Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.Br[C:12]1[C:17]([F:18])=[CH:16][C:15]([O:19][CH3:20])=[C:14]([F:21])[CH:13]=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[F:18][C:17]1[CH:16]=[C:15]([O:19][CH3:20])[C:14]([F:21])=[CH:13][C:12]=1[N:34]1[CH2:35][CH2:36][CH:31]([CH2:30][CH2:29][CH2:28][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:32][CH2:33]1
Reactant: COc1cc(F)c(Br)cc1F
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: COc1ccc(Br)cc1C
Product: COc1cc(F)c(N2CCC(CCCc3ccccc3)CC2)cc1F
Yield: 33.7 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-(2-phenethyl)piperazine were replaced with 4-bromo-2,5-difluoroanisole (446 mg) and 4-(3-phenylpropyl)-piperidine (1.220 g), respectively. The resulting crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=8:1) to provide 1-(2,5-difluoro-4-methoxyphenyl)-4-(3-phenylpropyl)piperidine (233 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[N:6]3[CH2:13][CH2:14][O:15][C:5]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:24]I.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:24])[C:7](=[O:12])[N:6]3[CH2:13][CH2:14][O:15][C:5]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)OCCN12
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)N2CCOC2(c2ccccc2)c2cc(Cl)ccc21
Yield: 76.4 %

Procedure:
To a solution of 1.5 g of 9-chloro-2,3,6,10b-tetrahydro-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one in 20 ml of dimethylformamide was added 0.21 g of 62.5% sodium hydride. The resultant mixture was stirred with heating at 50° - 55°C for 1 hour, and 1.42 g of methyl iodide was added thereto at room temperature. Then, the mixture was heated at 55° - 60°C for 3 hours. After cooling, the reaction mixture was poured into 100 ml of water and acidified with hydrochloric acid. The resulting mixture was extracted with 50 ml of chloroform and the chloroform layer was washed successively with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel using chloroform as an eluent to give 1.2 g of 9-chloro-2,3,6,10b-tetrahydro-6-methyl-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one, having a melting point of 124° - 125°C. Recrystallization from ethanol gave colorless prisms, having a melting point of 136° - 137°C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH:11]=[N:10]1>O1CCCC1>[Br:1][C:13]1[C:14]([OH:18])=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[N:10][NH:9]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccc2[nH]ncc2c1
Solvent: C1CCOC1
Product: Oc1ccc2[nH]ncc2c1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.6 %

Procedure:
N-bromosuccinimide (1.06 g, 5.96 mmol) was added to a solution of the 1H-indazol-5-ol (800 mg, 5.96 mmol) obtained in Reference Example 4 in tetrahydrofuran (20 ml) at room temperature. The resulting mixture was stirred for 14 hours while being maintained at room temperature. The mixture was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-bromo-1H-indazol-5-ol (1.15 g, 91%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(OC([N:18]1[C:23](=[O:24])[CH:22]2[CH:20]([CH:21]2[C:25]([O-:27])=[O:26])[CH:19]1[C:28]([O-:30])=[O:29])=O)(C)(C)C.O>C(Cl)Cl>[C:25]([CH:21]1[CH:22]([C:23]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[O:24])[CH:20]1[CH:19]([C:28]([OH:30])=[O:29])[NH2:18])([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Reactant: C1COCCN1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 112.9 %

Procedure:
To a solution of AlCl3 (73 mg, 0.54 mmol) in dry CH2Cl2 (3 mL) at 0° C., morpholine (90 μl, 1.04 mmol) in dry CH2Cl2 (3 mL) was added dropwise. The mixture was stirred at room temperature for 20 min, and then ethyl (1SR, 2SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (143 mg, 0.41 mmol) in dry CH2Cl2 (1 mL) was added. After stirring at room temperature for 1 h, a mixture of ice and water was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate 1/1) to give 126 mg of the desired compound (70% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:11])[F:10].CN(C)[CH:14]=[O:15].Cl>C1COCC1>[F:10][CH:9]([F:11])[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[CH:14]=[O:15]
Reactant: Fc1ccc(C(F)F)c(Br)c1
Reactant: CN(C)C=O
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1cc(F)ccc1C(F)F
Temperature: -20 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
Isopropylmagnesium chloride-lithium chloride complex (1M, 21.46 mL, 21.46 mmol) was added to 2-bromo-1-(difluoromethyl)-4-fluorobenzene (4.39 g, 19.51 mmol) in THF (120 mL) cooled to −20° C. under nitrogen. The resulting solution was stirred at −20° C. for 1 hour. N,N-Dimethylformamide (1.813 mL, 23.41 mmol) was added, and the mixture stirred for a further 1 hour, maintaining the temperature in the range −15 to −20° C. The mixture was allowed to warm to ambient temperature, then 2M hydrochloric acid (100 mL) was added and the mixture was extracted with EtOAc (150 mL). The organic layer was washed with saturated sodium bicarbonate (120 mL) and concentrated to yield crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 2-(difluoromethyl)-5-fluorobenzaldehyde (1.250 g, 36.8%) as a colourless liquid.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:18]1(=[O:27])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][O:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[S:1][CH2:2][CH2:3][CH2:4]3)[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Oc1cccc2c1SCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1cccc2c1SCCC2
Temperature: 60 °C
Yield: 97.6 %

Procedure:
Under argon and with stirring, 500 mg (3.01 mmol) of 8-thiochromanol and 930 mg (3.31 mmol) of N-(4-bromobutyl) phthalimide are dissolved in 4 cm3 of dimethylformamide (DMF). 1.25 g (9.03 mmol) of K2CO3 are added. The mixture is heated at 60° C. for 6 hours. The DMF is evaporated off. The residue is taken up in H2O. The product is extracted with CH2Cl2 and dried over MgSO4. Purification over a silica column (eluant: CH2Cl2) yields 1.08 g of the title compound (white solid).
Reaction SMILES: [OH-].[K+].O.[CH3:4][C:5]([O:14][OH:15])([CH2:7][CH2:8][C:9]([CH3:13])([O:11]O)[CH3:10])[CH3:6].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:16]([O:15][O:14][C:5]([CH3:6])([CH3:4])[CH2:7][CH2:8][C:9]([OH:11])([CH3:13])[CH3:10])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(CCC(C)(C)OO)OO
Reactant: CC(C)(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)CCC(C)(C)OOC(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
A jacketed reactor equipped with a mechanical stirrer, a thermometer and a dropping funnel was charged with 18.7 g (0.150 mole) of 45% KOH, 15.0 g of water, 27.6 g (0.120 mole) of 77.6% (wetted solid) 2,5-dimethyl-2,5-dihydroperoxyhexane and 100 ml of methylene chloride. To the resulting two liquid phase mixture at 28° to 30° C. was added 12.8 g (0.100 mole) of 94.3% pivaloyl chloride over a period of about 30 minutes. The resulting mixture was then stirred for 2.0 hours at 28° to 30° C. after which the mixture was cooled to 15° to 20° C. and was allowed to separate into phases. The upper aqueous layer was removed and was discarded. The resulting product solution was then washed with 50 ml of 20% KOH solution at 0° C. and then with 50 ml of 7.7% sodium hydrogen carbonate solution at 15° to 20° C. The methylene chloride solution was then cooled to 0° to 10° C. and was reacted with 187 g of buffered sodium sulfite solution (consisting of 7.6 g of acetic acid, 8.4 g of sodium acetate, 19 g of sodium sulfite and 152 g of water) in order to covert the 4-hydroperoxy-1,1,4,4-tetramethylbutyl peroxypivalate that was formed in the peroxidation reaction to 4-hydroxy-1,1,4,4-tetramethylbutyl peroxypivalate, the desired product. A thick emulsion resulted which required three days of storage in the refrigerator to separate into two liquid phases. The upper aqueous layer was removed and an equal volume of diethyl ether was added in order to facilitate further processing. The solution was dried over anhydrous MgSO4 and after separation of the spent desiccant by filtration the solvents were remove in vacuo at 0° to 10° C. Some solids were removed by filtration and the resulting liquid weighed 20.4 g. The assay of the product was 90.3% according to peroxyester active oxygen content. The corrected yield was 74.9%. An infrared spectrum of the product showed a broad OH band centered at 3300 to 3400 cm-1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:42]([O:41][C:39](=[O:40])[NH:1][C@H:2]([C:3](=[O:4])[NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[CH3:43]
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in general procedure D using ethyl chloroformate. The final product was obtained in 60% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=O.[O-:13][C:14]#[N:15].[K+].CC(O)C>C(O)(=O)C>[Cl:12][C:7]1[CH:6]=[C:5]([C:3]2[NH:15][C:14](=[O:13])[O:1][CH:2]=2)[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: N#C[O-]
Reactant: O=C(CO)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=c1[nH]c(-c2ccc(Cl)c(Cl)c2)co1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of 2-hydroxy-3′,4′-dichloroacetophenone (10.3 g), potassium cyanate (8.1 g) and 2-propanol (100 mL) was heated to 50° C., and acetic acid (6.0 g) was slowly added dropwise. The mixture was stirred at 50° C. for 2 h. The reaction mixture was concentrated and poured into iced water (200 mL). The precipitated solid was collected by filtration, washed with water and air-dried to give the title compound as crystals (6.0 g, 52%). Recrystallization from tetrahydrofuran-hexane gave pale-yellow prism crystals. melting point: 262-263° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O:7][P:8]([O:17]C)([C:10]([S:12]([O:15]C)(=[O:14])=[O:13])=[CH2:11])=[O:9].Br[Si](C)(C)C.O>C(Cl)(Cl)Cl>[N:1]1([CH2:11][CH:10]([P:8]([OH:17])([OH:9])=[O:7])[S:12]([OH:15])(=[O:14])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: C=C(P(=O)(OC)OC)S(=O)(=O)OC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=P(O)(O)C(Cn1ccnc1)S(=O)(=O)O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 0.68 g (0.01 mole) of imidazole and 2.30 g (0.01 mole) of methyl 1-dimethoxyphosphinylethenesulfonate (U.S. Pat. No. 5,011,938 issued to Barnett et al. on Apr. 30, 1991) in 20 ml of chloroform is stirred at 20°-50° for one day. The reaction is cooled to room temperature, and 10.7 g (0.07 mole) of bromotrimethylsilane is added. The mixture is stirred at 20°-30° for 2-3 days, and to it is then added 20 ml water. The mixture is stirred for about 30 minutes, and the layers are separated. The water layer is extracted several times with CHCl3 (extracts are discarded) and is evaporated to dryness under vacuum. The residue is triturated with acetone to give a solid, which is collected by filtration and recrystallized from water/acetone to afford 2-(1-imidazolyl)-1-phosphonoethanesulfonic acid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][O:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C1(C2CCC(O)CO2)C=CC=CC=1.C(N(CC)CC)C>O>[Cl:8][C:7]1[C:2]([NH:11][CH:12]2[CH2:17][O:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: NC1CCC(c2ccccc2)OC1
Agent: OC1CCC(c2ccccc2)OC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1ncnc(NC2CCC(c3ccccc3)OC2)c1Cl
Temperature: 85 °C

Procedure:
2.4 g (13.5 mmol) of 4,5-dichloro-6-ethylpyrimidine, 2.4 g (13.5 mmol) of 5-amino-2-phenyltetrahydropyran (prepared from 2-phenyltetrahydropyran-5-ol (cf. U.S. Pat. No. 4,388,104) analogously to the routes described in Example A) and 3 ml (21 mmol) of triethylamine were heated for 12 hours at 85° C. After cooling, the mixture was diluted with water and extracted with ether, and the organic phase was washed with saturated NaCl solution. After drying and concentrating, the residue was purified by column chromatography using petroleum ether/ethyl acetate (9:1, 8:2). This gave 0.65 g (15% of theory) of the trans isomer as a colorless oil and 2.17 g (51% of theory) of the cis isomer as a colorless oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].C(N(CC)CC)C>C(O)C>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH:14][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH3:10]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNCC(=O)OCC
Temperature: 37.5 °C

Procedure:
Ethyl acrylate (11.5 g, 0.115 mol) was added to a solution of glycine ethyl ester hydrochloride (187) (20 g, 0.144 mol) and triethylamine (17.6 mL, 0.127 mol) in ethanol (134 mL) and the mixture heated to 35-40° C. for 3.5 hrs. The mixture was concentrated and partitioned between water (100 mL) and ethyl acetate (1×300 mL). The organics were washed with 1×100 mL half saturated sodium bicarbonate, 1×50 mL saturated sodium chloride, and dried over Na2SO4. The dried organics were evaporated to 20.94 g of clear colorless oil that was used in the next step without further purification. MS (ESI) m/z 204 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]1[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=1)[C:9]1[CH:10]=[C:11]([C:16]2[S:20][C:19]([CH2:21][C@@H:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[N:18][CH:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[Li+].[CH3:41][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:28]1[N:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][N:29]=1)[C:9]1[CH:10]=[C:11]([C:16]2[S:20][C:19]([CH2:21][C:22]([CH3:41])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[N:18][CH:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](C)Cc1ncc(-c2cc(C)cc(N(C(=O)OC(C)(C)C)c3nccc(C(F)(F)F)n3)c2)s1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)Cc1ncc(-c2cc(C)cc(N(C(=O)OC(C)(C)C)c3nccc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
The product from Step 1 (700 mg, 1.305 mmol) and methyl iodide (926 mg, 6.52 mmol) were taken up in THF (18 mL) at room temperature, and LHMDS (1.0 M in THF, 6.52 mL, 6.52 mmol) was added dropwise. After stirring for 1 h at room temperature, the reaction was quenched with saturated NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-50% ethyl acetate in hexanes) afforded methyl 3-[5-(3-{(tert-butoxycarbonyl)[4-(trifluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-2,2-dimethylpropanoate (324 mg, 45%) as a yellow gum. MS ESI: [M+H]+ m/z 551.1.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[CH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[CH3:3].C(N(CC)CC)C.[CH3:25][O:26][C:27]([S:29]Cl)=[O:28]>C1C=CC=CC=1>[CH3:25][O:26][C:27]([S:29][C:5]([C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])=[CH:4][N:2]([CH3:3])[CH3:1])=[O:28]
Reactant: CN(C)C=CC(=O)c1ccccc1C(F)(F)F
Reactant: COC(=O)SCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)SC(=CN(C)C)C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
4.2 g of 1-(N,N-dimethylamino)-2-(2-trifluoromethylbenzoyl)ethene and 2.6 g of triethylamine were added to 50 ml of benzene. 2.4 g of methoxycarbonylsulfenyl chloride dissolved in 10 ml of benzene was added dropwise to the solution obtained above under cooling in an ice-bath. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled away under reduced pressure. After adding an aqueous solution of sodium hydrogencarbonate, the mixture was extracted with ether. Thus 5.0 g of 1-methoxycarbonylthio-1-(2-trifluoromethylbenzoyl)-2-(N,N-dimethylamino)ethene was obtained (Compound 209).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[N:11]([C:16]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[F:28])=[O:20])=[CH:17][N:18]=3)[N:12]=[C:13](Cl)[CH:14]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>CN1C(=O)CCC1>[F:28][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([C:16]1[N:11]2[N:12]=[C:13]([NH:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]3)[CH:14]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]4)[N:7]=3)[C:10]2=[N:18][CH:17]=1)=[O:20]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Nc3cccc(Br)n3)cc(Cl)nn12
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccncc1F)c1cnc2c(Nc3cccc(N[C@H]4CC[C@H](O)CC4)n3)cc(N[C@H]3CC[C@H](O)CC3)nn12
Temperature: 160 °C

Procedure:
A mixture of 8-(6-bromopyridin-2-ylamino)-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (40 mg, 0.086 mmol) and (trans)-4-aminocyclohexanol (100 mg, 0.868 mmol) in NMP (0.5 mL) was heated at 160° C. in a microwave for 1.5 h (300 W power). The reaction mixture was cooled to room temperature and purified by preparative reversed-phase HPLC to give 45B (39.7 mg, 62%) as yellow solid. HPLC Rt=2.780 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=576.
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C@H:4]1[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:8][O:7][C@@H:6]([CH3:20])[O:5]1.[H-].[Na+].[C:23]1([CH:29](Br)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(OCC)(=O)C>[C:23]1([CH:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:1]/[N:2]=[CH:3]/[C@H:4]2[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:8][O:7][C@@H:6]([CH3:20])[O:5]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1/C=N/O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1/C=N/OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4R,5S)-(E)-4-hydroxyiminomethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (100 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (14 mg 60% in oil) at 5° C. After being stirred at the same temperature for 30 minutes, to the solution was added diphenylmethyl bromide (86.6 mg) and the mixture was stirred in an ice bath for additional 2 hours. The solution was diluted with ethyl acetate and washed successively with water and brine, dried over magnesium sulfate. The solvent was evaporated in vacuo and the crude residue was purified with preparative TLC with a mixture of n-hexane and ethyl acetate (4:1) as an eluent to give (2R,4R,5S)-(E)-4-diphenylmethoxyiminomethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][C@H:4]([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:9]3[C:8]([CH3:16])([CH3:15])[C:7]2=[O:17])[CH2:3]1.Cl[C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[NH:1][C@H:2]1[CH2:5][C@H:4]([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:9]3[C:8]([CH3:15])([CH3:16])[C:7]2=[O:17])[CH2:3]1
Reactant: Clc1nc2ccccc2o1
Reactant: CC1(C)C(=O)N([C@H]2C[C@H](N)C2)c2nccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3nc4ccccc4o3)C2)c2nccnc21
Temperature: 90 °C
Reaction time: 17 h

Procedure:
To a round bottomed flask was added 5-(trans-3-aminocyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (Intermediate 30, 0.1663 g, 0.716 mmol, [00391]), 2-chlorobenzo[d]oxazole (0.132 g, 0.859 mmol, Sigma-Aldrich Chemical Company, Inc.), and diisopropylethylamine (0.249 ml, 1.432 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (2.386 ml) to stir at 90° C. for 17 hours. The crude product was purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over min. Product was taken up in DCM and loaded onto a Silicycle Si-carbonate cartridge to remove any salts to give 5-(trans-3-(benzo[d]oxazol-2-ylamino)cyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (32.2 mg, 0.092 mmol, 12.87% yield). LCMS showed product peak at 1.625 min (m+1=350.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 6 H) 2.42-2.48 (m, 1 H) 3.18-3.29 (m, 2 H) 4.47-4.60 (m, 1 H) 5.17 (quin, J=8.31 Hz, 1 H) 6.95-7.04 (m, 1 H) 7.12 (td, J=7.63, 0.98 Hz, 1 H) 7.28 (d, J=7.24 Hz, 1 H) 7.37 (d, J=7.63 Hz, 1 H) 8.18 (d, J=3.33 Hz, 1 H) 8.23 (d, J=3.13 Hz, 1 H) 8.42 (d, J=6.65 Hz, 1 H).
Reaction SMILES: [C:1]([N:9]1[C@H:13]([C:14]([O:16]COC)=[O:15])[CH2:12][S:11](=[O:21])(=[O:20])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.O>[C:1]([N:9]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][S:11](=[O:20])(=[O:21])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOC(=O)[C@@H]1CS(=O)(=O)CN1C(=O)c1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CS(=O)(=O)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
31.3 g of methoxymethyl (4R)-3-benzoyl-1,1-dioxothiazolidine-4-carboxylate (prepared as described in Preparation 11) were dissolved in 200 ml of a 1:1 by volume mixture of trifluoroacetic acid and water, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated by evaporation under reduced pressure to leave crystals. These crystals were washed with 150 ml of water and then recrystallized from ethyl acetate to give 21.6 g (80.3%) of the title compound in the form of colorless needles melting at 175°-176° C.