Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH:17]([CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].Cl>[OH-].[Na+]>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1)[O:13][CH:17]([CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: CC(Br)CCCCCCCCCC(=O)O
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(CCCCCCCCCC(=O)O)Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 255.2 %

Procedure:
3,5-Bis(trifluoromethyl) phenol (20.6 g) was dissolved in 1N sodium hydroxide (270 mL). The solution was refluxed under heating for 10 hours. Further, the solution was added with 11-bromododecanoic acid (4.7 g). After the reflux under heating was continued, the reaction solution was left to be cooled. The reaction solution was added with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed. The resulting crystals was washed with hexane and purified by silica gel column chromatography to obtain 11-(3,5-Bis(trifluoromethyl) phenoxy)dodecanoic acid (18.4 g, 50%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.P(Br)(Br)[Br:15].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:15][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(I)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1cc(I)ccc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
To a solution of [4-iodo-2-(trifluoromethyl)phenyl]methanol (2.1 g, 6.95 mmol) in DCM (15 ml) in an ice-water bath was added dropwise a solution of phosphorous tribromide (0.66 ml, 7.00 mmol, Aldrich) in DCM (15 ml). The resulting solution was allowed to warm to ambient temperature and stirred under nitrogen for 2 h. The reaction mixture was poured onto a mixture of ice-water (50 ml) and saturated sodium hydrogen carbonate (50 ml). The biphasic mixture was diluted with DCM (50 ml). The phases were separated and the aqeuous phase washed with DCM (50 ml). The combined organic phases were washed with water (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave 1-(bromomethyl)-4-iodo-2-(trifluoromethyl)benzene as a brown oil (1.24 g).
Reaction SMILES: C([N:3]([C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:26]=1[CH3:27])[C:4](=[O:8])[C:5]([O-])=[O:6])C.[C:30]([Mg]Cl)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[OH:6][CH:5]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:4]([NH:3][C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[C:13]=2[C:26]=1[CH3:27])=[O:8]
Reactant: CCN(C(=O)C(=O)[O-])c1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)C(O)C(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of ethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxamate (500 mg, 1.26 mmol) obtained in Example 15 in THF (10 mL) was added dropwise at 0° C. under an argon atmosphere tert-butylmagnesium chloride (2.0 M THF solution, 1.9 mL, 3.78 mmol) and the mixture was stirred for 30 minutes. After the reaction solution was warmed to room temperature and was stirred at the same temperature for 1 hour, the reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to obtain 194 mg (yield: 38%) of the title compound as a diastereomer mixture. Melting point: 165-166° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13]([CH3:15])=[CH2:14])[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([C:9](=[O:11])[CH3:10])[CH2:12][C:13]2([CH3:15])[CH3:14]
Reactant: C=C(C)CN(C(C)=O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1CC(C)(C)c2cc(F)ccc21
Temperature: 150 °C

Procedure:
According to the procedure described in S. Coulton et al. WO9925709 with the following modifications. N-(4-Fluoro-phenyl)-N-(2-methyl-allyl)-acetamide (5 grams, 24.12 mmol) was added to a microwave tube with aluminum trichloride (7 grams, 52.4 mmol). The tube was capped and heated to 150° C. for 20 minutes under microwave. The slurry was worked up with water and ethyl acetate, the organic layer was extracted with 3 washes of saturated sodium bicarbonate solution and the organic layer was dried over magnesium sulfate. The solution was then filtered and rotary evaporated to yield pure 1-(5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone in quantitative yield. This was converted to the free indoline by suspending the entire 5 grams of product in 20 mL of 6 M HCl and heating in a microwave to 200° C. for 10 minutes. The resulting 5-Fluoro-3,3-dimethyl-2,3-dihydro-1H-indole crystallized on cooling as the hydrochloride salt in quantitative yield. This material was identical to the previously reported compound.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[CH2:7][CH2:6]1.[Cl:16][C:17]1[CH:30]=[CH:29][C:20]2[S:21][C:22]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([CH3:24])[C:19]=2[CH:18]=1>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][S:25]([C:22]3[S:21][C:20]4[CH:29]=[CH:30][C:17]([Cl:16])=[CH:18][C:19]=4[C:23]=3[CH3:24])(=[O:27])=[O:26])[CH:12]=2)[CH2:7][CH2:6]1
Reactant: CN(C)CCN1CCc2ccc(N)cc21
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: Cc1c(S(=O)(=O)Nc2ccc3c(c2)N(CCN(C)C)CC3)sc2ccc(Cl)cc12

Procedure:
The title compound (E122) was prepared from 1-(2-dimethylaminoethyl)-2,3-dihydro-1H-indol-6-ylamine (WO95/32967 Description 4) (100 mg, 0.49 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (137 mg, 0.49 mmol) using the method of Example 1 (40 g, 18%) MH+=450/452.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH2:10])=[N:2]1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13]>CC#N.O.C([O-])(O)=O.[Na+]>[C:15]1([O:14][C:12](=[O:13])[NH:10][C:3]2[C:4]3[C:5](=[CH:6][N:7]=[CH:8][CH:9]=3)[O:1][N:2]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1noc2cnccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(Nc1noc2cnccc12)Oc1ccccc1
Temperature: 70 °C
Yield: 78.3 %

Procedure:
To a suspension of isoxazolo[5,4-c]pyridin-3-ylamine (1.49 g, 11.0 mmol) in CH3CN (50 mL) was added phenyl chloroformate (0.696 mL, 5.50 mmol). The reaction mixture was heated at 70° C. overnight, then cooled to rt, diluted with H2O (100 mL) and saturated aqueous NaHCO3 (10 mL). The resulting yellow precipitate was filtered and dried under vacuum to give isoxazolo[5,4-c]pyridin-3-yl-carbamic acid phenyl ester (1.099 g, 39%). MS (ESI+): calcd for C13H9N3O3 m/z 255.06, found 256.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:21]1([C:27]([N:13]2[CH2:14][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:4][CH:5]=3)[CH2:10][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COC(=O)C1CNCC(c2ccc(C(F)(F)F)cc2)C1
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1

Procedure:
According to General Method 3A, 9.25 g (32.2 mmol) of methyl 5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylate and 9.63 g (64.7 mmol) of morpholine-4-carbonyl chloride were reacted. This gave 16.3 g of crude product in 76% purity (LC-MS), which was converted without any further purifying operations.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[N:11]1([CH2:17][CH2:18][CH2:19][C:20]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[NH:22][CH:21]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[OH-].[Na+]>ClCCl>[N:11]1([CH2:17][CH2:18][CH2:19][C:20]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[NH:22][C:21]=2[CH:3]=[O:4])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: c1[nH]c2c(c1CCCN1CCOCC1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1[nH]c2c(c1CCCN1CCOCC1)CCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
To an ice-cooled solution of 0.32 mL (4.1 mmol) of dimethylformamide in 3 mL of dichloromethane was added dropwise 0.4 mL (4.1 mmol) of phosphorus oxychloride. The reaction mixture was stirred at room temperature for 15 minutes and a solution of 680 mg (2.7 mmol) of 3-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole in 20 mL of dichloromethane was added dropwise at 0° C. The mixture was refluxed at 60° C. for 4 hours and cooled in an ice bath. Ice cubes were slowly added to the mixture followed by addition of 2 N sodium hydroxide to pH 12. The mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude product which was purified on a silica gel column eluting with dichloromethane-methanol-ammonium hydroxide (98:2:1) to give 600 mg (83% yield) of 3-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde as a dark red oil. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.33 (s, br, 1H, NH). MS m/z 277 [M+1].
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12]>O>[CH:1](=[CH:12][CH2:11][CH2:10][CH2:9][NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCN
Solvent: O
Product: NCCCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.3 %

Procedure:
To a stirred mixture of 20 g of water and 21.2 g of benzaldehyde, butylamine (14.6 g) was added under an nitrogen atmosphere. After being stirred for 45 minutes at room temperature, the agitation was stopped and the reaction mixture was allowed to stand for at least 15 minutes. The lower aqueous layer was then separated from the reaction mixture. The upper layer was collected and dried over anhydrous magnesium sulfate to give 22.0 g of product. 1H NMR (300 Hz, CDCl3, ppm): 8.25 (1H, s), 7.69 (2H, m), 7.39 (3H, m), 3.60 (2H, t, J=7.0 Hz), 1.68 (2H, p, J=7.3 Hz), 1.39 (2H, hex. J=7.7 Hz), 0.94 (3H, t, J=7.3 Hz)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:40][C:41]([F:52])([F:51])[O:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47]Br)=[CH:45][CH:44]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([N:23]([C:24](=[O:33])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:47][C:46]3[CH:49]=[CH:50][C:43]([O:42][C:41]([F:40])([F:51])[F:52])=[CH:44][CH:45]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NC(=O)COc3ccccc3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N(Cc3ccc(OC(F)(F)F)cc3)C(=O)COc3ccccc3)c2)CC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 1 g (2.19 mmol) 4-[4-nitro-3-(2-phenoxy-acetylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, 1.07 g (3.29 mmol) cesiumcarbonate and 0.79 g (3.29 mmol) 4-(trifluoromethoxy)benzyl bromide (commercially available) in 6.6 ml DMF was stirred at 110° C. for 2 h. After cooling to room temperature the precipitate was filtered of. The residue was used without further purification. The title compound was isolated as brown solid (0.39 g; 37%). MS(ISP): 631.5 (M+H)+
Reaction SMILES: C(OC([N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[CH2:23][C@H:22]3[N:19]([C:20](=[O:27])[C@@H:21]3[C@H:24]([OH:26])[CH3:25])[C:18]=2[C:28]([O:30]CC2C=CC([N+]([O-])=O)=CC=2)=[O:29])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>P([O-])([O-])([O-])=O.[Pd]>[OH:26][C@@H:24]([C@H:21]1[C:20](=[O:27])[N:19]2[C@@H:22]1[CH2:23][C:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[C:18]2[C:28]([OH:30])=[O:29])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C3=CCN(C(=O)OCc4ccccc4)CC3)C[C@H]12
Reactant: [H][H]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C3CCNCC3)C[C@H]12
Yield: 58.6 %

Procedure:
To a solution of 4-nitrobenzyl (5R,6S)-3-(1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (500 mg) in 0.1M phosphate buffer (pH 6.93, 20 ml) was added 20% (W/W) palladium on carbon (50% wet) and the solution was stirred under atmospheric pressure of hydrogen at ambient temperature for 5 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to give a residual solution, which was chromatographed on "Diaion HP-20" (100 ml) eluting in turn with water and a mixture of water and acetone (50:1-20:1, V/V). The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(piperidin-4-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (150 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[CH3:12][S-:13].[Na+].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[S:13][CH3:12])[CH:5]=[O:6]
Reactant: C[S-]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1c(F)cc(C=O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
To a solution of 3,4,5-trifluorobenzaldehyde (30.0 g, 0.187 mol) in anhydrous THF (400 mL) cooled in a cold water bath was added sodium thiomethoxide (14.4 g, 0.20 mol) in portions over 30 minutes. The mixture was stirred at room temperature for 18 hours, then poured into water and extracted with dichloromethane (1×500 mL, 2×200 mL). The combined extracts were washed with water, dried using magnesium sulfate, and concentrated. Purification of the product by silica gel chromatography using 2% dichloromethane/5% ethyl acetate in hexanes gave the 3,5-difluoro-4-(methylthio)-benzaldehyde as a clear colorless liquid (22.0 g, 62%). 1H NMR (CDCl3/400 MHz) 9.86 (t, J=1.5, 1H), 7.34-7.39 (m, 2H), 2.55 (s, 3H). HRMS m/z 188.0099 (M+, calcd 188.0107).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:9]=[C:8]([CH3:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:6]=1)[NH2:4].C(N(CC)CC)C.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=O)=[CH:31][CH:30]=1>ClCCl>[CH3:10][C:8]1[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:6]=[C:5]([C:3]2[N:4]=[C:33]([C:32]3[CH:36]=[CH:37][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:30][CH:31]=3)[O:1][N:2]=2)[CH:9]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(Cn2nc(C(N)=NO)cc2C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(-c3noc(-c4ccc(OC(F)(F)F)cc4)n3)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mechanically stirred solution of N′-hydroxy-5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboximidamide (Intermediate KK, 110 mg, 0.45 mmol) and triethylamine (188 μL, 1.35 mmol) in dichloromethane (4 mL) was added 4-(trifluoromethyoxy)benzoyl chloride (101 mg, 0.45 mmol) at a temperature of 0° C. After stirring at rt for 1 h, when analytical HPLC indicated complete conversion of the starting materials, all volatiles were removed in vacuo. The residue was re-dissolved in DMSO (6 mL) and heated to 140° C. for 30 minutes in a microwave oven (CEM Discover). Then, the reaction mixture was diluted with a few mL of methanol and subjected to preparative HPLC. The title compound was obtained in pure form (110 mg, 59%): 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 2H), 7.37 (d, 2H), 7.12 (d, 2H), 7.05 (d, 2H), 6.71 (s, 1H), 5.40 (s, 2H), 2.31 (s, 3H), 2.23 (s, 3H); ES-MS m/z 415 (MH)+; HPLC RT (Method K) 1.58 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:30]1[CH:34]=[C:33]([C:35](O)=[O:36])[N:32]=[CH:31]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:33]4[N:32]=[CH:31][O:30][CH:34]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1cocn1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cocn2)c1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 28 mg, 0.07 mmol) and oxazole-4-carboxylic acid (8 mg, 0.07 mmol). Yield 26 mg (75%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[N:41]([CH:43]=[CH:44][N:45]=2)[N:42]=1>O>[N:45]1[CH:44]=[CH:43][N:41]2[C:40]=1[CH:39]=[CH:38][C:37]([CH2:36][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]3[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:6][CH:7]=1)=[N:42]2
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Reactant: ClCc1ccc2nccn2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5nccn5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (1.2 g, 3.8 mmol) was added to a mixture of cesium carbonate (3.7 g, 11.6 mmol) and DMF (25 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 6-(chloromethyl)imidazo[1,2-b]pyridazine (0.96 g, 5 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 30% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-(imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.8 g, 47%,) as Off-white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.35 (s, 1H), 8.2 (d, 1H), 7.8 (s, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.3 (s, 2H) 3.9 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=442.1. HPLC: (95.8%, Condition-A).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](I)[CH:3]=1.[NH2:11][NH2:12]>C(O)C>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[NH:12][N:11]=1
Reactant: N#Cc1ccc(Cl)cc1I
Reactant: NN
Solvent: CCO
Product: Nc1n[nH]c2cc(Cl)ccc12
Reaction time: 24 h

Procedure:
A mixture of 10.0 g. of 4-chloro-2-iodobenzonitrile, 5 ml. of 95% hydrazine and 50 ml. of ethanol is allowed to stand for 24 hours at 50° C. Working up as in Example 1 gives 3-amino-6-chloroindazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([CH2:21][N:22]([CH:38]3[C:47]4[N:46]=[CH:45][CH:44]=[CH:43][C:42]=4[CH2:41][CH2:40][CH2:39]3)[CH2:23][CH2:24][CH2:25][CH2:26][N:27]3C(=O)C4C(=CC=CC=4)C3=O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:20])[CH3:18])[C:11]([CH2:21][N:22]([CH:38]3[C:47]4[N:46]=[CH:45][CH:44]=[CH:43][C:42]=4[CH2:41][CH2:40][CH2:39]3)[CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(F)cc2)cnc1CN(CCCCN1C(=O)c2ccccc2C1=O)C1CCCc2cccnc21
Agent: NN
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(F)cc2)cnc1CN(CCCCN)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.1 %

Procedure:
To a solution of 2-{4-[[5-(4-Fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]—butyl}-isoindole-1,3-dione (0.3125 g, 0.48 mmol) in ethanol (5 mL) was added hydrazine monohydrate (0.12 mL), and the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated, and purified via column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) to yield 0.1838 g (73%) of N-[5-(4-Fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine. 1H NMR (CDCl3) δ 0.85 (t, 2H, J=8.1 Hz), 1.25-1.34 (m, 7H), 1.61-1.72 (m, 1H), 1.89-2.05 (m, 4H), 2.54-2.82 (m, 8H), 3.35-3.47 (m, 3H), 3.93 (s, 2H), 4.06 (t, 1H, J=8.1 Hz), 5.53 (d, 2H, J=10.5 Hz), 5.78 (d, 2H, J=10.8 Hz), 6.99-7.04 (m, 3H), 7.15 (s, 1H), 7.31 (d, 1H, J=7.5 Hz), 7.66-7.70 (m, 2H), 8.47 (d, 1H, J=3.6 Hz).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:12]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:13]2[C:18]([N:19]=1)=[C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:16]=[C:15]([C:26]1[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)[N:14]=2>CS(C)=O>[NH2:32][C:29]1[N:28]=[CH:27][C:26]([C:15]2[N:14]=[C:13]3[C:18]([N:19]=[C:11]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]3[CH2:33][CH:34]3[CH2:36][CH2:35]3)=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:16]=2)=[CH:31][N:30]=1
Reactant: NCCN1CCOCC1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Solvent: CS(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(NCCN4CCOCC4)n(CC4CC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
2-Morpholin-4-yl-ethylamine (168 mg, 1.29 mmol) and dimethyl sulfoxide (1 ml) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.26 mmol) and the resulting mixture was stirred at 150° C. for 4 hours. The reaction mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (85 mg, 62%) as a pale yellow solid.