Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH2:34][N+:35]#[C-:36])(=[O:33])=[O:32])=[CH:27][CH:26]=1.[C-]#N.[Na+]>CCO>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]4[O:23][CH:36]=[N:35][CH:34]4[S:31]([C:28]4[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=4)(=[O:33])=[O:32])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)C2N=COC2C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 1.6 mmol) and TosMIC (340 mg, 1.7 mmol) were dissolved in EtOH (20 ml), to which NaCN (12 mg, 0.25 mmol) was added. The solution immediately turned pale yellow and was allowed to stir for 2 hours at room temperature. The solvent was removed in vacuo and the residue was taken up in DCM (10 ml) and washed with saturated sodium bicarbonate solution (15 ml), followed by brine (15 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 5-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-yl}-4-(toluene-4-sulfonyl)-4,5-dihydro-oxazole as a pale brown foam (500 mg). LRMS ESI+ m/z 513 [MH]+
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][N:20]([CH3:42])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=3)=[C:28]([CH3:41])[CH:27]=2)[N:22]=1>>[CH3:19][N:20]([CH3:42])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([N:15]4[C:16]5[CH:17]=[C:18]6[C:5]7([CH2:8][O:9][C:10]6=[CH:11][C:12]=5[CH2:13][CH2:14]4)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]7)=[O:39])=[CH:34][CH:33]=3)=[C:28]([CH3:41])[CH:27]=2)[N:22]=1
Reactant: Cc1cc(-c2noc(N(C)C)n2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1cc(-c2noc(N(C)C)n2)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 4'-(5-dimethylamino-1,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carboxylic acid (D14) using a procedure similar to that of Example 1 (18%). This was converted to the oxalate salt, which precipitated from acetone/ether as a white solid.
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]=[C:7]1[CH3:20].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccccc1

Procedure:
Using the general method of Example 1, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.8 mmol) was reacted with benzoyl chloride (0.26 g, 1.8mmol) to provide N1-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide as a solid, m.p. 164-170° C. 1H NMR (500 MHz, DMSO-d6) δ8.47 (t, J=6.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.59 (dd, J=8.0, 1.2 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.38 (dt, J=8.0, 1.2 Hz, 1H), 7.17 (dt, J=8.0, 1.2 Hz, 1H), 6.48 (broad s, 2H), 4.53 (t, J=7.0 Hz, 2H), 3.31 (q, J=6.0 Hz, 2H), 2.60 (s, 3H), 1.88 (quintet, J=7.0 Hz, 2H), 1.68 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 373.1903 (373.1903 calcd for C22H23N5O)
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:24]O>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:24][O:6][C:5](=[O:7])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][CH2:2][Br:1]
Reactant: O=C(O)C(CCBr)(c1ccccc1)c1ccccc1
Reactant: CO
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)C(CCBr)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
4-Bromo-2,2-diphenylbutyric acid (5.0 g, 16 mmol), thionyl chloride (1.1 mL, 16 mmol), and N,N-dimethylformamide (0.02 mL, 0.20 mmol) in chloroform (16 mL) were mixed at room temperature under a stream of nitrogen. The reaction mixture was heated to reflux, stirred under reflux for 4 h, and cooled to 0° C. Methanol (50 mL) was added. The reaction mixture was warmed to room temperature and concentrated to dryness, yielding a brown oil. The crude material was purified on SiO2 (120 g) using 10% EtOAc/Hexanes as eluent to provide the title compound (3.9 g) as a clear oil that crystallized on standing. 1H NMR (DMSO-d6, 400 mHz) δ (ppm): 7.33-7.20 (m, 10H), 3.70 (s, 3H), 3.12-3.08 (m, 2H), 2.98-2.93 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23])=[O:2].[CH:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)([CH3:26])[CH3:25]>>[OH:2][CH:1]([C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23])[CH2:31][C:30]1[CH:33]=[CH:34][C:27]([CH:24]([CH3:26])[CH3:25])=[CH:28][CH:29]=1
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Product: Cc1c2c(c(C(O)Cc3ccc(C(C)C)cc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2
Yield: 92 %

Procedure:
Using N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 340 and 4-isopropylbenzyl chloride, the title compound was synthesized in the same manner as in Example 341. Yield: 92%. Amorphous substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1([CH3:32])[CH3:31])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:14]2[CH:15]=[CH:16][C:11]([C:10]3[O:9][CH:8]=[N:7][C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:13]=2)[CH2:27][C:26]1([CH3:32])[CH3:31])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Reactant: CCOC(=O)c1ncoc1-c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncoc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)C(C)(C)C2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 43.7 %

Procedure:
To a stirred solution of 5-(4-iodo-phenyl)-oxazole-4-carboxylic acid ethyl ester (11.0 g, 32 mmol) in dry toluene (300 mL) was added 2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (7.53 g, 35.2 mmol), Pd(AcO)2 (580 mg, 2.56 mmol), biphenyl-2-yldicyclohexylphosphine (0.9 g, 2.56 mmol) and Cs2CO3 (20.7 g, 64 mmol) under a nitrogen atmosphere at room temperature. The mixture was heated to 80° C. and stirred for 24 hrs. The solution was allowed to cool to room temperature and was then partitioned between water and EtOAc. The organic phase was dried over Na2SO4 and the solvent was removed to give the crude product. It was purified by silica gel column chromatography (PE/EtOAc=40/1˜10/1 to recover unreacted starting material; PE/EtOAc=8/1˜5/1 to yield the title compound (6.0 g, 43%) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:7]1([C:18]#[N:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][C:8]1=[O:17])C#N.Cl.C(O)(=[O:24])C>CO>[Cl:16][C:13]1[CH:14]=[C:15]2[C:7]3([CH2:4][C:3](=[O:2])[NH:19][C:18]3=[O:24])[C:8](=[O:17])[NH:9][C:10]2=[CH:11][CH:12]=1
Reactant: COC(=O)C(C#N)C1(C#N)C(=O)Nc2ccc(Cl)cc21
Reactant: CC(=O)O
Agent: Cl
Solvent: CO
Product: O=C1CC2(C(=O)N1)C(=O)Nc1ccc(Cl)cc12
Reaction time: 8 h

Procedure:
A stirred solution of the crude (5-chloro-3-cyano-2-oxo-2,3-dihydro-1H-indol-3-yl)-cyanoacetic acid methyl ester, intermediate 5 (53.3 g, 0.18 mol) in methanol (450 ml) was cooled in an ice-water bath and saturated with hydrogen chloride gas, keeping the temperature below 20° C. The resultant solution was left to stand at ambient temperature overnight and then heated cautiously under reflux for 5 hours to give a yellow suspension. The solvent was removed in vacuo to give a semi-solid residue, which was mixed with glacial acetic acid (375 ml) and heated under reflux, with stirring, for 16 hours. After cooling in an ice-water bath, the crude 5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione was removed by filtration, washed with cold glacial acetic acid (100 ml) followed by water (100 ml) and then diethyl ether (100 ml) and dried in vacuo to give an off-white solid. A second crop was obtained by removing the solvent in vacuo from the combined acetic acid filtrates and repeating the purification procedure to give a total of 30.5 g (66%). Sufficiently pure by 1H NMR for subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[C:32](Cl)(=[O:34])[CH3:33].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:32]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Nc3ncc4nc(N)sc4n3)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (135 mg, 314 μmol) produced in Example D3(iv) in pyridine (4 mL) was added acetyl chloride (45 μL, 628 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→30/70), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (121 mg, 82%) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CN(C=O)C.[Cl-].[Na+].O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[CH2:5][C:4](=[O:6])[NH:3][C:2]2=[O:7])=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CNC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2CC(=O)NC2=O)cc1

Procedure:
A mixture of imidazolidine-2,4-dione (5.01 g), Cs2CO3, and 4-methoxybenzyl chloride (8.0 mL) in DMF (250 mL) was allowed to react overnight. The reaction was added to 400 mL brine then extracted with ether. The desired product precipitated from the ether, and was collected by filtration to yield 1-(4-methoxybenzyl)-imidazolidine-2,4-dione as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=3)[N:10]=[N:9][C:8]=2[C:23]([OH:25])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[C:29]2N(O)N=[N:32][C:30]=2[CH:31]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.O>[CH:1]1([CH2:6][C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=3)[N:10]=[N:9][C:8]=2[C:23]([NH:32][CH:30]2[CH2:31][CH2:29]2)=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 200.4 %

Procedure:
5-(Cyclopentylmethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (359 mg, 1.05 mmol) obtained in Example 103b), HOBt (71.6 mg, 0.524 mmol, 0.5 eq.) and cyclopropylamine (0.097 ml, 1.36 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 4.5 ml), WSC (246 mg, 1.26 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 14 hr. Water (15 ml) was added to the reaction mixture and the mixture was stirred at 0° C. The precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (400 mg, 1.05 mmol, quant.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:8])([O-:3])=[O:2].[CH3:20]C(C)([O-])C.[K+].IC.C(=O)(O)[O-].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[C:7]([N:9]([CH3:20])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:8])([O-:3])=[O:2]
Reactant: CC(C)(C)[O-]
Reactant: O=C(NCc1cccnc1)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(Cc1cccnc1)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 85.3 %

Procedure:
To a stirred solution of 3-nitro-N-(3-pyridylmethyl)benzamide (2.00 g) in tetrahydrofuran (40 ml) was added potassium tert-butoxide (917 mg) in one portion in an ice-cooled bath. The stirring was continued for 40 minutes and then iodomethane (0.53 ml) was added thereto. The reaction mixture was stirred at 0° C. for one hour, then at ambient temperature for five hours. Saturated sodium bicarbonate solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution. After dried over anhydrous magnesium sulfate and filtered, the solvent was removed in vacuo and the residue was purified by flash chromatography (methanol-chloroform 3%, V/V) to afford 3-nitro-N-methyl-N-(3-pyridylmethyl)benzamide (1.8 g) as a yellow oil.
Reaction SMILES: C([C:3]1C=[CH:23][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[CH:5][CH:4]=1)C.ClCC1C=[N:29]C=CC=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:7][C:6]2[CH:23]=[N:29][CH:3]=[CH:4][CH:5]=2)[CH:10]=1
Reactant: ClCc1cccnc1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Product: COCOc1cc(SCc2cccnc2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 3-chloromethylpyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][OH:15])=[CH:10][CH:11]=2)[C:6]([CH3:22])([CH3:21])[CH2:5][CH2:4]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][O:15][C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=3)=[CH:10][CH:11]=2)[C:6]([CH3:21])([CH3:22])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCN2CC
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCN2CC
Yield: 46.5 %

Procedure:
1 g of (RS)-2-(N-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-heptanol dissolved in 20 ml THF were treated with 950 mg of triphenylphosphine, 550 mg of methyl 4-hydroxybenzoate and 0.57 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 100 ml of ether and washed with two portions of 25 ml of water and one portion of 25 ml of sat. aq. sodium chloride solution. The organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes), giving 670 mg (RS)-methyl 4-[2-(N-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-heptyloxy]-benzoate as a pale yellow oil. The ester (670 mg), dissolved in 5 ml THF/5 ml H2O/5 ml methanol, was treated with 260 mg of lithium hydroxide hydrate. The mixture was stirred at 40° C. for 6 hours. The mixture was diluted with 5 ml water and acidified to pH 2 with 1N hydrochloric. The resulting suspension was taken in 20 ml ether and the phases were separated. The aqueous phase was extracted with three portions of 10 ml ether. The combined extracts were dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by preparative tlc (10% methanol/methylene chloride), yielding 320 mg of a pale yellow oil. 1H NMR (CDCl3): 8.01 (d, J=9.0 HZ, 2H), 6.98 (d, J=2.1 Hz, 1H), 6.95-6.85 (m, 3H), 6.52 (d, J=8.4 Hz, 1H), 4.64 (quint, J=5.8 Hz, 1H), 3.32 (q, J=7.1 Hz, 2H), 3.25-3.15 (m, 2H), 2.88 (dd, J=14.1, 5.9 Hz, 1H), 2.78 (dd, J=14.1, 5.9 Hz, 1H), 1.80-1.65 (m, 4H), 1.55-1.25 (m, 6H), 1.24 (s, 3H), 1.18 (s, 3H), 1.11 (t, J=7.1 Hz, 3H), 0.86 (t, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[S:10][C:11]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.O>C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:19][NH2:20])[S:10][C:11]=2[S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2)c(Sc2ccccc2)s1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1nc(-c2ccccc2)c(Sc2ccccc2)s1
Temperature: 70 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a suspension of 2-{[4-phenyl-5-(phenylthio)-1,3-thiazol-2-yl]methyl}-1H-isoindole-1,3(2H)-dione (0.53 g) in ethanol (5 mL) was added hydrazine monohydrate (0.1 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 0.36 g, 97%).
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH3:7])=[N:5][NH:4][C:3]1=[O:8].[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[F:23][C:10]([F:9])([F:22])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:1][N:2]1[C:6]([CH3:7])=[N:5][NH:4][C:3]1=[O:8])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: Cc1n[nH]c(=O)n1N
Solvent: c1ccncc1
Product: Cc1n[nH]c(=O)n1NS(=O)(=O)c1ccccc1OC(F)(F)F
Temperature: -10 °C
Reaction time: 12 h
Yield: 77.6 %

Procedure:
10.0 g (0.088 mol) of 4-amino-5-methyl-2,4-dihydro-3H-1, 2,4-triazol-3-one are dissolved in 50 ml of dry pyridine, the mixture is cooled to -10° C., and 32.7 g (0.12 mol) of 2-trifluoromethoxy-benzenesulphonyl chloride are added. The reaction mixture is allowed to reach room temperature (approximately 20° C.) and stirred for approximately 12 hours. After the mixture has been concentrated, the residue is taken up in methylene chloride and shaken with 1N hydrochloric acid and then with water. The organic phase is dried with sodium sulfate and filtered. The solvent is carefully distilled off from the filtrate under a water pump vacuum. 23.1 g (80% of theory) of 4-(2-trifluoromethoxy-phenylsulphonylamino)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one are obtained as an oily residue.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]#[N:15])[CH:11]=2)[NH:6][CH2:5]1.[C:16](O)(=[O:25])[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[C:14]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH2:5][C@@H:4]([NH:3][C:16](=[O:25])[C@@H:17]([OH:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13]2)#[N:15]
Reactant: N#Cc1ccc2c(c1)CC(N)CN2
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: N#Cc1ccc2c(c1)C[C@H](NC(=O)[C@@H](O)c1ccccc1)CN2
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 3-amino-1,2,3,4-tetrahydroquinoline-6-carbonitrile, dihydrochloride (10.03 g, 40.7 mmol), prepared as described in Example 1D, in DMF (100 mL) was added (S)-(+)-mandelic acid (7.45 g, 48.9 mmol), followed by EDAC (9.37 g, 48.9 mmol), HOBt (7.49 g, 48.9 mmol) and NMM (16.1 mL, 146.1 mmol). The reaction mixture was stirred at RT overnight, then diluted with EtOAc (200 mL), washed with water (50 mL×3), 1N aqueous HCl (50 mL), water (50 mL) and saturated aqueous NaCl, dried (Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc/hexanes (2:1 ratio), and the purified compound crystallized from acetone three times to give the title compound as the (S, S) diastereoisomer (2.54 g, 20% yield).
Reaction SMILES: [CH3:1][C:2]([C:8]1[N:12]([CH3:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][N:9]=1)([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH3:7][C:2]([C:8]1[N:12]([CH3:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][N:9]=1)([CH3:1])[CH2:3][CH2:4][CH:5]=[O:6]
Reactant: Cn1c(-c2ccccc2)nnc1C(C)(C)CCCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(-c2ccccc2)nnc1C(C)(C)CCC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
To a solution of 4-methyl-4-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-1-pentanol (11 mg, 0.04 mmol) in DCM (0.5 ml) was added Dess Martin reagent (22 mg). The solution was stirred at r.t. for 2 h, then Na2S2O3 (68 mg) was added and the mixture stirred for 30 minutes more. The mixture was diluted in DCM and washed with water. The organic phase was recovered and dried over Na2SO4. After filtration, volatiles were evaporated in vacuo to give 11 mg of the title compound as pale yellow oil, which was used without further purification. MS (m/z): 258[MH]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][N:12](C(OCC2C=CC=CC=2)=O)[CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:14]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][NH:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:14]=1
Reactant: COc1cccc(C2C=C(c3cc(F)ccc3F)CCN2C(=O)OCc2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cccc(C2C=C(c3cc(F)ccc3F)CCN2)c1
Temperature: 0 °C

Procedure:
To a flask equipped with stir bar was added benzyl 4-(2,5-difluorophenyl)-6-(3-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1-4, 0.51 g, 1.17 mmol) and dichloromethane (20 mL). The resulting solution was cooled to 0° C. and treated with BBr3 (0.15 mL, 1.17 mmol). The reaction was stirred at 0° C. for 4 h, then warmed to 23° C. Upon completion, the reaction was diluted with dichloromethane (100 mL) and washed with water (3×100 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was carried into the subsequent acylation.