Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH2:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1.[N:42]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH:38][C:48]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[O:49])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(N)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(NC(=O)N3CCOCC3)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of compound 9D in anhydrous CH2Cl2 were slowly added 4-morpholinecarbonyl chloride (14D, 1.2 eq) and triethylamine (1.5 eq), successively. The reaction mixture was stirred at rt overnight. It was concentrated to small volume and purified with silica column chromatography eluting with dichloromethane/EtOAc to give the title compound (15D) which was recrystallized from hexanes/acetone to provide compound 15D as white powder in ˜60% yield. 1H NMR (CDCl3, 500 MHz) δ 10.67 (s, 1H), 8.93 (s, 1H), 8.70 (s, 1H), 7.93 (d, 2H, J=7.5 Hz), 7.63 (s, 1H), 7.55 (d, 2H, J=7.5 Hz), 7.45 (s, 5H), 7.19 (d, 1H, J=8.0 Hz), 6.97 (d, 1H, J=8.0 Hz), 5.60 (d, 1H, J=6.5 Hz), 5.28 (s, 1H), 5.18 (d, 1H, J=6.5 Hz), 4.86 (d, 1H, J=12.0 Hz), 3.97 (s, 3H), 3.83 (m, 4H), 3.70 (br s, 4H), 3.45 (m, 2H), 3.37 (m, 2H), 3.17 (m, 1H). LCMS (ESI) m/z 705.43 (MNa+), 683.39 (MH+). HPLC: tR=4.95 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CSCCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CSCCCCCOS(C)(=O)=O

Procedure:
A solution of 16.7 g. (0.146 mol) methanesulphonyl chloride and 150 ml. methylene chloride is added dropwise at -5° C., within the course of 30 minutes, to a mixture of 30.1 g. (0.146 mol) ethyl 8-hydroxy-3-thiaoctanoate, 200 ml. methylene chloride and 22,2 g. (0.219 mol) anhydrous triethylamine and the reaction mixture then stirred at 0° C. for a further 30 minutes. It is then extracted with ice-cold 2N sulphuric acid and subsequently with ice water, dried with anhydrous sodium sulphate and subsequently evaporated. Yield 38.3 g. (93% of theory) in the form of a colourless oil.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[Cl-].[CH3:10][CH2:11]O>>[NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][CH2:10][CH3:11])=[O:4]
Reactant: CCO
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cl-]
Product: CCOC(=O)[C@@H]1CCCN1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
Into a 500 ml 3-necked roundbottom flask, was placed a solution of proline (20.0 g, 174. mmol) in EtOH (100 ml). To the above was added thinyl chloride (40 ml). The resulting solution was heated to 70° C., with stirring, for 12 hours. The mixture was concentrated by evaporation. To afford ethyl prolinate that was used without further purification.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)(=[O:3])[CH3:2].S(Cl)([Cl:17])=O>>[C:1]([NH:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([Cl:17])=[O:14])[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Product: CC(=O)NC[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
trans-4-[(Acetylamino)methyl]cyclohexanecarboxylic acid (12.1 g) was added by portions to thionyl chloride (25 ml) under ice-cooling. After stirred at room temperature for 30 minutes, thionyl chloride was evaporated under reduced pressure to give crude crystals of trans-4-[(acetylamino)methyl]cyclohexanecarbonyl chloride. Then, aluminum chloride (24.0 g) was added by portions to a solution of the crude crystals and 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (12.1 g) in dichloromethane (30 ml) under ice-cooling. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice (300 g), extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as colorless crystals (12.9 g) having a melting point of 178 to 180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=O)[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1.C(O)(=O)C.C(N(C(C)C)C(C)C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]([N:33]3[CH2:34][C:31]([F:35])([F:30])[CH2:32]3)[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: FC1(F)CNC1
Reactant: O=C1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCC(N2CC(F)(F)C2)c2ccccc21
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a suspension of 1-[2-(2,5-dichloro-phenoxy)-pyridine-3-carbonyl]-2,3-dihydro-1H-quinolin-4-one (50 mg, 0.12 mmol, 1.0 equiv; Example 128) in ethanol (1.2 mL) was added 3,3-difluoroazetidine hydrochloride (31 mg, 0.24 mmol, 2.0 equiv; [CAS RN 288315-03-7]), acetic acid (27 mg, 26 μL, 0.48 mmol, 4.0 equiv; [CAS RN 64-19-7]) and N-ethyldiisopropylamine (31 mg, 42 μL, 0.24 mmol, 2.0 equiv; [CAS RN 7087-68-5]). The reaction mixture was heated by microwave irradiation to 100° C. for 10 min. Sodium triacetoxyborohydride (33 mg, 0.16 mmol, 1.3 equiv; [CAS RN 56553-60-7]) was added and heating at 100° C. continued for 15 min. The reaction mixture was extraction from a sat. solution of NaHCO3 (50 mL) with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO4. Purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate afforded 0.04 g (7%) of the title compound as a light yellow solid. MS (ISP): 490.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Br:17][C:16]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=12
Reactant: Fc1ccc(-c2cc3ncccn3n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nn3cccnc3c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine (5.8 g, 0.027 mol) in chloroform (60 mL) is added, at 0° C., N-bromosuccinimide (4.8 g, 0.027 mol). The mixture is stirred at room temperature for 1 h 30. The reaction mixture is then poured into water and extracted with dichloromethane (3×100 mL). The organic layer is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is filtered through a short pad of silica. 6 g (75%) of 3-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine are obtained as a brown solid which is used in the next step without further purification.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[C:7](#N)C.[Cl:10][C:11]1[CH:12]=[C:13]2[NH:20][C:19](SC)=[N:18][C:14]2=[N:15][C:16]=1[I:17]>O>[Cl:10][C:11]1[CH:12]=[C:13]2[NH:20][C:19]([S:3]([CH3:7])(=[O:5])=[O:2])=[N:18][C:14]2=[N:15][C:16]=1[I:17]
Reactant: CSc1nc2nc(I)c(Cl)cc2[nH]1
Reactant: CC#N
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nc2nc(I)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxone (20.8 g, 33.8 mmol) was added to an acetonitrile (100 mL)/water (100 mL) suspension of 6-chloro-5-iodo-2-(methysulfanyl)-1H-imidazo[4,5-b]pyridine (5.0 g, 15.4 mmol) and the reaction was allowed to stir for 18 h at rt. The suspension was filtered through a sintered glass funnel and the filtrate was partitioned between ethyl acetate and saturated sodium bisulfate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and concentrated to afford the title compound as a white solid that was used in subsequent steps without further purification. LC-MS: calculated for C7H5ClN3O2S 357.56, observed m/e: 357.07 (M+H)+ (Rt 1.36/4 min) 1H NMR δ (ppm) (DMSO-d6): 8.44 (1H, s), 3.53 (3H, s).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:42]=[CH:41][C:30]([O:31][CH2:32][C:33]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[O:34])=[CH:29][CH:28]=1>O1CCOCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([N:35]2[CH2:40][CH2:39][N:38]([C:2]3[C:3]4[N:11]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=5)[S:9][C:4]=4[N:5]=[C:6]([CH3:8])[N:7]=3)[CH2:37][CH2:36]2)=[O:34])=[CH:41][CH:42]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Reactant: Cc1nc(Cl)c2nc(-c3ccc(F)cc3)sc2n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 70 °C
Yield: 73 %

Procedure:
To a solution of 7-chloro-2-(4-fluorophenyl)-5-methylthiazolo[5,4-d]pyrimidine (30 mg, 0.11 mmol) and triethylamine (22 μl, 0.16 mmol) in dioxane (1 ml) was added 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (38 mg, 0.16 mmol). The reaction mixture was heated at 70° C. for 3 hours. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH2Cl2/MeOH 70:1) to yield the title compound as a white solid (40 mg, 75%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.Br[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=1>ClCCl.C(=O)([O-])O.[Na+]>[F:23][C:2]([F:22])([F:1])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=3)[CH2:20][CH2:21]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CN2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reaction time: 20 h
Yield: 65.3 %

Procedure:
To a stirred mixture of 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)-propan-2-ol (3.21 mmol, 1.1 g) and triethylamine (3.21 mmol, 0.448 ml, 0.325 g) in dichloromethane was added 1-(bromomethyl)-3-nitrobenzene (3.21 mmol, 0.694 g). The reaction was stirred for 20 hours then was diluted with dichloromethane and sodium hydrogen carbonate (aqueous). The organic layer was separated and poured onto a SCX column. The column was eluted with 2M ammonia in methanol and concentrated under reduced pressure to give the title compound (1 g). MS (ESI) m/z 478.1 [M+H]+
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][C:28]4[CH:41]=[CH:40][C:31]5[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=5[CH:29]=4)[CH:21]=3)=[C:15]([CH3:42])[CH:14]=2)[CH2:9]1.C(N(CC)CC)C.[C:50](Cl)(=[O:53])[CH2:51][CH3:52]>ClCCl>[CH3:19][C:17]1[CH:18]=[C:13]([O:12][CH:10]2[CH2:11][N:8]([C:50](=[O:53])[CH2:51][CH3:52])[CH2:9]2)[CH:14]=[C:15]([CH3:42])[C:16]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][C:28]2[CH:41]=[CH:40][C:31]3[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=3[CH:29]=2)[CH:21]=1
Reactant: CCC(=O)Cl
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CNC5)cc4C)c3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CC(Oc2cc(C)c(-c3cccc(COc4ccc5c(c4)OC[C@H]5CC(=O)OC)c3)c(C)c2)C1
Reaction time: 12 h
Yield: 94.4 %

Procedure:
The crude (S)-methyl 2-(6-((4′-(azetidin-3-yloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 2,2,2-trifluoroacetate 14c (40 mg, 0.09 mmol) was dissolved in 3 mL of dichloromethane, followed by addition of triethylamine (0.1 mL, 0.26 mmol) and propionyl chloride (11 mL, 0.13 mmol) successively. The reaction solution was stirred for 12 hours. The resulting solution was mixed with 10 mL of dichloromethane, washed with saturated sodium chloride solution (5 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-methyl 2-(6-((2′,6′-dimethyl-4′-((1-propionylazetidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 14d (45 mg) as a yellow oil, which was directly used in the next step without further purification.
Reaction SMILES: [I-:1].[Na+].C(Cl)(=O)C.Cl[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]2[S:20][C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:9]=12>C(#N)C>[I:1][C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]2[S:20][C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:9]=12
Reactant: CCOC(=O)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: CCOC(=O)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 25 °C
Reaction time: 30 h
Yield: 78.1 %

Procedure:
Sodium iodide (994.0 g, 6.63 Mol) was added over 5 minutes to a stirred solution of acetyl chloride (177 mL, 2.48 Mol) and ethyl (4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl)carboxylate (Preparation 4, 257 g, 0.83 Mol) in acetonitrile (2.0 L) at room temperature. The resulting mixture was heated to reflux and stirred for 30 hours. The mixture was allowed to cool to room temperature and stood for 72 hours. The solids were collected by filtration and washed with cold acetonitrile (500 mL). The solids were partitioned between dichloromethane (1.5 L) and water (0.75 L). The aqueous layer was basified to pH 9 by addition of 2 M sodium hydroxide solution and the two layers were separated. The organic layer was washed with 2 M sodium thiosulphate solution (800 mL), brine (800 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound (260.0 g, 78%) as a beige solid. This material was determined by 1H NMR spectroscopy to be a 13:1 mixture of ethyl (4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl)carboxylate and ethyl (4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl)carboxylate respectively.
Reaction SMILES: C1(C)C=CC=CC=1.C([Li])CCC.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[O:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1>CCCCCC.O1CCCC1>[OH:26][C:23]1([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Brc1cccnc1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: OC1(c2cccnc2)CCOCC1
Yield: 29.9 %

Procedure:
According to Reference Example 8-23, by use of toluene (3.3+1.1 mL), n-butyllithium (a 2.77 mol/L solution in hexane, 1.24 mL, 2.28 mmol), 3-bromopyridine (300 μL, 3.12 mmol), tetrahydrofuran (1.1 mL) and tetrahydropyran-4-one (345 μL, 3.74 mmol), the mixture was stirred and reacted at 0° C. for 2 hours. Then, purification by silica gel column chromatography (chloroform/methanol=19/1) was performed to give 4-hydroxy-4-(pyridin-3-yl)tetrahydropyran (Compound DF) (167 mg, yield: 30%).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[N:24](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:23]=[N:22][N:21]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].[C:46]([Cl:49])(Cl)=[O:47].[C:50]1([CH3:56])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O>[CH2:1]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[N:24]=[N:23][N:22]([C:56]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:21]=2)=[CH:10][CH:9]=1)[C:46]([Cl:49])=[O:47])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccccc1
Reactant: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1)C(=O)Cl
Temperature: -5 °C
Reaction time: 0.75 h

Procedure:
Pentyl[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine (2.9 g, 5.1 mmol) was dissolved in a mixture of toluene (30 mL), water (12 mL) and NaOH (5 equiv). The mixture was cooled to −5° C., and a solution of phosgene in toluene (20% w/w, 3 equiv) was added portionwise. The mixture was stirred vigorously for 0.75 hour at −5° C. The layers were then allowed to separate, the organic layer dried over Na2SO4, and the solvent evaporated to afford the title compound (3.2 g, 5.1 mmol), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl.[NH:11]([C:18]1[C:23]([Br:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)CCC>[NH:11]([C:18]1[C:23]([Br:24])=[CH:22][N:21]=[C:20]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=2)[N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Reactant: NCc1ccc(N)cc1
Agent: Cl
Solvent: CCCCO
Product: NCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 48.9 %

Procedure:
4-Aminobenzylamine (122 mg, 1.0 mmol) and ethereal hydrogen chloride (1.0 M; 1.0 ml, 1.0 mmol) were added to a solution of 4-anilino-5-bromo-2-chloropyrimidine (256 mg, 0.9 mmol) in n-butanol (4 ml) and the mixture was heated at 100° C. for 16 hours. The insoluble solid was filtered off and dissolved in methanol (5 ml). Silica (2 g) was added and volatile material was removed by evaporation. The residue was purified by bond elute chromatography, eluting with 0–4% 2.0 M methanolic ammonia solution in DCM, to give the product (163 mg, 49%): LCMS (MH+): 370, 372; HPLC (RT, System A): 2.04.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=1.C([O-])(O)=O.[Na+]>C(OCC)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:19])=[O:20])[CH:17]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(Br)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1.25 g (8.76 mmol) of orcinol monohydrate and 2.50 g (8.76 mmol) of 5-bromo-2-methoxybenzenesulfonyl chloride in 25 mL of diethyl ether was added 25 mL of saturated aqueous NaHCO3 and the biphasic mixture stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to 1.92 g (59%) of the desired product as a pale yellow crystalline solid: 1H-NMR (300 MHz; CDCl3) δ 7.93 (d, 1 H, J=2.5 Hz), 7.69 (dd, 1 H, J=8.9, 2.5 Hz), 6.98 (d, 1 H, J=8.9 Hz), 6.54 (br s, 1 H), 6.51 (br s, 1 H), 6.41 (t, 1 H, J=2.2 Hz), 3.98 (s, 3 H) and 2.24 (s, 3 H).
Reaction SMILES: [OH-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Cl>O.[Cu]I>[CH:6]1[CH:7]=[CH:8][C:3]([O:9][C:12]2[C:11]([Cl:10])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:5]=1
Reactant: Clc1ccccc1Cl
Reactant: Oc1ccccc1
Agent: [Cu]I
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Clc1ccccc1Oc1ccccc1
Temperature: 160 °C
Reaction time: 24 h
Yield: 56.7 %

Procedure:
85% Potassium hydroxide powders (2.18 g; 0.033 mol, 1.1 equimolar amount) were added to phenol (4.23 g; 0.045 mol, 1.5 eq.) under heating, and 1,2-dichlorobenzene (4.41 g; 0.03 mol) and copper(I) iodide (0.29 g; 0.0015 mol) were added thereto, followed by stirring at 160° C. for 24 hours. The reaction mixture was diluted with water and extracted with ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a mixture of benzene and n-hexane to give 3.48 g (yield, 56.7%) of 2-chlorodiphenyl ether as colorless crystals. m.p., 33° to 41° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].O.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1.CC(C)=O>C1(C)C=CC=CC=1>[CH3:18][C:17]1([CH3:22])[NH:1][C:2]2[S:3][C:4]([C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)=[CH:5][C:6]=2[C:7](=[O:8])[NH:9]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1cc(-c2ccncc2)sc1N
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC1(C)NC(=O)c2cc(-c3ccncc3)sc2N1
Yield: 18.1 %

Procedure:
A mixture of 2-amino-5-(pyridin-4-yl)thiophene-3-carboxamide (300 mg, 1.37 mmol), p-toluenesulfonic acid monohydrate (150 mg) and acetone (30 mL) in toluene (30 mL) was heated to reflux overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel (MeOH: dichloromethane=1:9) to afford the crude title compound (70 mg), which was further purified by preparative TLC to give the title compound (37 mg, yield 10%) as an orange solid:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=[O:14])=[C:8]([OH:16])[CH:7]=[CH:6]2)#[N:2].C(#N)C.[CH3:20][N:21]([CH3:26])[C:22]([CH2:24]Br)=[O:23]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH2:24][C:22](=[O:23])[N:21]([CH3:26])[CH3:20])=[O:14])=[C:8]([OH:16])[CH:7]=[CH:6]2)#[N:2]
Reactant: N#Cc1ccc2c(C(=O)O)c(O)ccc2c1
Reactant: CN(C)C(=O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(=O)COC(=O)c1c(O)ccc2cc(C#N)ccc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
To 28.4 g of 6-cyano-1-carboxy-2-naphthol were added 350 ml of acetonitrile, 18 ml of triethylamine and 33.2 g of dimethylcarbamoylmethyl bromide, followed by stirring for 24 hours at 70° C. and further 24 hours at room temperature. The resulting precipitate was collected by filtration and washed with water to obtain 31.2 g of the desired product.