Al2O3 catalyst is obtained.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH-:12].[K+]>>[CH2:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:9]([CH2:10][OH:12])[OH:11]
Reactant: CCCCCO
Reactant: [OH-]
Reactant: ClCC1CO1
Agent: [K+]
Product: CCCCCOCC(O)CO
Temperature: 115 °C

Procedure:
n-Pentanol (132 g) and 8.1 g of ferric chloride were heated to 100° C. while stirring, followed by the dropwise addition of 92.5 g of epichlorohydrin over 1 hour. The reaction mixture was then heated to 115° C. and reacted for 5 hours. After the removal of an excess alcohol at 100° C. under reduced pressure (5.32 kPa), 6 g of lauric acid, 118 g of a 48% aqueous solution of potassium hydroxide and 162 g of water were added to the residue. The resulting mixture was reacted at 200° C. for 5 hours in an autoclave. The reaction mixture was neutralized with 2.3 g of a 48% aqueous solution of potassium hydroxide. The reaction mixture was dehydrated at 100° C. under reduced pressure (6.67 kPa) and the residue was purified by distillation under reduced pressure (133 to 266 Pa, 114 to 115° C.), whereby 102 g of monopentyl glyceryl ether was obtained. As a result of GLC, it was found to that the resulting compound had a purity not less than 99% and the content of organochlorine compounds was not greater than 100 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[Cl:7].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:44][C@@H:45]([CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:65]([F:68])([F:67])[F:66])[CH2:46][N:47]1[C:55](=[O:56])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]1=[O:57]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:44][C@@H:45]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:66])[F:67])[CH2:46][N:47]2[C:55](=[O:56])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]2=[O:57])=[O:10])[S:5][C:6]=1[Cl:7]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: O=C(O)c1cc(Br)c(Cl)s1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1cc(Br)c(Cl)s1
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-5-chloro-2-thiophenecarboxylic acid (1.3 g, 5.42 mmol), PyBrOP (3 g, 6.5 mmol) and diisopropylethyl amine (4.7 mL, 27.1 mmol) in DCM (54 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (2.0 g, 5.42 mmol)[prepared in Preparation 6]. After 1 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and used directly: LCMS (ES) m/z=572 (M+H)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:24]=[CH:23][C:14]([CH:15]=[C:16]4[S:20][C:19](=[S:21])[NH:18][C:17]4=[O:22])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[NH4+]>>[O:22]=[C:17]1[C:16](=[CH:15][C:14]2[CH:13]=[CH:12][C:11]([N:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)=[CH:24][CH:23]=2)[S:20][C:19](=[S:21])[NH:18]1
Reactant: O=C1NC(=S)SC1=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: O=C1CCN(c2ccc(C=C3SC(=S)NC3=O)cc2)CC1
Yield: 89.2 %

Procedure:
5-[4(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-thioxothiazolidin-4-one (which was obtained in Example 33) (0.9 g, 2.5 mmol) was treated with concentrated hydrochloric acid (25 mL) at room temperature. After 15 hours ˜28% ammonium hydroxide (NH4OH) was added dropwise and the precipitate was collected by filtration, and dried over phosphorus pentoxide (P2O5) to give the title compound as a red solid (0.71 g, 89%); 1H NMR (300 MHz, DMSO-d6) δ 2.46 (t, J=6.1 Hz, 4 H), 3.79 (t, J=6.1 Hz, 4 H), 7.11 (d, J=9.0 Hz, 2 H), 7.48 (d, J=9.0 Hz, 2 H), 7.56 (s, 1 H); MS (ES) m/z: 316.9 (M−H)−; HRMS Calcd. C15H14N2O2S2(M+): 318.0497. Found: 31.8.0502.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:15]3[N:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:16]=3)[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[CH3:29][N:14]([C:15]1[N:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1)[C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1cnc(Nc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Yield: 97 %

Procedure:
Ethyl 2-[N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)amino]-pyrimidine-5-carboxylate (104 mg) was dissolved in dry DMF (3 ml), and the solution was added with a suspension of NaH (40 mg) in DMF (2 ml). The mixture was then added with methyl iodide (0.5 ml) and stirred. After the disappearance of the materials was observed with TLC, the reaction mixture was poured into water, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was evaporated. The residue was purified by silica gel flash column chromatography (n-hexane: AcOEt=20:1) to obtain white crystals of ethyl 2-[N-methyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)amino]pyrimidine-5-carboxylate (105 mg, 97%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@@H:37]([N:40]([CH:42]([CH3:44])[CH3:43])[CH3:41])[CH2:36][C@H:35]1[CH2:45][OH:46]>C1COCC1.O>[OH:46][CH2:45][C@@H:35]1[CH2:36][C@H:37]([N:40]([CH:42]([CH3:43])[CH3:44])[CH3:41])[CH2:38][CH2:39][C@@H:34]1[NH:33][C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=1
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CO)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CO)C1
Reaction time: 0.08 h
Yield: 43 %

Procedure:
A solution of (3-Trifluoromethyl-benzoylamino)-acetic acid (1.76 g, 0.0071 mol) in THF was cooled in an ice bath and treated with N-methylmorpholine(0.80 g, 0.0080 mol) and then drop-wise with isobutyl chloroformate (1.0 g, 0.007 mol). The resulting mixture was stirred for 5 min and then treated with a solution of ((1R,2S,5R)-2-amino-5-(isopropyl(methyl)amino)cyclohexyl)methanol (1.3 g, 0.0065 mol) in THF. The resulting mixture was stirred for 30 minutes and then diluted with water and extracted into CH2Cl2. The extract was washed with dilute NaOH, water, and brine and then concentrated under vacuum. The residue was chromatographed on silica gel (elution 5-8% [NH4OH/MeOH]/CH2Cl2) to give 1.2 g of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ(TMS): 8.15 (s, 1 H), 8.05 (d, J=7.8 Hz, 1 H), 7.76 (d, J=7.8 Hz, 1 H), 7.76 (bs, 1 H), 7.57 (t, J=7.8 Hz, 1 H), 7.17 (bs, 1 H), 4.26 (m, 1 H), 4.26 (dd, J=5 Hz, J=16 Hz, 1 H), 4.13 (dd, J=5 Hz, J=16 Hz, 1 H), 3.27 (m, 1 H), 3.17 (m, 1 H), 2.57 (m, 2 H), 2.24 (s, 3 H), 1.92-1.60 (m, 7 H), 1.05 (d, J=6.5 Hz, 6 H); MS found: (M+H)+=430.48.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH3:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:9])[C:4](=[O:23])O1.[CH2:25]=O.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CO>[CH3:22][N:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1)[C:8]([C:7]1[CH2:25][N:27]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:4](=[O:23])[C:5]=1[OH:6])=[O:9]
Reactant: NCCN1CCOCC1
Reactant: CN(Cc1ccc(C(F)(F)F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: C=O
Solvent: CO
Product: CN(Cc1ccc(C(F)(F)F)cc1)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 35 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methyl-N-(4-trifluoromethyl-benzyl)-acetamide (0.36 g, 1.05 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.16 g (35% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm); 2.46 (4H, m, 2×NCH2), 2.57 (2H, t, J=6.1 Hz, NCH2), 3.04 (3H, s, NCH3), 3.6 (6H, m, 2×OCH2 and NCH2), 4.25 (2H, s, NCH2), 4.72 (2H, s, NCH2), 7.41 (2H, d, J=8.0 Hz, aromatics), 7.62 (2H, d, J=8.0 Hz, aromatics). HRMS (FAB+) calculated for C20H25F3N3O4: [M+H]+: 428.179716. found: 428.179157.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:10][C:11]1[C:15](B(O)O)=[CH:14][N:13]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:10][C:11]1[C:15]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:14][N:13]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:12]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C#N)cn1
Temperature: 135 °C
Yield: 53 %

Procedure:
To a solution of 6-Chloro-nicotinonitrile (0.2 g, 1.49 mmol) and 3-methyl-1-trityl-1H-pyrazole-4-boronic acid* (0.5 g, 1.36 mmol) in ethylene glycol dimethyl ether (3 ml), was added sodium carbonate (0.36 g, 3.39 mmol) in water (1.5 ml). The reaction mixture was degassed with nitrogen before addition of tetrakis(triphenylphosphine)palladium (0) and then heated in a CEM microwave at 135° C. for 30 minutes (50 W power). Reaction partitioned between water and ethyl acetate, aqueous basified with 2N NaOH, organic extracts were combined, dried (MgSO4) and solvent removed. Crude product suspended in small volume of methanol, white precipitate filtered to afford the title compound (0.32 g, 53% yield). LC/MS: (PS-A2) Rt 4.52 [M+H]+ 427.26. * This starting material can be made by the method described in EP1382603A1
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20](O)=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][C@@H:31]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C@@H:32]([OH:46])[C:33]([F:45])([F:44])[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:30][C@@H:31]([CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:32](=[O:46])[C:33]([F:45])([F:44])[C:34](=[O:35])[NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccc2)c1=O
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)C(F)(F)C(=O)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccc2)c1=O)N[C@@H](Cc1ccccc1)C(=O)C(F)(F)C(=O)NCc1ccccc1

Procedure:
2-[5-Benzyloxycarbonylamino-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-[1(S)-benzyl-3,3-difluoro-2(R)-hydroxy-3-[N-(benzyl)caramoyl]propyl]acetamide was synthesized in the same manner as in Example 1. That is, 2-[5-benzyloxycarbonylamino-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 3, mixture with benzyl alcohol, 380 mg, 0.897 mmol) was treated with N-[4(S)-amino-2,2-difluoro-3(R)-hydroxy-5-phenylpentanoyl]benzylamine (title compound in Reference Example 6: 300 mg, 0.897 mmol), HOBT (242 mg, 1.79 mmol) and WSCI hydrochloride (206 mg, 1.08 mmol) in dichloromethane (30 mL) to give 590 mg (92%) of the target compound as colorless crystals.
Reaction SMILES: [Cl:1][CH:2]([C:14](=[O:16])[CH3:15])[CH2:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH:11][C:12]#[N:13])=[N:9][CH3:10].[Cl:17][O-].[Na+].C(OCC)(=O)C>CO>[C:12]([NH:11][C:8]([NH:7][CH2:6][CH2:5][S:4][CH2:3][C:2]([Cl:17])([Cl:1])[C:14](=[O:16])[CH3:15])=[N:9][CH3:10])#[N:13]
Reactant: [O-]Cl
Reactant: CN=C(NC#N)NCCSCC(Cl)C(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN=C(NC#N)NCCSCC(Cl)(Cl)C(C)=O
Reaction time: 3 h
Yield: 25 %

Procedure:
In 1 ml of methanol was dissolved 131 mg of N-[2-(2-chloro-3-oxobutylthio)]ethyl-N'-cyano-N"-methylguanidine, and 0.63 ml of an aqueous solution of sodium hypochlorite was added to the solution and reaction was carried out at room temperature for 3 hours. Then, 15 ml of ethyl acetate was added to the reaction liquid and the organic layer was recovered. The obtained organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was refined by silica gel column chromatography (developing solvent: ethyl/ethanol=10/1) to obtain 37 mg of a colorless oily product (the yield was 25%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Li]CCCC.CCCCCC.C1(OC)C=CC=CC=1.[N:29]1([C:34]2[CH:38]=[CH:37][NH:36][C:35]=2[C:39](OCC)=[O:40])[CH:33]=[CH:32][CH:31]=[CH:30]1.[NH4+].[Cl-]>C1COCC1>[N:29]1([C:34]2[CH:38]=[CH:37][NH:36][C:35]=2[C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])=[O:40])[CH:30]=[CH:31][CH:32]=[CH:33]1
Reactant: COc1ccccc1Br
Reactant: CCOC(=O)c1[nH]ccc1-n1cccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: COc1ccccc1
Product: COc1ccccc1C(=O)c1[nH]ccc1-n1cccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 2-bromoanisole (1.39 g, 7.43 mmol, 5.63 equiv) in anhydrous THF (5 mL) at −78° C., a 2.5M solution of BuLi in hexane (3 mL, 7.50 mmol, 5.68 eq.) was added dropwise, the resulting mixture was stirred for 1 h. at −78° C. to generate the lithiated anisole. In an oven-dried flask, compound (c) (270 mg, 1.32 mmol, 1 eq.) was dissolved in THF (5 mL) and cooled to −78° C., the lithiated anisole (d) was transferred into the solution containing (c) dropwise via syringe, and the resulting mixture was stirred for 1 h. at −78° C. To the reaction mixture, an aqueous solution of NH4Cl (5 mL) was added, the mixture was extracted with EtOAc, dried over anhydrous Na2SO4. The crude product was purified by flash column chromatography (10% EtOAc in Hexane) to give (e) as a light brown solid (0.30 g, 85% yield).
Reaction SMILES: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H]([O:16][C:17]3[C:26](=[O:27])[C:25]4[C:24]([OH:28])=[CH:23][C:22]([OH:29])=[CH:21][C:20]=4[O:19][C:18]=3[C:30]3[CH:31]=[CH:32][C:33]([OH:37])=[C:34]([OH:36])[CH:35]=3)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O>Cl>[CH:31]1[C:30]([C:18]2[O:19][C:20]3[CH:21]=[C:22]([OH:29])[CH:23]=[C:24]([OH:28])[C:25]=3[C:26](=[O:27])[C:17]=2[OH:16])=[CH:35][C:34]([OH:36])=[C:33]([OH:37])[CH:32]=1.[C:25]1([CH:26]=[CH:17][C:18]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:19])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H](Oc3c(-c4ccc(O)c(O)c4)oc4cc(O)cc(O)c4c3=O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O
Agent: Cl
Product: O=C(C=Cc1ccccc1)c1ccccc1
Product: O=c1c(O)c(-c2ccc(O)c(O)c2)oc2cc(O)cc(O)c12
Temperature: 25 °C

Procedure:
One hundred (100) grams of rutin was dissolved in one (1) liter of lN hydrochloric acid at a temperature of 80-90° C., and allowed to react at that temperature for a total of 3 hours, forming a yellowish-brown precipitate. The resultant mixture was allowed to cool to room temperature and the precipitate removed by filtration, with continual washing with distilled water, until a pH of 6.0-6.5 was obtained. The precipitate was dried and redissolved in 90% ethyl alcohol, and filtered to remove impurities, with the alcohol subsequently distilled off. The remaining precipitate was then suspended in 200 ml of distilled water. Gradually, a solution of lN sodium hydroxide was added, until a clear, golden-brown solution without a precipitate was obtained. This solution was oven dried at a temperature of 70-80° C., yielding a brown powder of quercetin chalcone. The quercetin chalcone produced by this method was soluble in distilled water, a concentration of 20% quercetin chalcone in water was readily produced. Quercetin, on the other hand, was almost totally insoluble in water.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:8][C:9]2[C:10]3[CH:17]=[CH:16][N:15]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:49][C:50]1[CH:51]=[C:52]([NH:57][CH2:58][C:59](O)=[O:60])[CH:53]=[C:54]([Cl:56])[CH:55]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:49][C:50]1[CH:51]=[C:52]([NH:57][CH2:58][C:59]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:8][C:9]3[C:10]4[CH:17]=[CH:16][N:15]([S:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=5)(=[O:19])=[O:20])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:2]2)=[O:60])[CH:53]=[C:54]([Cl:56])[CH:55]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCNC4)ncnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a solution of N-(azepan-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.6 g, 1.6 mmol), in DMF (10 mL) was added EDCI (335 mg, 1.9 mmol), HOBt (250 mg, 1.9 mmol), 2-(3,5-dichlorophenylamino)acetic acid (342 mg, 1.6 mmol) and DIEA (301 mg, 2.3 mmol) at 0° C. The reaction mixture was stirred at rt overnight, diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo to give the crude compound that purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (800 mg, 87%). LC-MS: m/z [M+1]=587.
Reaction SMILES: C(OC([NH:11][C:12](=[O:22])[C@@H:13]([C@H:15]([CH3:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH2:14])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:17]([O:16][C@@H:15]([CH3:21])[C@H:13]([C:12]([NH2:11])=[O:22])[NH2:14])([CH3:20])([CH3:18])[CH3:19]
Reactant: [H][H]
Reactant: C[C@H](OC(C)(C)C)[C@@H](N)C(=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](OC(C)(C)C)[C@@H](N)C(N)=O

Procedure:
10% Pd/C (1.5 g) is added to a solution of the compound obtained in step (a) in MeOH (200 ml), and hydrogen is bubbled through the reaction mixture for 1.5 h, checking the disappearance of the starting compound by tlc. When the reaction is over, excess hydrogen is removed by passing a nitrogen stream through the mixture, the reaction mixture is filtered over celite and the filtrate is concentrated to dryness thus yielding O-tert-butyl-D-threonineamide (2.55 g, 99%). Both mass and NMR spectra confirm the assigned structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([F:63])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([F:63])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(F)c2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 91 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(3,4-difluoro-phenyl)-ethyl]-amine in 2 ml DMF was added. After stirring for 18 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 95 mg light yellow viscous oil (66%). MS (ISP) 447.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18](Cl)[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)ccc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A mixture of di-tert-butyl(6-chloro-3-nitropyridin-2-yl)imidodicarbonate (700 mg, 1.87 mmol), phenylboronic acid (274 mg, 2.25 mmol) and tetrakistriphenylphosphine palladium (217 mg, 0.187 mmol) were blanketed with argon and taken up in THF (15.0 mL) and 2M aq. Na2CO3 (3.74 mL). The suspension was purged with bubbling argon for 20 min, then the reaction was sealed and heated via microwave to 120° C. for 2 h. The reaction was cooled, diluted with EtOAc and filtered through celite. The filtrate was washed with water, brine, dried (MgSO4) and concentrated to afford material purified via MPLC, silica cartridge, 5-20% EtOAc in heptanes to afford the product as a light yellow solid. 1H NMR (DMSO-d6, 600 MHz) d 8.68 (d, J=8.5 Hz, 1H), 8.29 (d, J=8.5 Hz, 1H), 8.16-8.12 (m, 2H), 7.57-7.54 (m, 3H), 1.35 (s, 18H); MS cal'd 438 (M+Na)+, exp 438 (M+Na)+.