Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]3[CH:12]=[C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:10]=[CH:9][C:8]2=3)=[CH:3][CH:2]=1.[Br:33]C1CC(=O)NC1=O>C(Cl)(Cl)Cl>[C:1]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:10][CH:9]=3)[CH2:14][C:15]3[CH:16]=[C:17]([Br:33])[CH:18]=[CH:19][C:20]2=3)=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccc(N3c4ccccc4Cc4cc(-c5ccccc5)ccc43)cc2)cc1
Reactant: O=C1CC(Br)C(=O)N1
Solvent: ClC(Cl)Cl
Product: Brc1ccc2c(c1)Cc1cc(-c3ccccc3)ccc1N2c1ccc(-c2ccccc2)cc1
Yield: 70 %

Procedure:
10-(biphenyl-4-yl)-2-phenyl-9,10-dihydroacridine (7.8 g, 19.0 mmol) was added with chloroform (300 ml), and with bromosuccinimide (3.7 g, 21.0 mmol). The resultant solution was stirred at room temperature for 2 hours. After the reaction was completed, the resultant solution was washed with distilled water. Then, an organic layer was extracted and dried with sodium sulfate so as to remove the solvent. The residue was purified by silica gel column chromatography (methylene chloride/n-hexane (1/10)) to obtain 10-(biphenyl-4-yl)-2-bromo-7-phenyl-9,10-dihydroacridine compound (pale yellow solid, 6.5 g, yield 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5](I)=[C:6]([F:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[O:23][C:22]([Si](C(C)C)(C(C)C)C(C)C)=[N:21][CH:20]=2)O1>>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([C:19]2[O:23][CH:22]=[N:21][CH:20]=2)=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(Br)cc(F)c1I
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Product: Fc1cc(Br)cc(F)c1-c1cnco1

Procedure:
The title compound is prepared from 5-bromo-1,3-difluoro-2-iodo-benzene and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole following a procedure analogous to that described in Intermediate 27. LC (method 1): tR=1.18 min; Mass spectrum (ESI+): m/z=260 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[CH:15]=[C:16]([OH:18])[CH:17]=1>ClCCl>[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:41])([CH3:42])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[CH:15]=[C:16]([OH:18])[CH:17]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)OC)c2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
Trifluoroacetic acid (0.17 mL) was added to a solution of [4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-5-hydroxy-2′-methyl-biphenyl-3-yl]-acetic acid methyl ester (Example 164-(3); 23.1 mg, 0.0358 mmol) in dichloromethane (0.85 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (17.5 mg, 92%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=S)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.O>C(OCCO)C>[N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccnc1
Reactant: S=C1Nc2ccccc2Nc2ncccc21
Solvent: CCOCCO
Solvent: O
Product: c1cncc(CNC2=Nc3ccccc3Nc3ncccc32)c1
Yield: 52.8 %

Procedure:
A solution of 0.5 g (2.2 mmol) of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione [(European Published Patent Application EP-393,604); C.A. 114, 143455] in 10 mL 2-ethoxyethanol was treated with 0.24 mL (10.8 mmol) of 3-(aminomethyl)pyridine and heated at reflux for 2 days. The mixture was poured into H2O and extracted with EtOAc. The EtOAc was washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with a gradient of CH2Cl2 /hexane (90/10) to CH2Cl2 /MeOH (94/6) gave 0.35 g (53% yield) of the product as a yellow solid, mp 192-194° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =302.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:10]=2)([O:3][CH2:4][CH3:5])=[O:2].[H-].[Na+].O.[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:10]=2)[C:15](=[O:16])[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:7]1)[CH3:27]
Reactant: CCOC(=O)c1cnc2cc(C3CCCCC3)ccc2c1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC)c2cc(C3CCCCC3)ccc2c1=O
Temperature: 25 °C

Procedure:
A suspension of 32.7 g of 3 -carboethoxy-4-hydroxy-7-cyclohexyl-quinoline and 7.1 g of sodium hydride (50% strength in mineral oil) in 400 ml of absolute dimethylformamide is stirred for 45 minutes at room temperature with exclusion of water. In the course thereof, the temperature of the reaction mixture rises to 35°C and a homogeneous solution is produced. 39 g of ethyl iodide are added dropwise to this solution over the course of 10 minutes whilst stirring and the mixture is stirred for a further 21/2hours at 55°C. It is then cooled to room temperature and 500 ml of water are added slowly, whilst stirring. The resulting precipitate is filtered off, well washed with water and recrystallised from ethanol-ether. 1-Ethyl-3-carboethoxy-4-oxo-7-cyclohexyl-1,4 -dihydroquinoline, thus obtained, melts at 176°-178°C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([CH2:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[OH:27])=[O:19])=[CH:16][C:15]=1[O:30][CH3:31])#[N:12]>ClCCl>[C:11]([CH2:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2=[O:27])=[O:19])=[CH:16][C:15]=1[O:30][CH3:31])#[N:12]
Reactant: COc1cc(C(=O)NC2CCCC[C@H]2O)ccc1CC#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(C(=O)NC2CCCCC2=O)ccc1CC#N
Temperature: 22 °C

Procedure:
To a solution of oxalyl chloride (0.2 mL, 2.2 mmol) in anhydrous dichloromethane (2 mL) at −78° C. was added DMSO (0.32 mL, 4.5 mmol) under Argon. The solution was maintained for 10 min where upon a solution of 4-(cyanomethyl)-N-[(2R)-2-hydroxycyclohexyl]-3-methoxybenzamide (430 mg, 1.5 mmol) in anhydrous dichloromethane (13 mL) was added dropwide. The reaction was stirred at −78° C. for 30 min, whereupon TEA (1 mL, 7.5 mmol) was added. The reaction was warmed to 22° C. for 2 h. Then, 50 mL dichloromethane was added to the mixture, washed with sat NaHCO3 (3×15 mL) and sat. brine (3×15 mL), dried (MgSO4), and concentrated to afford a yellow solid of 4-(cyanomethyl)-3-methoxy-N-(2-oxocyclohexyl)benzamide. MS (ESI) 287 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][CH2:9][C:10](=S)[N:11]([CH:12]([CH3:18])[C:13](OCC)=[O:14])[C:6]=2[CH:5]=1)([O-:3])=[O:2].O.[NH2:23][NH2:24]>CCO>[CH3:18][CH:12]1[C:13](=[O:14])[NH:24][N:23]=[C:10]2[CH2:9][S:8][C:7]3[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[N:11]12
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)CSc2ccc([N+](=O)[O-])cc21
Solvent: O
Solvent: CCO
Product: CC1C(=O)NN=C2CSc3ccc([N+](=O)[O-])cc3N21
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To a solution of ethyl 2-(6-nitro-3-thioxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)propanoate (0.475 g, 1.455 mmol) in EtOH (30 mL) was added hydrazine hydrate (0.364 g, 7.28 mmol) and the mixture was then heated at reflux for 16 h. After cooling to ambient temperature gradually, the precipitate was collected by filtration to give 1-methyl-9-nitro-3,5-dihydrobenzo[5,6][1,4]thiazino[3,4-c][1,2,4]-triazin-2(1H)-one (0.312 g, 77%), which was used in the next step directly without further purification. TLC (eluting with 33% EtOAc in petroleum ether) Rf=0.3.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH:13]([CH2:15][CH3:16])[CH3:14])[N:7]=1)=O)C.[Li+].[BH4-].O>C1COCC1>[CH:13]([S:12][C:8]1[N:7]=[C:6]([CH2:4][OH:3])[CH:11]=[CH:10][CH:9]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCOC(=O)c1cccc(SC(C)CC)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)Sc1cccc(CO)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
6-sec-Butylsulfanyl-pyridine-2-carboxylic acid ethyl ester (0.17 g, 0.71 mmol) obtained in Step A was dissolved in anhydrous THF (3 mL). 2.0 M LiBH4 solution (0.5 mL, 1.0 mmol) was added thereto, and the mixture was stirred at 40° C. for 1 hour. After the termination of the reaction, the reactant was cooled to room temperature. The reactant was added with water and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.126 g, 90%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>CN(C)C=O>[CH2:2]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[CH2:3][CH2:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC(=O)CCCBr
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCC(=O)CCCn1ccnc1

Procedure:
1-Bromo-4-dodecanone 6.45 and imidazole (8.34 g) in dimethylformamide (10 ml) at 0° C. were stirred overnight at ambient temperature, then one day at 80° C. The resulting mixture was poured into water (200 ml), extracted with ether (3×75 ml) and the extracts were dried (magnesium sulfate) and evaporated. Chromatography of the product on silica gel eluting with 7% methanol in methylene chloride gave 1-(dodecan-4-on-1-yl)imidazole.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[CH:20](=O)C>C(O)C>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[CH2:20][O:19][CH2:18]1)=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Reactant: CC=O
Solvent: CCO
Product: COc1cc2c(cc1OC)C1C(CO)COCN1CC2

Procedure:
0.01 mole (2.67 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is dissolved in 30 ml of ethanol, and the solution is stirred with 0.015 mole of acetaldehyde for one hour. The reaction mixture is evaporated to dryness to yield the aimed compound in a crystalline form.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:8][N:9]([CH3:14])[CH2:10][CH2:11][CH2:12][NH2:13]>>[N:9]([CH2:10][CH2:11][CH2:12][NH:13][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])([CH3:14])[CH3:8]
Reactant: CCCCN=C=O
Reactant: CN(C)CCCN
Product: CCCCNC(=O)NCCCN(C)C
Reaction time: 1 h

Procedure:
With stirring and cooling to 55°-60° C., 49.5 g of freshly distilled butyl isocyanate are added dropwise to freshly distilled 3-dimethylamino-1-propylamine under nitrogen in the course of 15 minutes. After 1 hour at 60° C., low boiling constituents are removed at a pressure of 0.1 torr and a maximum bath temperature of 140° C. Yield: 98.7 g (98%) of product of the above structure. Titration: 1 equivalent=208.3 g (theory 201.3 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[CH2:10][OH:11].C(N(CC)CC)C>ClCCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][S:2]([O:11][CH2:10][C:9]1[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=[C:7]([Br:6])[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(Br)cc(C(F)(F)F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(Br)cc(C(F)(F)F)c1
Temperature: -78 °C
Yield: 65.6 %

Procedure:
Methanesulfonyl chloride (342 mg) was added dropwise to a stirred solution of 3-bromo-5-(trifluoromethyl)benzyl alcohol (560 mg) and triethylamine (417 μl) in dry dichloromethane (20 ml) at -78° C. under a dry nitrogen atmosphere. The reaction was maintained at -78° C. for 30 minutes and then allowed to warm to room temperature over 2 hours. After this period the reaction mixture was diluted with 5% aqueous citric acid and the organic layers were separated, dried over MgSO4, filtered and the solvent removed under reduced pressure to give 1-(methanesulfonyloxymethyl)-3-bromo-5-(trifluoromethyl)benzene as a yellow oil (480 mg) 1H NMR (360 MHz,CDCl3) δ 3.06 (3H,s),5.24 (2H, s), 7.59 (1H, s), 7.75 (1H, s), 7.94 (1H, s).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:13][C:14]1[CH:15]=[C:16]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-:31])=[O:30])[S:20][C:17]2=[N:18][CH:19]=1.O>CC#N>[N+:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[S:20][C:17]2[C:16]([N:22]=1)=[CH:15][C:14]([CH2:13][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:19][N:18]=2)([O-:31])=[O:30]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cc(CCl)cnc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
Pyrrolidine (2.8 mol, 203 g) and K2CO3 (2.8 mol, 395 g) were added to a suspension of 6-(chloromethyl)-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine (0.52 mol, 175 g) in CH3CN (1.7 L). The reaction mixture was stirred at room temperature for 16 h. H2O (1 L) was added and the mixture stirred for 30 min. The CH3CN was removed under vacuum and the resulting mixture was extracted with CH2Cl2 (3×1.5 L). The combined organics were washed with brine, dried (Na2SO4) and concentrated under vacuum to give 2-(2-nitrophenyl)-6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridine as a dark oil (150 g, 76% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]=[C:13]=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:27])[N:20]=[C:21]2[CH3:26].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C:13]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[C:19]([CH3:27])[N:20]=[C:21]3[CH3:26])=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN=C=O)cc1
Reactant: Cc1cc2c(N)cccc2c(C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(C)(C)C)cc3)cccc2c(C)n1

Procedure:
The product from Example 186A (3.42 mmol) in toluene (12 mL) was treated with 5-amino-1,3-dimethylisoquinoline (245 mg, 1.42 mmol) and DIEA (5 mL). The mixture was heated at 800 for 3 hours, cooled to room tempoerature, and filtered. The precipitate thus obtained was purified by silica gel chromatography (97:3 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.21 (d, 1H, J=7.1 Hz), 7.78 (d, 1H, 8.5 Hz), 7.59 (s, 1H), 7.48 (t, 1H, J=8.0 Hz), 7.36-7.40 (m, 2H), 7.27-7.29 (m, 2H), 6.98 (m, 1H), 4.31 (d, 2H, J=5.8 Hz), 2.84 (s, 3H), 2.58 (s, 3H), 1.28 (s, 9H); MS (ESI+) m/z 362 (M+H).
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[NH2:12][C@:13]1([C:21]2[C:29]3[O:28][C:27]([F:31])([F:30])[O:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)[C@H:18]([CH2:19]O)[CH2:17][CH2:16][O:15][CH2:14]1>ClCCl>[F:30][C:27]1([F:31])[O:26][C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C@@:13]34[N:12]=[C:10]([NH2:9])[S:11][CH2:19][C@@H:18]3[CH2:17][CH2:16][O:15][CH2:14]4)[C:29]=2[O:28]1
Reactant: N[C@@]1(c2cccc3c2OC(F)(F)O3)COCC[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: NC1=N[C@@]2(c3cccc4c3OC(F)(F)O4)COCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzoyl isothiocyanate (372 μl) was added to a solution of (±)-[(3S*,4R*)-3-amino-3-(2,2-difluorobenzo[1,3]dioxol-4-yl)tetrahydropyran-4-yl]methanol (661 mg) in dichloromethane (9.53 ml). The mixture was stirred at room temperature for three hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in methanol (20 ml). Concentrated hydrochloric acid (five drops) was added and the mixture was heated under reflux for five hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (20 ml) and DBU (700 μl) was added, followed by heating under reflux for five hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (350 mg). 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.43-1.48 (m, 1H), 2.08-2.19 (m, 1H), 2.64 (dd, J=2.8, 12.4 Hz, 1H), 2.74-2.80 (m, 1H), 2.98 (dd, J=4.4, 12.4 Hz, 1H), 3.69 (ddd, J=2.4, 11.6, 12.8 Hz, 1H), 3.79 (d, 11.2 Hz, 1H), 3.93 (d, J=10.8 Hz, 1H), 4.10 (dd, J=5.2, 11.2 Hz, 1H) 6.99 (dd, J=2.0, 7.2 Hz, 1H), 7.03-7.09 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]3)[CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.[N:22]1([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([NH:37][C:16]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[C:7]([O:6][CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH:15]=[CH:14][CH:13]=4)=[O:18])[CH2:35][CH2:36]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCC3CCC3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (preparation see below) and amine 5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Cl)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:5])[CH3:2].CC(C)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:26]=[N+:27]=[N-:28])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccc(C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(N=[N+]=[N-])nc1-c1ccc(C(F)(F)F)cc1
Yield: 99.3 %

Procedure:
To a stirred solution of 2.41 g (7.18 mmole) of 2-chloro-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester, 2.4 mL of acetone and 2.4 mL of water was added 2.34 g (35.63 mmole) of sodium azide. The reaction mixture was heated at 70 degrees for 16 hours and then partitioned between 200 mL of ethyl acetate and 75 mL of water. The aqueous layer was extracted twice with 55 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2.44 g of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a dark amber oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].CI.[C:12]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:12]
Reactant: Cc1cccc(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(C)cccc1Cl
Temperature: 25 °C

Procedure:
2-Chloro-6-methyl-phenol (12.00 g, 84.20 mmol) was mixed with MeI (10.50 mL, 0.17 mol) and K2CO3 (17.40 g, 0.13 mol) in acetone in acetone and the resulting reaction mixture was refluxed for 14 hours. The reaction mixture was cooled to room temperature, and then concentrated. The residue was diluted with Et2O. The resulting solution was washed with H2O (3×150 mL) and brine (1×200 mL), then dried over MgSO4 and concentrated. Purification by column chromatography using hex:EtOAc (4:1) as the eluant afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:6]=1.OS(O)(=O)=O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]([CH3:11])[C:8]([O:10][CH3:17])=[O:9])[CH:6]=1
Reactant: CO
Reactant: CC(C(=O)O)n1cc(Br)cn1
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)n1cc(Br)cn1
Temperature: 68 °C
Yield: 82 %

Procedure:
To a solution of 2-(4-bromo-1H-pyrazol-1-yl)propanoic acid (0.20 g, 0.91 mmol) in MeOH (4.0 mL) was added conc H2SO4 (0.20 mL) and the resulting reaction mixture was heated to 68° C. for 2 h. After the completion of reaction (TLC monitoring), the solvent was evaporated and the residue was basified with saturated NaHCO3 solution followed by extraction with EtOAc (3×25.0 mL). The combined organics was dried (Na2SO4), filtered and concentrated to obtain the desired product (0.175 g, 82%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1>[CH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Yield: 70.3 %

Procedure:
In the same manner as that described in Example 2(1), a reaction was carried out using commercially available 4-(trifluoromethyl)aniline (446 mg, 2.8 mmol), triethylamine (0.6 ml, 4.4 mmol), 4-formylbenzoyl chloride (700 mg, 4.2 mmol) and 4-(dimethylamino)pyridine (a catalytic amount) and the reaction mixture was treated according to a similar procedure to that described in Example 2(1) to afford 4-formyl-4′-(trifluoromethyl)benzanilide (577 mg, yield 71%) as a white solid which was recrystallized from ethyl acetate-hexane to give white fluffy crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([N:20]1[C:32]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[CH:24][C:23]=2[N:22]=[C:21]1[CH2:33]Cl)[CH2:11][O:12][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:20]2[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][C:23]=3[N:22]=[C:21]2[CH2:33][O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)n1c(CCl)nc2cnc3ccccc3c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1ccc(COC[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Temperature: -78 °C
Yield: 85.1 %

Procedure:
1-[(1S)-2-(Benzyloxy)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)ethyl]-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline (1.61 g, 3.13 mmol) was dissolved in 250 mL of anhydrous CH2Cl2 and the solution was cooled to −78° C. under N2. A 1.0 M solution of tetrabutylammonium fluoride in THF (3.43 mL, 3.43 mmol) was added and the stirred solution was allowed to warm to ambient temperature overnight. The reaction mixture was then washed successively with 50 mL of saturated NaHCO3 solution and brine (4×50 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 0-3% methanol/CHCl3) gave 0.92 g of (11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as a colorless syrup.