Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:22][CH:23]([N:26]([CH3:28])[CH3:27])OC)(=O)=O)(C)C.[CH:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH:36]1([CH:35]([OH:42])[C:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:22][CH2:23][N:26]([CH3:27])[CH3:28])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=Cc1ccccc1
Reactant: COC(CC(=NNS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)c1ccccc1)N(C)C
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1

Procedure:
By using a method similar to that described in Example 22, but starting from β-dimethylamino-3-methoxypropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (21.7 g) and from benzaldehyde (5.4 cc), 4-dimethylamino-2-(3-methoxyphenyl)-1-phenyl-2-buten-1-ol (Z) hydrochloride (11.9 g) is obtained in the form of a white solid melting at 166° C. after recrystallisation from isopropanol (100 cc).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:18][C:19](=O)[CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[OH:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([C:13](=[O:14])[NH:15][C:19]([CH:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[OH:21])=[N:18]2)=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1NC(=O)C(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]c(C(O)c2ccc(F)cc2)nc2cc(OCc3ccccc3)ccc12
Temperature: 80 °C
Reaction time: 20 h
Yield: 89.7 %

Procedure:
To 4-(benzyloxy)-2-(2-(4-fluorophenyl)-2-hydroxyacetamido)benzamide (4.1 g, 10.4 mmol) in absolute EtOH (50 mL) was added 20% aq potassium carbonate (5 mL). After heating and stirring at 80° C. for 20 h, the solution was cooled and concentrated to a solid. The solid was washed with water and dried under vacuum to afford 7-(benzyloxy)-2-((4-fluorophenyl)(hydroxy)methyl)quinazolin-4(3H)-one as a white solid (3.51 g, 90%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.25 (s, 2H) 5.55 (s, 1H) 7.10-7.21 (m, 4H) 7.36-7.48 (m, 5H) 7.56-7.61 (m, 2H) 7.97 (d, J=8.67 Hz, 1H). LC-MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:40])[N:18]([C@H:29]3[CH2:32][C@H:31]([O:33][CH2:34]C(OCC)=O)[CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:41])[CH:10]=1)#[N:2].[CH3:42][Mg]Br.[O:45]1[CH2:49][CH2:48]CC1>O1CCCC1.[Cl-].[NH4+]>[F:41][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:40])[N:18]([C@H:29]2[CH2:30][C@H:31]([O:33][CH2:34][C:49]([OH:45])([CH3:48])[CH3:42])[CH2:32]2)[C:19]2[N:20]([N:25]=[C:26]([CH3:28])[N:27]=2)[C:21]=1[CH2:22][CH2:23][CH3:24]
Reactant: C1CCOC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](OCC(=O)OCC)C2)c2nc(C)nn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](OCC(C)(C)O)C2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl [(trans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate (557 mg) in tetrahydrofuran (5 mL) was added 1 M methylmagnesium bromide-tetrahydrofuran solution (5 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=65/35→40/60 (volume ratio)] to give the title compound as a colorless amorphous compound (437 mg, 80%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:12]([O:20][CH2:21][Cl:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl-:22].[C:12]([O:20][CH2:21][N+:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: O=C(OCCl)c1ccccc1
Product: CCOC(=O)c1ccc[n+](COC(=O)c2ccccc2)c1
Product: [Cl-]

Procedure:
A mixture of 3.00 g (0.02 mol) ethyl nicotinate and 3.50 g (0.02 mol) chloromethyl benzoate was heated at 70° under nitrogen for 10 hrs. Trituration in anhydrous ether and recrystallization from ethanol-ether gave 2.18 g (0.007 mol), 35%, 1-benzoyloxymethyl-3-carboethoxypyridinium chloride, mp 138°-141°; ir (KBr) 1730 cm-1 ; pmr (CDCl3) δ 1.43 (t, 3H), 4.47 (q, 2H), 7.7-7.3 (m, 5H), 8.2-7.95 (m, 2H), 9.17-8.50 (m, 4), 10.0 (bs, 1H) and 10.2 (bd, 1H) ppm.
Reaction SMILES: [CH2:1]([C:5]1([CH3:29])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[N:17]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:31]>O>[CH2:1]([C:5]1([CH3:29])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:26])(=[O:27])[N:17]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].[Na+:31]
Reactant: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A suspension of the product of Example 30A (0.067 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.163 mL, 0.163 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.070 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.55 (m, 1 H) 0.68 (m, 3 H) 0.87 (m, 1 H) 1.06 (m, 2 H) 1.38 (m, 3 H) 1.72 (m, 1 H) 2.13 (m, 1 H) 7.29 (m, 3 H) 7.49 (m, 3 H) 7.64 (m, 1 H) 8.05 (m, 1 H) 15.46 (m, 1 H). MS (ESI−) m/z 409 (M−H)−.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)=O)[CH2:3][CH2:2]1.[F:13][C:14]1[CH:19]=[CH:18]C([Mg]Br)=CC=1.[Cl:22][CH2:23][CH2:24][CH:25]=C(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]([C:1]2[CH:3]=[CH:2][C:14]([F:13])=[CH:19][CH:18]=2)=[CH:25][CH2:24][CH2:23][Cl:22])=[CH:11][CH:10]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C(c1ccc(F)cc1)C1CC1
Reactant: ClCCC=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Fc1ccc(C(=CCCCl)c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of cyclopropyl-(4-fluorophenyl)ketone (520 mg, 3.17 mmol) in THF (10 mL) was added 4-fluorophenyl magnesium bromide dropwise at 0° C. under N2 atmosphere. The reaction mixture was stirred for 1 h at 0° C., quenched by addition of brine and extracted with Et2O. The organic layer was then washed with NaHCO3 saturated aqueous solution and brine. It was then dried over MgSO4, filtered, concentrated in vacuo to give crude bis(4-fluorophenyl)-cyclopropylmethanol. It was used for ring opening reaction by following the procedure for formation of 4-chloro-1,1-diphenyl-1-butene without further purification. 1,1-Bis(4-fluorophenyl)-4-chloro-1-butene (780 mg, 88%) was obtained as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ2.57 (q, 2H, J=6.9 Hz), 3.58 (t, 2H, J=6.9 Hz), 6.04 (t, 1H, J=7.3 Hz), 6.92-7.21 (m, 8H) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH:6]=[C:7]([C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=1)[CH2:8]2.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([OH:34])[CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2.[H-].[Na+].CS(C)=O>CCO.O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([O:34][CH2:2][CH2:3][N:4]3[CH:9]4[CH2:10][CH2:11][CH:5]3[CH:6]=[C:7]([C:12]3[CH:21]=[CH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[CH:13]=3)[CH2:8]4)[CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2
Reactant: COc1cc(O)c2ncccc2c1
Reactant: ClCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OCCN2C3C=C(c4ccc5ccccc5c4)CC2CC3)c2ncccc2c1
Yield: 38 %

Procedure:
8-(2-Chloroethyl)-3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-2-ene (0.50 g, 1.70 mmol), 0.39 g (2.20 mmol) 6-methoxyquinolin-8-ol, 0.08 g (2.00 mmol) NaH (60% dispersion in mineral oil) and 3 mL DMSO are stirred at 50 C for 16 h. The reaction mixture is poured into 100 mL of H2O and extracted with 3×50 mL EtOAc. The combined organics are washed with 3×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered, and the volatiles are evaporated. The crude product is subjected to flash chromatography on SiO2 gel, eluting with EtOAc and then 40/1 EtOAc/2M NH3 in MeOH, to produce an off-white solid. This solid is treated with 0.06 g (0.67 mmol) (CO2H)2 in 4 mL of absolute EtOH to give 0.33 g (0.13 mmol, a 38% yield) of the oxalate salt of the title compound as a white solid. mp: 100-103° C.; MS (ES) m/z 437 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:27][C:28]([Si](C)(C)C)([F:30])[F:29]>C1COCC1.O.C(Cl)Cl>[F:27][C:28]([F:30])([F:29])[CH2:7][OH:8].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: OCC(F)(F)F
Product: c1ccncc1
Temperature: 25 °C
Yield: 42.1 %

Procedure:
To a solution of O-protected pyridine aldehyde (5.0 g, 19.9 mmol) and TBAF 1 N in THF (1.5 mL, 1.5 mmol) in THF (60 mL) at 0° C. was slowly trifluoromethyltrimethylsilane (3.4 mL, 20.9 mmol) and the reaction was allowed to warm to RT overnight. The reaction was diluted with water and DCM, extracted with DCM, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography over silica gel (eluting hexane/AcOEt 8:2) to afford 1.5 g (24%) of O-protected pyridine trifluoroethyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1)#[N:23]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:21][C:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)=[O:32])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(N)c2ccccc2N2CCCCC2)cc1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Product: Cc1ccc(C(NC(=O)Cc2ccc(C#N)cc2)c2ccccc2N2CCCCC2)cc1

Procedure:
Prepared from α-(4-methyl-phenyl)-2-piperidino-benzylamine and 4-cyano-phenylacetic acid analogously to Example 55.
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[N:8]=[C:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:19]=1Br.C([Mg]Br)(C)C.O>C(OCC)(=O)C>[Br:6][C:7]1[N:8]=[C:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[CH:19]=1
Reactant: COC(=O)C1CCn2c(nc(Br)c2Br)C1
Agent: CC(C)[Mg]Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CCn2cc(Br)nc2C1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
A tetrahydrofuran (150 ml) solution of the methyl 2,3-dibromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate (13 g) obtained in (Example 2.7) <Step 1> was cooled to −35° C. Thereafter, isopropylmagnesium bromide (95 ml, 1 M tetrahydrofuran solution) was added to the solution over 20 minutes, while keeping the temperature at −30° C. or less, and the reaction solution was then stirred at −35° C. for 30 minutes. Thereafter, water (350 ml) and ethyl acetate (250 ml) were added to the reaction solution, and insoluble matters were then removed by filtration with Celite. Subsequently, the filtrate was separated into an organic layer and a water layer. The water layer was extracted with ethyl acetate (250 ml), and the organic layers were then gathered. The gathered organic layer was washed with a saturated saline, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=70:30-30:70), so as to obtain the title compound (6.8 g) in the form of a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:27]([N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)(=[O:29])[CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C.O.C(N(CC)CC)C>[C:27]([N:30]1[CH2:31][CH2:32][CH:33]([C:36]([N:14]2[CH2:15][CH2:16][C@@H:11]([N:9]([CH3:10])[C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:26][CH:25]=3)[C@H:12]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:13]2)=[O:37])[CH2:34][CH2:35]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.5 %

Procedure:
To a solution of 4-chloro-N-[(3R,4R)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methylbenzamide monohydrochloride (200 mg) obtained in Example 137a, 1-acetylpiperidine-4-carboxylic acid (118 mg) and triethylamine (127 μL) in acetonitrile (5 mL) were added WSC.HCl (176 mg) and HOBt (140 mg), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 15→100% ethyl acetate/hexane) to give the title compound (113 mg, 44%) as a white powder.
Reaction SMILES: [C:1]([C:4]1(C(OC)=O)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(C)C.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O>[O:7]1[CH2:8][CH2:9][CH:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1
Reactant: COC(=O)C1(C(C)=O)CCOCC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)C1CCOCC1
Temperature: 100 °C
Yield: 46.6 %

Procedure:
Combine methyl 4-acetyltetrahydro-2H-pyran-4-carboxylate (23.06 g, 123.84 mmol) with isopropyl alcohol (124 mL) and water (124 mL). Add sulfuric acid (33.00 mL, 5.0 eq). Heat the reaction mixture to 100° C. over two nights. Cool and add the reaction mixture slowly to a mixture of sodium bicarbonate (136 g) in water (1 L). Extract with dichloromethane. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 25% ethyl acetate in hexanes to 50% ethyl acetate in hexanes, to give the title compound (7.39 g, 34%). 1H NMR (400 MHz, DMSO-d6) δ 3.79 (m, 2H), 3.27 (m, 2H), 2.54 (m, 1H), 2.05 (s, 3H), 1.66 (m, 2H), 1.38 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[N:25][C:26]([NH:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:27][CH:28]=1.[ClH:38].O1CCOCC1>CC(N(C)C)=O>[ClH:19].[ClH:38].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][C:23]3[CH:24]=[N:25][C:26]([NH:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:27][CH:28]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnc(NC(=O)c2ccccc2)nc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cnc(NC(=O)c4ccccc4)nc3)ncnc2cc1OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of 7-benzyloxy-4-chloro-6-methoxy-quinazoline (760 mg, 2.53 mmol) and N-(5-amino-pyrimidin-2-yl)-benzamide (542 mg, 2.53 mmol) in DMA was added 4N HCl in dioxane (822 μl, 3.29 mmol) and the reaction heated at 50° C. for 4 hours under nitrogen. The reaction was cooled and filtered. The precipitate was washed with Et2O and dried under reduced pressure to provide the title compound as a light tan brown solid (706 mg).
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[OH:15]O>C(O)(=O)C>[N+:1]1([O-:15])[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1cccc2ccc3cccnc3c21
Temperature: 55 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Referring to scheme 7, a mixture of 30 g [1,10]phenanthroline, 26 g 30% hydrogen peroxide and 200 ml acetic acid was added to a flask, and the mixture was then heated to 50-60° C. and stirred overnight. After completion of reaction, the reaction mixture was cooled to room temperature, and vacuum distillated to remove acetic acid, and then 300 ml CH2Cl2 was added. Next, the solution was filtered to remove solids, and neutralized by adding K2CO3(aq). The organic layer was separated, concentrated, and purified by column chromatography with silca gel (Methanol), so as to obtain solids [1,10]phenanthroline-N-oxide (23 g, yield 70.4%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][Br:16])=[CH:11][CH:10]=1)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccncc2C#N)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cnccc1-c1ccc(CBr)cc1

Procedure:
A solution of 3-cyano-4-(4-tolyl)pyridine (485 mg, 2.66 mmol), N-bromosuccinimide (929 mg, 5.22 mmol), and dibenzoylperoxide (64 mg, 0.266 mmol) in CCl4 (15 mL) was heated to reflux for 6 h. The mixture was cooled and water (50 mL) and CH2Cl2 (30 mL) were added. The organic layer was dried (MgSO4) and purified by flash chromatography (10% EtOAc/hexanes). The product is not kept in concentrated form for more than 5 minutes and stored only in CH2Cl2 at 0° C. to minimize polymerization.
Reaction SMILES: [OH-].[K+].[C:3]1(/[C:9](/[C:19]2[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=2)=[C:10](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27][C:28]#[N:29]>O>[C:3]1([C:9]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH:27][C:28]#[N:29])=[CH:21][CH:20]=2)=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC#N
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=O)cc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(=C(c1ccccc1)c1ccc(C=CC#N)cc1)c1ccccc1
Yield: 57 %

Procedure:
A suspension of potassium hydroxide (85%, 260 mg, 3.9 mmol) in CH3CN (25 mL) was heated to reflux and (Z)-1,2-Diphenyl-1-(4-formylphenyl)-1-butene (4a) (Willson J. Med. Chem. 1994, 37, 1550–1552) (1.0 g, 3.18 mmol) was added in portions. After refluxing 5 min, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO4). The solvent was removed under reduced pressure and the residue chromatographed (silica gel, 15% EtOAc/hexanes) to give nitrile (4b) as a white solid (616 mg, 57%): 1H NMR (CDCl3) δ 7.39–7.07 (m, 13H), 6.91 (d, J=8.4 Hz, 2H), 5.69 (d, J=16.9 Hz, 1H), 2.48 (q, J=7.3 Hz, 2H), 0.94 (t, J=7.3 Hz, 3H); HRMS calcd. for C25H21N (M+H+) 335.1674; found 335.1679.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]([C:24]([OH:26])=[O:25])=[N:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].CCN(C(C)C)C(C)C.Cl[C:37]1[N:42]=[CH:41][C:40]([CH2:43][CH2:44][CH3:45])=[CH:39][N:38]=1.CCOC(C)=O>CN1C(=O)CCC1>[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:19][CH2:20][N:21]([C:37]4[N:42]=[CH:41][C:40]([CH2:43][CH2:44][CH3:45])=[CH:39][N:38]=4)[CH2:22][CH2:23]3)[C:12]([C:24]([OH:26])=[O:25])=[N:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCCc1cnc(Cl)nc1
Reactant: O=C(O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCNCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cnc(N2CCC(Oc3cc(=O)n(-c4ccc(Cl)c(Cl)c4)nc3C(=O)O)CC2)nc1
Temperature: 100 °C
Yield: 52.1 %

Procedure:
To a stirring solution of 1-(3,4-dichlorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylic acid HCl (83 mg, 0.217 mmol) in NMP (2 mL) at room temperature under argon was added DIPEA (84 mg, 0.651 mmol) and 2-chloro-5-propylpyrimidine (51 mg, 0.326 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was directly purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give 1-(3,4-dichlorophenyl)-6-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylic acid (57 mg, white solid, 52%). MS (ESI) 504 (M+H).
Reaction SMILES: Cl[C:2](Cl)=[N:3][C:4](=[O:7])[O:5][CH3:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:21]=2)(=[O:19])=[O:18])=[CH:12][C:11]=1[NH2:33].C(N(CC)CC)C>C(Cl)Cl>[F:32][C:27]([F:31])([O:26][C:22]1[CH:21]=[C:20]([S:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:2]([NH:3][C:4]([O:5][CH3:6])=[O:7])[NH:33][C:11]=3[CH:12]=2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=1)[CH:28]([F:30])[F:29]
Reactant: Nc1ccc(OS(=O)(=O)c2cccc(OC(F)(F)C(F)F)c2)cc1N
Reactant: COC(=O)N=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3cccc(OC(F)(F)C(F)F)c3)cc2[nH]1
Reaction time: 1 h

Procedure:
A solution of 15.6 g of methyl N-dichloromethylenecarbamate in 50 ml of methylene chloride is added slowly, with stirring, to a mixture of 38 g of 1,2-diamino-4-[3-(1,1,2,2-tetrafluoroethoxy)phenylsulfonyloxy]benzene (see Example 2), 20.2 g of triethylamine and 300 ml of methylene chloride at a temperature of about 20° C. The mixture is stirred for one hour and the precipitate is filtered off with suction and washed with diisopropyl ether. For purification, it is recrystallized from methanol, melting point 186° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(N(CC)CC)C.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH:16][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: COc1cccc(N)c1
Reactant: Cc1ccccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: COc1cccc(NC(=O)c2ccccc2C)c1
Yield: 95 %

Procedure:
A 13.6 g (0.1 mol) portion of o-methylbenzoic acid, 10.9 g (0.1 mol) of m-methoxyaniline and 10.1 g (0.1 mol) of triethylamine were dissolved in 250 ml of toluene. A 4.6 g (0.033 mol) amount of phosphorus trichloride was added dropwise to the above solution with stirring at 20°-60°C. After the addition, the reaction mixture was stirred at 80°-90°C for 3 hours. The reaction mixture was cooled and washed with water to remove the triethylamine hydrochloride, and the product was dried over anhydrous sodium sulfate. The toluene was removed to give 22.8 g (95%) of fine white prismatic crystals having a melting point of 142°-143°C.