Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([OH:32])=O.[NH:33]1[CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:33]1([C:30](=[O:32])[CH2:29][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=4)[CH2:16][CH2:15]3)=[CH:7][C:2]=2[F:1])[CH2:36][CH2:35][CH2:34]1
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {2-fluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid (500 mg, 1.13 mmol) in 8 ml of anhydrous DMF at RT was added azetidine (129 mg, 2.26 mmol) and N,N-diisopropylethylamine (0.591 ml, 3.38 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (643 mg, 1.69 mmol) was added to the solution and stirred at RT for 4 hrs. The mixture was purified by column chromatography by loading directly to a preparative biotage reverse phase column (C-18) (50 g column) and eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%). The material was further purified by column chromatography on silica gel Biotage 40S, eluting with EtOAc/hexanes (30% to 90%) to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.29 (s, 2H), 7.27 (t, J=8.4 Hz, 1H), 6.64 (d, J=2.1 Hz, 1H), 6.20 (d, J=2.3 Hz, 1H), 4.74 (t, J=13.2 Hz, 2H), 4.27 (s, 2H), 4.17 (t, J=7.7 Hz, 2H), 4.04 (m, 4H), 3.40 (s, 2H), 3.35 (s, 3H), 2.85 (m, 2H), 2.14-2.29 (m, 3H), 1.85 (m, 2H), 1.41 (m, 1H), 1.36 (m, 2H), 1.11 (m, 1H), 0.93 (m, 1H), 0.60-0.71 (m, 2H), −0.08 (m, 1H). LC/MS (m/z): 482.4 (M+H)+. GPR119 Human EC50: 0.77 nM
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:30]([Cl:33])(=[O:32])[CH3:31]>ClCCl>[C:30]([Cl:33])(=[O:32])[CH3:31].[C:30]([N:17]1[CH2:18][CH2:19][C@@H:15]([CH2:14][C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([Br:2])=[CH:4][CH:5]=3)[C:10](=[O:20])[NH:11][N:12]=2)[CH2:16]1)(=[O:32])[CH3:31]
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reaction time: 0.02 h
Yield: 101.1 %

Procedure:
In 4 mL screwcap vial was placed 4-(4-bromophenyl)-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.417 mmol) and 1 mL dichloromethane. N,N-Diisopropylethylamine (1.374 mmol) was added. The vial contents were stirred for 1 min. In a separate vial, acetyl chloride (0.417 mmol) was diluted with 1 mL dichloromethane and added to the prior solution dropwise via pipette. The vial was capped and the reaction was stirred at room temperature overnight. Analysis by LCMS displayed the reaction had only progressed to 70% completion. A solution of acetyl chloride (0.050 mL) in 1 mL dichloromethane was prepared and 0.100 mL of this solution was added to the reaction. After 1 h, the reaction had progressed to 90% completion via LCMS analysis. Another 0.100 mL of the acetyl chloride solution in dichloromethane was added to the reaction. After 1 h, LCMS analysis displayed the reaction was complete. The solution was washed with saturated aq NH4Cl. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-20% methanol:ethyl acetate) afforded the title compound (77 mg, 50% yield). MS(ES)+ m/e 365.0, 366.7 [M+H]+.
Reaction SMILES: CC([Si](C)(C)[O:6][CH:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2([C:27]2[CH:31]=[CH:30][O:29][CH:28]=2)O)[CH2:8]1)(C)C.Cl.C(Cl)Cl>O1CCOCC1>[O:29]1[CH:30]=[CH:31][C:27]([C:16]2[C@:17]3([CH2:19][CH2:20][C@H:21]4[C@@H:12]([CH2:11][CH:10]=[C:9]5[C@:22]4([CH3:25])[CH2:23][CH2:24][C@H:7]([OH:6])[CH2:8]5)[C@@H:13]3[CH2:14][CH:15]=2)[CH3:18])=[CH:28]1
Reactant: CC(C)(C)[Si](C)(C)OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2(O)c2ccoc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3ccoc3)=CC[C@@H]12
Yield: 58.4 %

Procedure:
Combine (3β,17β)-3β,17β)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-17-(3-furanyl)-androst-5-en-17-ol (2.50 g, 5.31 mmol) prepared as in Scheme III, step B above, with 4N hydrogen chloride in 1,4-dioxane (35 mL) under an atmosphere of nitrogen. Stir the reaction for 40 minutes at room temperature and then dilute the reaction with methylene chloride (150 mL). Wash the organic layer with water (35 mL), saturated sodium bicarbonate (2×50 mL), brine (30 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (ethyl acetate/hexane, 3:7, silica gel) to provide 1.05 g of product as a white solid. Recrystallize a portion of the product from aqueous acetone and dry under high vacuum over refluxing ethanol for 4 hours to provide the title compound as a white crystallize solid, Rf =0.43 (ethyl acetate/hexane, 35:65, silica gel), mp 186°-189° C.; 1H NMR (CDCl3) δ7.47 (broad singlet, 1H), 7.36 (t, 1H, J=1.7 Hz), 6.48 (dd, 1H, J=0.8, 1.8 Hz), 5.83 (dd, 1H, J=1.9, 3.2 Hz), 5.41-5.37 (m, 1H), 3.60-3.48 (m, 1H), 1.07 (s, 3H), 0.96 (s, 3H); MS (CI/CH4) m/z (rel. intensity) 339 (MH+, 68), 338 (55), 337 (28), 321 (100); HRMS C23H31O2 (MH+) calcd 339.2324, observed 339.2304.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1.Br[CH2:28][C:29]1[N:34]=[C:33]2[CH:35]=[CH:36][O:37][C:32]2=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:28][C:29]4[N:34]=[C:33]5[CH:35]=[CH:36][O:37][C:32]5=[CH:31][CH:30]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1
Reactant: BrCc1ccc2occc2n1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4occc4n3)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A solution of 440 mg(1.18 mmol) of methyl 3-[1-(4-chlorobenzyl) -5-hydroxyindol-2-yl]-2,2-dimethylpropanoate, 5(bromomethyl)furo[3,2-b]pyridine (274 mg (1.3 mmol) from Step 3), and 772 mg (2.4 mmol) of Cs2CO3 in 6 mL of acetonitrile was stirred at r.t. for 18 hr. The reaction was diluted with aqueous NH4OAc 25% w/v (50 mL) and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by chromatography on silica gel eluted with 25-30 % EtOAc in hexane to give the title compound as a colorless gum.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])=[O:4].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][C:7]1[C:6]2[O:12][CH2:2][C:3](=[O:4])[C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(C(=O)CCl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc2c1OCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
A solution of 2-chloro-1-(2-hydroxy-3-methylphenyl)ethanone (Tetrahedron, Vol. 66, p. 3499, 2010, 6.40 g, 34.7 mmol) in acetonitrile (170 mL) was added with potassium carbonate (14.4 g, 104 mmol), and the mixture was stirred at room temperature for 1 hour, and then filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 7-methylbenzofuran-3(2H)-one (2.23 g, 43%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[N:8][NH:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[N:8][N:9]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][C:21]([F:20])([F:32])[F:33])[CH:24]=2)[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2cncnc2)n[nH]c1C1CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: CCOC(=O)c1c(-c2cncnc2)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Yield: 31 %

Procedure:
In analogy to the procedure described in Example 162C], 5-cyclopropyl-3-pyrimidin-5-yl-1H-pyrazole-4-carboxylic acid ethyl ester (Example 177B]) and 3-(trifluoromethoxy)benzeneboronic acid gave the title compound as a yellow oil (31%). MS: 419.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:64]1[CH:65]=[CH:66][C:67]2[O:71][CH:70]=[CH:69][C:68]=2[CH:72]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[O:71]1[C:67]2[CH:66]=[CH:65][C:64]([NH:1][C:2]3[CH:14]=[C:13]([CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:72][C:68]=2[CH:69]=[CH:70]1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: Brc1ccc2occc2c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc2occc2c1
Temperature: 25 °C

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-phenethylbenzoate 0.10 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8 mg, tris(dibenzylideneacetone)dipalladium(0) 3 mg and cesium carbonate 0.22 g was added 5-bromobenzofuran 0.19 g, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8 mg and tris(dibenzylideneacetone)dipalladium(0) 3 mg were added to it, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.0 mg and tris(dibenzylideneacetone)dipalladium(0) 3 mg were added to it, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=20:1] to give tert-butyl 2-((benzofuran-5-yl)amino)-4-phenethylbenzoate. Trifluoroacetic acid 3.0 mL was added to the obtained tert-butyl 2-((benzofuran-5-yl)amino)-4-phenethylbenzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate:acetic acid=30:10:1] to give 2-((benzofuran-5-yl)amino)-4-phenethylbenzoic acid 21 mg of white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>>[Br:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Cl:1])[CH:9]=1)[O:11][C:12](=[O:14])[CH:13]=[CH:5]2
Reactant: O=Cc1cc(Br)cc(Cl)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: O=c1ccc2cc(Br)cc(Cl)c2o1
Temperature: 136 °C

Procedure:
To a 5 L round bottom flask fitted with a mechanical stirrer and condenser was placed 3-chloro-5-bromosalicylaldehyde (554.1 g, 2.35 mol, 1 equiv.), acetic anhydride (1203 g, 11.8 mol, 5 equiv.) and triethylamine (237.4 g , 2.35 mol, 1 equiv.). The reaction solution was heated at reflux (131-141° C.) overnight. The dark brown reaction mixture was cooled to 50° C. and ice (2 L) added (ice-bath cooling) with stirring. After one hour the mixture was filtered and the filtrate combined with EtOH (1 L). To this mixture was added EtOH (300 mL) and the reaction mixture stirred for one hour. The precipitate that formed was collected by filtration and washed with water: EtOH (3×1.3 L), vacuum and dried then dried on a fluid-bed drier. The total isolated yield is 563 g or 92%.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33](O)=[N:34][C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[N:36]2)=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:33]2[C:32]3[C:37](=[CH:38][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)[N:36]=[C:35]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:34]=2)[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: COc1ccc2c(O)nc(-c3ccccc3)nc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3ccccc3)nc3cc(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 68.1 %

Procedure:
Compound 15 (700 mg, 1.9 mmol), 7-methoxy-2-phenyl-quinazolin-4-ol (670 mg, 2.66 mmol) and triphenyl phosphine (1245 mg, 4.75 mmol) were dissolved in THF (50 ml) and cooled to 0° C. Diisopropyl azidocarboxylate (960 mg, 4.75 mmol) was added slowly and the slurry was allowed to reach room temperature. After 12 h, the solvent was removed under reduced pressure and the residue taken up in ether and filtrated. Purification by column chromatography (SiO2; 1% methanol in dichloromethane) gave the pure title compound (778 mg, 68%). MS (M+H)+ 603.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Br-].[C:22]1([CH:28]([Zn+])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C(C2C=NC(N3CCNCC3)=NC=2)C)C=CC=CC=1.CO.ClCCl>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]1([CH:28]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC([Zn+])c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(c1ccccc1)c1cnc(N2CCNCC2)nc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC(c1ccccc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (4.1 g, 12.0 mmol) and tetrakis(triphenylphosphine)palladium (708 mg, 1.0 mmol) in THF (80 mL, dry) was added dropwise a solution of (1-phenylethyl)zinc(II) bromide in THF (20 mL, 1 M, 20 mmol) under nitrogen atmosphere, and the mixture was stirred at 70° C. overnight. The reaction mixture was cooled to RT and filtered through a pad of Celite. The filtration was concentrated and purified by silica gel chromatography to give tert-butyl 4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazine-1-carboxylate (1.0 g, yield 23%) as a white solid (ethyl acetate/petroleum ether=1/5 as elute) and 5-(1-phenylethyl)-2-(piperazin-1-yl)pyrimidine (2.4 g, 75%) as a yellow oil (methanol/dichloromethane=1/20 as elute). MS (ES+) C16H20N4 requires: 268. found: 269 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]
Reactant: [H][H]
Reactant: [N-]=[N+]=Nc1cncc(C(N)=O)c1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cncc(N)c1
Yield: 36 %

Procedure:
97A was hydrogenated in MeOH with 10% Pd/C (20 mg) with a hydrogen balloon for 0.5 h. The Pd/C was removed by filtration. The filtrate was concentrated to give 97B (25 mg, 36% yield for two steps). 1H NMR (400 MHz, Methanol-d4) δ ppm 7.43-7.49 (m, 1H) 8.07 (d, J=2.64 Hz, 1H) 8.22 (d, J=1.76 Hz, 1H).
Reaction SMILES: [CH:1]1([P:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8]C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([S:24][CH3:25])[N:18]=1>ClC1C=CC=CC=1Cl>[CH:1]1([P:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)([C:17]2[CH:22]=[C:21]([P:7]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[N:20]=[C:19]([S:24][CH3:25])[N:18]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COP(C1CCCCC1)C1CCCCC1
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: Clc1ccccc1Cl
Product: CSc1nc(P(=O)(C2CCCCC2)C2CCCCC2)cc(P(=O)(C2CCCCC2)C2CCCCC2)n1
Yield: 5.3 %

Procedure:
A mixture of 2.50 g of methyl dicyclohexylphosphinite and 1.00 g of 4,6-dichloro-2-methylthiopyrimidine in 20 ml of o-dichlorobenzene was refluxed under nitrogen for 6.5 hours. Volatiles were removed from the mixture under vacuum, and the resulting oily residue was recrystallized twice from cyclohexane with decolorizing charcoal treatment and dried at 100° C./0.1 mm (13 Pa) to give 0.15 g of 4,6-bis(dicyclohexylphosphinyl)-2-methylthiopyrimidine (shown by formula in Claim 11) as white crystals, mp 197°-198.5° C. Anal. Calcd for C29H48N2O2P2S: C, 63.25; H, 8.79; N, 5.07; S, 5.82. Found: C, 63.19; H, 8.81; N, 4.89; S, 6.04.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](O)=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:17])=O>CN(C=O)C>[Cl:17][C:8]1[C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1ccc2c(O)ncnc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Yield: 70 %

Procedure:
A mixture of 7-nitroquinazolin-4-ol (3.4 g, 17.79 mmol), thionyl chloride (20 mL), and DMF (0.5 mL) was refluxed for 48 h. After the mixture was cooled, excess thionyl chloride was removed by evaporation and the residue was azeotroped with toluene to afford 2.61 g (70%) of 4-chloro-7-nitroquinazoline as a yellowish solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=3[O:31][CH2:32][CH3:33])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:32]([O:31][C:18]1[C:19]([C:27]([CH3:30])([CH3:28])[CH3:29])=[CH:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:22][C:17]=1[C:13]1[C:11]2[O:12][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:34])=[O:3])=[CH:9][C:10]=2[CH:16]=[CH:15][CH:14]=1)[CH3:33]
Reactant: CCOC(=O)C=C(C)c1cc2cccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3OCC)c2o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1c(-c2cccc3cc(C(C)=CC(=O)O)oc23)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of 210 mg (0.450 mmol) of 3-[7-(2-ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[7-(2-Ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid was isolated as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])=[N:8][C:7]([CH3:17])=[C:6]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.I[CH2:25]C>>[CH2:16]([S:13]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([CH3:17])[N:8]=1)(=[O:14])=[O:15])[CH3:25]
Reactant: CCI
Reactant: COc1ccc2c(S(C)(=O)=O)nc(C)c(-c3ccccc3)c2c1
Product: CCS(=O)(=O)c1nc(C)c(-c2ccccc2)c2cc(OC)ccc12

Procedure:
Following the procedure 6-methoxy-3-methyl-1-(methylsulfonyl)-4-phenylisoquinoline, using (in Step B) iodoethane in place of iodomethane, the titled compound was synthesized.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.[OH-].[Na+].Cl>O.CS(C)=O.ClC1C=CC=CC=1Cl>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:19])[F:20])[CH:13]=2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Oc1cc(Cl)nnc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
3.0 g (purity: 90%; 16.4 mmol) of 4-hydroxy-3,6-dichloropyridazine, 7.96 g (49.1 mmol) of 3-trifluoromethylphenol, and 2.03 g (purity: 97%; 49.1 mmol) of sodium hydroxide were added to a mixture of 19.1 g of 1,2-dichlorobenzene and 3.0 g of dimethyl sulfoxide and matured at 180° C. for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 50 g of pure water was added to the cooled mixture. A 35% aqueous hydrochloric acid solution was added to the resultant mixture so that the pH of the aqueous phase was adjusted to 2.1, and then the deposited solids were taken out by filtration. 25 mL of methyl t-butyl ether was added to the solids to obtain a slurry. The resultant solids were dried under a reduced pressure to obtain 3.32 g of 6-chloro-3-[3-(trifluoromethyl)phenoxy]-4-pyridazinol in the form of pale brown solids (yield: 69.7%).