Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:15][CH:16]([CH3:18])[CH3:17])[C:5]([NH:8][CH2:9][C:10](OCC)=[O:11])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>CO>[Br:1][C:2]1[N:3]=[C:4]2[N:15]([CH:16]([CH3:18])[CH3:17])[C:10](=[O:11])[CH2:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1NC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)N1C(=O)CNc2ncc(Br)nc21
Temperature: 90 °C
Yield: 58.8 %

Procedure:
A mixture of ethyl 2-(5-bromo-3-(isopropylamino)pyrazin-2-ylamino)acetate (780 mg, 2.26 mmol), methanol (5 mL) and TFA (10 mL) in a sealable vessel was purged with nitrogen, sealed, stirred vigorously and heated at 90° C. with an oil bath for 16 h. The resulting mixture was diluted with methanol and the solvent was removed under reduced pressure. Methanol (10 mL) was added and the solvent was removed under reduced pressure again. Methanol (10 mL) and sodium bicarbonate were added. The resulting mixture was stirred at room temperature until pH=6 (in water), the solvent was removed under reduced pressure. Water (20 mL) was added. The mixture was extracted with methylene chloride (20 mL×3). The organic layer was dried over anhydrous sodium sulfate, concentrated to give the crude product and purified on silica column chromatography (10-20% ethyl acetate in petroleum ether) to give the title compound (360 mg, 39.4% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[OH:11][C:12]1[C:20]([CH2:21]/[CH:22]=[C:23]2/[C@H:24]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:26][CH2:27]/2)=[C:19]([O:34][CH3:35])[C:18]([CH3:36])=[C:17]2[C:13]=1[C:14](=[O:37])[O:15][CH2:16]2.[CH3:38]I.[Cl-].[NH4+]>O1CCCC1.CN1CCCN(C)C1=O.C(OCC)(=O)C>[OH:11][C:12]1[C:20]([CH2:21]/[CH:22]=[C:23]2/[C@H:24]([CH:28]([CH3:38])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:26][CH2:27]/2)=[C:19]([O:34][CH3:35])[C:18]([CH3:36])=[C:17]2[C:13]=1[C:14](=[O:37])[O:15][CH2:16]2
Reactant: CCOC(=O)C[C@@H]1CCC/C1=C\Cc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)[C@@H]1CCC/C1=C\Cc1c(O)c2c(c(C)c1OC)COC2=O
Reaction time: 0.5 h

Procedure:
To a solution of 1M sodium bis(trimethylsilyl)amide in tetrahydrofuran (31.7 ml ) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.74 ml) at -78° C. was added ethyl (E) 2-{2-[2-(1,3-dihydro -4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) ethylidene]cyclopent -1-(S)-yl}acetate (3.39 g) in tetrahydrofuran (35 ml), over a period of 30 minutes. After an additional 30 minutes methyl iodide (2.25 ml) was added. After an additional two hours saturated aqueous ammonium chloride (10 ml) and ethyl acetate were added. The organic solution was dried and evaporated and the residue chromatographed on silica gel, eluting with 4:1 hexane:ethyl acetate, to afford one diastereomer of ethyl (E) 2-{2-[2-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran -5-yl)ethylidene]cyclopent-1-(S)-yl}propionate as a low-melting solid.
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:20]1[CH:19]=[C:18]2[C:23](/[C:15](=[C:10]3/[CH:9]=[C:8]([C:33]4[CH:34]=[CH:35][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:31][CH:32]=4)[C:12]([CH3:14])([CH3:13])[O:11]/3)/[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)ccc43)OC2(C)C)cc1
Temperature: 80 °C

Procedure:
To 30 mL of 1,4-dioxane, was added the following reagents: (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (500 mg, 1.54 mmol), 4-methoxycarbonylphenylboronic acid (333 mg, 1.85 mmol), PdCl2(PPh3)2 (54 mg, 0.077 mmol), 1M Na2CO3 aqueous solution (6.2 mL, 6.2 mmol). The mixture was heated at 80° C. under N2 for 1 hour, cooled to room temperature and poured into 200 mL of water. The brown precipitates were filtered, washed with water and dried to give the crude product. Purification through silica gel column with 1-5% MeOH/CHCl3 led to methyl 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate as orange/red solid. Yield: 500 mg, 86%.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:5].Cl.C(N(CC)CC)C.[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[CH:29][CH:28]=1)([CH3:26])[CH3:25]>CCOCC>[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:15][CH:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[S:35])=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: CCOC(=O)C(N)Cc1ccc(Cl)cc1
Reactant: CC(C)c1ccc(N=C=S)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(Cl)cc1)NC(=S)Nc1ccc(C(C)C)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
DL-4-Chlorophenylalanine ethyl ester hydrochloride(5 g, 18.9 mmol) was converted to the free base using triethylamine. A solution of the free base in 75 mL ether was added to a solution of 4-isopropylphenylisothiocyanate in 150 mL ether, cooled on an ice-salt bath. The temperature was maintained at about 0° C. during addition. The reaction was stirred for four and one-half hours, at which time the reaction temperature was 12° C.. The reaction mixture was filtered, the filtrate concentrated, and the resulting foamy residue triturated with petroleum ether while cooling on ice. This resulted in 6.1 g (15.1 mmol, 80%) N-(4-isopropylphenyl)-N'-[2-(4-chlorophenyl)-1-(ethoxycarbonyl)ethyl]thiourea, mp 73°-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:14]=[O:15]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:19][C:18]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=2[F:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: Clc1ccc(CBr)cc1
Product: O=Cc1ccc(OCc2ccc(Cl)cc2)c(F)c1

Procedure:
Additional aldehydes were prepared using the protocol of Scheme 10, replacing either 4-chlorobenzyl bromide 45 with a suitable alkylating agent, and/or 3-fluoro-4-hydroxy-benzaldehyde 44 with a suitable aldehyde. The following table indicates the alkylating agent (column 1) and the starting aldehyde (column 2) used to afford the aldehyde (column 3) synthesized following this protocol.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:15]([OH:18])[CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=1.C1(C)C=C[C:22]([S:25](Cl)(=[O:27])=[O:26])=CC=1>N1C=CC=CC=1>[CH3:22][S:25]([O:17][CH2:16][C@@H:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=1)[OH:18])(=[O:27])=[O:26]
Reactant: OC[C@H](O)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H](O)c1cccc(Cl)c1

Procedure:
Into toluene (30 ml) were added (R)-2-(3-chlorophenyl)-2-hydroxyethanol obtained in 1) above (7 g), pyridine (8.0 g) and further, under ice-cooling and dropwise, p-toluenesulfonyl chloride (9.3 g), and then the resulting mixture was stirred at the same temperature for 24 hours. The solid thus precipitated was filtered off, the filtrate was concentrated, and the residue was dissolved in toluene (40 ml) and then washed with dilute hydrochloric acid. The organic layer was collected by layer separation, washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether and hexane to obtain a colorless oily compound mentioned above (10.6 g, 80.0%).
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH2:4].[C:5]1([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH:3]([CH:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:2][CH3:1])[CH3:4]
Reactant: C=CCC
Reactant: c1ccc(Cc2ccccc2)cc1
Product: CCC(C)C(c1ccccc1)c1ccccc1

Procedure:
Using the same catalyst as that of Preparation Example 1, reaction was carried out with butene-1 and diphenylmethane to obtain sec-butyldiphenylmethane of 96 wt. % purity. The boiling point of the reaction product was 301° to 309° C. and the flash point thereof was 162° C. This reaction product is called as diarylalkane 2 (hereinafter referred to as "DAA2") and the physical properties thereof are shown in the following Table 1.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:10]=2)=[CH:5][CH:4]=1.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>C(OCC)(=O)C>[OH:32][CH2:31][CH2:30][CH2:29][NH:28][S:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=3)[CH:14]=[CH:13][N:12]=2)=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: NCCCO
Reactant: O=S(=O)(Cl)c1ccc(Nc2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Solvent: CCOC(C)=O
Product: O=S(=O)(NCCCO)c1ccc(Nc2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Yield: 88.4 %

Procedure:
To a solution of 4-({4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)benzenesulfonyl chloride (0.10 g, 0.25 mmol) in 2 ml of ethyl acetate is added 3-amino-1-propanol (0.19 g, 2.5 mmol) with stirring, at 0° C. The mixture is stirred at room temperature for 1 hr and then quenched with water (10 ml). The ethyl acetate is evaporated, the resulting suspension is filtered, and the precipitate is washed with water, and hexanes, and then dried in vacuo to give 0.10 g of a white solid; mp 204-205° C.; HRMS: calcd for C20H19F3N4O3S, 452.1130; found (ESI-FTMS, [M+H]1+), 453.12161.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:17][CH3:18])[CH2:2][CH2:3][CH3:4].[Cl:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.CN(C)C1C=C[NH+]=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Cl:19])=[O:15])=[CH:8][C:7]=1[O:17][CH3:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(/C=C/C(=O)O)cc1OC
Reactant: OCCCCCCCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1cc[nH+]cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCCCOc1ccc(/C=C/C(=O)OCCCCCCCl)cc1OC

Procedure:
Preparation was carried out analogously to Example 5 using 4.24 g (16.94 mmol) (2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoic acid, 2.20 g (16.13 mmol) 6-chloro-1-hexanol, 1.90 g (6.45 mmol) 4-(dimethylamino)pyridinium p-toluenesulfonate and 4.16 g (20.17 mmol) N,N′-dicyclohexylcarbodiimide to give 6-chlorohexyl (2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoate as colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>CN(C=O)C>[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(CBr)Nc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1F
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1F)Nc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 63.8 %

Procedure:
A solution of 4-((bromoacetyl)amino)nitrobenzene (12.0 g, 46.3 mmol) and 2-fluoroaniline (11.0 g, 102 mmol) in anhydrous DMF (60 mL) was heated to 90°-100° C. for 2 days with stirring under N2. The solution was cooled, poured into 500 mL of ice-water, and then extracted with CH2Cl2 (200 mL). The organic layer was dried (MgSO4) and filtered, a small amount of silica gel was added to the CH2 Cl2 solution, and then the mixture was concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (3:1), afforded 8.54 g (63.7%) of the title compound as yellow crystals, mp 150°-153° C.; 1H NMR (DMSO-d6) δ10.65 (s, 1H), 8.22 (d, J=9.2, 2H), 7.86 (d, J=9.2, 2H), 7.04 (ddd, J=9.6, J=8.4, J=1.6, 1H), 6.94 (dt, J=7.2, J=1.2, 1H), 6.65-6.61 (m, 2H), 5.80 (bs, 1H), 4.02 (s, 2H); 13C NMR (DMSO-d6) δ170.06, 150.91 (d, J=236), 144.99, 142.23, 136.31 (d, J=11.3), 124.98, 124.75 (d, J=3.5), 118.90, 116.36 (d, J=6.4), 114.44 (d, J=17.6), 112.17 (d, J=14.0), 46.79; MS (El, m/z) 289 (M+). Anal. Calcd for C14H12N3 O3F: C, 58.12; H, 4.18; N, 14.53. Found: C, 58.04; H, 4.20; N, 14.36.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18]C)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1nc(Br)ccc1OCc1ccccc1
Yield: 97.9 %

Procedure:
A solution of methyl 3-(benzyloxy)-6-bromopicolinate (2.0 g, 6.20 mmol) and LiOH.H2O (0.71 g, 18.60 mmol) in 1,4-dioxane/H2O (100 mL/20 mL) was stirred at 40° C. overnight. The mixture was filtered and the filtrate was acidified to pH=3 by aqueous HCl (2 M) and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to afford the product of 3-(benzyloxy)-6-bromopicolinic acid (1.87 g, yield: 97.9%) without further purification. 1H-NMR (CDCl3, 400 MHz) δ 7.52˜7.54 (m, 1H), 7.39˜7.41 (m, 2H), 7.24˜7.34 (m, 4H), 5.24 (s, 2H). MS (M+H)+: 308/310.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].OS(O)(=O)=O.O1CCCC1>O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reaction time: 4 h
Yield: 91 %

Procedure:
A mixture of 12.97 g (0.0436 mol) of the ketal of (A) and 200 ml of 10% H2SO4 /tetrahydrofuran (2:1) solution is stirred at 60°-70° C. for 4 hrs and is then allowed to stand at room temperature for 3 days. The mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Trituration with ethyl ether gives 10.07 g (91%) of title compound as a white solid: m.p. 183°-185° C.; IR (KBr) 3410, 1710, 1585, and 1160 cm-1 ; NMR (CDCl3) δ 7.79 (d, 2H), 6.98 (d, 2H), 3.79 (t, 4H), 3.04 (s, 3H), and 2.61 (t, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([CH2:13][SH:14])[CH:11]([OH:15])[N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][C:26](=[O:28])[CH3:27]>C1COCC1>[CH2:1]([N:8]1[CH:12]([CH2:13][S:14][CH2:25][C:26](=[O:28])[CH3:27])[CH:11]([OH:15])[N:10]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccccc2)C(O)C(CS)N1Cc1ccccc1
Reactant: CC(=O)CCl
Solvent: C1CCOC1
Product: CC(=O)CSCC1C(O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of 1.85 g (5.63 mmol) of (4 RS, 5 R) 1,3-dibenzyl-2-oxo-5-mercaptomethylimidazolidin-4-ol (prepared according to Example 2) and 7.0 ml of THF is treated at 0°-5° C. with 0.855 g (1.18 ml, 8.45 mmol) of TEA and 0.547 g (0.47 ml, 5.91 mmol) of chloroacetone. The mixture is stirred at 0° C. for 2 hours and then at room temperature for 2 hours. The precipitate is filtered off and the solvent is removed by distillation. After flash chromatography, 1.956 g (90% of theory) of (4 RS, 5 R)-1,3-dibenzyl-2-oxo-5-(4-oxo-2-thiapentyl)imidazolidin-4-ol, Rf =0.24 (EtOAc/hexane 3:2) are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc(=O)oc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ccc(CBr)cc2o1
Yield: 50.8 %

Procedure:
7-Methylcoumarin (28 g), 70% benzoylperoxide (1.68 g), and N-bromosuccinimide (30.8 g) was added to 140 mL chloroform in a one liter flask, and the suspension was refluxed overnight. The solution was diluted with 100 mL chloroform. The resulting crude product was recrystallized from 750 mL acetone. A white solid (21 g) with a melting point of 172-176° C. was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9]CC)=[O:8])=[CH:3]1.[OH-].[Na+].Cl.[Cl-].[Na+]>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3]1
Reactant: CCOC(=O)c1ccn(C)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: Cn1ccc(C(=O)O)c1
Temperature: 0 °C
Yield: 92.2 %

Procedure:
7.66 g (50 mmole) of ethyl 1-methyl-3-pyrrolecarboxylate prepared in Example 1 and 37.5 ml (75 mmole) of 2N sodium hydroxide aqueous solution were charged into a reaction vessel and refluxed for two hours. The reaction mixture was cooled to 0° C. and about 7 ml of 6N hydrochloric acid solution was added while stirring. After the addition of 15 g of sodium chloride, the mixture was stirred for one hour over an ice-acetone bath to collect precipitated crystals. The crystals were washed with cold water and dried under reduced pressure to obtain 5.77 g (yield 92.2%) of colorless or light-yellow powdery crystals of 1-methyl-3-pyrrolecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][C:13]#[N:14].C([OH:17])C.[ClH:18]>CCOCC>[ClH:18].[CH3:11][C:4]1[CH:5]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:12][C:13](=[NH:14])[OH:17]
Reactant: CCO
Reactant: Cc1cc(C(C)C)cc(C)c1CC#N
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(C(C)C)cc(C)c1CC(=N)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of 2,6-dimethyl-4-isopropylphenylacetonitrile (Example 4c); (0.2 g, 1.07 mmol) in anhydrous ether (20 mL) was added absolute ethanol (0.05 g, 1.07 mmol) and an excess of HCl gas was passed into the solution with cooling in an ice bath. The resulting solution was allowed to stir at 0° C. for 2 hours and kept in a refrigerator for 4 days. The white solid was collected by filtration, washed with ether (2×5 mL) and dried to give 0.12 g (42%) of 2-(2,6-dimethyl-4-isopropylphenyl)acetimidate hydrochloride as a white solid, mp 231-233° C. A solution of ethylenediamine (0.053 g, 0.89 mmol) in absolute ethanol (1 mL) was added to a solution of the imidate hydrochloride (0.12 g, 0.44 mmol) in absolute ethanol (4 mL) cooled at ice-bath temperature. After stirring at 0° C. for 2 hour, the solution was heated at reflux for 20 minutes. The solvent was evaporated and the oily residue was washed with water (2×1 mL) and extracted with methylene chloride (3×10 mL). The solution was dried (MgSO4), filtered and evaporated under reduced pressure to afford the free base of the title compound as a white solid (mp 112-114° C.). A solution of the free base in anhydrous ether was treated with dry HCl gas. The crude salt was collected and recrystallized from ethanol/ether to give 0.08 g (65%) of the title compound as a white solid. mp 296-298° C.; Anal. C15H22N2 ·HCl·0.1H2O: C, H, N.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[N:20][CH:21]=1.[OH:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O.O>ClCCl>[Br:15][C:16]1[CH:17]=[C:18]([NH:22][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[OH:23])[CH:19]=[N:20][CH:21]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=Cc1ccccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccccc1CNc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
295 mg (1.4 mmol, 1.4 eq) of sodium triacetoxyborohydride are added to a solution of 173 mg (1 mmol, 1 eq) of 5-bromopyridin-3-ylamine (starting material 1) and 122 mg (1 mmol, 1 eq) of 2-hydroxybenzaldehyde (starting material 2) in 20 ml of dichloromethane. The solution is stirred at room temperature for 24 h. The medium is poured into water and stirred for 2 h. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water, and then dried over sodium sulphate. The residue is chromatographed on silica gel (80/20 heptane/ethyl acetate). 2-[(5-Bromopyridin-3-ylamino)methyl]phenol is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:11](#[N:14])[CH:12]=[CH2:13]>C(O)C>[C:11]([CH2:12][CH2:13][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:4][CH2:3][C:2]#[N:1])#[N:14]
Reactant: C=CC#N
Reactant: NCCCCCCCCN
Solvent: CCO
Product: N#CCCNCCCCCCCCNCCC#N

Procedure:
Dissolve 14.4 g (0.1 mol) of 1,8-diaminooctane and 14.5 ml (0.22 mol) of acrylonitrile in 100 ml of ethanol and reflux overnight. Remove the solvent at reduced pressure. Analysis showed the title compound to be >98% pure.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]1([N:17]2[C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)[C:28](=[O:30])[CH3:29].[Cl-].[NH4+]>C1COCC1>[C:11]1([N:17]2[C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[C:28](=[O:30])[CH3:29])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)N(C)C
Reactant: c1ccc(-n2cnc3ccncc32)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)c1nc2ccncc2n1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
LiHMDS (2.0M in THF/heptane/ethyl benzene, 3.9 mL, 7.79 mmol) was added to a stirred solution of 3-phenyl-3H-imidazo[4,5-c]pyridine (0.95 g, 4.87 mol) in THF (20 mL) at −78° C. under nitrogen. The resultant mixture was stirred at −78° C. for 10 minutes then at −10° C. for 15 minutes. The reaction mixture was re-cooled to −78° C. and N,N-dimethylacetamide (0.72 mL, 7.79 mmol) added then stirred at −78° C. for 5 minutes then at −10° C. for 15 minutes. The reaction mixture was poured into saturated aqueous ammonium chloride solution (30 mL) and extracted with EtOAc (3×30 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (SiO2 0-4% (2M ammonia in methanol) in DCM) to give the title compound as an off white solid (0.96 g, 76%) LCMS (method H): Rt 1.76 min, [M+H]+ 238
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][C:12]=1[Cl:26]>>[Cl:26][C:12]1[CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:15]([N+:1]([O-:4])=[O:2])=[CH:16][C:11]=1[Cl:10]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCCc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Product: CCCCCCCCCc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred and cooled (0°-5° C.) mixture of 110 parts of concentrated nitric acid solution and 314 parts of concentrated sulfuric acid solution are added dropwise 60 parts of 1,2-dichloro-4-nonylbenzene. Upon completion, stirring is continued for 30 minutes at 0° C. The reaction mixture is poured onto crushed ice and the product is extracted with 2,2'-oxybispropane. The extract is washed successively with water and a sodium hydrogen carbonate solution, dried, filtered and evaporated, yielding 70 parts (100%) of 1,2-dichloro-4-nitro-5-nonylbenzene as an oily residue.