Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.[Mg].BrCCBr.C(O[C@H:12]1[NH:15][C:14](=[O:16])[C@@H:13]1[C@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])(=O)C.Br[CH:28]([CH3:47])[C:29]([N:31]1[C:36]2([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[O:35][C:34]2[CH:42]=[CH:43][CH:44]=[CH:45][C:33]=2[C:32]1=[O:46])=[O:30].Cl.[NH4+]>O1CCCC1>[Si:20]([O:19][C@@H:17]([C@@H:13]1[C@@H:12]([C@@H:28]([CH3:47])[C:29]([N:31]2[C:36]3([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[O:35][C:34]3[CH:42]=[CH:43][CH:44]=[CH:45][C:33]=3[C:32]2=[O:46])=[O:30])[NH:15][C:14]1=[O:16])[CH3:18])([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22]
Reactant: CC(Br)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Temperature: 5 °C
Yield: 80.4 %

Procedure:
A mixture of 10 ml of tetrahydrofuran and a small amount of iodine is added to 437 mg of magnesium piece at a room temperature and 0.75 g of 1,2-dibromoethane are added dropwise thereto with stirring. When the exothermic reaction starts and the mixture begins to reflux, a solution of 1.51 g of 1,2-dibromoethane in 3 ml of tetrahydrofuran is added dropwise thereto. Then, the mixture is refluxed for 30 minutes. The mixture is cooled to a temperature of 5° C. and to this cooled liquid is added dropwise a mixture of 1.15 g of (3R, 4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-azetidinone and 2.11 g of 3-(2-bromopropionyl)-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one in 5 ml of tetrahydrofuran. Then, the mixture is stirred at 10° C. for one hour. 60 ml of aqueous saturated ammonium hydrochloride are added thereto and the mixture is extracted with ethyl acetate. The extract is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=6:1-3:1) to obtain 1.61 g of 3-{(2R)-2-[(3S, 4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one
Reaction SMILES: [Mg].Cl[Si:3]([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.Cl[C:13]([F:20])([F:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O>[CH2:17]([O:16][C:14](=[O:15])[C:13]([F:20])([F:19])[Si:3]([CH3:6])([CH3:5])[CH3:4])[CH3:18]
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(F)(F)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
According to the above-described scheme, magnesium (243 mg, 10.0 mmol), chlorotrimethylsilane (Me3SiCl; 2.17 g, 20.0 mmol) and DMF (15 mL) were put into a two-neck reaction tube under nitrogen atmosphere. Ethyl chlorodifluoroacetate (Compound 3; 793 mg, 624 μL, 5.0 mmol) was added thereto with the reaction container being cooled in water bath, and then the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was extracted with diethyl ether and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Diethyl ether was distilled away under reduced pressure, and by carrying out the production by silica gel column chromatography, difluorotrimethylsilanylacetic acid ethyl ester (Compound 3a) was obtained with a yield of 43%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[CH3:18][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:13])([F:14])[F:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CI
Reactant: COC(=O)c1ccc(C(F)(F)F)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(F)(F)F)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-hydroxy-4-(trifluoromethyl)benzoate (see WO 2007/129745) (2.00 g) in N,N-dimethylformamide (9.00 mL), sodium hydride (60% dispersion in mineral oil, 545 mg) was added in small portions under cooling with ice. After stirring the mixture at room temperature for 30 minutes, methyl iodide (0.849 mL) was added. After stirring the reaction mixture at room temperature for 2.5 hours, iced water was added and two extractions were conducted with ethyl acetate. The combined organic layers were washed with water three times and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-85:15) to give methyl 3-methoxy-4-(trifluoromethyl)benzoate as a colorless solid (2.11 g).
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([C:15]1(O)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[C:17](=[O:25])[NH:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(C1(O)C2C(=CC(Cl)=CC=2)C(=O)N1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH2:8]([CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[C:17](=[O:25])[NH:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1NC(O)(Cc2ccccc2)c2cc(Cl)ccc21
Agent: CC[SiH](CC)CC
Agent: O=C1NC(O)(Cc2ccccc2)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(Cc2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under N2 protection, triethylsilane (23 g, 200 mmol) and TFA (10 mL) were added successively to a mixture of 3-benzyl-5-chloro-3-hydroxy-2,3-dihydro-isoindol-1-one and 3-benzyl-6-chloro-3-hydroxy-2,3-dihydro-isoindol-1-one (5.47 g, 20 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was treated with a satd. aq. NaHCO3 solution (30 mL) and extracted with DCM (2×30 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude mixture of products. The desired regioisomer, 3-benzyl-5-chloro-2,3-dihydro-isoindol-1-one was obtained by prep-HPLC separation as a white solid (1.03 g, 20%). MS: 258.1 (M+H+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1([F:22])[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)#[N:8]>C1COCC1>[NH2:8][CH2:7][C:9]1([F:22])[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCC(F)(C#N)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(F)(CN)C1
Reaction time: 3 h
Yield: 69.2 %

Procedure:
To a stirred and cooled (0° C.) suspension of lithium aluminium hydride (1.02 g, 26.8 mmol) in dry THF (50 mL) was added drop-wise a solution of tert-butyl 3-cyano-3-fluoropiperidine-1-carboxylate (5.50 g, 24.0 mmol) in dry THF (30 mL). The reaction was stirred at 0° C. for 1 hour then at room temperature for 3 hours. The mixture was quenched with water (1.0 mL) at 0° C., and stirred at room temperature for 20 minutes. Then 15% sodium hydroxide aqueous solution (2.0 mL) was added, and stirred at room temperature for 20 minutes. Finally, water (1.0 mL) was added, and stirred at room temperature for 20 minutes. The mixture was filtered through Celite pad washing with tetrahydrofuran (25 mL). The filtrate was concentrated to afford the title product as pale yellow oil 3.86 g. MS (m/z): 233 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)[N:11]=[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12.C(O)C>[Pd].CN(C=O)C>[CH:13]1([C:12]2[C:3]3[C:4](=[C:5]([O:8][CH3:9])[N:6]=[CH:7][CH:2]=3)[N:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)[N:11]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COc1ncc(Br)c2c(C3CCCC3)nn(-c3csc(C(N)=O)c3)c12
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1nccc2c(C3CCCC3)nn(-c3csc(C(N)=O)c3)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 123 %

Procedure:
A mixture of 4-(4-bromo-3-cyclopentyl-7-methoxy-1H-pyrazolo[3,4-c]pyridin-1-yl)thiophene-2-carboxamide (60 mg) obtained in Step A of Example 67 and 10% palladium/carbon (50% wet, 15 mg) in a mixed solvent of ethanol (10 mL) and DMF (3 mL) was stirred under hydrogen atmosphere at room temperature for 15 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (60 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([Cu])#[N:10]>CN(C=O)C>[OH:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=1)[C:9]#[N:10]
Reactant: Oc1cncc(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1cncc(O)c1
Temperature: 135 °C
Yield: 38.5 %

Procedure:
A mixture of 5-bromo-pyridin-3-ol (9.94 mL, 54.0 mmol) and CuCN (7.4 g, 82.62 mmol) in DMF (20 mL) was heated at 135° C. for 5 hour. DMF was removed under reduced pressure, the residue was diluted with NH4OH (10 mL) at 0° C. The mixture was bubbled with ammonia gas for 1 hour, cooled to 0° C. and acidified with conc. HCl (35 mL) until pH reached to ˜4. The resulting mixture was extracted with EtOAc (5×100 mL). The organic layer was washed with water (2×100 mL) and brine (2×100 mL) solution, dried over anhydrous Na2SO4, filtered, and concentrated to give yellow solid. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (2.5 g, 39%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.41 (d, J=2.7 Hz, 1H), 7.61-7.57 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.C1COCC1.[Pd]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[N:16][CH:17]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(-c2ccc(OCc3ccccc3)cc2)nc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Yield: 67.5 %

Procedure:
To a solution of 2-(4-Benzyloxy-phenyl)-5-trifluoromethyl-pyridine (2.55 g) in ethanol (100 mL) and THF (25 mL) is added Pd/C (5%, 0.253 g), the mixture is stirred under 60 psi of hydrogen overnight. The catalyst is filtered off, concentration of the filtrate gave the title compound (1.25 g, 67.5%).
Reaction SMILES: ClC1N=C(CI)C=C(N2CCOC[C@@H]2C)N=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].[Cl:22][C:23]1[N:28]=[C:27]([CH2:29][OH:30])[CH:26]=[C:25]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]2[CH3:37])[N:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:30][CH2:29][C:27]1[CH:26]=[C:25]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]2[CH3:37])[N:24]=[C:23]([Cl:22])[N:28]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1cc(CO)nc(Cl)n1
Agent: C[C@H]1COCCN1c1cc(CI)nc(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(Cl)n1
Temperature: 25 °C
Yield: 100 %

Procedure:
2-Chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine can also be prepared by the dropwise addition of methanesulfonyl chloride (91 mL, 1169.52 mmol) to [2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol (190 g, 779.68 mmol) and triethylamine (163 mL, 1169.52 mmol) in DCM (2293 mL) at 0° C. under air. The resulting solution was allowed to warm up slowly to RT over a period of 4 hours. The reaction mixture was quenched with water, extracted with DCM and the organic layer dried over MgSO4, filtered and evaporated to afford [2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methyl methanesulfonate as a yellow gum (251 g). Sodium iodide (234 g, 1560.07 mmol) was added to this material in acetone (3679 mL) and the resulting suspension stirred at RT for 16 hours. The reaction mixture was evaporated to dryness and redissolved in DCM and washed three times with water then with a saturated aqueous solution of sodium thiosulphate. The organic layer was dried over MgSO4, filtered and evaporated to afford crude desired product (270 g). This was purified by chromatography to give an off white solid which was further triturated with ether to give the desired material which was identical to previous samples.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:17][C:6]2=[CH:7][C:8]3[C:9]([CH3:16])=[CH:10][C:11]([CH3:15])=[N:12][C:13]=3[CH:14]=[C:5]2[CH:4]=[CH:3]1.CN1C=CN=C1.Cl[O-].[Na+].S([O-])([O-])(=[O:30])=S.[Na+].[Na+]>C(OCC)(=O)C.O>[O:30]1[C@@H:4]2[C:5]3[C:6]([O:17][C:2]([CH3:18])([CH3:1])[C@H:3]12)=[CH:7][C:8]1[C:9]([CH3:16])=[CH:10][C:11]([CH3:15])=[N:12][C:13]=1[CH:14]=3
Reactant: Cc1cc(C)c2cc3c(cc2n1)C=CC(C)(C)O3
Reactant: O=S([O-])([O-])=S
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2cc3c(cc2n1)[C@H]1O[C@H]1C(C)(C)O3
Yield: 68 %

Procedure:
To a solution of 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline (4.64 g, 19.4 mmol) in ethyl acetate (70 mL), N-methyl imidazole (0.303 mL, 3.88 mmol) and Ph,Ph salen manganese complex (201 mg, 0.194 mmol) were added at room temperature and sodium hypochlorite aqueous solution (25.6 g, 1.513 mol/kg, 38.8 mmol) was added dropwise in water bath, and the resulting mixture was stirred in water bath for 1 hour. Further, in water bath, sodium hypochlorite aqueous solution (25.6 g, 1.513 mol/kg, 38.8 mmol) was added, and the resulting mixture was stirred in water bath for 1 hour. Upon the completion of the reaction, sodium thiosulfate aqueous solution was added to the reaction solution, the resulting mixture was filtered through celite and extracted. The organic phase was washed with sodium hydrogencarbonate aqueous solution and then with sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=1/3) and the aimed product was obtained (yield: 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9](=[O:11])[NH2:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17]([N:19]=[C:20]=[S:21])=[O:18]>CC(C)=O>[C:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20]([NH:19][C:17]([O:16][CH3:15])=[O:18])=[S:21])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:11])[NH2:10]
Reactant: NC(=O)Sc1ccc(N)c([N+](=O)[O-])c1
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1[N+](=O)[O-]

Procedure:
1 G. of 1-amino-4-carbamoylthio-2-nitrobenzene in 20 ml. acetone is treated with 3.0 g. methoxy carbonyl isothiocyanate at room temperature for several days. The solution is concentrated and the residue triturated with methanol to afford 4-carbamoylthio-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene.
Reaction SMILES: C([Mg]Br)C.[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:12][CH2:13][C:14]#[C:15][CH2:16]Cl.[NH4+].[Cl-]>C1COCC1.[Cu]Cl>[Cl:12][CH2:13][C:14]#[C:15][CH2:16][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: ClCC#CCCl
Reactant: C#CCCCCC
Agent: Cl[Cu]
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCCC#CCC#CCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
54.6 ml of a 1M solution of ethyl magnesium bromide in THF were added dropwise, at room temperature, to a solution of 5 grams of 1-heptyne in 15 ml of anhydrous THF, under an inert atmosphere. With the addition complete, the mixture was maintained under stirring for 30 min at room temperature and then heated under reflux for 1 h 30 min. The mixture was cooled to room temperature and then 412 mg of copper(I) chloride were added and the mixture was again heated under reflux for 1 hour. The mixture was then cooled to room temperature and 14.2 ml of 1,4-dichloro-2-butyne were added fairly rapidly. The mixture was refluxed for 1 h, 30 min and then maintained under stirring for 15 h at room temperature before heating again under reflux for 2 h, 30 min. The reaction medium was then cooled to 4° C. and hydrolyzed with care with a saturated aqueous solution of NH4Cl. The medium was then extracted 3 times with diethyl ether and the combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried over Na2SO4, filtered and concentrated under vacuum in a rotary evaporator. The oily residue containing 1,4-dichloro-2-butyne in excess was purified by distillation under reduced pressure to give 6.55 g of 1-chloro-2,5-undecadiyne in the form of a pale yellow oil (yield 69%).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9](O)([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:15]O>>[CH3:15][O:3][C:1]([C:4]1[O:8][C:7](/[C:9](/[CH2:12][CH3:13])=[CH:10]/[CH3:11])=[CH:6][CH:5]=1)=[O:2]
Reactant: CCC(O)(CC)c1ccc(C(=O)O)o1
Reactant: CO
Product: C/C=C(\CC)c1ccc(C(=O)OC)o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-(5-Carboxy-2-furanyl)pentan-3-ol (200 mg, 1.1 mmol) is dissolved in methanol (20 mL). HCl (g) is bubbled through the solution for 30 seconds. The reaction is stirred for 20 minutes at room temperature with no reaction. The solution is heated to 60° C. for 2 hours. The solution is concentrated and water is added followed by solid NaHCO3 until the pH was basic. Ethyl acetate is added and the solution is extracted. The organic layer is washed with water, dried over MgSO4 and filtered. The filtrate is concentrated to 213 mg of an orange oil which is used as is.
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)=O.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1>C(O)(=O)C>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[N:29]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(NC=O)cc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(N)cc2)n(-c2ccc(F)cc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A mixture of ethyl 4-[4-(formylamino)phenyl]-2,4-dioxobutanoate (6 g) and 4-fluorophenylhydrazine hydrochloride (4.1 g) in acetic acid (30 ml) was stirred at 100° C. for 2 hours. The mixture was concentrated, and the residue was treated with 10% hydrochloric acid (10 ml) and methanol (40 ml) at 60° C. for 2 hours. The solvent was evaporated, and the residue was dissolved in water. The obtained solution was neutralized and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated in vacuo. The residue was washed with ethanol to give crystals of ethyl 5-(4-aminophenyl)-1-(4-fluorophenyl)pyrazole-3-carboxylate (3.4 g).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:12]1=[O:29].[OH-].[Na+]>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([N:13]2[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:12]2=[O:29])=[CH:23][CH:24]=1
Reactant: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccc(F)cc2)c1=O

Procedure:
The product is produced as described in example 18 from 16.4 g of 8-[3-(4-fluorophenyl)-2-oxo-4-phenyl-4-imidazolin-1-yl] caprylic acid methyl ester and 1.6 g of NaOH in 80 cc. of methanol. Further purification by chromatography on silicic acid gel using chloroform as eluant.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)(O)[CH2:6]2.C(O)(=O)C.Cl.[C:26]([OH:32])(=[O:31])[CH2:27][C:28]([OH:30])=[O:29]>C(O)C>[C:26]([OH:32])(=[O:31])[CH2:27][C:28]([OH:30])=[O:29].[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1)[CH2:6]2
Reactant: CN1C2CCC1CC(O)(c1ccc(C(F)(F)F)cc1)C2
Agent: Cl
Agent: O=C(O)CC(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: CN1C2C=C(c3ccc(C(F)(F)F)cc3)CC1CC2

Procedure:
The title compound was prepared from 8-methyl-3-(4-trifluoromethylphenyl)-8-azabicyclo[3.2.1]octan-3-ol (5 g, 17.5 mmol), glacial acetic acid (16 mL) and concentrated hydrochloric acid (16 mL). The free base of the title compound was dissolved in ethanol (96%) and added malonic acid (1.17 g, 11.2 mmol) in ethanol (96%), the solution was concentrated to dryness, and the residue was trituated in diethyl ether, the title compound precipitated as powder and was isolated by filtration. Yield 3.9 g (60%), m.p. 106.7-107.8° C.
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH:27][C:28]2[CH:49]=[CH:48][CH:47]=[C:30]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]5[CH2:45][CH2:46]5)=[O:43])[N:40]=4)[N:37]=3)[CH:29]=2)=[O:12])[CH2:4][CH2:5][CH2:6]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CCC1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)cn5n4)c3)c2)CCC1
Yield: 60.5 %

Procedure:
Using 3-(1-cyanocyclobutyl)benzoic acid (110 mg, 0.56 mmol), oxalyl chloride (60 μL, 0.70 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.47 mmol) and N-methylpyrrolidone (3.0 mL) as starting materials and in the same manner as in Example 335, the title compound (140 mg, 60%) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:3]=1.[Li]CCCC.[C:24]([Si:28]([CH3:43])([CH3:42])[O:29][C@H:30]1[C@H:37]2[C@H:33]([O:34][C:35]([CH3:39])([CH3:38])[O:36]2)[O:32][C@H:31]1[CH:40]=[O:41])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:24]([Si:28]([CH3:43])([CH3:42])[O:29][C@H:30]1[C@H:37]2[C@H:33]([O:34][C:35]([CH3:38])([CH3:39])[O:36]2)[O:32][C@H:31]1[C@H:40]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:3]=1)[OH:41])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC1(C)O[C@@H]2O[C@@H](C=O)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@H](O)[C@@H]3O[C@H]4OC(C)(C)O[C@H]4[C@@H]3O[Si](C)(C)C(C)(C)C)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-ethoxy-benzyl)-benzene from step C (3.6 g, 11.1 mmol) in THF (60 ml) under N2 at −78° C. was added dropwise BuLi (2.5 M in hexanes, 4.4 ml, 11.1 mmol). After 30 minutes, aldehyde from step B (2.4 g, 64% clean, 5.1 mmol) in THF (20 ml) was added dropwise, and the reaction was stirred for 30 min at −78° C., allowed to warm to room temperature and stirred for 60 minutes, quenched with sat. aq. NH4Cl, diluted with Et2O, and washed with H2O and brine. The combined aqueous washes were back extracted with Et2O, which was washed by the same sequence. The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (120 g SiO2, 0-20% EtOAc:Hexanes, 75 minutes, 85 ml/min) to give clean (S)-[(3aS,5S,6R,6aS)-6-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl]-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-methanol (0.84 g, 1.5 mmol, 30%) plus the C5 epimer (0.83 g) and some mixed fractions (0.51 g).