Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH3:27])[C:10]2=[O:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:29][CH2:30][O:31][C:32]([CH2:34]Br)=[O:33].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:30]([O:31][C:32](=[O:33])[CH2:34][N:16]1[CH2:17][C@@H:18]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[C@:12]2([N:11]([CH3:27])[C:10](=[O:28])[N:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]2=[O:14])[CH2:15]1)[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1C[C@@H](c2ccc(C#N)cc2)[C@]2(C1)C(=O)N(c1cc(Cl)cc(Cl)c1)C(=O)N2C
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A mixture of Example 15 (100 mg, 0.24 mmol), ethyl bromo acetate (29 μl, 0.26 mmol) and K2CO3 (36.6 mg, 0.26 mmol) in toluene (2 ml) was heated to 100° C. for 5 h. After cooling to room temperature, the precipitate (unreacted starting material) was removed by filtration. The filtrate was concentrated and purified by chromatography over silica gel (eluent: DCM then acetone) to yield the above-titled compound as an oil (47.2 mg). 1H NMR (CDCl3): 7.63 (2H, d, J=8.3 Hz), 7.25–7.30 (3H, m), 6.68 (2H, d, J=1.5 Hz), 4.23 (2H, q, J=7.1 Hz), 3.89 (1H, dd, J1=11.7 Hz, J2=6.3 Hz), 3.55–3.65 (2H, m), 3.3–3.5 (3H, m), 3.26 (3H, s), 3.05 (1H, d, J=10.8 Hz), 1.31 (3H, t, J=7.1 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][OH:20])[CH2:14][CH2:13]3)=[C:8]([CH3:22])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][OH:20])[CH2:14][CH2:13]4)=[C:8]([CH3:22])[C:6]=3[N:7]=2)=[CH:38][N:39]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1c(CN2CCN(C(=O)CO)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(C(=O)CO)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 10.1 %

Procedure:
1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone (60 mg) was reacted with 34 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A. The product was purified by reverse phase HPLC to yield 6.9 mg of 178. MS (Q1) 485.1 (M)+
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:22]>>[ClH:22].[F:21][C:18]([F:19])([F:20])[CH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(CC(F)(F)F)cc2C1
Agent: Cl
Product: FC(F)(F)Cc1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-(2,2,2-trifluoro-ethyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester and hydrochloric acid. Off-white solid. MS (m/e): 202.4 ([M+H]-+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][C:24]([O:26]CC)=[O:25])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][C:24]([OH:26])=[O:25])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3,5-dibenzyloxyphenylacetate (4.1 g, 10.9 mmol) in 50 ml of EtOH is added 21 ml (6 eq) of 1N NaOH. The reaction is stirred at room temperature for 2 hours at which time it is extracted with Et2O and H2O. The H2O layer is acidified to pH~1 using 1N HCl and extracted with Et2O. The organics are dried (MgSO4) and concentrated in vacuo to obtain 3,5-dibenzyloxyphenylacetic acid which is confirmed by NMR and used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=O)[CH2:11][CH2:10]3)=[CH:5][CH:4]=[C:3]1[C:17]#[N:18].Cl.[NH2:20][OH:21]>>[OH:21]/[N:20]=[C:12]1\[CH2:11][CH2:10][C:9]2[C:13]\1=[CH:14][CH:15]=[C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:17]#[N:18])=[CH:4][CH:5]=1)[CH:8]=2
Reactant: NO
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)CCC2=O
Agent: Cl
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)CC/C2=N\O

Procedure:
The title compound was prepared from 1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile and hydroxylamine hydrochloride according to the procedure described in example 1. MS (ESI) m/z 252; HRMS: calcd for C15H13N3O+H+, 252.11314; found (ESI, [M+H]+), 252.1133
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:26][CH2:27][CH2:28][CH3:29]>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCNC3)c2n1
Reactant: CCCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(CCCC)C3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(3-piperidinylmethyl)-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: COC(=O)C1C=CC(N[C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=NC=1.[CH2:33]([O:35][C:36](=[O:44])[CH2:37][C:38]1[N:39]=[C:40]([NH2:43])[S:41][CH:42]=1)[CH3:34]>>[CH2:33]([O:35][C:36](=[O:44])[CH2:37][C:38]1[N:39]=[C:40]([NH:43][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[S:41][CH:42]=1)[CH3:34]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Product: CCOC(=O)Cc1csc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)n1

Procedure:
The product from Example 1, Part C (160 mg, 0.5 mmol) and (2-aminothiazol-4-yl)-acetic acid ethyl ester (92 mg, 0.5 mmol) were reacted as described in Example 5. After evaporation of the reaction solvent the residue was partitioned between water and EtOAc, and the organic phase was washed with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and evaporated. The title compound was obtained by silica gel chromatography (90 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 9.80 (br s, 1H), 7.22 (d, J=8 Hz, 2H), 6.83 (d, J=8 Hz, 2H), 6.80 (s, 1H), 5.19 (d, J=15 Hz, 1H), 4.60 (s, 1H), 4.15 (m, 3H), 3.77 (s, 3H), 3.61 (s, 3H), 3.06 (d, J=16 Hz, 1H), 2.98 (d, J=16 Hz, 1H), 1.90 (s, 3H), 1.81 (s, 3H). MS: m/z (MH+) 490.
Reaction SMILES: C([C@H]1CC[C@H](C(Cl)=O)C1)CCCC.C(C1CC(=O)CCC1)CCCC.[CH2:26]([CH:31]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32]1)[CH2:27][CH2:28][CH2:29][CH3:30].S(Cl)(Cl)=O.[CH2:45]([C@H:48]1[CH2:53][CH2:52][C@H:51]([C:54]2[CH:59]=CC(O)=[CH:56][CH:55]=2)[CH2:50][CH2:49]1)[CH2:46][CH3:47]>CCOCC.C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:26]([C@H:31]1[CH2:35][CH2:34][C@H:33]([C:36]([O:38][C:39]2[CH:56]=[CH:55][C:54]([C@H:51]3[CH2:50][CH2:49][C@H:48]([CH2:45][CH2:46][CH3:47])[CH2:53][CH2:52]3)=[CH:59][CH:40]=2)=[O:37])[CH2:32]1)[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reactant: CCCCCC1CCC(C(=O)OCC)C1
Agent: CCCCCC1CCCC(=O)C1
Agent: CCCCC[C@H]1CC[C@H](C(=O)Cl)C1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](C(=O)Oc2ccc([C@H]3CC[C@H](CCC)CC3)cc2)C1

Procedure:
4.0 g of trans-3-n-pentylcyclopentanecarbonyl chloride (obtainable from 5-n-pentylcyclohexanone through chlorination, Faworski rearrangement of the α-chloroketone using sodium alcoholate in ether, hydrolysis of the ethyl 3-n-pentylcyclopentanecarboxylate, alkaline isomerization of the acid and subsequent reaction with thionyl chloride) are added dropwise at 100° to a solution of 4.4 g of 4-(trans-4-n-propylcyclohexyl)-phenol and 1.6 g of pyridine in 10 ml of toluene. The mixture is allowed to react for a further 3 hours, the pyridine hydrochloride is filtered off under suction, the filtrate is washed with water and dried, and the solvent is evaporated. The residue is crystallized from ethanol. 4-(trans-4-propylcyclohexyl)-phenyl trans-3-pentylcyclopentanecarboxylate is obtained; smectic B/isotropic phase transition: 49°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=1.C[O-].[Na+]>CO.[Cu]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:13]2[C:14]3[C:15](=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:10]=[C:11]([CH3:16])[N:12]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(I)cn1
Reactant: COc1ccc(N)nc1
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Nc2nc(C)nc3ccccc23)nc1
Temperature: 160 °C
Yield: 31 %

Procedure:
2-Amino-5-methoxy-pyridine. A mixture of 2-amino-5-iodo-pyridine (1 g, 4.54 mmol) in 20 mL of absolute methanol with 400 mg of copper powder and sodium methoxide (6 mmol) was heated at 160° C. overnight in a seal tube. The reaction mixture was cooled to room temperature, diluted with 80 mL of methanol and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by chromatography (80% ethyl acetate/hexane) to give the title compound (174 mg, 31%). 1H NMR (CDCl3): 7.78 (d, J=2.7, 1H), 7.09 (dd, J=3.0, 9.0, 1H), 6.48 (d, J=9.0, 1H), 3.78 (s, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH:6]=O)[CH2:2]1.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].S([O-])([O-])(=O)=O.[Mg+2]>ClCCCl>[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1ccc(CNCCNC(=O)OC(C)(C)C)cc1
Reactant: O=CC1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCCl
Product: COc1ccc(CN(CCNC(=O)OC(C)(C)C)CC2CCOC2)cc1
Yield: 80.9 %

Procedure:
This compound was made in a manner analogous to that set forth in Step D of Example 5, using 0.2 gram (0.0020 mole) of (oxolan-3-yl)formaldehyde, 0.56 gram (0.0020 mole) of (tert-butoxy)-N-(2-{[(4-methoxyphenyl)methyl]amino}-ethyl)carboxamide (prepared in Step A of Example 9), 0.64 gram (0.0030 mole) of sodium triacetoxyborohydride and 2.5 grams (0.021 mole) of magnesium sulfate in 50 mL of 1,2-dichloroethane. The reaction product was purified with column chromatography on silica gel. Elution was accomplished using a mixture of 1% methanol in methylene chloride as an eluant. Appropriate fractions were combined and concentrated under reduced pressure, yielding 0.59 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30](=[O:51])[NH:31][C@H:32]([C:40]1[O:41][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:43][N:44]=1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:6])[CH3:5].O=[CH:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68].C(O)(=O)C.FC(F)(F)C(O)=O>CO>[C:67]([CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][N:2]([CH3:1])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30](=[O:51])[NH:31][C@H:32]([C:40]1[O:41][C:42]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[N:43][N:44]=1)[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:5])[CH3:6])([OH:69])=[O:68]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCCCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
25 mg (30 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 55) and 23 mg (180 μmol) of 6-oxohexanoic acid were taken up in 3 ml of methanol and acidified with acetic acid. At room temperature, 15 μl (144 μmol; 9.4M) of borane-pyridine complex were subsequently added. The reaction mixture was subsequently stirred at RT for 20 h, and acetic acid and 15 μl (144 μmol; 9.4M) of borane-pyridine complex were added again after 8 h. The reaction mixture was subsequently adjusted to pH 2 with trifluoroacetic acid and purified by means of preparative HPLC. The product fractions were combined and concentrated, and the residue was lyophilized. 21 mg (74% of theory) of the title compound were thus obtained as a foam.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[C:20]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)(O)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH2:13][CH2:12][C:11]=2[CH:29]=1)#[N:6]>>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[C:20](=[C:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH2:13][CH2:12][C:11]=2[CH:29]=1)#[N:6]
Reactant: CN1CCC(C2(O)c3ccc(C#N)cc3CCc3cccnc32)CC1
Solvent: O=S(Cl)Cl
Product: CN1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Yield: 62.6 %

Procedure:
Thionyl chloride (15 ml) was added to 2.7 g of 8-cyano-6,11-dihydro-11-(1-methyl-4-piperidyl)-5H-benzo[ 5,6]cyclohepta[1,2-b]pyridin-11-ol, followed by reflux for 8 hours. The reaction mixture was concentrated under reduced pressure. An aqueous solution of sodium hydroxide was added to the residue to render the latter basic, followed by extraction with chloroform. The extract was dried over anhydrous Na2SO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol (50:1), 1.6 g of 8-cyano-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine were obtained (yield: 63%).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([OH:17])=[C:11]([CH2:18][CH:19]=[CH2:20])[C:10]=1[CH3:21])(=[O:7])[CH3:6].[Br:22]Br>C(N(CC)CC)C>[C:5]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]2[O:17][CH:19]([CH2:20][Br:22])[CH2:18][C:11]=2[C:10]=1[CH3:21])(=[O:7])[CH3:6]
Reactant: C=CCc1c(C)c(OC(C)=O)c(C)c(C)c1O
Reactant: BrBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CBr)O2
Yield: 93.9 %

Procedure:
To a chloroform (15 ml) solution of 4-acetoxy-2-allyl-3,5,6-trimethylphenol [2.0 g (8.5 mmol)] was added dropwise while stirring, bromine [1.36 g (8.5 mmol)]. To the mixture was then added triethylamine (0.3 ml), which was heated for two hours under reflux. The reaction mixture was cooled, washed with water, dried and then concentrated. The concentrate was crystallized from hexane to obtain 5-acetoxy-2-bromomethyl-4,6,7-trimethyl-2,3-dihydrobenzofuran [2.5 g (yield 93.2%)].
Reaction SMILES: C([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)OC(C1C=CC=CC=1)=C(O)C2=O)=C.BrC1C=CC([CH:32]=[O:33])=CC=1>>[C:21]1([C:4]2[CH:3]=[CH:12][CH:11]=[CH:10][CH:5]=2)[CH:22]=[CH:23][C:24]([CH:32]=[O:33])=[CH:25][CH:26]=1
Reactant: C=Cc1ccc2oc(-c3ccccc3)c(O)c(=O)c2c1-c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Product: O=Cc1ccc(-c2ccccc2)cc1

Procedure:
Alternatively, a vinyl phenyl hydroxyflavone may be prepared by synthesizing 4-styrene trimethyltin and combining it with 4-bromobenzaldehyde to produce 4'-vinyl, 4-biphenyl aldehyde. This intermediate compound is then reacted with 2-hydroxyacetophenone to produce the vinyl phenyl hydroxyflavone. This reaction scheme proceeds as follows: ##STR10##
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]([NH:2][CH2:3][CH2:4][S:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)=[O:26]
Reactant: COC(=O)c1ccc(SCCN)cc1
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCCNC(=O)c2cc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
Methyl 4-(2-aminoethylsulfanyl)benzoate hydrochloride (0.248 g, 1.00 mmol), was combined with benzofuran-2-carboxylic acid (0.162 g, 1.00 mmol) and HBTU (0.379 g, 1.00 mmol) in DMF (5 ml) at room temperature. Triethylamine (0.307 ml, 2.2 mmol) was added and the reaction mixture was stirred at room temperature overnight. Saturated aqueous NaHCO3 (15 ml) was added to give precipitates which was broken up by the addition of water (20 ml). The solid was filtered and the cake was dissolved in ethyl acetate. The residual water was removed by pipette and hexane was added to give methyl 4-{2-[(benzofuran-2-yl-carbonyl)-amino]ethylsulfanyl}benzoate (0.138 g) as a gum which was used in the next step without further purification.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[Cl:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:26][CH:25]=1.[NH2:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40]([NH:46][CH2:47][C:48]4[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=4)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:44][CH:45]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccc(Cl)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(Cl)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 32 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-chlorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 32% yield: mp 178-179° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.48 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.30-7.16 (m, 5H), 6.42 (t, J=5.7 Hz, 1H), 4.56 (d, J=5.7 Hz, 2H), 4.40 (s, 2H), 4.09-3.97 (m, 2H), 3.44-3.39 (m, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3) d 162.6, 157.3, 155.4, 153.6, 149.0, 148.5, 135.9, 134.0, 133.9, 129.6, 129.0, 123.7, 117.0, 47.3, 42.0, 41.7, 41.3, 17.2; MS (ES+) m/z 442.3 (M+1), 444.3 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>C(#N)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42.5 %

Procedure:
Potassium carbonate (2.00 g; 14.6 mmol) was added to a stirred solution of 1-(bromomethyl)-4-nitrobenzene (3.20 g; 14.8 mmol) and imidazole (1.00 g; 14.7 mmol) in acetonitrile (60 mL). The mixture was stirred at room temperature for 17 hr and then concentrated under reduced pressure. The residue was partitioned between EA and water and the phases separated. The aqueous phase was extracted twice with EA; and the combined organic layers washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 1-(4-nitrobenzyl)-1H-imidazole (1.27 g) as a red/brown oil. A solution of 1-(4-nitrobenzyl)-1H-imidazole (2.67 g; 13.1 mmol) in ethanol (100 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (0.285 g) at room temperature for 4.5 hr. The mixture was filtered through diatomaceous earth and then concentrated under reduced pressure to give 4-[(1H-imidazol-1-ylmethyl]benzenamine (2.24 g) as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F.[Cl:32][C:33]1[CH:34]=[C:35]([S:40]([NH:43][C:44]2[CH:45]=[C:46]3[C:51](=[CH:52][CH:53]=2)[C:50]([C:54]([OH:56])=O)=[CH:49][CH:48]=[CH:47]3)(=[O:42])=[O:41])[CH:36]=[C:37]([Cl:39])[CH:38]=1.[CH2:57]([NH2:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C)C=O.O>[CH2:57]([NH:64][C:54]([C:50]1[C:51]2[C:46](=[CH:45][C:44]([NH:43][S:40]([C:35]3[CH:34]=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=3)(=[O:42])=[O:41])=[CH:53][CH:52]=2)[CH:47]=[CH:48][CH:49]=1)=[O:56])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1cccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.50 ml diisopropylethylamine and 2.81 g O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate are added to 3.47 g 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid in 15 ml N,N-dimethylformamide. The reaction mixture is stirred for 15 minutes at ambient temperature, then 0.97 ml benzylamine and 1.50 ml diisopropylethylamine are added and the mixture is stirred for a further two hours at ambient temperature. For working up the reaction mixture is mixed with water and extracted with ethyl acetate. The combined organic extracts are washed with 1N hydrochloric acid, 1N sodium hydroxide solution and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The foam-like flask residue is stirred overnight with cyclohexane/ethyl acetate and the resulting crystalline precipitate is suction filtered, washed with cyclohexane and dried.