Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([Cl:15])[C:8]([Cl:14])=[CH:9][CH:10]=2)[CH2:5]1)(=O)[CH3:2].B#B.CO>O1CCCC1>[ClH:14].[Cl:14][C:8]1[C:7]([Cl:15])=[C:6]2[C:11]([CH2:12][CH2:13][N:4]([CH2:1][CH3:2])[CH2:5]2)=[CH:10][CH:9]=1
Reactant: CC(=O)N1CCc2ccc(Cl)c(Cl)c2C1
Agent: B#B
Solvent: C1CCOC1
Solvent: CO
Product: CCN1CCc2ccc(Cl)c(Cl)c2C1
Product: Cl

Procedure:
2-Acetyl-7,8-dichloro-1,2,3,4-tetrahydroisoquinoline is treated with excess diborane in tetrahydrofuran and refluxed for 16 hours. Methanol is added to destroy excess diborane and the solvent is removed in vacuo. The residue is dissolved in ether, treated with hydrogen chloride and filtered to give 7,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH:14]=[N:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8])[CH3:13]
Reactant: Nc1ccncc1O
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1ccncc1O

Procedure:
A solution prepared from of 4-amino-3-pyridinol (1.10 g) and 10 ml of N,N-dimethylformamide dimethyl acetal was refluxed for 30 minutes. At the end of this time, the reaction mixture was concentrated under reduced pressure and the residue was passed over a short column of florisil, eluting with 5% methanol/ethyl acetate. The eluate was concentrated and the residue and recrystallized from ethyl acetate/pentane to afford 0.91 g of analytically pure product, m.p. 121°-123°.
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)[C:20]=1[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:15])[CH2:10]2>CO>[CH:3]12[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)[C:20]=1[C:21]([CH3:23])([CH3:24])[CH3:22])=[O:15])[CH2:12]2
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
2M aqueous sodium hydroxide solution (51.7 mL, 103.32 mmol) was added to methyl 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoate (Intermediate#56) (4.5 g, 10.33 mmol) in methanol (100 mL). The mixture was stirred at 70° C. for 1 hour and then cooled to ambient temperature, concentrated under reduced pressure and diluted with water (100 mL). The reaction mixture was adjusted to pH 3 with 2M HCl. The reaction mixture was extracted with EtOAc (500 mL) and washed sequentially with water (2×100 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to give a pale yellow solid. The solid was washed with EtOAc (20 mL), collected by filtration and dried under vacuum to give 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (3.89 g, 89%) as a cream crystalline solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]2[C:6]=1[NH:7][CH:8]([O:18][CH3:19])[CH:9]([O:16][CH3:17])[NH:10]2)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]2[C:6]=1[NH:7][CH:8]([O:18][CH3:19])[CH:9]([O:16][CH3:17])[NH:10]2
Reactant: COC1Nc2cc(Br)cc(CN=[N+]=[N-])c2NC1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC1Nc2cc(Br)cc(CN)c2NC1OC
Temperature: 20 °C
Reaction time: 4 h

Procedure:
4.47 g (13.8 mmol) of 5-azidomethyl-7-bromo-2,3-dimethoxy-1,2,3,4-tetrahydroquinoxaline are dissolved in 35 ml of tetrahydrofuran, and 3.98 g (1.1 equiv.) of triphenylphosphine are added. The mixture is stirred at 20° C. for 4 hours. 746 mg of water are added and the mixture is stirred for a further three hours. The solid is filtered off and the filtrate is extracted with ethyl acetate and sodium carbonate solution. The organic phases are combined, washed with brine, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/petroleum ether (1:1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>CCOCC.O>[N:21]1([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: FC(F)(F)c1ccc2c(c1)ncn2-c1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: FC(F)(F)c1ccc2c(c1)ncn2-c1cccc(-n2ccnc2)c1
Temperature: 200 °C

Procedure:
A mixture of 1-(3-iodophenyl)-5-trifluoromethyl-benzimidazole (2a)(1.0 g, 2.58 mmol), imidazole (0.19 g, 2.73 mmol), potassium carbonate (0.38 g, 2.78 mmol), CuBr (20 mg, 0.15 mmol), and 1-methyl-2-pyrrolidone was heated to 200° C. for 18 hours. Dilution with water and extractive workup with ether was followed by chromatography on silica gel. Yield: 0.43 g, 1.51 mmol, 51%. mp 177°-180° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[N:26])[C@H:20]([CH3:27])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:28]([C:30]1[S:31][C:32]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:33]=2[N:34]=1)#[N:29].C1C[O:44]CC1>>[C:11]([N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:25]#[N:26])[C:28]([C:30]2[S:31][C:32]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:33]=3[N:34]=2)=[NH:29])[C@H:20]([CH3:27])[CH2:19]1)(=[O:44])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1CC#N
Reactant: C1CCOC1
Reactant: COc1ccc2sc(C#N)nc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COc1ccc2sc(C(=N)C(C#N)N3CCN(C(=O)c4ccccc4)C[C@H]3C)nc2c1
Reaction time: 10 h

Procedure:
NaHMDS (0.77 ml, 1M in THF) was added into a solution of (R)-N-benzyl-3-methyl-N′-cyanomethylpiperazine (100 mg) and 2-cyano-5-methoxy-benzothiazole (58 mg) in THF (10 ml). The reaction was stirred for 10 hours. Then 4 ml of the reaction mixture was separated and quenched with MeOH. After solvents were removed under vaccum, the residue was purified using Shimadzu automated preparative HPLC System to give (R)-N-(benzoyl)-3-methyl-N′-[2-(5-methoxy-benzothiazol-2-yl)-2-imino-1-cyano-ethyl]-piperazine (1.3 mg).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH2:33])=[CH:27][CH:26]=1>>[C:25]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][NH:33][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)[CH:18]=2)=[CH:29][CH:30]=1
Reactant: NCCc1ccc(-c2ccccc2)cc1
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCCc3ccc(-c4ccccc4)cc3)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(1,1′-biphenyl-4-yl)ethylamine gave the title compound as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>ClCCl>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: c1cc2c(cn1)NCCO2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCOc3ccncc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
In a 25 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (370 mg, 2.72 mmol) and 4-methoxy-benzenesulfonyl chloride (618 mg, 2.99 mmol) were dissolved in dichloromethane (10 ml). Triethylamine (0.45 ml, 3.23 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain pale-green solid (700 mg, 84.1%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH3:13].[Cl:14][C:15]1[N:16]=[C:17](Cl)[C:18]2[S:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CN1C(=O)CCC1.O>[Cl:14][C:15]1[N:16]=[C:17]([O:3][C:4]2[C:5]([CH3:13])=[CH:6][C:7]([C:8]#[N:9])=[CH:10][C:11]=2[CH3:12])[C:18]2[S:23][CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2ccsc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 315 %

Procedure:
A stirred suspension of NaH (29.7 mg, 0.74 mmol) in dry NMP (3.5 mL) was added 4-hydroxy-3,5-dimethylbenzonitrile (108.2 mg, 0.74 mmol) and stirred at room temperature for 30 min under Argon. The reaction mixture was added to a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (39.6 mg, 0.19 mmol) in dry NMP (4 mL) and heated at 50° C. for 5 h. The resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1) to give the product as a white solid (189 mg, 81%):
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:21][CH:22]([CH3:26])[N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH2:13])[C:6]3[CH2:21][CH:22]([CH3:26])[N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1Cc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccncc2)CN1C
Solvent: O=S(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(Cn1c2c(c3cc(Cl)ccc31)CN(C)C(C)C2)c1ccncc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 9.4 %

Procedure:
1-(8-Chloro-2,3-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-4-yl-propan-2-ol (900 mg, 2.43 mmol) was dissolved in 5 mL DCM. To this, thionyl Chloride (2 mL in DCM) was added dropwise at 0° C. and stirred for 2.5 h at RT. After completion of starting material (TLC) excess thionyl chloride and solvent was evaporated under vacuum. The residue was neutralized with saturated solution of Sodium bicarbonate at 0° C. and extracted with EtOAc (3 times). The combined organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated to obtain 720 mg of crude which was subjected to reverse phase chromatography to obtain 80 mg of product as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.70 (d, 2H), 7.95 (d, 2H), 7.55 (s, 1H), 7.42 (d, 1H), 7.20 (d, 1H), 5.85 (s, 1H), 5.30 (s, 2H), 4.78 (s, 1H), 4.70 (m, 1H), 4.40 (m, 1H), 4.10 (m, 1H), 3.85 (m, 1H), 3.05 (s, 3H), 2.95 (m, 1H), 1.50 (m, 2H).
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[N:10]=[C:9]([S:11][CH3:12])[NH:8][N:7]=1.[C:13]([CH2:21][C:22](=O)[CH3:23])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)CCC>[CH3:23][C:22]1[CH:21]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=1
Reactant: CSc1nc(N)n[nH]1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CCCCCl
Solvent: CC(=O)O
Product: CSc1nc2nc(C)cc(-c3ccccc3)n2n1
Yield: 27.2 %

Procedure:
To 50 ml of stirring glacial acetic acid, 2.5 g (19.2 mmol) of 3-amino-5-methylthio-1,2,4-triazole and 3.1 g (19.1 mmol) of benzoylacetone was added followed by heating at reflux for 2 h. The solvent was evaporated in vacuo and excess water added to the residue followed by extraction with 200 ml of ethyl acetate. The extract was washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and evaporated in vacuo to give an oil. Addition of n-butyl chloride resulted in crystallization of a solid which was filtered and washed with n-butyl chloride to give 1.33 g of the pure title compound, m.p. 121°-123° C.
Reaction SMILES: C(O[CH2:5][C:6]1[C@H:7]2[CH2:20][CH2:19][C@H:18]([CH3:21])[C@H:8]2[C@H:9]([O:12][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[O:10][CH:11]=1)(=O)C.[H][H]>C(OCC)(=O)C.N1C=CC=CC=1.[C].[Pd]>[CH2:16]([O:15][CH:13]([O:12][C@H:9]1[C@@H:8]2[C@@H:18]([CH3:21])[CH2:19][CH2:20][C@@H:7]2[C:6]([CH3:5])=[CH:11][O:10]1)[CH3:14])[CH3:17]
Reactant: CCOC(C)O[C@@H]1OC=C(COC(C)=O)[C@H]2CC[C@H](C)[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(C)O[C@@H]1OC=C(C)[C@H]2CC[C@H](C)[C@@H]12

Procedure:
5.0 g of this colorless oily substance, i.e., (1S, 4aS, 7S, 7aR)-4-(acetoxymethyl)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[c]pyran, was dissolved in a mixed solvent of 100 mS of ethyl acetate and 3 mι of pyridine, and after 150 mg of 10% palladium carbon was added, the reaction mixture was stirred at room temperature for 20 hours in a hydrogen atmosphere of 1 atm. After the catalyst was filtered by celite, extraction was carried out by adding 100 mι of ethyl acetate to the reaction mixture solution. The organic layer was washed with 100 mι of 2N hydrochloric acid solution and saturated sodium chloride solution, and was then dried by magnesium sulfate. After filtration, the solvent was distilled off under a reduced pressure, and a colorless oily substance was obtained (1S, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-4, 7-dimethylcyclopenta[c]pyran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][CH:27]([NH2:32])[C:28]([F:31])([F:30])[F:29].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:32][C@@H:27]([CH3:26])[C:28]([F:31])([F:30])[F:29])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(N)C(F)(F)F
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) and L-2,2,2-trifluoro-1-(methyl)ethylamine (32 mg, 0.28 mmol) in THF (10 mL) were added at 0° C., 1-hydroxybenzotriazole hydrate (43.3 mg, 0.28 mmol), N-ethyldiisopropylamine (121 μL, 0.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (54.2 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=2:8 to 1:0, then silica, dichloromethane:methanol=99:1 to 95:5) to afford the title compound (75 mg, 60%) as a white solid. MS: m/e=454.1 [M−H]−.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH2:33])=[CH:28][N:27]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)(C)(C)C>C(Cl)Cl>[NH2:14][CH:15]([CH:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[O:34])=[CH:28][N:27]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)[CH3:1]
Reactant: CC(C)(C)OC(=O)NCC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)C1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.8 %

Procedure:
Add TFA (6.54 g, 57.4 mmol) to a suspension of [5-(5-carbamoyl-pyridin-2-yloxy)-indan-1-ylmethyl]-carbamic acid tert-butyl ester (1.05 g, 2.87 mmol) in DCM (20 ml) and stir at ambient temperature for four hours. Concentrate mixture on rotary evaporator and purify on cation exchange column (10 g, Varian) to give the title compound (519 mg) as a white solid. Mass spectrum (ion spray): m/z=284 (M+1); 1HNMR (DMSO-d6): 8.58 (s, 1H), 8.21 (d, 1H), 8.00 (br s, 1H), 7.44 (br s, 1H), 7.27 (d, 1H), 7.01 (d, 1H), 6.96 (s, 1H), 6.87 (d, 1H), 3.05 (m, 1H), 2.84 (m, 2H), 2.77 (m, 1H), 2.62 (m, 1H), 2.18 (m, 1H), 1.82 (m, 1H), 1.71 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([F:13])[CH:3]=1.[C:14](Cl)(Cl)=[S:15].[OH-].[Na+]>O.Cl>[F:13][C:4]1[CH:3]=[C:2]([N:1]=[C:14]=[S:15])[C:11]([CH3:12])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: Cc1c(N)cc(F)c2cccnc12
Reactant: S=C(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N=C=S)cc(F)c2cccnc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7-amino-5-fluoro-8-methylquinoline (0.39 g) and thiophosgene (0.2 mL) in water (5 mL) and 1N hydrochloric acid (5 mL) is stirred at room temperature for 1.5 hours. An additional amount of thiophosgene (0.1 mL) is added and the mixture stirred another hour. The mixture is treated with 1N sodium hydroxide (25 mL) and extracted with methylene chloride (4×50 mL). The combined extracts are dried over sodium sulfate and rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 15% ethyl acetate/hexane, to afford 5-fluoro-8-methyl-7-quinolinylisothiocyanate as a tan solid.
Reaction SMILES: O1CCCC1.[S:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[C:20]([S:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:19]([Cl:28])=[CH:18][C:17]=1[Cl:29])C#N.[F:30][C:31]([Si](C)(C)C)([F:33])[F:32].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OC(=O)C)C.CCCCCC>[F:30][C:31]([F:33])([F:32])[S:6][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[C:20]([S:22][CH2:23][C:24]([F:27])([F:25])[F:26])[C:19]([Cl:28])=[CH:18][C:17]=1[Cl:29]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#CSCCCCCCOc1cc(SCC(F)(F)F)c(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)CSc1cc(OCCCCCCSC(F)(F)F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To 30 ml of tetrahydrofuran were added 1.04 g (2.49 mmol) of 6-thiocyanatohexyl-[2,4-dichloro-5-(2,2,2-trifluoroethylthio)phenyl]ether and 1.06 g (7.45 mmol) of trifluoromethyltrimethylsilane. Thereto was added 0.25 ml (concentration: 1 mol/liter, 0.25 mmol) of tetrahydrofuran solution of tetra-n-butylammonium fluoride at 0° C., and reaction mixture was stirred for 2 hours at room temperature. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane ethyl acetate=20:1), to obtain 0.73 g (yield: 64%) of an intended product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].I[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>C(O)(C)C>[CH:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:13])[CH3:12]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1cccc(C=O)c1
Yield: 66.7 %

Procedure:
EX-645A) 3-Hydroxybenzaldehyde (5.60 g, 45.9 mmol) and 2-iodopropane (7.86 g, 46.2 mmol) were dissolved in 50 mL of isopropanol. Potassium carbonate (20 g, 145 mmol) was added, and the mixture was heated to reflux for 8 h, at which time TLC analysis indicated that the reaction had gone to completion. Water was added to dissolve all solids, and the mixture was extracted with ether (3×). The combined ether layer was washed with water, 2 M NaOH, again with water until clear (4×), and finally with brine. The solution was dried over MgSO4, filtered, and evaporated to give 5.03 g (67%) of the desired 3-isopropoxybenzaldehyde product as a pale oil. 1H NMR (C6D6) δ 9.62 (s, 1H), 7.29 (s, 1H), 7.03 (m, 1H), 6.91 (t, 1H), 6.84 (m, 1H), 4.03 (septet, 1H), 0.96 (d, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[N+](C(C)C)([O-])=[O:22].[O-]CC.[Na+]>C(OCC)(=O)C>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:19]=[C:18]([CH3:20])[CH:17]=1)[CH:2]=[O:22])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(CBr)cc(OCCO[Si](C)(C)C(C)(C)C)c1
Reactant: CC(C)[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(C=O)cc(OCCO[Si](C)(C)C(C)(C)C)c1
Temperature: 90 °C

Procedure:
To a solution of [2-(3-bromomethyl-5-methyl-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane (2.17 g, 6.04 mmol) under nitrogen in 2-nitropropane (2.0 mL, 20 mmol) was added sodium ethoxide (0.620 g, 9.06 mmol). The resulting mixture was heated at 90° C. for 15 hours, and was then diluted with ethyl acetate and quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate and the combined organic layers were backwashed with water and brine, dried over sodium sulfate, and concentrated. The crude material (1.81 g) was purified by column chromatography (silica gel 230-400 mesh; 1/0 to 4/1 hexanes/EtOAc as eluent) to give 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-benzaldehyde as a yellow oil. Yield: 0.97 g (55%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: COc1ccc(N)nc1
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(O)cc3)cn2c1
Temperature: 90 °C
Yield: 81.6 %

Procedure:
2.15 g (corresponding to 10.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 1.25 g (corresponding to 10.0 mmol) of 2-amino-5-methoxypyridine were dissolved in 50 mL, of acetonitrile. The resulting solution was refluxed in an oil bath at 90° C. for 3.5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 40 mL of water and 40 mL of methanol. Then, about 20 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using a ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 1.96 g (corresponding to 8.16 mmol) of 2-(4′-hydroxyphenyl)-6-methoxyimidazo[1,2-a]pyridine (FIG. 2, Step 5).