Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4].[NH2:19][NH:20][C:21]([NH2:23])=S>C(O)C>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]3[N:14]([C:21]([NH2:23])=[N:20][N:19]=3)[N:13]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4]
Reactant: NNC(N)=S
Reactant: CC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CC(=O)N(C)c1cccc(-c2ccc3nnc(N)n3n2)c1
Yield: 25.3 %

Procedure:
A solution of 2.2 g of N-methyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide and 1.5 g of thiosemicarbazide in 100 ml of ethanol was refluxed for 5 hours, then the solvent was removed in vacuo. To the residue was added 100 ml of glacial acetic acid, this mixture was refluxed 18 hours, then the acetic acid was removed in vacuo. Saturated aqueous sodium bicarbonate was added to neutralize the mixture which was then extracted with dichloromethane:methanol (9:1). The extract was washed with water, dried and evaporated. The residue was chromatographed on a silica gel column, eluting with dichloromethane:methanol (9:1). The product was crystallized from dichloromethane-hexane, giving 0.6 g of the desired compound as yellow crystals mp 196°-197° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:19][CH2:20][C:21](Br)=[O:22].N1C=CC=CC=1>>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C@H:2]([O:1][C:21](=[O:22])[CH2:20][Br:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Solvent: c1ccncc1
Product: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)CBr
Yield: 89.8 %

Procedure:
To a rapidly-stirred slurry of 1.29 g (4.99 mmol) methyl (R)-3-hydroxytetradecanoate and 0.45 mL (5.2 mmol) bromoacetyl bromide in 25 mL hexanes at 0° C. in a flame-dried flask under N2 was added 0.42 mL (5.2 mmol)pyridine all at once. The mixture was removed from the cold bath for 30 min. The mixture was suction filtered through celite, washing with 75 mL ether. The filtrate was washed with 2×100 mL H2O and with 50 mL 10% NaHCO3. The ether was dried over MgSO4 and removed by rotary evaporation, giving 1.70 g (90%) crude (R)-3-[(bromoacetyl)oxy]tetradecanoic acid methyl ester as a yellow oil. Analytically pure samples could be prepared by subjecting the oil to radial chromatography, eluting with CH2Cl2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[O:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=1)[C:39]([O:41][CH3:42])=[O:40]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:35][C:36]3[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=3)[C:39]([O:41][CH3:42])=[O:40])[CH3:23])=[C:18]([CH3:24])[CH:17]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[O:11][N:10]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CNc1ccc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN(C)c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of N-(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenyl)-N-methylamine (0.45 g, 1.1 mmol) in dimethylformamide (4 mL) was treated with potassium carbonate (0.15 g, 1.1 mmol) followed by methyl 3-(bromomethyl)benzoate (0.25 g, 1.1 mmol). After stirring at ambient temperature for 24 h, the reaction was partitioned with ethyl acetate and water. The organic layer was washed with water (2×50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered and condensed to a residue which was chromatographed on silica gel eluting with 20% ethyl acetate/hexanes. Yield=0.43 g. (70%) of methyl 3-{[(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenyl)(methyl)-amino]methyl}benzoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]C)=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:27])[CH3:26])=[O:5])[CH3:2].[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)OC)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)O)c1)N2
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.9 %

Procedure:
To a stirred mixture solution of 2-(3-methoxycarbonyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.7 g, 10.0 mmol) in tetrahydrofuran (20.0 mL) was added 4.0 N lithium hydroxide in water (12.0 mL). The reaction mixture was stirred at room temperature for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-carboxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.6 g, quant.) as a light white solid which was used for next step without further purification: MS (ESI) M+1=354.1.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[NH2:7][C:8]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:10](=[O:21])[N:9]=1>CN(C=O)C>[Cl:1][CH2:2][C:3]1[N:7]=[C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10](=[O:21])[N:9]2[CH:5]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Solvent: CN(C)C=O
Product: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
1,3-Dichloroacetone (2.27 g, 11.92 mmol) was added to a solution of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one (4.6 g, 12 mmol) in DMF (135 mL). The mixture was stirred at 150° C. for 30 minutes under microwave irradiation and then the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one (2.5 g, 75% yield) as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([S:20][CH:21]([NH:28][C:29](=[O:32])[CH2:30]O)[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:35])=O>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([S:20][CH:21]([NH:28][C:29](=[O:32])[CH2:30][Cl:35])[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2SC(NC(=O)CO)c2ccncc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2SC(NC(=O)CCl)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N-(4-tert-Butylphenyl)-2-(2-hydroxyacetylaminopyridin-4-ylmethylthio)pyridine-3-carboxamide (Compound No. 12-8, 250 mg, 0.55 mmol) was suspended in anhydrous dichloromethane (5.0 mL) under ice-cooling, and thionyl chloride (80 μL, 1.1 mmol) was added thereto. The mixture was stirred for 6 hours at room temperature, and the solvent was evaporated under reduced pressure. The resulting solid was filtered off with ethyl acetate and washed with diethyl ether to give 270 mg of the target compound quantitatively as a pale yellow solid.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].BrC[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C)C=O>[CH:23]1([CH2:22][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:25][CH2:24]1
Reactant: BrCCC1CC1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
To a mixture of 4-difluoromethoxy-3-hydroxy-benzaldehyde (5.0 g, 27 mmol) and potassium carbonate (5.5 g, 40 mmol) in dimethylformamide (30 ml) under inert atmosphere at 60° C. was added bromoethylcyclopropane (5 g, 37 mmol). The mixture was stirred and heated at 65° C. After 1.5 hour, the mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure. The mixture was extracted with ethyl acetate (2×25 ml) and water (25 ml). The organic layer was washed with water (25 ml), brine (25 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give 3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde as an oil (6.4 g, 100%). 1HNMR (CDCl3): 0.38-0.44 (m, 2H), 0.62-0.75 (m, 2H), 1.15-1.36 (m, 1H), 3.98 (d, J=4.5 Hz, 2H), 6.78 (t, JH-F=75 Hz, 1H), 7.30-7.50 (m. 3H), 9.96 (s, 1H).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].CO.OS(O)(=O)=O.[C:17]([O-])(O)=O.[Na+]>C1COCC1>[CH3:17][O:8][C:7](=[O:9])[C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1
Reactant: O=C([O-])O
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A 500 g sample of L-pyroglutamic acid was added to 2.8 L of anhydrous methanol, 28 mL of H2SO4 was added, and the mixture was stirred for 4 hr at 60° C. The reaction mixture was cooled to room temperature, 262 g of NaHCO3 was added, and the mixture was stirred for an additional 16 hr. The mixture was dried by addition of 314 g of Na2SO4 with stirring for 1 hr, then the mixture was filtered and the solvent was evaporated under vacuum to yield a pale yellow oil. The oil was dissolved in THF, and a small amount of unreacted acid was filtered off. The THF was removed under vacuum, and the residual oil was dried by azeotropic distillation with toluene.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[CH2:7]2.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:16]1>O>[CH:22]1[CH:21]=[CH:20][C:19]2[S:15][N:16]=[C:17]([N:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]4[CH:5]=[C:6]5[CH2:7][C:8](=[O:14])[NH:9][C:10]5=[CH:11][C:12]=4[Cl:13])[CH2:28][CH2:29]3)[C:18]=2[CH:23]=1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Solvent: O
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Temperature: 99 °C
Reaction time: 1.17 h

Procedure:
To de-ionized water (2.0 Lit), was added 5-(2-chloroethyl)-6-chloro-oxindole (100 g) and 1-(1,2-benzisothiazol-3-yl)piperazine (210 g) at 30-35° C. The mixture was slowly heated under stirring to 98-100° C. over 60-80 minutes. The resultant mass was stirred for 10-15 hours at 98-100° C. After completion of reaction as monitored by HPLC, the suspended solid material was filtered at 98-100° C. The wet cake so obtained was suspended in de-ionized water (2.0 Lit) and heated to 90-95° C. and maintained at this temperature for 30 minutes. The solid suspension was filtered at 90-95° C. The wet cake was further added to isopropyl alcohol (1.5 Lit) and stirred for 2 hours at 30-35° C. The solids were filtered and washed with isopropyl alcohol (500 ml) and dried under vacuum at 50-55° C. for 7-8 hours till moisture content was not more than 1.0% w/w.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([Sn:13](Cl)([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O>[CH2:22]([Sn:13]([N:1]=[N+:2]=[N-:3])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCC[Sn](Cl)(CCCCCCCC)CCCCCCCC
Agent: [Na+]
Solvent: O
Product: CCCCCCCC[Sn](CCCCCCCC)(CCCCCCCC)N=[N+]=[N-]
Temperature: 8 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
In 30 ml of pure water was dissolved 10.19 g of sodium azide and the solution was cooled to 8° C. Then, 50.0 g of trioctyltin chloride was added dropwise over a period of 10 minutes and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was then extracted with 88 ml of methylene chloride and further with 25 ml of the same solvent, and the extract was washed with 25 ml of 10% aqueous sodium chloride solution and concentrated to provide 50.05 g of trioctyltin azide.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1CCCC([Cl:24])C1=O)(C)(C)C>>[Cl:24][CH:9]1[CH2:10][CH2:11][CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]1=[O:13]
Reactant: O=C1CCCCC1c1ccccc1
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Product: O=C1C(Cl)CCCC1c1ccccc1

Procedure:
The chlorination of 2-phenylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: CC([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=O.[OH-].[Na+]>O.C(O)C>[Cl:11][C:10]1[CH:9]=[C:8]([Cl:12])[C:7]([O:13][CH3:14])=[CH:6][C:5]=1[NH2:4]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Cl)cc1Cl
Yield: 54.3 %

Procedure:
In the manner of Example 2, Step C, the reaction of 37.4 g (0.16 mole) of 2,4-dichloro-5-methoxyacetanilide with 12.8 g (0.32 mole) of sodium hydroxide in 30 mL of water and 30 mL of ethanol produced 16.7 g of 2,4-dichloro-5-methoxyaniline.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1cccc2ccccc12
Product: Cc1nc(NC(=O)c2cccc3ccccc23)sc1C(=O)NCc1ccccc1
Yield: 12 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use naphthalene-1-carbonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 12% yield; m.p. 99-101° C.; 1H NMR (CDCl3, 300 MHz) δ 8.40 (d, J=7.5 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.79-7.76 (m, 8H), 5.93 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 2.09 (s, 3H); MS (ES+) m/z 402.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: CO
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 4-bromo-2-methyl-benzoic acid 10.0 g, 46.5 mmol) in methanol (100 mL) at room temperature was added sulfuric acid (conc. 1 mL) dropwise. The solution was heated at reflux for 16 h. The solution was removed from heat and sulfuric acid (conc. 0.5 mL) was added. The solution was heated at reflux 2 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, then with saturated sodium chloride. The solution was dried (MgSO4), filtered, and concentrated in vacuo to a crude colorless oil. Flash chromatography (SiO2, 5% ethyl acetate/hexane) gave the title compound as a colorless oil (9.2 g, 87%). 1H NMR (400 MHz, CDCl3): δ ppm 2.58 (s, 3H) 3.88 (s, 3H) 7.38 (dd, J=8.46, 1.89 Hz, 1H) 7.42 (d, J=1.52 Hz, 1H) 7.78 (d, J=8.34 Hz, 1H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH:3]=[CH2:4].[F:7][C:8]([F:37])([F:36])[C:9]1[CH:10]=[C:11]([C@H:19]([O:21][C@@H:22]2[C@@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:26]([CH:34]=[O:35])[CH2:25][CH2:24][O:23]2)[CH3:20])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[CH2:1]([CH:34]([C@@H:26]1[CH2:25][CH2:24][O:23][C@H:22]([O:21][C@@H:19]([C:11]2[CH:10]=[C:9]([C:8]([F:36])([F:7])[F:37])[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=2)[CH3:20])[C@H:27]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:35])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC[Mg]Br
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCC(O)[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
3-Butenylmagnesium bromide (0.5M in tetrahydrofuran, 75 mL, 37.5 mmol) was added slowly to a stirred, cooled −78° C. solution of (2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde (WO 00/56727A1; 11.1 g, 24.9 mmol) in tetrahydrofuran (125 mL). The mixture was stirred at −78° C. for 3 hours, then at room temperature for 1.5 hour. Saturated aqueous ammonium chloride (20 mL) was added slowly, followed by ethyl acetate (300 mL). The layers were separated and the organic layer was washed with brine (100 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL), the combined organic layers were dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (97:3 increasing to 80:20), to give the title compound (8:1 mixture of alcohol diastereoisomers) as a colorless oil (10 g, 80%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1I.[C:16]([O:22][CH3:23])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]>C1COCC1.CCOC(C)=O.[Cu]I>[CH3:23][O:22][C:16]([C:17]1[C:9]2[CH:10]=[C:11]([Br:14])[CH:12]=[CH:13][C:8]=2[O:19][C:18]=1[CH3:20])=[O:21]
Reactant: COC(=O)CC(C)=O
Reactant: Brc1ccc(Br)c(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)oc2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of 100 mg (0.525 mmol) copper(I)iodide and 1.90 g (13.7 mmol) potassium carbonate in 10 mL THF was added 1.75 g (4.84 mmol) 1,4-dibromo-2-iodo-benzene and 520 μL methyl acetoacetate under argon atmosphere. Then the mixture was stirred at 100° C. for 5 h under reflux. The reaction mixture was diluted with EtOAc and extracted with water. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=9/1).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.F[C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[N:26][CH:27]=1.O>CC(N(C)C)=O>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][CH:8]([O:7][C:22]2[CH:27]=[N:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=[N+]([O-])c1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])nc2)CC1
Reaction time: 1 h
Yield: 49.7 %

Procedure:
Add potassium tert-butoxide (4.84 g) to a solution of tert-butyl 4-hydroxy-1-piperidine-carboxylate (8.76 g) in dimethylacetamide (DMA, 39 mL) at 0° C. under nitrogen. Stir for 1 h and add drop wise a solution 5-fluoro-2-nitro-pyridine (5 g) in DMA (78 mL). Let the reaction stir at RT overnight. Add water and stand for 1 h. Filter, wash with water. Purify by silica gel column chromatography eluting with DCM/EA (0-15%) to afford 5.65 g of the title compound. MS (ES+): m/z=324 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5](N=CN(C)C)=[CH:4][CH:3]=1.Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[O:24])=[CH:21][N:22]=2)[N:19]=1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]([C:20]2[N:18]3[N:19]=[C:14]([C:3]4[CH:2]=[N:7][N:6]([CH3:5])[CH:4]=4)[CH:15]=[CH:16][C:17]3=[N:22][CH:21]=2)=[O:24])=[CH:26][CH:27]=1
Reactant: CN(C)C=Nc1ccc(Cl)nn1
Reactant: COc1ccc(C(=O)c2cnc3ccc(Cl)nn23)cc1
Product: COc1ccc(C(=O)c2cnc3ccc(-c4cnn(C)c4)nn23)cc1

Procedure:
The title compound was prepared in analogy to the synthesis of compound of Example 1, starting with (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(4-methoxy-phenyl)-methanone (Stage 3.2) (tR 1.1 min (conditions 2), MH+=334)
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[CH2:18]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([F:17])([F:16])[CH2:11][OH:12])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(F)(F)CN(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCC(F)(F)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.4 %

Procedure:
At −78° C. to a solution of ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (1.19 g, 3.5 mmol) in THF (20 mL) was added DIBAL-H (15 mL, 1.0 M in hexane, 15 mmol) dropwise. The temperature was maintained at below −70° C. during the addition. After the addition, the acetone-dry ice bath was removed and the reaction mixture was allowed to warm up to room temperature and stirred for 18 h. Celite was added to the reaction mixture, followed by the slow addition of H2O (5 mL), 2 N NaOH (5 mL) and H2O (5 mL). The reaction mixture was filtered, concentrated in vacuo and purified by ISCO chromatography to give 3-(dibenzylamino)-2,2-difluoropropan-1-ol as a colorless oil (810 mg, 80% yield) LCMS: RT=2.48 min [M+H] 292.15 (LCMS Method 1).
Reaction SMILES: [NH2:1][C:2]1([CH2:20][O:21][CH2:22][C:23]#[N:24])[C:15]2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2.C[Al](C)C>ClCCCl>[Br:19][C:5]1[CH:4]=[C:3]2[C:8]([O:9][C:10]3[C:11]([F:18])=[CH:12][C:13]([O:16][CH3:17])=[CH:14][C:15]=3[C:2]32[N:1]=[C:23]([NH2:24])[CH2:22][O:21][CH2:20]3)=[CH:7][CH:6]=1
Reactant: COc1cc(F)c2c(c1)C(N)(COCC#N)c1cc(Br)ccc1O2
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(F)c2c(c1)C1(COCC(N)=N1)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of 2-((9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methoxy)acetonitrile (7.72 g, 19.63 mmol) in DCE (115 mL) was added trimethylaluminum (2M in toluene) (19.63 mL, 39.3 mmol) at RT. The reaction mixture was stirred for 10 min at RT and then heated to 75° C. for 1 hour. The reaction mixture was cooled to RT and quenched with sodium sulfate decahydrate. The reaction mixture was vigorously stirred for 30 minutes, diluted with EtOAc and stirred overnight. The mixture was filtered through a pad of celite and filter cake was washed with EtOAc. The solvent was removed under reduced pressure to obtain an oily residue which crystallized to give 7′-bromo-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (7.49 g, 19.05 mmol, 97% yield) as a cream-colored solid.