Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH2:7]C(Cl)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][Li].CC[O:15][CH2:16][CH3:17]>O1CCCC1>[CH:1]1([CH2:6][CH2:7][C:16]([CH3:17])([OH:15])[CH3:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCC
Reactant: O=C(Cl)CCC1CCCC1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(C)(O)CCC1CCCC1
Temperature: 5 °C
Reaction time: 26 h
Yield: 65 %

Procedure:
262.25 g (1.6 mol) of 3-cyclopentylpropionyl chloride (origin: Aldrich) and 500 ml of anhydrous THF (tetrahydrofuran) were charged into a 5 1 4-neck round bottom flask equipped with a mechanical stirrer and a reflux condenser. Upon cooling to 5° C., 3.2 1 of 1.4 M methyllitium in ether (4.48 mol) was added dropwise to the stirred solution at a rate which maintained the pot temperature between 15-25° C. The reaction mixture was then stirred at room temperature for 26 h and subsequently quenched, at 5° C., with the addition of 350 ml of water. The organic layer was separated and the ether and THF were stripped at reduced pressure. The resulting crude product was fractionally distilled with a 10-plate Oldershaw column at high vacuum to give 162 g of 4-cyclopentyl-2-methyl-2-butanol (purity>97%; yield=65%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=1)[C:4]([NH2:6])=[O:5].[CH3:20][C:21]1[CH:22]=[C:23]([CH:45]=[CH:46][CH:47]=1)[CH2:24][C@@H:25]([C:42](O)=[O:43])[NH:26][C:27](=[O:41])[CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC.Cl>C(Cl)Cl>[CH3:19][O:18][C:16]([C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][CH2:7][C@H:3]([NH:2][C:42](=[O:43])[C@H:25]([CH2:24][C:23]2[CH:45]=[CH:46][CH:47]=[C:21]([CH3:20])[CH:22]=2)[NH:26][C:27](=[O:41])[CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:4]([NH2:6])=[O:5])[CH:15]=[CH:14][CH:13]=1)=[O:17]
Reactant: COC(=O)c1cccc(CCC[C@H](N)C(N)=O)c1
Reactant: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(CCC[C@H](NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)C(N)=O)c1

Procedure:
To a solution of (S)-2-amino-5-(3-carbomethoxyphenyl)-pentanamide HCl (0.30 g, 0.80 mmol), of 3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanine (0.23 g, 0.80 mmol), 1-hydroxybenzotriazole hydrate (0.135 g, 0.89 mmol) and N-methylmorpholine (0.35 ml, 3.2 mmol) in CH2Cl2 (25 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (0.23 g, 1.2 mmol) in one portion, and the mixture is stirred at room temperature for 16 hours. The solution is then washed with 1 N HCl (100 mL), saturated aqueous NaHCO3 (1×50 mL), water (1×50 mL) and brine (1×50 mL), dried over MgSO4, and evaporated. The residual solid is triturated with ether to yield N-[4-(3-methoxycarbonyl-phenyl)-1(S)-(aminocarbonyl)-butyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide as a light yellow solid.
Reaction SMILES: [CH2:1]([N:11]1[C:15]([Cl:16])=[C:14]([CH3:17])[N:13]=[CH:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl-:16].[CH2:1]([N+:11]1[C:15]([Cl:16])=[C:14]([CH3:17])[N:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: ClCc1ccccc1
Reactant: CCCCCCCCCCn1cnc(C)c1Cl
Product: CCCCCCCCCC[n+]1cn(Cc2ccccc2)c(C)c1Cl
Product: [Cl-]
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
25.5 g (0.1 mole) of 1-decyl-4-methyl-5-chloroimidazole were heated to 100° C., 12.6 g (0.1 mole) of benzyl chloride were added dropwise in the course of 10 minutes, and the mixture was then stirred for a further 30 minutes at 125° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1)=[O:2].[CH3:13][C:14]([CH3:16])=O>C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>[CH3:13][C:14]1([CH3:16])[O:12][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][C:7]=2[C:8](=[O:10])[O:9]1
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(C=O)ccc2O1
Temperature: 90 °C
Yield: 35 %

Procedure:
A suspension of 5-formylsalicylic acid (Aldrich, 4.12 g, 24.8 mmol) in TFA (30 ml), TFAA (10 ml) and acetone (10 ml) was heated at 90° C. overnight. The reaction mixture was concentrated under reduced pressure. The residual oil was taken up in EtOAc and washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried- over MgSO4 and the solvent was removed under reduces pressure. The crude product was purified by flash chromatography on silicagel (EtOAc/c-Hex (80/20)) to give 1.8 g (35%) of the title compound as a white powder. 1H NMR (CDCl3) δ: 1.80 (s, 6H), 7.09 (d, J=8.7 Hz, 1H), 8.09 (dd, J=8.7, 2.3 Hz, 1H), 8.45 (d, J=1.9 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].N1C2C(=CC=CC=2)[CH:17]=N1.CO.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c2cc(C(=O)O)ccc12
Reactant: c1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.35 g (7.1 mmol) of 3-ethyl-1H-indazol-6-yl-carboxylic acid, [Marfat, A., et al., “Indazole Derivatives and Their Use as Inhibitors of Phosphodiesterase Type IV and the Production of Tumor Necrosis Factor TNF, U.S. Pat. No. 6,262,040], 2.9 mL (71 mmol) of methanol, and 0.95 g (7.8 mmol) of DMAP in 60 mL of CH2Cl2 was added 1.5 g (7.8 mmol) of EDCI-HCl. This mixture was stirred at room temperature overnight, concentrated and the residue dissolved in 50 ML of ethyl acetate. The organic layer was successively washed with 40 mL of 1N HCl, 40 mL of water and 40 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography over silica gel using a gradient of 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant to yield 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. 1H-NMR (CDCl3) δ 11.7 (s, 1H), 8.18 (s, 1H), 7.73. (apparent q, 9.0 Hz, 2H), 3.94 (s. 3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([C:10]1[C:11](B(O)O)=[CH:12][S:13][CH:14]=1)=[O:9].ClC1C=CC(CC2SC(C=O)=CC=2)=CC=1>>[C:2]1([C:11]2[C:10]([CH:8]=[O:9])=[CH:14][S:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: O=Cc1cscc1B(O)O
Agent: O=Cc1ccc(Cc2ccc(Cl)cc2)s1
Product: O=Cc1cscc1-c1ccccc1
Yield: 48 %

Procedure:
The title compound was synthesized from iodobenzene and 4-formylthiophen-3-ylboronic acid using the conditions to synthesize 5-(4-chlorobenzyl)thiophene-2-carbaldehyde. Double elution by prep-TLC (10% heptane/DCM) allowed for the isolation of 4-phenylthiophene-3-carbaldehyde (300 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (d, J=3.29 Hz, 1H), 7.39-7.50 (m, 5H), 8.27 (d, J=3.29 Hz, 1H), 9.87 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 185.80, 143.82, 138.91, 134.68, 134.28, 129.30, 128.58, 128.05, 124.76.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O.O.Cl>[CH3:22][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: O=C([O-])[O-]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 gm (10 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 164°-165° C., were dissolved in 15 ml of dimethyl sulfoxide, 2 gm of potassium carbonate and 1.5 ml of methyl iodide were added, and the mixture was stirred at room temperature for one hour. Subsequently, the mixture was diluted with water, hydrochloric acid was added and the reaction product was extracted with ethyl acetate. After washing, drying and evaporating the extract, the residue was recrystallized from isopropanol (10 ml). Yield: 1.4 gm (44% of theory); m.p. 79° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.I[CH3:14].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][O:12][CH3:14])[CH:3]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cc(Br)cc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 89 %

Procedure:
To a solution of (3-bromo-5-nitrophenyl)methanol (500 mg, 2.155 mmol) in DMF (7.2 mL) was added iodomethane (0.40 mL, 6.46 mmol. The solution was cooled to 0° C. before NaH (60% dispersion in mineral oil, 172 mg, 4.31 mmol) was added. The reaction was stirred at 0° C. and allowed to come to room temperature. After 2 hours the reaction was quenched with water and ethyl acetate was then added. Extraction was done with ethyl acetate (3×). The combined organic layer was dried over magnesium sulfate and then filtered. Ethyl acetate was then removed in vacuo to afford 1-bromo-3-(methoxymethyl)-5-nitrobenzene (470 mg, 1.910 mmol, 89% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 4.53 (s, 2H), 3.33 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-])=O.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([NH2:22])[CH:19]=[C:18]([O:23][CH3:24])[N:17]=1.N1C=CC=CC=1.[O:31]1CCOC[CH2:32]1>>[CH3:24][O:23][C:18]1[CH:19]=[C:20]([N:22]2[C:32](=[O:31])[NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:10]2(=[O:12])=[O:11])[CH:21]=[C:16]([O:15][CH3:14])[N:17]=1
Reactant: C1COCCO1
Reactant: COc1cc(N)cc(OC)n1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(N2C(=O)Nc3ccccc3S2(=O)=O)cc(OC)n1

Procedure:
The title compound (0.40 g, 1.19 mmol) was prepared in three steps from 2-nitrobenzenesulfonyl chloride (2.66 g, 12.0 mmol), 2,6-dimethoxypyridin-4-amine (2.04 g, 13.2 mmol) and pyridine (2.9 mL, 36.0 mmol) in 1,4-dioxane (48 mL) using the methods of (IntA19).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:14]2[CH:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][C:16]=3C(OCC)=O)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:31][Li].[C:33]([OH:36])(=O)[CH3:34]>C1COCC1.C(OCC)C>[CH3:1][C:2]1([CH3:30])[C:14]2[CH:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][C:16]=3[C:33]([OH:36])([CH3:34])[CH3:31])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: [Li]C
Reactant: CCOC(=O)c1ccc2ccccc2c1-c1ccc2c(c1)C(C)(C)c1ccccc1-2
Reactant: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2ccccc2c1-c1ccc2c(c1)C(C)(C)c1ccccc1-2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
100.6 g of ethyl 1-(9,9-dimethyl-9H-fluoren-2-yl)naphthalene-2-carboxylate (256 mmol) are initially introduced in 1000 ml of dried THF, 510 ml of a 1.5 M methyllithium solution in diethyl ether are added dropwise at −70° C., and the mixture is stirred at this temperature for 2 h. For work-up, 100 ml of ice-water followed by 300 ml of 50% acetic acid are added. The organic phase is separated off, washed twice with water, dried and evaporated in vacuo. The colourless solid which remains is recrystallised twice from heptane/toluene. Yield: 82 g (85%) of colourless crystals.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.ClC1SC2C=C([C:39]([F:42])([F:41])[F:40])C=CC=2N=1>>[NH:23]1[CH2:22][CH2:21][CH:20]([N:18]2[CH:19]=[C:15]([C:13]3[CH:14]=[C:9]([C:7]4[S:8][C:4]5[CH:3]=[C:2]([C:39]([F:42])([F:41])[F:40])[CH:28]=[CH:27][C:5]=5[N:6]=4)[C:10]([NH2:26])=[N:11][CH:12]=3)[CH:16]=[N:17]2)[CH2:25][CH2:24]1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: FC(F)(F)c1ccc2nc(Cl)sc2c1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(C(F)(F)F)cc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-6-trifluoromethyl-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.11-2.30 (m, 4H), 3.11 (q, J=10.8 Hz, 2H), 3.41 (d, J=12.4 Hz, 2H), 4.47-4.58 (m, 1H), 7.92 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.43 (br. s., 2H), 8.58 (br. s., 1H), 8.76 (br. s., 1H). MS (ES+): m/z=445.08 [MH+]. HPLC: tR=2.25 min (ZQ2, polar—5 min).
Reaction SMILES: [CH:1]1([CH2:11][C:12](O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[C:18]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:19][C:20]2[O:24][CH2:23][CH2:22][C:21]=2[CH:25]=1>>[CH3:15][O:16][C:17]1[C:18]([N:26]2[CH2:27][CH2:28][N:29]([CH2:12][CH2:11][CH:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)[CH2:30][CH2:31]2)=[CH:19][C:20]2[O:24][CH2:23][CH2:22][C:21]=2[CH:25]=1
Reactant: COc1cc2c(cc1N1CCNCC1)OCC2
Reactant: O=C(O)CC1CCCc2ccccc21
Product: COc1cc2c(cc1N1CCN(CCC3CCCc4ccccc43)CC1)OCC2

Procedure:
Prepared as described in Example 9, starting from 1,2,3,4-tetrahydronaphthalen-1-ylacetic acid and 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of the title compound melts at 219°-220° C. after recrystallisation from ethanol.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[N:8]([CH3:13])[C:7](=[O:14])[CH:6]3[CH2:15][O:16][CH2:17][CH2:18][N:5]3[C:4]=2[N:3]=1.IC.[CH3:21]C([O-])(C)C>CS(C)=O.O>[Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[N:8]([CH3:13])[C:7](=[O:14])[C:6]3([CH3:21])[CH2:15][O:16][CH2:17][CH2:18][N:5]3[C:4]=2[N:3]=1
Reactant: CN1C(=O)C2COCCN2c2nc(Cl)nc(Cl)c21
Reactant: CC(C)(C)[O-]
Solvent: CS(C)=O
Solvent: O
Solvent: CI
Product: CN1C(=O)C2(C)COCCN2c2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
2,4-Dichloro-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (20 mg, 0.069 mmol) and iodomethane (9.82 mg, 0.069 mmol) were stirred in DMSO (2 mL). The mixture was frozen then 2-methylpropan-2-olate (19.94 mg, 0.208 mmol) was added as a solid followed by a layer of DMSO. The mixture was refrozen then allowed to warm up to room temperature and stirred for 1 hour. The reaction was diluted with water and extracted twice with EtOAc, the organic layers combined, dried over magnesium sulfate, filtered and evaporated in vacuo to give 20 mg (95%) of 2,4-dichloro-5,6a-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a white solid. MS [M+H] Found 303.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].N1C(CN[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:24][CH:23]=2)=NN=N1.[CH3:36]N(C=O)C>>[CH2:28]([C:25]1[CH:24]=[CH:23][C:22]([CH2:36][N:6]2[CH2:5][CH2:4][N:3]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]2=[O:1])=[CH:27][CH:26]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCc1ccc(NCc2nnn[nH]2)cc1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)CN1CCNC1=O
Product: CCCCCCCCc1ccc(CN2CCN(CC(=O)OC(C)(C)C)C2=O)cc1
Reaction time: 1 h
Yield: 16 %

Procedure:
To a solution of the product of Step A (0.03 g; 0.15 mmol) in anhydrous DMF (5 ml) 60% NaH in mineral oil (0.006 g; 0.15 mmol) was added at room temperature, under N2. After stirring for 1 h, the product of Example 4, Step B (0.042 g; 0.15 mmol) was added. The resulting mixture was stirred for additional 4 h and solvents were removed in vacuo. The residue was diluted to 10 ml with EtOAc, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.01 g; 16%) as a colourless solid. 1H-NMR (CDCl3) 7.16 (d, 2H, J=8.1 Hz); 7.11 (d, 3H, J=8.1 Hz); 4.34 (s, 2H); 3.95 (s, 2H); 3.4 (m, 2H); 3.21 (m, 2H); 2.56 (t, 3H, J=7.9 Hz); 1.65 (m, 2H); 1.43 (s, 9H); 1.26 (m, 10H); 0.86 (t, 3H, J=7 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3C4C([C:18]5[C:23]=3[C:22]=2[CH:21]=[CH:20][CH:19]=5)=CC=CC=4)=[CH:4][CH:3]=1.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl.[CH3:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>O1CCCC1>[CH:20]1[C:21]2=[C:22]3[C:8]([C:5]4[C:6]2=[CH:7][CH:2]=[CH:3][CH:4]=4)=[CH:9][CH:10]=[CH:11][C:23]3=[C:18]([C:45]2[CH:44]=[CH:43][C:48]([B:29]([OH:34])[OH:30])=[CH:47][CH:46]=2)[CH:19]=1
Reactant: CCCCCC
Reactant: Brc1ccc(-c2ccc3c4c(cccc24)-c2ccccc2-3)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2ccc3c4c(cccc24)-c2ccccc2-3)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
In the atmosphere of argon, 9.2 g of 3-(4-bromophenyl)fluoranthene and 129 mL of tetrahydrofuran were placed in a flask. The reaction solution was cooled to −70° C., and 17.2 mL of a 1.65M hexane solution of n-butyllithium was added dropwise. Stirring was conducted at −70° C. for 2 hours. To the reaction solution, 17.7 mL of triisopropyl borate was added dropwise, and the resultant was stirred at −70° C. for 1 hour. While heating the reaction solution to room temperature, stirring was conducted for 5 hours. 2M hydrochloric acid was added to the reaction liquid to allow it to be acidic, and the reaction solution was extracted with ethyl acetate. After removing an aqueous phase, an organic phase was washed with saturated saline, and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, residues were washed with a hexane-ethyl acetate mixed solution, whereby 7.9 g (yield 95%) of 4-(fluoranthen-3-yl)phenylboronic acid was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH:5](O)[CH2:4][CH:3]1[CH3:10].S(Cl)([Cl:13])=O>C1C=CC=CC=1.O>[CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH:5]([Cl:13])[CH2:4][CH:3]1[CH3:10]
Reactant: CC1CC(O)CC(C)N1C
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: CC1CC(Cl)CC(C)N1C
Temperature: 70 °C
Yield: 58 %

Procedure:
The starting material, 1,2,6-trimethyl-4-piperidinol, may be prepared by the method disclosed in Archi Kem, Volume 27, pages 189°-192 (1955). To a cooled (ice-bath) solution of 1,2,6-trimethyl-4-piperidinol (12.2 g, 85.3 mmol) in 120 mL of dry benzene was slowly added thionylchloride (17 mL, 233 mmole). The dark reaction mixture was then warmed to 70° C. for 20 min. The reaction was cooled and then suspended in water followed by filtration. The filtrate was extracted once with diethylether. The aqueous layer was separated and then basified with 30% NaOH solution. The product was then extracted twice with CH2Cl2, washed once with brine, dried (Na2SO4), filtered and solvent removed to give a crude brown liquid which was distilled (2-4 mmHg, 62°-64° C.) to give the title compound (8.0g, 58% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[N:11][N:12]=2)[CH:9]=1)(=[O:3])[CH3:2].Br.C(O)(=O)C.[Br:18]N1C(=O)CCC1=O.ClCCl>C(O)(=O)C.C(OCC)(=O)C>[Br:18][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[N:11][N:12]=2)[CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc2nnnn2c1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CBr)c1ccc2nnnn2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Acetyl tetrazolo[1,5-a] pyridine (10 g, 62 mmol) in acetic acid (160 mL) was treated with 30% HBr/acetic acid (14.7 mL, 247 mmol) at 0° C. N-bromosuccinimide (11 g, 62 mmol) was slowly added and the reaction stirred for 30 minutes. Another 4 equivalents of 30% HBr/acetic acid (14.7 mL, 247 mmol) was slowly added and the reaction was allowed to warm to room temperature. After 3 hours, the reaction was diluted with ethyl acetate (500 mL) and washed with water (3×300 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford an oil. Hexanes (75 mL) and dichloromethane (10 mL) were added to the oil and reconcentrated to afford a yellow solid (12.8 9, 86%). Rf =0.2 (CH2Cl2); mp 108-110° C.; 1H NMR (300 MHz, CDCl3) δ 10.2 (s, 1 H), 8.29 (dd, J=9, 10 Hz, 1 H), 8.18 (dd, J=8, 10 Hz, 1 H), 5.06 (s, 2 H); MS (EI) m/z 241 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Cl:17])[C:9]=3[CH:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:43])[CH2:26][CH:27]4[CH2:31][CH2:30][N:29]([C:32](=[N:40][C:41]#[N:42])OC5C=CC=CC=5)[CH2:28]4)[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1.[NH4+:44].[OH-]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Cl:17])[C:9]=3[CH:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:43])[CH2:26][CH:27]4[CH2:31][CH2:30][N:29]([C:32](=[NH:44])[NH:40][C:41]#[N:42])[CH2:28]4)[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: N#CN=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Agent: [OH-]
Solvent: CC(C)O
Product: N#CNC(=N)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve the product of Example 7 in 2-propanol and add concentrated NH4OH. Stir the mixture at 25° C. for 24 h and then evaporate to dryness. Triturate the residue with Et2O (2×250 ml) and discard the ether. Chromatograph the resulting product on a silica gel column using 4% (10% concentrated NH4OH in CH3OH)--CH2Cl2 as the eluant to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[S-:11][C:12]#[N:13].[K+].CN(C=[O:19])C>[I-].[K+]>[C:5]1([C:3]2[NH:13][C:12](=[O:19])[S:11][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: N#C[S-]
Reactant: CN(C)C=O
Agent: [I-]
Agent: [K+]
Product: O=c1[nH]c(-c2ccccc2)cs1
Temperature: 80 °C
Yield: 75 %

Procedure:
A suspension of 2-bromoacetophenone (5 g, 0.0251 mol), potassium thiocyanate (8.6 g, 0.088 mol) and potassium iodide (0.25 g, 0.0015 mol) in dry DMF (25 mL) was heated to 80° C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in glacial acetic acid (25 mL) and 50% aqueous H2SO4 was added to it. The reaction mixture was heated to 100° C. for 10 min. The reaction mixture was poured in ice water and the precipitate formed was filtered and dried under reduced pressure to get 4-phenylthiazol-2(3H)-one (3.3 g, yield 75%) as brown solid, which was carried through without further purification.