Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([Li])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1.O>O1CCCC1>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:4]=[C:5]([C:21]3[CH:25]=[CH:15][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:23][CH:22]=3)[N:7]=[C:8]([Cl:9])[N:1]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: C1CCOC1
Reactant: [Li]c1ccc(C(C)(C)C)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Product: CC(C)(C)c1ccc(-c2nc(Cl)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -70 °C
Reaction time: 4 h

Procedure:
Under an argon stream, 1-bromo-4-tert-butylbenzene (125 g, 587 mmol) and tetrahydrofuran (470 mL) were charged in a reactor, and cooled to −70° C. An n-butyl lithium/hexane solution (1.6 M, 367 mL, 587 mmol) was dropped to this solution over 90 minutes at −70° C. After dropping was completed, the solution was stirred at −70° C. for 2 hours to obtain a 4-tert-butylphenyllithium/THF solution. Under an argon stream, cyanuric chloride (50.8 g, 276 mmol) and tetrahydrofuran (463 mL) were charged in another reactor, and cooled to −70° C. The 4-tert-butylphenyllithium/THF solution prepared previously was slowly dropped to this solution while the solution was cooled so that the reaction temperature might be not more than −60° C. After dropping was completed, the reaction solution was stirred at −40° C. for 4 hours, and stirred at room temperature for 4 hours. Water (50 mL) was added to this reaction mixture to complete the reaction, and tetrahydrofuran was distilled off. Water (1 L) and chloroform (2 L) were added to this residue, and an organic layer was extracted. The organic layer was further washed with water (1 L), and subsequently the solvent was distilled off. This residue was dissolved in acetonitrile (600 mL), and an insoluble solid was removed by filtration at the time of heating. The obtained filtrate was condensed to approximately 100 mL, and cooled to −70° C. to filter and collect the solid deposited. The collected solid was dissolved in a mixed solvent of chloroform (200 mL)/hexane (600 mL), and purified with silica gel column chromatography (developing solvent: chloroform/hexane). The solvent was distilled off, and this residue was recrystallized from acetonitrile. Thereby, 4,6-bis(4′-tert-butylphenyl)-2-chloro-1,3,5-triazine (41.3 g, 109 mmol) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([OH:15])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:16]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([O:15][CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:16]=1)[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCc1nc2cnc3cc(O)ccc3c2n1CCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2cnc3cc(OCC(=O)C(C)(C)C)ccc3c2n1CCOc1ccccc1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
A suspension of 2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol (1.0 g, 3.0 mmol) and cesium carbonate (1.49 g, 4.57 mmol) in DMF was stirred for 15 minutes; 1-bromopinacolone (0.6 mL, 4.5 mmol) was added dropwise. The reaction was heated at 65° C. and stirred for 20 hours, and then the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed sequentially with water (3×) and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.3 g of 1-[2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yloxy]-3,3-dimethylbutan-2-one as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]([N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)=[O:9]
Reactant: Cc1ccc(F)cc1C(=O)N1CCOCC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1cc(F)ccc1CBr)N1CCOCC1
Yield: 38.3 %

Procedure:
A mixture of intermediate 41, (5-fluoro-2-methylphenyl)(morpholino)methanone, (2.1 g, 9.5 mmol) and N-bromosuccinimide (2.0 g, 11 mmol) in CCl4 (30 mL) was heated at reflux. To this mixture was added benzoylperoxide (242 mg, 1 mmol) and the mixture heated at reflux for 2 hrs. After cooling, the insoluble materials were filtered and the filtrate purified by column chromatography (SiO2, 0–10% ether in CH2Cl2) to give 1.1 g (Yield 38%) of the title compound as a clear oil: 1H NMR (300 MHz, CDCl3) δ ppm: 3.31 (2H, t, J=4.94 Hz) 3.55–4.02 (6H, m) 4.56 (2H, dd, J=128.81, 9.51 Hz) 6.89 (1 H, dd, J=8.23, 2.74 Hz) 6.96–7.12 (1H, m) 7.33–7.49 (1H, m); LC/MS m/z 302 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:16])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(C(=O)O)ccc(F)c1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)Cl)ccc(F)c1Cl
Reaction time: 3 h

Procedure:
3-chloro-4-fluoro-2-methylbenzoic acid (I57)(0.754 g, 4 mmol) in dichloromethane (DCM) (30 mL) was cooled to 0° C., before oxalyl chloride (0.385 mL, 4.40 mmol) and a few drops of DMF (cat.) were added. The solution was then stirred under argon for 3 hours, before the solvent was evaporated in vacuo. The remaining residue was then azeotroped with toluene to yield the product in 0.819 g.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CS(C)=O>[ClH:21].[ClH:21].[C:1]1([CH:7]([N:9]2[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][Cl:21])[CH2:13][CH2:14]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)N1CCNCC1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(c1ccccc1)N1CCN(CCCCl)CC1
Product: Cl
Yield: 409.8 %

Procedure:
The procedure described in Example 17(a) was followed, using 16.5 g of 1-(1-phenylethyl)piperazine, 8.0 g of potassium hydroxide, 125 ml of dimethyl sulfoxide and 9.5 g of 1-bromo-3-chloropropane. Work-up, as described above, gave 28.0 g (96% of theory) of 1-(1-phenylethyl)-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5](CC)[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH:25]([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:25]([CH3:27])[CH3:26])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2]
Reactant: CC(C)I
Reactant: CCOC(=O)C(CC)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(OC(C)C)c(OC)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 88.6 %

Procedure:
A mixture of ethyl (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester (11.22 g, 53.4 mmol) and K2CO3 (22.13 g, 160 mmol) in DMF (100 ml) was heated at 60° C. 2-Iodopropane (9.06 ml, 91 mmol) was added and the mixture was vigorously stirred at 60° C. for 5 h. The reaction mixture was cooled to RT, diluted with AcOEt and washed with water. The aqueous phase was separated and further extracted with AcOEt. The combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/AcOEt 98:2→3:1) to yield the title compound (11.94 g, 47.3 mmol, 89%) as a colorless oil.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:18][C:19]1[N:20]=[C:21](C)[NH:22][C:23]=1C#N.[C:27](O)(=O)C>>[CH3:27][C:3]1[CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=2)[N:20]2[CH:21]=[N:22][C:23]([C:19]#[N:18])=[C:17]2[N:2]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)O
Reactant: Cc1nc(N)c(C#N)[nH]1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)n2cnc(C#N)c2n1

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 50 ml. of glacial acetic acid and 0.01 mole of 4-amino-2-methyl-5-imidazolecarbonitrile is refluxed for 5 hours. The solvent is removed under reduced pressure and the residue worked up as for Example 29 to give the product of the example.
Reaction SMILES: [SH:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][CH3:9])[NH:4][N:3]=1.Cl[C:11]1[C:12]2[N:20]=[C:19](Cl)[CH:18]=[CH:17][C:13]=2[N:14]=[CH:15][N:16]=1.[N:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[S:24][C:23]=1[NH2:31]>>[CH3:9][O:8][CH2:7][C:5]1[NH:4][N:3]=[C:2]([S:1][N:31]([C:23]2[S:24][C:25]3[C:30]([N:22]=2)=[CH:29][CH:28]=[CH:27][N:26]=3)[C:11]2[C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[N:6]=1
Reactant: COCc1nc(S)n[nH]1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Nc1nc2cccnc2s1
Product: COCc1nc(SN(c2nc3cccnc3s2)c2ncnc3cccnc23)n[nH]1

Procedure:
The compound of Example 41 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 3-mercapto-5-methoxymethyl[1,2,4]triazole, 4,6-dichloro-pyrido-[3,2-d]pyrimidine and thiazolo[5,4-b]pyridin-2-yl-amine.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].C(=O)([O-])OC1C(C)=C([C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH2:28][O:29][C:25]=3[CH:24]=2)C=CN=1.[O:34]1[C:38]2C=CC(C3C=CN(C([O-])=O)C(=O)C=3C)=CC=2[O:36][CH2:35]1>O.C1COCC1>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([N:1]([C:35]([O:34][CH3:38])=[O:36])[C@H:2]([C@@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: Cc1c(-c2ccc3c(c2)OCO3)ccnc1OC(=O)[O-]
Reactant: Cc1c(-c2ccc3c(c2)OCO3)ccn(C(=O)[O-])c1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(c1ccc2c(c1)OCO2)[C@@H](C(=O)O)[C@H](C)O
Reaction time: 15 h
Yield: 92 %

Procedure:
To a stirred mixture of D-threonine (0.146 g, 1.23 mmol) and NaHCO3 (0.155 g, 1.85 mmol) in H2O (3.0 mL), the crude mixture containing 1,3-benzodioxol-5-yl-methyl-2-pyridyl carbonate and 1,3-benzodioxol-5-yl-methyl-2-oxopyridine-1-carboxylate (0.506 g, 1.85 mmol) in THF (3.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.337 g, 92%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 315 [M−NH4]+; (ESI) m/z: 296 [M−H]−. 1H NMR (DMSO-d6): δ 1.09 (d, J=6.4 Hz, 3H), 3.95 (dd, J=3.5, 9.0 Hz, 1H), 3.99-4.08 (dq, J=3.5, 6.4 Hz, 1H), 6.01 (s, 2H), 4.95 (s, 2H), 6.78-7.00 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([S:37]N=C=O)C.[C:41](#[N:43])[CH3:42]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:35]([NH:43][CH2:41][CH3:42])=[S:37])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: CCSN=C=O
Reactant: CC#N
Product: CCNC(=S)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (150 mg) was dissolved in 4 ml of acetonitrile, 710 mg of ethyl thioisocyanate was added to the solution, and the mixture was heated under reflux for 4 days. The reaction solution was evaporated, and the resulting residue was purified by silica gel column chromatography using hexane:ethyl acetate (7:3) as the eluent to give 171 mg of 1-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-1-[(7-cyano-2-naphthyl)methyl]-3-ethylthiourea.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:15][C@@:7]3([OH:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26](CO)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][CH2:19][C:26]4[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)=[O:17])[CH2:15][C@@:7]3([OH:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CO)cc1
Reactant: COC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(COC(=O)[C@@H]2C[C@@]3(O)c4cccc(Cl)c4N(C)O[C@H]3N2)cc1
Yield: 85.6 %

Procedure:
A stirred solution of methyl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1, 2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 118 25 g), para-methoxybenzyl alcohol (115 g) and titanium tetraethoxide (1.5 g) in toluene (300 ml) was heated at reflux for 1 hour. The reaction mixture was cooled, evaporated to a small volume and purified by flash column chromatography on silica gel eluting with a gradient of ethyl acetate:hexane (1:4 to 2:3) to give the product (29 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=O>CO>[CH2:15]([O:14][C:10]([CH:11]=[N:9][NH:8][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C=O
Reactant: NNc1ccc(Cl)nn1
Solvent: CO
Product: CCOC(=O)C=NNc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A mixture of compound 3-chloro-6-hydrazinylpyridazine (8.85 g, 0.061 mol) and ethyl glyoxalate (6.16 g, 0.061 mol) in 50 mL of methanol containing about 30% acetic acid was stirred at room temperature for 2 h. The yielded solid was collected by filtration and washed with methanol to give product 1-ethoxycarbonylmethylene-2-(6-chloro-3-pyridazinyl) hydrazine as a white solid (9.5 g, 68%). LRMS (M+H+) m/z: calcd 229.03; found 229. 1H NMR (300 MHz, CDCl3): δ 12.40 (s, 1H), 7.80-7.31 (d, J=9.6 Hz, 1H), 7.60-7.56 (d, J=9.3 Hz, 1H), 7.50 (s, 1H), 4.25-4.23 (q, 2H), 1.31-1.26 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[N:14]=O>C(O)C.ClCCl.[Pd]>[NH2:14][C:3]1[C:4]([CH3:13])=[N:5][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:2]=1[NH2:1]
Reactant: Cc1nn(-c2ccccn2)c(N)c1N=O
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Cc1nn(-c2ccccn2)c(N)c1N
Yield: 99.4 %

Procedure:
By the method of Preparation 8(b), 5-amino-3-methyl-4-nitroso-1-(2-pyridyl)pyrazole (1.37 g, 6.75 mmol) in ethanol/dichloromethane=4:1 (50 ml) was hydrogenated over 10% palladium on carbon at 20 p.s.i. to give the title compound (1.27 g, 100%).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[CH2:18]([Mg]Br)[CH3:19]>C1COCC1.C(OCC)(=O)C>[OH:2][CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH2:18][CH3:19]
Reactant: NC(=O)c1ccc(-c2ccc(C=O)nc2)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)c1ccc(-c2ccc(C(N)=O)cc2)cn1
Reaction time: 3 h
Yield: 50.2 %

Procedure:
To a solution of 4-(6-formylpyridin-3-yl)benzamide (0.30 g, 1.32 mmol), in THF (30 mL) was added ethyl magnesium bromide (0.53 g, 3.97 mmol, 3M in diethyl ether) under nitrogen at 0° C. and the contents were stirred for 3 h at the same temperature. The contents were diluted with ethyl acetate (150 mL), quenched with ammonium chloride solution (100 mL), the organic layer washed with brine solution (2×100 mL), the layers separated, the organic layer dried over sodium sulphate and distilled off to get the crude product. The compound was purified by flash chromatography (100-200 micron; 60% ethyl acetate in hexane) to give 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzamide (0.17 g, 51% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.83 (s, 1H), 8.10 (dd, 1H), 8.00 (s, 1H), 7.97 (d, 2H), 7.79 (d, 2H), 7.55 (d, 1H), 7.36 (s, 1H), 5.30 (d, 1H), 4.53 (q, 1H), 1.17 (m, 1H), 1.65 (m, 1H), 0.86 (t, 3H); LC-MS m/z calcd for [M+H]+ 257.31. found 257.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[N:19][N:18]=[C:17]1[CH2:33]Cl.[S:36]([O-:40])([O-:39])(=[O:38])=[S:37].[Na+:41].[Na+]>C(O)C.O>[Na+:41].[S:36]([OH:40])([O-:39])(=[O:38])=[S:37].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([CH2:33][SH:36])=[N:18][N:19]=[C:20]1[CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(NCc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl)OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(NCc1nnc(CS)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl)OCc1ccccc1
Product: O=S([O-])(O)=S

Procedure:
To a solution of 2',5-dichloro-2-(5-carbobenzoxyaminomethyl-3-chloromethyl-1,2,4-triazol-4-yl)benzophenone (12.8 g) in ethanol (600 ml) is added a solution of sodium thiosulfate (7.2 g) in water (200 ml), and the resultant mixture is refluxed for 1.5 hours. The reaction mixture is evaporated under reduced pressure to remove the solvent, whereby 2',5-dichloro-2-(3-carbobenzoxyaminomethyl-5-mercaptomethyl-1,2,4-triazol-4-yl)-benzophenone thiosulfate monosodium salt is obtained. This substance is dissolved in water (600 ml), mixed with thiol type thiamine sodium salt (10.8 g) and stirred overnight. The colorless precipitate is filtered, washed with water and dissolved in a mixture of chloroform and methanol. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate to give bis[4-{2-(2-chlorobenzoyl)-4-chlorophenyl}-5-carbobenzoxyaminomethyl-1,2,4-triazol-3-methyl]disulfide (7.4 g) as crystals melting at 113°-115° C. This compound is recrystallized from ethyl acetate/n-hexane to give colorless crystals.
Reaction SMILES: [O:1]1[C:5]2=[C:6]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Li+].CC([N-]C(C)C)C.[Cl:33][C:34](Cl)(Cl)[C:35]([Cl:38])(Cl)Cl>C1COCC1>[Cl:33][C:2]1[O:1][C:5]2=[C:6]([N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[Cl:33][C:34]1[O:1][C:5]2=[C:6]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[C:35]=1[Cl:38]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2ccoc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2c(Cl)c(Cl)oc12
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(Cl)oc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 18 %
Yield: 65 %

Procedure:
Di-tert-butyl furo[2,3-c]pyridin-7-ylimidodicarbonate (25 g, 75.3 mmol) in dry THF (350 mL) was cooled to between −65° C. and −75° C. and LDA (1.8 M in THF/heptanes/ethylbenzene, 50 mL, 90 mmol) was added via syringe over a period of 10 min. The mixture was stirred for 1.5 h between −65° C. and −75° C. and then treated with hexachloroethane (71.2 g, 0.30 mol) in dry THF (150 mL) added via syringe over a 30 min period. The mixture was allowed to warm to RT over 16 h and was quenched by the addition of water (100 mL) and stirred for 10 min. The reaction was diluted with EtOAc, the phases were separated and the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude product thus obtained was purified by flash chromatography using triethylamine coated silica gel eluting (EtOAc:hexane mixtures) to provide 18 g (65%) of di-tert-butyl (2-chlorofuro[2,3-c]pyridin-7-yl)imidodicarbonate and 5 g (18%) of di-tert-butyl (2,3-dichlorofuro[2,3-c]pyridin-7-yl)imidodicarbonate.
Reaction SMILES: C1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2C=C1)[CH2:7]3.C=C[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:13]1([C:6]23[CH2:7][CH:8]([CH2:4][CH2:5]2)[CH:9]=[CH:10]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=Cc1ccccc1
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Solvent: Cc1ccccc1
Product: C1=CC2(c3ccccc3)CCC1C2
Temperature: 180 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
DCPD (Aldrich, 55 mL, 0.41 mol), styrene (Aldrich, 146 mL, 1.27 mol), and 4-t-butylcartechol (1.9 g, 11.4 mmol) were put in a 2 L autoclave. After heating to 180° C., reaction was carried out for 4 hours while stirring the autoclave at 300 rpm. After the reaction was completed, the reaction mixture was cooled down. The reaction mixture was diluted with toluene and precipitated in ethanol. After the obtained polystyrene was filtered, the solvent was removed, and the filtrate was transferred to a distillation unit. The filtrate was distilled at 1 torr twice using a vacuum pump at 70° C. to obtain the product (yield: 43%).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([OH:22])[N:14]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:23]>CO>[NH2:23][C:2]1[C:11]2[N:12]=[C:13]([OH:22])[N:14]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Oc1nc2c(Cl)nc3ccccc3c2n1Cc1cccnc1
Reactant: N
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc(O)n2Cc1cccnc1
Temperature: 165 °C

Procedure:
4-Chloro-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol (2.64 g, 8.52 mmol) and ammonia (40 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 165° C. for 42 hours and allowed to cool. A solid was present and was isolated by filtration washed with diethyl ether to provide 1.2 g of 4-amino-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol. A second crop of solid (550 mg) was collected from the filtrate. A portion of the first crop was washed with dichloromethane, methanol, diethyl ether, and acetonitrile to provide a sample as tan needles, mp greater than 250° C.