Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([N+:24]([O-])=O)[CH:16]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:28]1([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:15]3[CH:20]=[CH:19][C:18]4[NH:21][C:38]([C:37]5[CH:36]=[CH:35][C:34]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[CH:41][CH:40]=5)=[N:24][C:17]=4[CH:16]=3)=[O:27])=[CH:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1

Procedure:
Compound 211 was prepared according to the procedure similar to that described in Scheme III from N-(4-morpholinylphenyl)-3,4-dinitrobenzamide and 4-morpholinylbenzaldehyde. [M+H]+ calcd for C28H29N5O3: 484.23; found: 483.92.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][O:10][C:11]1[C:12](=[O:21])[CH:13]=[C:14]([CH3:20])[C:15](=[O:19])[C:16]=1[O:17][CH3:18]>O.C(OCC)C>[CH3:20][C:14]1[C:15]([OH:19])=[C:16]([O:17][CH3:18])[C:11]([O:10][CH3:9])=[C:12]([OH:21])[CH:13]=1
Reactant: COC1=C(OC)C(=O)C(C)=CC1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1c(O)cc(C)c(O)c1OC
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
A solution of sodium dithionite (95.4 g, 0.548 mols) in water (330 ml) was added to a solution of 2,3-dimethoxy-5-methyl-1,4-benzoquinone (50 g, 0.274 mols) in diethyl ether (330 ml), and shaken for 15 minutes. The ether layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated in vacuo. The resulting crystals were washed with hexane to obtain 2,3-dimethoxy-5-methyl-1,4-hydroquinone (46.1 g).
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[F:37].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:34]2[CH:33]=[CH:32][C:31]([F:30])=[C:36]([F:37])[CH:35]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(F)c(F)c3)cc2)C(N)=O)CCOCC1
Temperature: 85 °C
Yield: 104.5 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 300 mg) and 3,4-difluorophenylboronic acid (92 mg) in acetonitrile (8 mL) were treated with aqueous sodium carbonate solution (2M, 0.58 mL) and nitrogen was bubbled through the reaction mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (8 mg) was added and the mixture was heated at 85° C. for 18 h. The mixture was purified by chromatography on silica eluting with 50-100% ethyl acetate/isohexane as eluent to yield the sub-titled compound (305 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=[O:16])=[O:11])=O)(C)(C)C.Cl.CCOCC>ClCCl>[NH2:8][C@H:9]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=[O:16])=[O:11]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)[C@H](N)CCCCN)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl 3-{[(2R)-2,6-di(tertbutoxycarbonylamino)hexanoyl]amino}propanoate (1) (0.123 g; 0.162 mmol) in dichloromethane (10 ml) was treated with a 4.8M solution of hydrogen chloride in ether (170 μl; 0.81 mmol). The mixture was stirred at ambient temperature for 1 hour and the resulting precipitate was filtered, washed with ether and dried to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl 3-{[(2R)-2,6-diaminohexanoyl]amino}propanoate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][CH:40]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:32]=[C:31]([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)[CH:30]=[CH:29][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[C:15]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:11].Cl>CO.O1CCOCC1>[CH3:10][OH:11].[NH2:21][CH2:20][C:15]1[C:14]([CH2:13][NH:12][C:10](=[O:11])[C:9]2[CH:29]=[CH:30][C:31]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[N:32][C:8]=2[NH:7][CH2:6][CH2:5][C:4]2[CH:38]=[CH:39][CH:40]=[C:2]([F:1])[CH:3]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)NCc1ncccc1CNC(=O)c1ccc(-c2cn[nH]c2)nc1NCCc1cccc(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCc1ncccc1CNC(=O)c1ccc(-c2cn[nH]c2)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 179.7 %

Procedure:
To a solution of tert-butyl (3-((2-(3-fluorophenethylamino)-6-(1H-pyrazol-4-yl)nicotinamido)methyl)pyridin-2-yl)methylcarbamate (737 mg, 1.27 mmol) in methanol (6 mL) at 0° C. was added a solution of 4M HCl in 1,4-dioxane (3 mL). The mixture was warmed to room temperature and stirred for 2 hrs. Concentration of the mixture followed by the purification on RP-HPLC using a mixture of acetonitrile and H2O gave N-((2-(aminomethyl)pyridin-3-yl)methyl)-2-(3-fluorophenethylamino)-6-(1H-pyrazol-4-yl)nicotinamide compound with methanol (1:1) as a pale yellow solid (545 mg, 89%). LRMS (M+H+) m/z 446.2.
Reaction SMILES: C(Cl)Cl.[CH2:4]([CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7]([OH:9])=[O:8])[CH3:5].CC(C)([O-])C.[K+:19]>C1COCC1>[CH2:4]([CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7]([O-:9])=[O:8])[CH3:5].[K+:19]
Reactant: CCCCC(CC)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCC(CC)C(=O)[O-]
Temperature: 0 °C

Procedure:
To a dry flask under N2 atmosphere there was added 37.5 ml. of methylene chloride, 2.5 ml. of THF and 0.88 ml. of 2-ethylhexanoic acid. The solution was cooled to 0° C. and 3.25 ml. of potassium tertbutoxide in THF solution (1.6M of t-BuOK) was added to form in situ the potassium 2-ethylhexanoate salt base. To this mixture there was added 3.10 g. of the 3-hydroxymethyl-cephalosporin reactant, named in Example 1, part D, and 0.122 g. of DMAP and 0.84 ml. of triethylamine, followed by 3 ml. of CH2Cl2 containing 0.485 ml. of α-chloropropionyl chloride. When the addition was complete, a second 0.84 ml. portion of triethylamine and 3 ml. of CH2Cl2 solution containing 0.485 ml. of α-chloropropionyl chloride was added. The resulting reaction mixture was then added to 40 ml. of water containing 5 ml. of 1M sulfuric acid. Then 8 ml. of hexane were added. The reaction mixture was filtered and dried to obtain 2.29 g. of the hereinabove named 3-(α-chloropropionyloxymethyl)-compound. The NMR spectrum for this product was similar to that described in Example 1, but with the 3'-CH2 reading at 4.9(m), the -CHCl at 4.4(q) and the CHCl-CH3 at 1.5(d).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](OC)=[O:12])[CH:9]=2)[CH:4]=[N:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH:4]=[N:3]1
Reactant: COC(=O)c1ccc2cnn(C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc2ccc(CO)cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
A solution of methyl 1-methyl-1H-indazole-6-carboxylate (230 mg, 1.21 mmol, PREPARATION 4) in anhydrous THF (4 mL) was cooled to 0° C., LiAlH4 (92 mg, 2.42 mmol) was added in portions below 0° C., and the mixture was then stirred at 0° C. for 1.5 h, added water: 10% NaOH:water=0.2 mL:0.2 mL:0.6 mL carefully, filtered, and the filtrate was concentrated and purified by silica gel flash column to give 192 mg of crude product which was used directly for next step (98%). [M+H] Calc'd for C9H10N2O, 163. Found, 163.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12]>C1(C)C=CC=CC=1>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][N:12]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CN)OC
Reactant: O=Cc1cccs1
Solvent: Cc1ccccc1
Product: COC(CN=Cc1cccs1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.5 %

Procedure:
A solution of thiophene-2-carboxaldehyde (7.5 mL, 82.3 mmol, Alfa Aesar), aminoacetaldehyde dimethyl acetal (8.82 mL, 82.3 mmol, Alfa Aesar) in 100 mL toluene was heated to 115° C. using a Dean-Stark trap to remove water. After 3 hours, the reaction was cooled to room temperature. The reaction was placed on a rotary evaporator to evaporate the toluene, which yielded a brown liquid (about 17.3 g), which was used without further manipulation in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.42 (6H, s), 3.73 (1H, d, J=5.3 Hz), 4.65 (1H, t, J=5.3 Hz), 7.07-7.41 (3H, m).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>O1CCOCC1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(OCCCBr)cc1
Reactant: c1c[nH]cn1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(OCCCn2ccnc2)cc1
Temperature: 100 °C
Yield: 35.6 %

Procedure:
A mixture of imidazole (0.8 g, 11.6 mmol) and 4-(3-bromopropoxy)nitrobenzene (1.5 g, 5.8 mmol) in 1,4-dioxane (75 ml) was heated at 100° C. for 12 hours. Volatile material was removed by evaporation and the residue was dissolved in ethyl acetate (150 ml). The solution was washed with saturated sodium bicarbonate (3×50 ml), water (3×50 ml) and saturated sodium chloride (50 ml) and then dried. The solvent was removed by evaporation and the residue was purified by column chromatography, eluting with 0-5% methanol in DCM, to give the product as a yellow oil (0.51 g, 22%). MS (MH+): 248.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:33])=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:46]1([C@@H:52]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)[C:53](O)=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:33])=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:53](=[O:54])[C@@H:52]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:56]3[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H](c1ccccc1)N1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccc(F)cc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1
Yield: 58.3 %

Procedure:
The product from Example 114A (0.26 g, 0.42 mmol) and (R)-2-phenyl-2-(piperidin-1-yl)acetic acid (0.12 g, 0.55 mmol) was processed as in Example 81A to give 0.20 g (58%) of the title compound as a white solid.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[C@:11]([C:14]#[CH:15])([CH2:12][OH:13])[O:10][C@@H:9]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:8]1)(C)(C)C.[CH3:27]O>>[CH2:14]([C@:11]1([CH2:12][OH:13])[O:10][C@@H:9]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:8][C@@H:7]1[OH:6])[CH:15]=[CH2:27]
Reactant: CO
Reactant: C#C[C@@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Product: C=CC[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O

Procedure:
Physical data for 10b: mp 96-98° C.; UV (MeOH): λmax 267 nm (ε9300), λmin 235 nm (ε1700). 1H NMR (CDCl3) δ0.08 and 0.13 (6H, each as s, SiMe), 0.89 (9H, s, SiBu-t), 1.93 (3H, d, J6,CH3=0.9 Hz, Me), 2.12-2.17 (1H, m, H-2′a), 2.63 (1H, br, OH), 2.71-2.77 (1H, m, H-2′b), 2.75 (1H, s, ethynyl), 3.67 (1H, d, Jgem=11.5 Hz, H-5′a), 3.74 (1H, d, Jgem=11.5 Hz, H-5′b), 4.47 (1H, t, J2′a,3′=J2′b,3′=5.3 Hz, H-3′), 6.30 (1H, dd, J1′,2′a=4.8 Hz and J1′,2′b=6.9 Hz, H-1′), 7.80 (1H, d, J6,CH3=0.9 Hz, H-6), 9.00 (1H, brs, NH); FAB-MS m/z 381 (M++H). Anal. Calcd for C18H28N2O5Si: C, 56.82; H, 7.42; N, 7.36. Found: C, 56.57; H, 7.58; N, 7.19.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.[F:23][C:24]1([F:31])[CH2:26][CH:25]1[CH2:27][C:28](Cl)=[O:29]>O1CCCC1.CN(C)C1C=CN=CC=1>[F:23][C:24]1([F:31])[CH2:26][CH:25]1[CH2:27][C:28]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:29]
Reactant: O=C(Cl)CC1CC1(F)F
Reactant: CCCCCCCCCCCCCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOC(=O)CC1CC1(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2.08 g (9.7 mmol) 1-tetradecanol in 20 ml tetrahydrofuran (THF) was treated with 200 mg 4-dimethylaminopyridine (DMAP) and 1.35 ml (9.7 mmol) triethylamine and cooled to 0° C. A solution of 1.5 g (9.7 mmol) 2-(2,2-difluorocyclopropyl)acetyl chloride in 10 ml tetrahydrofuran at 0°-5° C. was added dropwise. The mixture was then stirred for 2 hours at room temperature. The precipitated triethylamine hydrochloride was separated, the solution concentrated under reduced pressure, and the residue dissolved in 50 ml diethyl ether. After washing with in turn 10 ml water, 10% caustic soda and water until neutral, the ether solution was dried over magnesium sulphate and evaporated in vacuo (200 mbar). The residue was distilled under an oil pump vacuum.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C:3]1=O.[NH2:19][C:20]([NH2:22])=[S:21].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([CH:4]2[C:3]3[N:19]=[C:20]([NH2:22])[S:21][C:2]=3[CH2:7][CH2:6][CH2:5]2)=[CH:9][CH:10]=1
Reactant: NC(N)=S
Reactant: O=C1C(Br)CCCC1c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nc2c(s1)CCCC2c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
The diastereomer mixture of 2-bromo-6-(4-trifluoromethylphenyl)cyclohexanone (500 mg) was dissolved in ethanol (10 mL). Thiourea (130 mg) was added and the mixture was stirred at room temperature overnight. A sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (394 mg).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=O.[F:20][C:21]([F:29])([F:28])[C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25]>C(O)(=O)C.S(=O)(=O)(O)O>[F:20][C:21]([F:29])([F:28])[C:22]([C:23]1[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:24]=1[CH3:25])=[O:27]
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCC3)cc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(C(=O)C(F)(F)F)c(C)nc3sc4c(c23)CCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 28.4 %

Procedure:
To a stirred solution of 50 mg (0.18 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone in 2 ml acetic acid was added 0.022 ml (0.18 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9:1) afforded 20 mg (28%) 2,2,2-trifluoro-1-[4-(4-methoxy-phenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a white solid. ES-MS m/e (%): 392 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1
Reactant: C1CCNC1
Reactant: BrCc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Brc1ccc(CN2CCCC2)cn1
Yield: 84 %

Procedure:
A solution of 2-bromo-5-(bromomethyl)pyridine (9.06 g, 36.1 mmol), pyrrolidine (3.62 ml, 43.3 mmol) and potassium carbonate (9.98 g, 72.2 mmol) in acetonitrile (45 ml) was stirred at room temperature for 6 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous potassium carbonate solution and saturated, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (developing solvent; ethyl acetate) to give the title compound (7.31 g).
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][CH:13]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14]O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([N:22](CC)CC)C.O>CS(C)=O>[CH2:16]([C:13]1[N:12]=[C:3]2[C:2]([NH2:22])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]2[CH:14]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CC(CO)Nc1nc2ccccc2nc1Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Cc1cn2c(n1)c(N)nc1ccccc12
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of the 2-(3-chloroquinoxalin-2-ylamino)-4-methylpentan-1-ol (1.90 g, 6.79 mmol) in 10 mL of DMSO was added triethyl amine (1.92 g, 19.0 mmol) and followed by sulfur trioxide pyridine complex (2.38 g, 14.9 mmol) at room temperature. The reaction mixture was stirred at that temperature overnight. And then 100 mL of water was added to reaction mixture. The resulting mixture was extracted with ethyl acetate (75 mL×2). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography eluted with ethyl acetate and hexanes to give the titled compound (1.25 g, 64%). MS: MH+=278:280=3:1
Reaction SMILES: CO[C:3]1[C:4](=[O:22])[C:5]([N:10]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH3:11])=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH3:23]>CO>[NH2:23][C:3]1[C:4](=[O:22])[C:5]([N:10]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH3:11])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccccc(N(C)S(=O)(=O)c2ccc(C)cc2)c1=O
Reactant: N
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(C)c2ccccc(N)c2=O)cc1
Temperature: 80 °C

Procedure:
A solution at -25° C of 2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6cycloheptatrien-1-one (described above, 4.0 g) in methanol (40 ml) is saturated with ammonia gas and heated in a pressure bottle at 80° C for 4 hours. The solution is cooled to -70° C, the bottle is opened and the solvent is evaporated to yield 2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one, mp 221°-222° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[Br:14][CH2:15][C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([NH:32][CH:33]=[O:34])[CH:19]=1)[OH:17]>ClCCl>[Br:14][CH2:15][C@H:16]([O:17][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([NH:32][CH:33]=[O:34])[CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 0 °C
Reaction time: 22 h
Yield: 91.9 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (40.1 g, 0.26 mol) in dichloromethane (DCM) (37.5 mL) was added to a slurry of imidazole (21.86 g, 0.32 mol) and (R)-2-bromo-1-(3-formamido-4-benzyloxyphenyl)ethanol (74.54 g, 0.21 mol) in DCM (260 mL) over 8 min. The mixture was stirred for 22 h. The reaction was quenched with water (190 mL) and the aqueous layer was extracted with DCM (37.5 mL). The combined DCM layers were distilled at atmospheric pressure to a volume of ca. 110 mL. On cooling, spontaneous crystallisation occurred. Isooctane (750 mL) was added dropwise over 20 min. The slurry was cooled to 0° C. and the solids were collected by filtration then washed with 9:1 v/v isooctane:DCM (3×75 mL) and dried in vacuo to give the title compound as a colorless solid (89.65 g, 90% th). 1H NMR in accord with structure (400 MHz, CDCl3) δ (ppm): −0.06 (3H) s; 0.11 (3H) s; *0.12 (3H) s; *0.89 (9H) s; 0.90 (9H) s; *3.38-3.49 (2H) m; 4.78-4.87 (1H) m; *5.09 (2H) s; 5.10 (2H) s; 6.96 (1H) d, J=8.6 Hz; *7.06 (1H) d of d, J=8.3, 2.0 Hz; 7.11 (1H) d of d, J=8.3 Hz, 2.0 Hz; 7.25-7.27 (1H) m; 7.36-7.45 (5H) m; *7.70 (1H) d, J=11.0 Hz; 7.79 (1H) s; 8.38 (1H) d, J=2.0 Hz; 8.42 (1H) d, J=1.5 Hz; *8.76 (1H) d, J=11.8 Hz. * Peaks are due to ca 25M % of the minor rotamer.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1>>[N:1]1([C:11]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC(=O)C1
Reactant: c1ccc2c(c1)CCCN2
Product: O=C1C=C(N2CCCc3ccccc32)CCC1
Yield: 15.6 %

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (5 g) and 1,3-cyclohexanedione (4.21 g) was heated at ca. 150° for 5 h. The cooled reaction mixture was purified by FCC eluting with ethyl acetate to give the title compound (1.33 g) as an oil, t.l.c. (ethyl acetate) Rf 0.34.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([CH:27]([CH3:31])[C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[CH:27]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: CC(Oc1ccccc1)C(=O)Cl
Product: CC(Oc1ccccc1)C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-phenoxypropionyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxypropanamide as a white powder, m.p. 85.0-87.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.07 (t, J=6.0 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.62 (dd, J=8.4, 1.2 Hz, 1H), 7.43 (dt, J=7.5, 1.2 Hz, 1H), 7.28-7.16 (m,3H), 6.91-6.81 (m, 3H), 6.57 (s, 2H), 4.62-4.53 (m, 3H), 3.10 (q, J=6.9 Hz, 2H), 1.76 (quintet, J=7.1 Hz, 2H), 1.43 (quintet, J=7.1 Hz, 2H), 1.33 (d, J=6.6 Hz, 3H); MS (EI) m/e 403.2005 (403.2008 calcd for C23H25N5O2).