Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:28][S:29]([OH:32])(=[O:31])=[O:30]>CC(C)=O>[CH3:28][S:29]([O-:32])(=[O:31])=[O:30].[C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH+:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CS(=O)(=O)O
Reactant: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Solvent: CC(C)=O
Product: CS(=O)(=O)[O-]
Product: C[NH+]1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a solution of 2-(4-(Adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, in acetone (2 mL) was added methanesulfonic acid (0.18 mL, 2.7 mmol) and stirred at room temperature for 3 h. The reaction mixture was filtered and dried in vacuum to afford a 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium methanesulfonate as a crystalline white solid (1.1 g, 87% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[CH3:21][N:22]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[N:31][C:32]2[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)[CH3:23]>CN(C=O)C>[CH3:21][N:22]([CH3:23])[C:24]1[CH:25]=[CH:26][C:27]([N:30]=[N:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([NH:1][CH2:2][C:3]3[CH:16]=[CH:15][C:14]4[O:13][C:12]5[C:7]6=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]6[C:5]=4[CH:4]=3)[CH:9]=[CH:10][CH:11]=5)(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[CH:28][CH:29]=1
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Solvent: CN(C)C=O
Product: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)NCc3ccc4c(c3)-c3n[nH]c(=O)c5cccc(c35)O4)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of compound 49 (0.5 mmol) in anhydrous DMF (20 mL) was added 4-dimethylaminoazobenzene-4′-sulfonyl chloride (0.5 mmol). The mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated in vacuo, and 50 mL of 50% EtOAc in hexanes was added. The precipitate was formed and collected through filtration. The crude product was recrystallized in 50% ethanol to afford a orange solid 55 in 59% yield. MS (ES+): 553; Mp: >300° C.; 1H-NMR (DMSO-d6, 400 MHz): 12.63 (s, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.86-7.74 (m, 6H), 7.67 (d, J=9.0 Hz, 2H), 7.62 (dd, J=6.6 and 2.5 Hz, 1H), 7.44 (dd, J=8.5 and 2.0 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 6.81 (d, J=9.0 Hz, 2H), 4.15 (s, 2H), 3.09 (s, 6H); Anal. Calcd. for C29H24N6O4S.(1.3H2O): C, 60.47; H, 4.65; N, 14.59; S, 5.57. Found: C, 60.72; H, 4.93; N, 15.39; S, 4.93.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][P:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])([CH3:18])=[O:17])[CH3:14].[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]([CH2:32][N+:33]([O-:35])=[O:34])[CH2:18][P:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])(=[O:17])[O:15][CH2:13][CH3:14])=[CH:36][CH:37]=1
Reactant: O=[N+]([O-])C=Cc1ccc(F)cc1
Reactant: CCOC(OCC)P(C)(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(F)cc1)OCC
Reaction time: 0.17 h

Procedure:
To a solution of 5.8 g of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 35.7 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 10.0 g of ethyl(diethoxymethyl)methylphosphinate in 20 ml of tetrahydrofuran is added. This mixture is then stirred for a period of 1 hour at -78° C. after which time a solution of 7.96 g of 4-fluoro-β-nitrostyrene in 20 ml of tetrahydrofuran is introduced. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product chromatographed on silica gel using ethyl acetate as an eluent to give ethyl 2-(4-fluorophenyl)-3-nitropropyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+42.3 and +41.9 ppm (CDCl3).
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[C:22](=O)([O-])[O-].[K+].[K+]>[Cl-].C[N+](C)(C)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3[CH:1]=[CH:2][C:3]([O:4][CH3:22])=[C:5]4[O:9][C@H:8]5[C@@H:10]([OH:11])[CH:12]=[CH:13][C@@H:14]2[C@:7]5([C:6]=34)[CH2:21][CH2:20]1
Reactant: O=C([O-])[O-]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Yield: 99 %

Procedure:
Morphine of purity 35% 815 parts (1 mole parts), potassium carbonate 552 parts (4 moles part) and trimethylphenyl-ammonium chloride 188 parts (1.1 moles part) are heated under stirring in toluene (5000 parts) at 45° to 120° C. for 2 to 5 hrs. to yield 296 parts codeine (99% yield), after workup as in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccc(Cl)cc2)cnc1N
Yield: 100.3 %

Procedure:
A solution of 1.19 g of 2-amino-5-(4-chlorophenyl)-3-nitro-pyridine in 17 ml of ethanol is treated with 5.5 g of SnCl2.2H2O at 90° C. for 17 h under a nitrogen atmosphere. Thereafter, the solution is concentrated in vacuo to dryness. The residue is dissolved in 300 ml of water and adjusted to pH 8 using a 1.0 M solution of aqueous sodium hydroxide. Subsequently, the aqueous layer is extracted four times each with 50 ml of ethyl acetate. The combined organic phases are extracted once with 50 ml of brine, dried using MgSO4, filtered with suction, and evaporated to dryness to yield 1.05 g of the pure title compound of m.p. 178° C. MS: 220.3 (MH+). MS: 220.3/222.3 (MH+, 100%/20%). TLC: Rf=0.30 (dichloromethane/methanol 5:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:14][C:13](=[O:15])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([C:10]([O:12][CH2:13][C:6]2[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=2)=[O:11])[CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(C(=O)OCc2ccccc2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
In DMF (60 mL) was stirred 5-nitro-1,3-benzenedicarboxylic acid (2.1 g, 10 mmol) and potassium carbonate (8.3 g, 60 mmol). To this was added benzyl bromide (3.60 g, 21 mmol) and the mixture stirred at room temperature for 18 hours. The mixture was then filtered free of solids and the DMF solution evaporated at reduced pressure to give an oil. The oil was partitioned between methylene chloride (100 mL) and 10% citric acid solution (100 mL). The organic phase was separated, washed successively with saturated sodium bicarbonate solution (100 mL) and then brine (100 mL). The organic phase was dried over magnesium sulfate and evaporated at reduced pressure to give 1.5 g (39%) of the solid diester. MS: M-benzyl=300.1.
Reaction SMILES: N1C2CCNCC=2SC=1.[N:10]([CH2:13][CH2:14][CH2:15][C:16]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:20]([C:21]2[S:22][C:23]3[CH2:24][N:25]([C:30](OC(C)(C)C)=O)[CH2:26][CH2:27][C:28]=3[N:29]=2)[N:19]=[C:18]([C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[F:44])[S:17]1)=[N+]=[N-].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:44][C:38]1[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=1[C:18]1[S:17][C:16]([CH2:15][CH2:14][CH2:13][NH2:10])([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:20]([C:21]2[S:22][C:23]3[CH2:24][N:25]([CH3:30])[CH2:26][CH2:27][C:28]=3[N:29]=2)[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN=[N+]=[N-])c3ccccc3)sc2C1
Agent: c1nc2c(s1)CNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN)c3ccccc3)sc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Preparation of 24243-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine: To a solution of tert-butyl 2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (0.313 g, 0.524 mmol) in 10.0 mL of DCM at 0° C. was added TFA (1 mL). The mixture was stirred for 1 hour at 0° C. then at room temperature for 1 hour. The reaction mixture was then concentrated to dryness and partitioned between EtOAc (30 mL) and a saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo to afford the desired product as a yellow gum, 0.251 g, 96%.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:9])=[O:8]>ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH3:2]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Diethylamine (Aldrich, 2.5 mL, 24 mmol) was added to a solution of 3-(chlorosulfonyl)benzoic acid (Aldrich, 2.0 g, 9.1 mmol) in anhydrous dichloromethane (20 mL) at 0° C. The mixture was then stirred at 0° C. for 2 hours. The volatiles were removed under reduced pressure. The residue was treated with aqueous potassium hydrogensulfate (1 M, 10 mL) and then extracted with ethyl acetate (3×50 mL). The combined extracts were dried over magnesium sulfate filtered and then concentrated to give the title compound. 1H NMR (300 MHz, CD3OD) δ 1.13 (t, J=7.1 Hz, 6H), 3.22-3.30 (m, 4H), 7.69 (t, J=7.8 Hz, 1H), 8.03 (ddd, J=7.9, 1.9, 1.4 Hz, 1H), 8.25 (dt, J=7.8, 1.4 Hz, 1H), 8.40 (t, J=1.7 Hz, 1H) ppm; MS (DCl/NH3) m/z 275 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][O:6][S:5](=[O:8])[O:4][CH2:3]1.Cl[O-:11].[Na+]>C(Cl)Cl.O.C(O)(C)C.[Ru](Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:9])[CH2:7][O:6][S:5](=[O:11])(=[O:8])[O:4][CH2:3]1
Reactant: CC1(C)COS(=O)OC1
Reactant: [O-]Cl
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: CC1(C)COS(=O)(=O)OC1
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
10.0 g (0.064 mol) of 5,5-dimethyl-1,3,2-dioxathiane-2-oxide was introduced at 20° C. in 100 ml of methylene chloride and 50 ml of water in a 250 ml three-necked flask. 0.02 g of 90 percent ruthenium trichloride was added as a catalyst. 152.45 g (0.0727 mol) of sodium hypochlorite in water was added with stirring for 20 minutes, and the temperature increased to 30° C. The reaction mixture was stirred for five more hours and mixed with 10 drops of isopropanol; the yellow color faded and a black precipitate formed. The water phase was extracted twice with methylene chloride (50 ml), and the combined organic phases were extracted with NaHCO3 solution (100 ml), dried with Na2SO4 and concentrated by evaporation. The white crystalline product was dried overnight at room temperature at a pressure of 15 mbars and weighed 10.65 g, which corresponded to a yield of 99 percent, relative to the 5,5-dimethyl-1,3,2-dioxathiane-2-oxide used.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:43]=[CH:42][C:20]([CH2:21][N:22]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:23](=[O:33])[C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([N:22]([CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:21][C:20]2[CH:19]=[CH:18][C:17]([C:14]3[N:13]=[C:12]([NH:11][S:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])[O:16][N:15]=3)=[CH:43][CH:42]=2)=[O:33])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(CN(CC(=O)OC(C)(C)C)C(=O)c4ccc([N+](=O)[O-])cc4)cc3)no2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(CN(CC(=O)OC(C)(C)C)C(=O)c4ccc(N)cc4)cc3)no2)cc1
Temperature: 65 °C
Yield: 65 %

Procedure:
Prepared using General Procedure 5. To a stirred solution of tert-butyl 2-(N-(4-(5-(4-methylphenylsulfonamido)-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate INT-68 (20 mg, 0.033 mmol) in THF (3 mL) and water (1 mL) was added sodium dithionite (17.2 mg, 0.099 mmol) and heated to 65° C. for 2 h. The reaction mixture was extracted with EA (10 mL) and washed with brine (10 mL). The organics were concentrated in vacuo to afford 13 mg (65%) of tert-butyl 2-(4-amino-N-(4-(5-(4-methylphenylsulfonamido)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-69 as a white solid. LCMS-ESI (m/z) calculated for C29H31N5O6S: 577; found 576 [M−H]−, tR=2.41 min (Method 5).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:25]2[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[C:27]([CH3:38])[CH:26]=2)([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][C:15]=1[CH3:39])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:25]2[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([OH:35])([CH:1]([CH3:3])[CH3:2])[CH:32]([CH3:33])[CH3:34])=[C:27]([CH3:38])[CH:26]=2)([CH2:21][CH3:22])[CH2:23][CH3:24])=[CH:16][C:15]=1[CH3:39])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)[Mg]Cl
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)C)c(C)c1)c1ccc(OCc2ccccc2)c(C)c1
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCc2ccccc2)c(C)c1)c1ccc(OCC(O)(C(C)C)C(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Anhydrous CeCl3 (0.82 g) is suspended in THF (30 mL) with stirring overnight. It is cooled to 0° C., treated with 2.0 M iPrMgCl (1.3 mL) and stirred at 0° C. for 1 h. A solution of 1-{4-[1-(4-benzyloxy-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-3-methyl-butan-2-one (1.01 g, 2.21 mmol) in THF (10 mL) is added. The mixture is stirred at 0° C. for 1 h, before it is quenched with 0.1 M HCl (20 mL). It is extracted with EtOAc (200 mL), washed with 0.1 M HCl (3×50 mL); MgSO4 dried and concentrated to give the title compound (1.10 g, 2.19 mmol, 99%). 1H NMR (CDCl3), δ 0.62 (t, J=7.0 Hz, 6H), 1.01 (d, J=7.1 Hz, 6H), 1.04 (d, J=7.1 Hz, 6H), 1.57 (b, 2H), 2.04 (q, J=7.0 Hz, 4H), 2.17 (s, 3H), 2.24 (s, 3H), 3.88 (s, 2H), 5.04 (s, 2H), 6.70 (d, J=8.3 Hz, 1H), 6.77 (d, J=9.2 Hz, 1H), 6.90 (d, J=2.2 Hz, 1H), 6.93-6.98 (m, 3H), 7.29-7.47 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C@@H:12]3[CH2:14][C@H:13]3[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:11][C:7]=2[C:6](F)=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:4]=1[CH3:27])#[N:2].C(N(CC)CC)C.[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C@@H:12]3[CH2:14][C@H:13]3[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:11][C:7]=2[C:6]([N:39]2[CH2:40][CH2:41][C@H:37]([N:36]([CH3:42])[CH3:35])[CH2:38]2)=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:4]=1[CH3:27])#[N:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1C[C@H]1c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 95 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
Ethyl (1R*,2R*)-2-[4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-yl]cyclopropanecarboxylate (I-216) (200 mg, 0.55 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (146 μl, 1.10 mmol) and (3S)-3-(dimethylamino)pyrrolidine (146 μl, 1.15 mmol) were added, followed by stirring at 95° C. for 4 hours. After cooled, this was concentrated under reduced pressure, diluted with chloroform, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative TLC. The eluate with chloroform/methanol (5:1, v/v) gave the entitled compound (105 mg, 42%) as a red brown solid.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:7]([C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:7]([C:11]1[CH:16]=[C:15]([NH:17][C:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C/C=C/C(=O)Nc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
N-(3,5-di tert.butyl-4-hydroxyphenyl)crotonamide was prepared by adding a solution of 11.5 grams to crotonyl chloride in 50 milliliters of benzene to a solution of 2,6-di tert.butyl-4-aminophenol prepared as described in Example 2 to which had been added 6 grams of sodium carbonate. The addition was accomplished in 30 minutes at 25° C. to 38° C. The mixture was stirred for 11/4 hours and the solid product was filtered, washed thoroughly with 2% hydrochloric acid, and dried. The yield was 12.8 grams of product which melted at 211° C. to 214° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[N:15]1[CH2:16][CH2:17][N:12]([C:10]([C:5]2[CH:4]=[CH:3][C:2]([N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])=[CH:9][C:6]=2[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C#N)CC2)c(C)c1

Procedure:
Using 5-bromo-2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]benzonitrile (398 mg) described in Preparation Example 188 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (377 mg) was obtained.
Reaction SMILES: [Ti:1]([Cl:5])([Cl:4])([Cl:3])[Cl:2].NC(N)=[O:8].N>O>[Ti:1]([Cl:5])([Cl:4])([Cl:3])[Cl:2].[OH-:8].[Ti+4:1].[OH-:8].[OH-:8].[OH-:8]
Reactant: NC(N)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: N
Solvent: O
Product: [OH-]
Product: [Ti+4]

Procedure:
An aqueous solution of titanium tetrachloride was prepared in the same manner as Example 1. 197 mL of ion-exchanged water was added to the aqueous solution of titanium tetrachloride, and then 283 g of aqueous solution of urea having a concentration of 30% by weight and kept at 80° C. was added over 100 minutes. After the resulting solution was heated and refluxed for 10 hours, an aqueous solution of ammonia having a concentration of 5% by weight was added to the solution so that it had a pH of 10. The solution was washed with water until chlorine was no longer detected, thereby providing a slurry of titanium hydroxide. Then, using the slurry of titanium hydroxide, a slurry of titanium oxide was prepared in the same manner as Example 8 (the first process). The titanium oxide was found to have an average particle diameter of 0.03 μm by electron microscopic measurement.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([CH3:24])[C:9]2[C:8]([OH:25])=[CH:7][CH:6]=[C:5]([F:26])[C:4]=2[N:3]=1.[C:27](B1OC(C)(C)C(C)(C)O1)([CH3:29])=[CH2:28].O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[F:26][C:5]1[C:4]2[N:3]=[C:2]([C:27]([CH3:29])=[CH2:28])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[C:10]([CH3:24])[C:9]=2[C:8]([OH:25])=[CH:7][CH:6]=1
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(Cl)nc2c(F)ccc(O)c12
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1nc2c(F)ccc(O)c2c(C)c1Cc1ccc(-n2cccn2)cc1
Temperature: 90 °C

Procedure:
A mixture of 2-chloro-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.22 g), 2-isopropenyl-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (0.23 mL), potassium phosphate monohydrate (0.68 g) and N,N-dimethylformamide (3.0 mL) was purged with argon for 20 minutes, and then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.048 g), and the mixture heated at 90° C. for 12 hours. The mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure. The residue was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with water (5.0 mL) and saturated aqueous sodium chloride solution (5.0 mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 1:1 by volume) gave title compound as a white solid (0.082 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:9]2[CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c([N+](=O)[O-])c1
Yield: 98.1 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.829 g, 3.10 mmol), 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.26 g, 4.61 mmol), KI (115 mg, 0.69 mmol), and DIPEA (1.20 mL, 6.89 mmol) in DMF (16 mL) was heated at 60° C. for 18 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 1.40 g (98%) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-nitro-benzoic acid methyl ester as a tan solid. To a solution of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-nitro-benzoic acid methyl ester (1.40 g, 3.03 mmol) in MeOH (15 mL) and EtOAc (15 mL) was added palladium (50% wet with water), 10 wt. % on activated carbon (0.30 g). The resultant mixture was hydrogenated at 30 psi on a Parr shaker for 3 hours. The mixture was vacuum filtered through celite and the cake was washed with MeOH and EtOAc. The solvent was removed from the filtrate under reduced pressure and the thus obtained oil was purified by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) and provided 0.90 g (69%) of 3-amino-4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester.