Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[O:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:6]([CH3:21])[C:5]2=[O:22].C([O-])(=O)C.[Na+].[H][H]>[C].[Pd].C(O)(C)C>[CH3:21][C:6]1[C:5](=[O:22])[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=[CH:2][CH:3]=2)[O:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)O)cc(Cl)cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)O)cccc2c1=O
Reaction time: 6 h
Yield: 92.8 %

Procedure:
Into a pressure reactor were placed 3.15 g (0.01 mole) of 6-chloro-3-methylflavone-8-carboxylic acid, 4.0 g (0.03 mole) of sodium acetate, 150 ml of isopropanol and 0.2 g of 5% palladium-carbon catalyst. After the atmosphere was replaced with hydrogen gas, reaction was performed at a pressure of 5.0 kg/cm2G at 70° C. for 6 hours. Then the reaction mixture was treated in the same manner as in Example 13, affording 2.6 g (93%) of 3-methylflavone-8-carboxylic acid which was recrystallized from alcohol, giving a product melting at 230° to 233° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)=[N:10][NH:9][C:8](=[O:14])[CH:7]=3.Br[CH2:18][CH2:19][CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)=[N:10][NH:9][C:8](=[O:14])[CH:7]=3
Reactant: O=c1cc2c(n[nH]1)CCc1cc(O)ccc1-2
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1cc2c(n[nH]1)CCc1cc(OCCCCl)ccc1-2

Procedure:
In a 50 mL round bottom flask, 8-hydroxy-5,6-dihydro-3H-benzo[f]cinnolin-2-one (575 mg, 2.69 mmol), 1-bromo-3-chloro-propane (0.27 mL, 2.69 mmol), and potassium carbonate (371 mg, 2.69 mmol) in acetonitrile (20 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, separated, dried over MgSO4. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 106 mg (14%) as an amorphous solid. MS m/z 291 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11](C(OCC)=O)[C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].C(O)(=O)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(O)CCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 164.2 g of oil containing diethyl (2-nitrophenylmethyl)-1,3-propanedioate, from Step A, was combined with 1 L of acetic acid and 1 L of aqueous 20% hydrochloric acid, and heated under reflux for 16 hours. The reaction mixture was cooled to ambient temperature, and concentrated under reduced pressure to give a residue. The residue was stirred with 450 mL of water, then 450 mL of aqueous 10% sodium hydroxide solution was added. The mixture was stirred for one hour, then was extracted with four portions of 450 mL each of diethyl ether. The organic layer was discarded. The aqueous layer was acidified with hydrochloric acid, and extracted with three portions of 300 mL each of diethyl ether. The combined extracts were dried with sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a solid residue. The solid was dissolved with heating in 200 mL of toluene, and the solution was stirred for 16 hours while cooling to ambient temperature. The resultant slurry was further cooled to 10° C., and the solid collected by filtration. The solid was washed with pentane to give 74.2 g of 3-(2-nitrophenyl)propionic acid, m.p. 111°-112° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35]2[N:40]=[C:39]([C:41]3[S:45][C:44](Cl)=[N:43][C:42]=3[C:47]([F:50])([F:49])[F:48])[CH:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]>C(#N)C>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35]2[N:40]=[C:39]([C:41]3[S:45][C:44]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[N:43][C:42]=3[C:47]([F:49])([F:50])[F:48])[CH:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CCOC(=O)c1cccc(Nc2nccc(-c3sc(Cl)nc3C(F)(F)F)n2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(Nc2nccc(-c3sc(NCCCCNC(=O)OC(C)(C)C)nc3C(F)(F)F)n2)c1
Temperature: 25 °C

Procedure:
Diisopropylethylamine (0.1 mL, 0.6 mmol) and 4-t-butoxycarbonylamino-butylamine (25 mg, 1.4 mmol) are added to a solution of N-[3-ethoxycarbonyl-phenyl]-4-[2-chloro-4-trifluoromethyl-5-thiazolyl]-2-pyrimidineamine (52 mg, 0.12 mmol) in 50 mL anhydrous acetonitrile. The mixture is then heated to reflux overnight. The reaction is stopped, cooled to room temperature and concentrated. Water (30 mL) is added and the reaction mixture is extracted with ethyl acetate (3×100 mL). The combined organic layers are dried over MgSO4, filtered and concentrated. The residue is used in the next step without further purification; ESI-MS (m/z): 567.2 (M++H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12.[H][H]>C1COCC1.CCO.[Pd]>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12
Reactant: Cc1c([N+](=O)[O-])cnc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(N)cnc2c1ccn2S(=O)(=O)c1ccccc1
Yield: 99.8 %

Procedure:
To a mixture of 4-methyl-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine, (410 mg, 1.29 mmol) in THF (15 mL) and EtOH (10 mL) was added 10% palladium on carbon (10 wt % of Pd/C; 45 mg) under argon. The mixture was hydrogenated using a hydrogen balloon at room temperature for 16 hours. The reaction mixture was flushed with nitrogen and filtered through a plug of Celite® and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using hexane:EtOAc (4:6) to get 4-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine, (370 mg). 1H NMR (300 MHz, CD3OD) δ: 7.96-8.04 (m, 2H), 7.83 (s, 1H), 7.53-7.64 (m, 2H), 7.42-7.52 (m, 2H), 6.65 (d, J=4.1 Hz, 1H), 2.26 (s, 3H).
Reaction SMILES: C([NH:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:7][CH:6]=1)(=O)C.S(=O)(=O)(O)O.[C:23]([O-])(=O)C.[Na+]>CO>[NH2:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([CH2:11][CH2:12][C:13]([O:15][CH3:23])=[O:14])=[O:10])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Reactant: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(=O)c1ccc(N)cc1
Temperature: 35 °C

Procedure:
A mixture of 35 g. of 3-(4-acetamidobenzoyl)propionic acid, 700 ml. of methanol and 1.4 ml. of concentrated sulfuric acid is refluxed for 76 hours. The solution is cooled to 35° C. and poured onto 7 g. of anhydrous sodium acetate while stirring. The reaction mixture is stirred in an ice-bath. The solid is collected and washed with cold methanol to yield methyl 3-(4-aminobenzoyl)propionate as a white solid. A mixture of this solid, 9.2 g. of 15-(trifluoromethyl)pentadecyl bromide and 4.2 g. of potassium carbonate is stirred for 20 hours at 125° C. under nitrogen. The mixture is then cooled to 25° C. and 30 ml. of water is added. After stirring, the product is filtered and washed with water. Recrystallization from methanol affords methyl 3-{4-[15-(trifluoromethyl)pentadecylamino]benzoyl}propionate as a white solid.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]2[C:11](=[O:25])[N:12]([CH3:24])[CH2:13][C:14]3[N:15]([CH:16]=[N:17][C:18]=3[C:19]([O:21]CC)=O)[C:9]=2[CH:8]=[CH:7][C:6]=1[F:26]>C(O)C>[Cl:4][C:5]1[C:10]2[C:11](=[O:25])[N:12]([CH3:24])[CH2:13][C:14]3[N:15]([CH:16]=[N:17][C:18]=3[C:19]([NH:2][NH2:3])=[O:21])[C:9]=2[CH:8]=[CH:7][C:6]=1[F:26]
Reactant: NN
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c-2ccc(F)c1Cl
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)NN)ncn2-c2ccc(F)c(Cl)c2C1=O
Yield: 63 %

Procedure:
9.15 ml of hydrazine hydrate were added to a suspension of 5.47 g (0.00162 mol) of ethyl 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate in 55 ml of ethanol and the mixture was heated at reflux for 18 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 3.28 g (63%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide as white crystals; m.p. 308°-310°.
Reaction SMILES: N[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.N([O-])=O.[Na+]>CO.[PH2](O)=O>[CH3:11][C:9]1([CH3:12])[CH:8]=[CH:7][C:6]2[CH:13]=[CH:2][C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]=2[O:10]1
Reactant: CC1(C)C=Cc2cc(N)c([N+](=O)[O-])cc2O1
Agent: O=N[O-]
Agent: O=[PH2]O
Agent: [Na+]
Solvent: CO
Product: CC1(C)C=Cc2ccc([N+](=O)[O-])cc2O1
Temperature: 25 °C
Yield: 61 %

Procedure:
To a mixed solution of 6-amino-2,2-dimethyl-7-nitro-1-benzopyran (19.5 g, 88.7 mmol) in methanol-concentrated hydrochloric acid (1:1 v/v, 280 mL) and hypophosphorous acid aqueous solution (100 mL), an aqueous solution of sodium nitrite (12.2 g, 178 mmol) was added dropwise over 30 minutes at −3° C., and the resulting solution was stirred at room temperature until bubbling ceased. The reaction solution was diluted with ethyl acetate, washed with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and then concentrated under a reduced pressure. The resulting solid was recrystallized in methanol to obtain 2,2-dimethyl-7-nitro-1-benzopyran (yield: 61%).
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:12]1[N:13]([CH2:16][C@H:17](O)[CH3:18])[CH:14]=[CH:15][C:11]=1[C:10]2([CH3:26])[CH3:25].C(N(CC)CC)C.[N-:34]=[N+:35]=[N-:36].[Na+]>ClCCl.CN(C)C=O.O>[N:34]([C@@H:17]([CH3:18])[CH2:16][N:13]1[CH:14]=[CH:15][C:11]2[C:10]([CH3:26])([CH3:25])[C:9]3[C:20]([C:12]1=2)=[CH:21][C:22]([O:23][CH3:24])=[C:7]([Cl:6])[CH:8]=3)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc2c(cc1Cl)C(C)(C)c1ccn(C[C@@H](C)O)c1-2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1Cl)C(C)(C)c1ccn(C[C@H](C)N=[N+]=[N-])c1-2
Yield: 79.4 %

Procedure:
0.93 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.84 g of (R)-1-(6-chloro-7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.35 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 90 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 90 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The green oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.78 g of sodium azide and the reaction mixture was heated to 60° for 17 hours while stirring. After cooling the solution was poured into 70 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (hexane/ethyl acetate 3:1). 1.58 g (80%) of (S)-1-(2-azido-propyl)-6-chloro-7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a red oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC#N>[O:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]1=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 53 %

Procedure:
A mixture of N-(4-bromobutyl)phthalimide) (2.00 g, 7.09 mmol), phenol (0.67 g, 7.09) and K2CO3 (1.96 g, 14.18 mmoml) in dry MeCN (30 ml) was stirred at rt for 66 h. The reaction mixture was then warmed to 50° C. for 20 h before more phenol (0.33 mg, 3.54 mmol) was added and the resulting mixture was warmed at reflux. After 4 h EtOAc was added, the mixture was washed with brine, then 1N NaOH, and brine again before evaporated the organic phase to dryness to give the title compound (1.11 g, 53%) which was used without further purification. 1H NMR (500 MHz CDCl3): δ 7-90-7.83 (m, 2H), 7.76-7.70 (m, 2H), 7.28 (t, 2H), 6.93 (t, 1H), 6.89 (d, 2H), 4.01 (t, 2H), 3.79 (t, 2H), 1.96-1.82 (m, 4H); Mass Spectrum: M+H+ 296.
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[C:2]#[CH:3].Br[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1>C(N(CC)CC)C.[Cu]I.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>[N+:21]([C:17]1[CH:16]=[C:15]([C:3]#[C:2][CH2:1][N:4]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: C#CCN1CCc2ccccc2C1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(C#CCN2CCc3ccccc3C2)c1
Temperature: 90 °C
Yield: 66.1 %

Procedure:
To a solution of 81 (2.06 g, 10.2 mmol) in anhydrous triethylamine (30 mL) were sequentially added 1-bromo-3-nitrobenzene (1.83 g, 10.67 mmol), CuI (0.39 g, 2.05 mmol) and Pd(PPh3)4 (1.17 g, 1.0 mmol). The mixture was heated at 90° C. for 1 hour before it was filtered through Celite® and the filtrate was diluted with EtOAc (150 mL). The resulting solution was washed with water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated. The residue was purified via flash silica gel chromatography to provide 93 (1.97 g, 66%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:19]([C:21]1[O:25][C:24]([C:26](Cl)=[O:27])=[CH:23][CH:22]=1)#[N:20].CCN(C(C)C)C(C)C>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:26]([C:24]3[O:25][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)=[O:27])=[C:8]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(-n2ccnc2)cc1N1CCCCC1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)Nc2ccc(-n3ccnc3)cc2N2CCCCC2)o1
Yield: 44 %

Procedure:
Using a procedure similar to Example 3, step (d), 4-imidazol-1-yl-2-piperidin-1-yl-phenylamine (69 mg, 0.28 mmol, as prepared in the previous step) was allowed to react with 5-cyano-furan-2-carbonyl chloride (56 mg, 0.36 mmol) in the presence of DIEA (138 μL, 0.790 mmol) to afford 44.9 mg (44%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 9.65 (br s, 1H), 8.57 (d, 1H, J=9.3 Hz), 7.84 (s, 1H), 7.34 (d, 1H, J=3.7 Hz), 7.28-7.27 (m, 2H), 7.22-7.20 (m, 3H), 2.93-2.90 (m, 4H), 1.88-1.85 (m, 4H), 1.72 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C20H19N5O2, 362.1 (M+H), found 362.2.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([NH:13][CH3:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([N:13]([CH3:14])[C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: CNc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)N(C)c1ccc(Br)cc1
Reaction time: 2.5 h

Procedure:
3,3-Dimethylacryloyl chloride (3 mL, 27 mmol) was added to a solution of 4-bromo-N-methyl-aniline (4.55 g, 25 mmol) in 150 mL of dichloromethane followed after 5 minutes by triethyl amine (5 mL, 33 mmol). After 2.5 h at ambient temperature, the reaction mixture was washed with water and the organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to afford the title product as a brown oil in quantitative yield.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([CH3:27])[CH:18]=3)[N:8]=2)[CH:6]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:35]([Sn:39](Cl)([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH3:38].[Cl-].[NH4+]>C1COCC1>[CH3:27][C:19]1[CH:18]=[C:17]([C:9]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=[C:7]([N:5]3[CH:6]=[C:2]([Sn:39]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:35][CH2:36][CH2:37][CH3:38])[N:3]=[CH:4]3)[N:8]=2)[CH:22]=[CH:21][C:20]=1[C:23]([F:26])([F:25])[F:24]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)ccc1C(F)(F)F
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)c(C)c3)cc(C(F)(F)F)n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 16.6 %

Procedure:
To a stirred solution of 2-(4-iodo-imidazol-1-yl)-6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (Example E.73) (1.49 g, 3.0 mmol) in THF (21 mL) was added at 0° C. isopropyl-magnesium chloride lithium chloride (1M in THF, 3.6 mL, 3.6 mmol). The reaction mixture was allowed to stir for 15 min at 0° C., tributyltin chloride (1.27 g, 3.9 mmol) was added, the reaction mixture was stirred at room temperature for 16 h, poured into saturated ammonium chloride solution (70 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (70 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on alox (ethylacetate/heptane) to yield the title compound (0.33 g, 17%) as a light brown oil. MS (ISP) 663.3 [(M+H)+].
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)#[N:3].[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>CCO>[NH2:17][C:16]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[CH:5][CH:6]=2)[N:11]=[C:14]([C:13]([CH3:20])([CH3:19])[CH3:12])[CH:15]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 64 h
Yield: 94.9 %

Procedure:
A cream suspension of 4-cyanophenylhydrazine hydrochloride (1.70 g, 10.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.31 g, 10.5 mmol) in EtOH (25 mL) was stirred at reflux for 4 h, then at RT for 64 h, and again at reflux for 24 h. The solution was cooled to RT, concentrated in vacuo, and partitioned between water (50 mL) and EtOAc (75 mL). The organics were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave an orange solid (2.28 g, 95%). LCMS (Method 3): Rt 3.45 min, m/z 241 [MH+].
Reaction SMILES: C[O-].[Na+].[ClH:4].Cl.[NH2:6][C@H:7]1[C@H:11]([O:12][CH3:13])[CH2:10][NH:9][CH2:8]1.[CH:14]1([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:30])=[C:24](F)[C:25]=3[O:27][CH3:28])[C:20](=[O:31])[C:19]([C:32]([OH:34])=[O:33])=[CH:18]2)[CH2:16][CH2:15]1.[B](F)F.C(N(CC)CC)C>CS(C)=O.O>[ClH:4].[NH2:6][C@H:7]1[C@H:11]([O:12][CH3:13])[CH2:10][N:9]([C:24]2[C:25]([O:27][CH3:28])=[C:26]3[C:21]([C:20](=[O:31])[C:19]([C:32]([OH:34])=[O:33])=[CH:18][N:17]3[CH:14]3[CH2:16][CH2:15]3)=[CH:22][C:23]=2[F:30])[CH2:8]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CO[C@@H]1CNC[C@H]1N
Agent: C[O-]
Agent: Cl
Agent: F[B]F
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(N2C[C@@H](N)[C@H](OC)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.19 g (0.0036 mole) of sodium methoxide was added to a suspension of 0.34 g (0.0018 mole) of trans-3-amino-4-methoxypyrrolidine dihydrochloride (prepared as described in Preparation 18) in 1.5 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 30 minutes. 0.31 g (0.0009 mole) of a chelate (IV) of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and boron difluoride (prepared as described in Preparation 7) were added to the resulting solution, followed by 0.27 g (0.0027 mole) of triethylamine. The mixture was then allowed to stand at room temperature overnight. At the end of this time, 50 ml of water were added to the mixture, and a chelate (V) separated out. This was collected by filtration to give yellow crystals. These were worked up in a similar manner to that described in Example 22, to give 0.22 g of 7-(trans-3-amino-4-methoxy-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4 -dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride as a fine yellow powder, melting at 192°-195° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][C:28]([CH2:29][NH:30][CH3:31])=[CH:27][CH:26]=1>>[CH3:31][N:30]([CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:33][CH:32]=1)[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: CNCc1ccc(C(F)(F)F)cc1
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)Cc1ccc(C(F)(F)F)cc1
Yield: 5 %

Procedure:
The title compound was prepared in 5% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-trifluoromethyl-N-methylbenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.22 (3H, s), 2.73 (2H, t, J=5.8 Hz), 3.62 (2H, s), 4.16 (2H, t, J=5.9 Hz), 7.12 (1H, m), 7.21 (1H, m), 7.38 (2H, d, J=7.8 Hz), 7.54 (2H, d, J=8.2 Hz), 7.75 (1H, s), 8.29 (1H, s), 8.54 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H19F3N4O2, 405. Found, 405.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:29])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH2:27][CH3:28])=[CH:25][CH3:26])[C:5]2=[CH:4][CH:3]=1.[CH3:30][O:31][CH:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])[CH3:33].[H-].[Li+].[Cl:40][CH2:41][CH2:42][CH2:43]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:29])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:43][CH2:42][CH2:41][Cl:40])[CH:11]3[C:24]([CH2:27][CH3:28])=[CH:25][CH3:26])[C:5]2=[CH:4][CH:3]=1.[CH3:30][O:31][CH:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])[CH3:33]
Reactant: ClCCCI
Reactant: CC=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC=C(CC)C1N(CCCCl)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (2.4 g, 4.3 mmol) prepared in example 81a was reacted with LiH (1 g, 125 mmol) and 1-chloro-3-iodo-propane (8 g, 39 mmol) in N,N-dimethyl-formamide (40 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white form (Yield: 0.61 g, 22%).