Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:15]Br>ClCCl>[C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([Br:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Yield: 32.4 %

Procedure:
N-boc-4-piperidone (100 gm, 0.5 mole) obtained in step H1 was dissolved in 4.0 L of dichloromethane. Bromine (96.3 gm, 0.6 mole) in 100 ml of dichloromethane was added at room temperature under stirring and nitrogen bubbling. After completion of bromine addition, the reaction mixture was stirred further at room temperature for additional 30 minutes and then filtered. Filtrate was concentrated and crystallized by dichloromethane/petroleum ether to get the product N-boc-3-bromo-4-piperidone (45.0 gm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[C:26](O)=[O:27])(=[O:19])=[O:18])[CH2:13][CH2:12]1.Cl.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCOCC1.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:30]([O:37][NH:38][C:26]([C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[S:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1)(=[O:18])=[O:19])=[O:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NOCc1ccccc1)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (0.46 g, 1.12 mmol) [prepared as described Step 2 above] in methylene chloride (10 ml) was added O-benzylhydroxylamine hydrochloride salt (0.54 g, 3.36 mmol), followed by 4-dimethylaminopyridine (0.15 g, 1.23 mmol), 4-methylmorpholine (0.38 ml, 3.47 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.43 g, 2.24 mmol). The reaction was stirred at RT for 2 h, diluted with methylene chloride (50 ml) and washed with 1M HCl. The organic layer was washed with brine, dried over MgSO4, and concentrated to give N-benzyloxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (95%) as a clear oil. This material was used without further purification.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:10]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH:11]=1)=[O:6].[CH3:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH:37]=3)=[CH:14][CH:13]=2)[CH:11]=1)=[O:6]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=C(NCC(F)(F)F)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NCC(F)(F)F)nc3-c3ccccc3Cl)cc2)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a 50 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 1-(4-Bromo-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (249 mg, 540 μmol), 3-methylsulfonylphenyl boronic acid (130 mg, 650 μmol), PdCl2dppf (40 mg, 10 mol %), K2CO3 (260 mg, 1.90 mmol), 1,2-dimethoxyethane (14 mL) and H2O (2 mL). The reaction solution was allowed to stir at 75° C. for 2 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 2% EtOAc to 90% EtOAc to afford 212 mg (74% yield) of the title compound. MS (ES): 534 [M+H]+, 557 [M+Na]+. 1H NMR. (400 MHz, CDCl3): δ 8.13 (s, 1H), 7.99 (s, 1H), 7.92 (d, 1H), 7.65 (t, 1H), 7.57 (d, 2H), 7.52 (d, 2H), 7.41-7.34 (m, 3H), 7.24 (d, 2H), 4.11 (q, 2H), 3.08 (s, 3H); 19F NMR (400 MHz, CDCl3) 5-72.4 ppm.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:9](O)(=O)[C:10](C)([CH3:12])[CH3:11].S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[OH-].[NH4+]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[C:10]([CH3:12])([CH3:11])[CH3:9]
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)C(=O)O
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CC(C)(C)c1cc(Cl)nnc1Cl
Reaction time: 0.25 h

Procedure:
A 375 g. portion of 3,6-dichloropyridazine was slurried with 578 g. of pivalic acid in 367 g. of sulfuric acid and 1500 ml. of water, and the mixture was warmed to 40°. Then 48.2 g. of silver nitrate was added, and the mixture was heated to 62°. To it was added 1 kg. of ammonium persulfate in 2 liters of water over a period of 1 hour. The temperature rose exothermically, and was controlled at 80° maximum. After the addition, the mixture was stirred for 15 minutes, and was then cooled to 15° with an ice-water bath. The mixture was then cooled further by the addition of ice, and its pH was adjusted to 9 with ammonium hydroxide. It was then stirred vigorously for 1 hour, while gummy material was scraped from the sides of the vessel as needed. It was then filtered, and the solids were washed with 2 liters of water and dried on the filter pad. The solids were then slurried in 5 liters of diethyl ether and the slurry was filtered. The filtrate was washed three times with 500 ml. portions of 1N sodium hydroxide, and the washes were combined and extracted with 500 ml. of diethyl ether. That ether was combined with the first ether filtrate, and was washed with 500 ml. of brine. The organic layer was dried over magnesium sulfate and carbon treated at the reflux temperature. It was then cooled and filtered through diatomaceous earth, and the filtrate was evaporated under vacuum to obtain 449 g. of the desired intermediate.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C)C=CC=CC=1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([C:24]#[C:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Temperature: 70 °C

Procedure:
In an inert atmosphere glovebox, 4-bromo-4′-fluorobenzophenone (10 g, 35.8 mmol), PdCl2(PPh3)2 (250 mg), CuI (680 mg), phenylacetylene (4.02 g, 1.1 eq), triethylamine (3.6 g, 1 eq), and toluene (25 mL) were combined. The flask was closed and heated to 70° C. for 24 h. The mixture was poured over ice and extracted with methylene chloride, which was separated and evaporated. The residue was recrystallized twice from hot ethanol using decolorizing charcoal to give the title product as white crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11]C(=O)OC(C)(C)C)[N:10]=2)[N:7]=1.CCOCC.[ClH:24]>O1CCOCC1>[ClH:24].[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(I)ccc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 3B was synthesized according to a procedure analogous to that described in International Patent Publication No. WO 2008/06192 (Takeda Pharmaceutical Company Limited), which is incorporated by reference herein in its entirety. Specifically, tert-butyl 6-iodoimidazo[1,2-b]pyridazin-2-ylcarbamate (3A, 5.9 g, 16.38 mmol) was dissolved in 4N HCl in dioxane (60 mL) and stirred at ambient temperature for 4 hours. Ether (140 mL) was added to the reaction and a brown precipitate formed. The precipitate was filtered and washed with ether to give 6-iodoimidazo[1,2-b]pyridazin-2-amine hydrochloride in quantitative yield. This material was used without purification. ESI-MS:m/z 261.0 (M+H)+.
Reaction SMILES: [CH3:1][SiH:2]([O:5][CH3:6])[O:3][CH3:4].C1(C)C=CC=CC=1.C(O)(=O)C.[CH3:18][SiH:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=1>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH3:28][SiH:19]([CH3:18])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][CH2:25][CH2:1][SiH:2]([O:5][CH3:6])[O:3][CH3:4])=[CH:22][CH:21]=1
Reactant: C=Cc1ccc([SiH](C)C)cc1
Reactant: CO[SiH](C)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CO[SiH](CCCc1ccc([SiH](C)C)cc1)OC
Temperature: 50 °C
Yield: 4.9 %

Procedure:
325 mg Of 4-imethylsilylstyrene, 212 mg of methyldimethoxysilane, and 83 mg of toluene were placed in a glass reaction vessel and 0.005 ml of acetic acid was added. Next, 0.001 ml of an isopropyl alcohol solution of chloroplatinic acid (platinum content: 0.39 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 0.5 hours in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of 4-dimethylsilylstyrene was 63.6% and (4-(dimethylsilyl) phenethyl)methyldimethoxysilane was produced at a yield of 4.9%. The yield of α-(4-(dimethylsilyl)phenyl)ethyl) methyldimethoxysilane was 1.8%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the product of EXAMPLE 30A (0.3 g, 0.96 mmol) in ethanol (2 mL) was added 2N aqueous sodium hydroxide (2 mL) and the mixture was stirred at room temperature for 12 hours. Ater concentration, the residue was diluted with water and extracted with ethyl acetate. The aqueous phase was acidified to pH 2-3 with concentrated HCl and extracted with ethyl acetate (3×5 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was used in the next step without further purification.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](O)=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C.ClCCl>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:3])=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 94.2 %

Procedure:
N,N-Dimethylformamide (100 mL) (DMF) was cooled to 0° C., and phosphorous oxychloride (27.5 mL, 0.295 mol) was added dropwise. The resulting solution was stirred for 25 minutes and then added dropwise to a mixture of 7-benzyloxy-3-nitroquinolin-4-ol (72.87 g, 0.2459 mol) in DMF (400 mL). Following the addition, the reaction was heated at 100° C. for 5 minutes, cooled to ambient temperature, and poured into ice water with stirring. A tan precipitate formed, which was isolated by filtration and dissolved in dichloromethane. The resulting solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 72.9 g of 7-benzyloxy-4-chloro-3-nitroquinoline as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:18][N:17]=2)[CH3:11])=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:18][N:17]=2)[CH3:11])=[CH:6][CH:7]=1)[C:27]([CH3:28])=[O:29]
Reactant: CN(CCCOc1nsc(-c2ccccc2)n1)CCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCN(C)CCCOc2nsc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg of 3-{3-[N-(2-(4-aminophenyl)-ethyl)-N -methylamino]-propyloxy}-5-phenyl-1,2,4-thiadiazole (for preparation, see Example 62) were dissolved in 4 ml pyridine. 1 ml of acetic acid anhydride was added to the solution and the reaction mixture was stirred for 2 hours at room temperature. For workup, it was poured over ice and the mixture made alkaline by adding sodium carbonate solution. Then extraction was performed with ethyl acetate, the organic phase was separated, and concentrated to dryness. The crude oily title compound obtained was purified by medium-pressure chromatography over fine-grained silica gel (Lichroprep Si 60®) using 95:5 ethyl acetate/methanol as the eluent. 0.12 g of the title compound were obtained as an oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.[H-].[Na+]>CN(C=O)C.O.CCOC(C)=O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(-n2cccn2)cc1
Temperature: 145 °C
Yield: 76.6 %

Procedure:
To a solution of 4-fluorobenzonitrile (1.5 g, 12.35 mmol) and pyrazole (0.843 g, 12.38 mmol) in DMF (10 mL) was added NaH (60% in oil, 0.644 g, 16.09 mmol). The reaction was heated to 145° C. for 20 h. The reaction was cooled to room temperature and was diluted with water and EtOAc The aqueous layer was washed with EtOAc (3×) and the combined organic layers were washed with water (4×). The organic solution was dried (MgSO4, filtered, and concentrated. Medium pressure chromatography (4:1 hexanes:EtOAc) provided 4-pyrazol-1-yl-benzonitrile (1.6 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 1H), 7.82 (d, 2H), 7.73 (m, 3H), 6.87 (d, 1H); MS 170 (M+1).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH2:13][C:14]([OH:16])=[O:15])=[CH:7][CH:6]=1)(=O)C.Cl.[CH3:18]O.S(=O)(=O)(O)O>[OH-].[K+]>[NH2:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[CH2:13][C:14]([O:16][CH3:18])=[O:15])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(/C=C/CC(=O)O)cc1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)C/C=C/c1ccc(N)cc1

Procedure:
7.5 g of (E)-4-(4-(acetylamino)phenyl)-3-butenoic acid was dissolved in a 1N aqueous solution of potassium hydroxide. The obtained solution was heated under reflux for 4 hours and cooled by allowing to stand. After the pH of the solution had been adjusted to about 3 by the addition of concentrated hydrochloric acid, the resulting solution was concentrated under a reduced pressure, followed by the addition of benzene. The obtained mixture was concentrated and freed from the water by azeotropic distillation to obtain a solid. 300 ml of methanol and 1 ml of concentrated sulfuric acid were added to the solid. The obtained mixture was heated under reflux for 3 hours, cooled by allowing to stand and concentrated under a reduced pressure. An aqueous solution of potassium carbonate was added to the residue and the obtained mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of common salt successively and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (2:1)] to obtain 5.38 g of the title compound as a lightly orange-colored oil (yield: 82%).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7](=[N:20][CH:21]1[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C#C>C1COCC1.CC(O)C>[C:7](=[N:20][C:21]1([CH2:3][C:2]#[CH:1])[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CN1CCC(N=C(c2ccccc2)c2ccccc2)C1=O
Agent: C#CCBr
Agent: [K+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCN(C)C1=O
Reaction time: 2 h

Procedure:
Potassium tert-butoxide 1.7M in THF (32.8 mL, 55.76 mmol) was added dropwise over a period of 80 minutes (by syringe pump) to a solution of the 3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (14.11 g, 50.692 mmol) (which may be prepared as described in Description 1) and propargyl bromide (6.78 mL, 60.83 mmol) in THF (250 mL) at 0° C. under nitrogen. The reaction was stirred for 2 hours. Additional KOtBu (5 ml) was added dropwise and stirring was continued for 15 mins. The reaction was quenched by the addition of satd. aq. NaHCO3 and diluted with EtOAc. The phases were separated, the organic layer was dried (Na2SO4) and the solvent evaporated to afford a crude brown oil which solidified on standing. This waxy-solid was suspended in IPA (approx. 30 ml) and stirred for 1 hr. The solid was filtered off, washed with a little IPA to afford 3-(benzhydrylidene-amino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (D2) as a light brown solid (6.26 g);
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Ce+3:5].[C:6](=[O:9])([O-])[O-:7].[C:10](=[O:13])([O-])[O-:11].[Ce+3]>C(O)(=O)C>[C:1]([O-:2])(=[O:4])[CH3:6].[Ce+3:5].[C:6]([O-:7])(=[O:9])[CH3:10].[C:10]([O-:11])(=[O:13])[CH3:1]
Reactant: O=C([O-])[O-]
Agent: [Ce+3]
Solvent: CC(=O)O
Product: CC(=O)[O-]

Procedure:
In general, we start with a wet cerium carbonate which is treated with acetic acid to form a cerium acetate. The cerium acetate is dried and calcined suitably at a temperature of about 425° C. to 450° C. to form a high surface area ceric oxide, CeO2 (HSA ceric oxide). A mixture of 70 mole percent high surface area cerium oxide and 30 mole percent of the cerium acetate is then prepared. This mixture is wet milled with alumina in proportions that will ultimately yield about 50 to 80 weight percent alumina and the balance cerium oxide. Small amounts of other materials such as known oxide stabilizers may be added if desired. The wet mixture is milled for a period of time so as to achieve a substantially uniform mixture of the ceric oxide and alumina and cerium acetate. Some of the cerium acetate dissolves in the water and the solution is adsorbed onto the alumina. Ultimately, a mixture of average particle size of about 0.5 to 1 micron is obtained. The viscosity of the milled slurry may be adjusted if necessary, and the material is then applied as a thin layer to the exhaust gas treatment surfaces of a ceramic or metal monolith configured for the treating of automotive engine exhaust gases.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[H-].[Al+3].[H-].[H-].Cl>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([Cl:10])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1ccc(Br)cc1Cl
Yield: 88.7 %

Procedure:
To a solution of 4-bromo-2-chlorobenzonitrile (2 g, 9.24 mmol) in Tetrahydrofuran (THF) (10 ml) was added aluminum hydride (37.0 ml, 18.48 mmol) in THF. The reaction mixture was acidified with 1N HCl to pH=4. The mixture was washed with ether (2×50 ml). The aqueous layer was separated and it was adjusted with 1N NaOH to pH=10. The mixture was extracted with ether. The organic layer was separated and dried over Na2SO4. The solvent was evacuated to give 1-(4-bromo-2-chlorophenyl)methanamine (1.8 g, 8.2 mmol, 88%). MS (ES+): m/e 220, 222 [M+H]+.
Reaction SMILES: [ClH:1].Cl.Cl.Cl.[CH2:5]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH3:26])[CH3:6].Cl.C([OH:30])C>C(OCC)C>[OH2:30].[ClH:1].[ClH:1].[ClH:1].[ClH:1].[CH2:25]([NH:24][CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:5][CH3:6])[CH3:26].[CH2:25]([NH:24][CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:5][CH3:6])[CH3:26].[ClH:1].[ClH:1].[ClH:1].[ClH:1]
Reactant: CCO
Agent: CCNCCCNCCCCCCCCNCCCNCC
Agent: Cl
Solvent: CCOCC
Product: O

Procedure:
Dissolve 3.3 g (0.0046 mol) of the product of Step A in 7 ml ethanol and treat with 70 ml of 2 N HCl in diethyl ether stirring overnight. Filter the mixture and dry the residue at 70° C. at reduced pressure to yield 1.95 g of the title 46.09, H-10.10, N-11.95, Cl-30.24; Found C-46.23, H-9.94, N-12.11, Cl-29.99.
Reaction SMILES: B.[Na].[F:3][C:4]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:5]=1[C:6](O)=[O:7]>O1CCCC1>[F:14][C:9]1[C:10]([F:13])=[CH:11][CH:12]=[C:4]([F:3])[C:5]=1[CH2:6][OH:7]
Reactant: O=C(O)c1c(F)ccc(F)c1F
Agent: B
Agent: [Na]
Solvent: C1CCOC1
Product: OCc1c(F)ccc(F)c1F
Temperature: 0 °C
Yield: 102 %

Procedure:
To a solution of sodium boron hydride (51.6 g) in tetrahydrofuran (500 ml) is added dropwise a solution of 2,5,6-trifluorobenzoic acid (120 g) in tetrahydrofuran (200 ml) with stirring at below 10° C., and thereto is further added dropwise a solution of BF3 ·(C2H5)2O (232 ml) in tetrahydrofuran (500 ml) under ice cooling. The mixture is stirred at room temperature overnight. The reaction mixture is poured into ice water (1.5 liter) and is extracted with diethyl ether. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure to give 2,3,6-trifluorobenzyl alcohol (112.7 g), as pale yellow oil, b.p. 112° C. (30 mmHg).
Reaction SMILES: N[C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:11])[C:3]=1[Br:12].N([O-])=O.[Na+].C(OCC)(=O)C>C(O)(=O)C.P(P(O)(O)=O)(O)(O)=O.O>[Br:12][C:3]1[C:4]([F:11])=[C:5]([CH:8]=[C:9]([F:10])[CH:2]=1)[CH:6]=[O:7]
Reactant: Nc1c(F)cc(C=O)c(F)c1Br
Agent: O=N[O-]
Agent: O=P(O)(O)P(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cc(F)cc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
4-amino-3-bromo-2,5-difluorobenzaldehyde (3.4 g, 14.3 mmol) was dissolved in acetic acid (18 mL) before addition of hypophosphoric acid (50% in water, 39 mL). A solution of sodium nitrite (1.4 eq, 1.4 g) in water (8 mL) was then added dropwise under ice-cooling. After stirring at rt for 2 h, the reaction mixture was poured onto a mixture ice/water and the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and evaporated. A column chromatography (0 to 10% ethyl acetate in petroleum ether) afforded 3-bromo-2,5-difluorobenzaldehyde (1.3 g, 6.3 mmol, 44%). 1H NMR (d6-DMSO) δ 10.15-10.12 (m, 1H), 8.13 (ddd, J=8.0, 5.0, 3.0 Hz, 1H), 7.66 (ddd, J=8.0, 5.0, 3.0 Hz, 1H).