Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9]O.CN(C)C=O.[OH-].[Na+].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][Cl:20]
Reactant: OCc1c(F)cccc1Br
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(Br)c1CCl

Procedure:
After dissolving (2-bromo-6-fluorophenyl)methanol (CAS 261723-33-5) (4.07 g) in toluene (50 ml), thionyl chloride (2.21 ml) was added dropwise while stirring on ice. N,N-Dimethylformamide (0.1 ml) was then added and the mixture was stirred for 6 hours. The reaction mixture was diluted with water, a 1N aqueous solution of sodium hydroxide was added and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (4.45 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH:20]=[C:21]1C(=O)O[C:24](C)([CH3:28])[O:23][C:22]1=[O:30].B.[Na]>CO.C(OCC)(=O)C.C(O)C.N1C=CC=CC=1.[Cu]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][C:22]([O:23][CH2:24][CH3:28])=[O:30]
Reactant: COCOc1cc(OC)c(OCOC)c(CC=C2C(=O)OC(C)(C)OC2=O)c1OC
Agent: [Cu]
Agent: B
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CCCc1c(OC)c(OCOC)cc(OC)c1OCOC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2.9 Grams of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethane was dissolved in a mixed solvent of 90 ml of methanol with 90 ml of ethyl acetate, then under an ice-cooled condition, 3 g of sodium boron hydride was added thereto. 1 Hour later, the reaction mixture was concentrated under a reduced pressure, to the residue obtained was added 300 ml of ethyl acetate, and this mixture was washed twice with 200 ml of water, further washed twice with 200 ml of a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. The dehydrated ethyl acetate solution was concentrated under a reduced pressure to obtain the residue, and the residue was dissolved in a mixed solvent of 20 ml of ethanol with 40 ml of pyridine, then a catalytic amount of copper powder was added thereto and the mixture was heated at 100° C. in an oil bath and stirred for 8 hours. The reaction mixture was concentrated under a reduced pressure, to the residue thus obtained was added 300 ml of ethyl acetate, then the solution was washed twice with 200 ml of a diluted aqueous solution of hydrochloric acid (pH 3), further washed 4 times with 200 ml of water, next washed twice with 200 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The residue thus obtained was purified by a silica gel column chromatography (diameter 5 cm×length 15 cm, eluent: 40% ethyl acetate-n-hexane solution, "Wakogel C-200") to yield 1.9 g of ethyl 4-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]butyrate. Colorless oily substance.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH:6]1[C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([C:27]([NH2:29])=[O:28])=[CH:22][CH:21]=2)(=[O:4])[CH:2]=[CH2:3].C(OC([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=O)(C)(C)C.Cl>>[N:37]1([CH2:3][CH2:2][C:1]([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][CH:6]2[C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][C:23]([C:27]([NH2:29])=[O:28])=[CH:22][CH:21]=3)=[O:4])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1
Reactant: C=CC(=O)N1CCC(Cc2ccccc2)CC1c1cc2cc(C(N)=O)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Product: NC(=O)c1ccc2[nH]c(C3CC(Cc4ccccc4)CCN3C(=O)CCN3CCNCC3)cc2c1

Procedure:
The 1-acryloyl-(4-benzyl)-piperidinyl-indole-5-carboxamide above was reacted with tert-butyl-1-piperazine carboxylate as described before. The product was deprotected using methanolic HCl. M+ 458.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.B1([O-])O[O:17]1.O.O.O.O.[Na+]>C1COCC1>[OH:17][CH:3]1[CH2:4][CH2:5][CH:1]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:2]1
Reactant: O=C(OCc1ccccc1)C1CC=CC1
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)C1CCC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The benzyl cyclopent-3-ene-1-carboxylate (2.0 g, 9.89 mmol) was dissolved in 20 mL of THF and cooled to 0° C. under nitrogen. Borane-THF complex (0.95 mL, 9.89 mmol) was added via syringe and the mixture was stirred for 30 minutes at 0° C. Sodium perborate tetrahydrate solution (100 mL of 0.33 M aqueous solution) was added, and after 30 minutes the reaction mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine and then dried over sodium sulfate. Filtration and concentration provided the crude product which was purified by chromatography on silica gel eluting with 10 to 30% EtOAc in hexanes to provide benzyl 3-hydroxycyclopentanecarboxylate.
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][N:9]=1)#[N:7].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:20][CH3:21])[N:11]=[CH:10][N:9]=[C:8]2[C:6]1[NH:24][N:23]=[N:22][N:7]=1
Reactant: COc1cc2ncnc(C#N)c2cc1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(-c3nnn[nH]3)c2cc1OC
Temperature: 30 °C
Reaction time: 0.29 h
Yield: 59.16 %

Procedure:
Experimental Procedure: 400.0 ml of dimethyl formamide and 20.0 g (0.09 mol) of 4-cyano-6,7-dimethoxy-quinazoline were charged into a 1.0 L 4necked round bottom flask, connected to a mechanical stirrer, thermometer socket and condenser under nitrogen atmosphere. 6.80 g (0.10 mol) of Sodium azide and 5.50 g (0.10 mol) of ammonium chloride were charged at 25-35° C. Stirred the mass for 15-20 min at 25-35° C. Stirred the mass for 15-20 min at 25-35° C. Reaction mass temperature was raised to 110-115° C. Maintained the mass temperature at 110-115° C. for 8-9 hours. Inorganic solid was filtered at 110-115° C. and the filtrate was collected into a conical flask. Cooled the filtrate to 25-30° C. 4000.0 ml of ethyl acetate was charged into a 5.0 L 4necked round bottom flask, connected to a mechanical stirrer, thermometer socket and addition flask. Reaction mass of dimethyl formamide solution was added to ethyl acetate solution under stirring. Maintained the mass temperature at 25-30° C. for 60-90 min. Cooled the mass temperature to 0-5° C. Maintained the mass temperature at 0-5° C. for 150-180 min. Filtered the solid and solid was washed with 100.0 ml of ethyl acetate. Compound was dried at 25-30° C. under vacuum. Obtained 14.20 g (yield is 59.16% by theory) of product Melting range 207.2° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:19]([C:23](=O)[CH3:24])[CH2:20][C:21]#[N:22].C(=O)(O)[O-].[Na+]>C(COC)OC>[C:21]([CH2:20][C:19]1[N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:2]2=[N:1][C:23]=1[CH3:24])#[N:22]
Reactant: CC(=O)C(Cl)CC#N
Reactant: Nc1ncccc1OCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nc2c(OCCCc3ccccc3)cccn2c1CC#N
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A mixture of 5.3 g of 2-amino-3-(3-phenylpropoxy)pyridine, 3.2 g of 3-chloro-4-oxopentanonitrile, 2.0 g sodium bicarbonate, and 50 ml dimethoxyethane was heated at reflux for 24 hrs., then stirred at room temperature 66 hrs. the solvent was removed in vacuo, the brown residue was taken up in 100 ml methylene chloride, filtered, dried over potassium carbonate and evaporated in vacuo to leave a brown gum residue. The residue was chromatographed on silica gel using first chloroform, then switching to 1:1 chloroform/ethyl acetate. The early eluates were combinedand evaporated and the resultant residue crystallized from isopropyl/ether to give the title compound (m.p. 143°-145° C.).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[NH:14][C:13]2=[O:22])[CH2:8][CH2:7]1)=O)C.[NH4+].[Cl-].[OH-].C([O-])([O-])=O.[Na+].[Na+]>[OH-].[Na+]>[F:21][C:19]1[CH:18]=[CH:17][C:16]2[N:12]([CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[C:13](=[O:22])[NH:14][C:15]=2[CH:20]=1
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Product: O=c1[nH]c2cc(F)ccc2n1C1CCNCC1

Procedure:
A suspension of 1-ethoxycarbonyl-4-(5-fluoro-2-oxo-1-benzimidazolinyl)piperidine (5.22 g, 17 mmol.) in 2 N NaOH (55 mL) was refluxed for twelve hours. The clear amber solution was cooled to room temp. and solid NH4Cl (5.9 g, 110 mmol.) was added to neutralized the hydroxide. After addition of aq. Na2CO3 and 5 N NaOH (2 mL), the product was extracted into chloroform. The extract was dried (Na2SO4) and filtered through a pad of charcoal and then evaporated to give 4-(5-fluoro-2-oxo-1-benzimidazolinyl)piperidine as a pale yellow viscous oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:37][S:38]([C:41]3[CH:46]=[CH:45][C:44](I)=[CH:43][CH:42]=3)(=[O:40])=[O:39])[CH2:27][O:28][C:29]3[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=3)[C:32]#[N:33])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH2:57]([O:64][C:65](C1C=CC=CC=1S(Cl)(=O)=O)=[O:66])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>O1CCOCC1>[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:37][S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:65]([O:64][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:66])(=[O:40])=[O:39])[CH2:27][O:28][C:29]3[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=3)=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(OCc1ccccc1)c1ccccc1S(=O)(=O)Cl
Reactant: N#Cc1cccc(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccc(I)cc2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1cccc(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccccc2C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5 ml of 4 N hydrogen chloride in dioxane and 2.5 ml of dioxane were added to 500 mg (0.854 mmol) of 3-[(2S)-3-[4-[1-(benzyloxycarbonyl)-4-piperidyloxy]phenyl]-2-(4-iodobenzenesulfonylamino)propoxy]benzonitrile. The mixture was stirred at room temperature for 24 hours, and the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 8 ml of DMF, and 0.49 ml (2.56 mmol) of di-isopropylethylamine and 398 mg (1.28 mmol) of 2-(benzyloxycarbonyl)benzene sulfonyl chloride were added thereto at 0° C. The mixture was stirred for 1 hour, then allowed to reach room temperature, and stirred for additional 24 hours. The reaction solution was extracted with ethyl acetate, washed with water, 1 N hydrogen chloride and saturated saline, and dried over powdery magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain the title compound.
Reaction SMILES: CC([O-])(C)C.[Na+].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:12]=[CH:11]2.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH:33]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:12]=[CH:11]3)[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNC(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(ccn3[Si](C)(C)C(C)(C)C)c2)C(Cc2ccccc2)C1
Temperature: 80 °C
Yield: 74.1 %

Procedure:
To a mixture of Pd(OAc)2 (0.054 g, 0.2 mmol), NaOtBu (0.64 g, 6.6 mmol) in xylene (7.0 mL) in a screw-capped tube was added tBu3P (0.049 g, 0.2 mmol). After 10 minutes a solution of 5-bromo-1-(tert-butyl-dimethyl-silanyl)-1H-indole (1.30 g, 4.4 mmol) in xylene (7.0 mL) and a solution of 3-benzyl-piperazine-1-carboxylic acid tert-butyl ester (1.34 g, 4.8 mmol) in xylene (8.0 mL) were added. The mixture was heated to 80° C. for 30 minutes, then cooled to room temperature. The reaction mixture was taken up in ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. Purification via flash chromatography (gradient: 2% to 20% EtOAc in hexane) afforded 3-Benzyl-4-[1-(tert-butyl-dimethyl-silanyl)-1H-indol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (1.65 g, 74%) as a pale yellow solid; MS (M+H)=506.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1.Br>CO>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=O)c2ccc(CCCN(C)C)nc2)cc1
Agent: Br
Solvent: CO
Product: CN(C)CCCc1ccc(C(=O)c2ccc(O)cc2)cn1
Yield: 100 %

Procedure:
To a solution of (6-(3-(dimethylamino)propyl)pyridin-3-yl)(4-methoxy-phenyl)methanone (298 mg, 1 mmol) in 10 mL of methanol was added 10 mL of 48% HBr at rt and the mixture was heated to reflux for 3 h and cooled. The solvent was evaporated to give the crude product, which was used without further purification (284 mg, 100% yield).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:13])[C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[CH:8]=[CH:7][CH:6]=2.[B:14]1(B2OC(C)(C)C(C)(C)O2)[O:18]C(C)(C)C(C)(C)[O:15]1.CC([O-])=O.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([B:14]([OH:18])[OH:15])[NH:3][C:4]2=[O:13]
Reactant: Cc1cccc2c(=O)[nH]c(Cl)cc12
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cc1cccc2c(=O)[nH]c(B(O)O)cc12
Yield: 48.3 %

Procedure:
3-Chloro-5-methyl-2H-isoquinolin-1-one (100 mg, 0.52 mmol), bis(pinacolato)diboron (157 mg, 0.62 mmol), Pd(dppf)Cl2 (42 mg, 0.054 mmol) and KOAc (153 mg, 1.56 mmol) in 1,4-dioxane (2 mL) were added to a microwave vial and the reaction mixture purged with N2 for 10 min. The reaction mixture was irradiated using a microwave reactor (300 W, 120° C., 20 min). The reaction mixture was passed through a Si-thiol cartridge and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC-MS to afford 5-methyl-1-oxo-1,2-dihydro-isoquinoline-3-boronic acid as a white solid (51 mg, 49%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][C:17]=2[CH2:25][O:26][CH2:27][C:28](Cl)=[O:29])=[CH:10][CH:9]=1.O>ClCCl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][C:17]=2[CH2:25][O:26][CH2:27][C:28]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:29])=[CH:10][CH:9]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(COCc1nc2ccccn2c1C#Cc1ccc(F)cc1)N1CCOCC1
Yield: 58 %

Procedure:
0.806 ml (9.25 mmol) of morpholine were solubilised in 4 ml of dichloromethane with magnetic stirring, a solution of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)acetyl chloride in 4 ml of dichloromethane was added and then the mixture was added at r.t. for 1 h before being treated with 10 ml of water. The aqueous phase was extracted with 2×5 ml of dichloromethane. The combined organic phases were washed with 5 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: ethyl acetate 100%). 0.211 g (yield=58%) of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)-1-morpholino ethanone were obtained as a pale yellow solid. LC-MS: m/z=394 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.62 (d, J=6.8 Hz, 1H), 7.74 (dd, J=8.7, 5.5 Hz, 2H), 7.67 (d, J=9.0 Hz, 1H), 7.50-7.39 (m, 1H), 7.33 (t, J=8.9 Hz, 2H), 7.12 (t, J=6.8 Hz, 1H), 4.75 (s, 2H), 4.27 (s, 2H), 3.55-3.46 (m, 4H), 3.39 (s, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([CH:11]=[N:12][OH:13])=[CH:9][CH:8]=2)=[C:4](Cl)[CH:3]=1.BrC1C=CC(OC2C=CC(C=O)=CC=2)=C([C:35]([F:38])([F:37])[F:36])C=1>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([CH:11]=[N:12][OH:13])=[CH:9][CH:8]=2)=[C:4]([C:35]([F:38])([F:37])[F:36])[CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(Br)cc2C(F)(F)F)cc1
Reactant: ON=Cc1ccc(Oc2ccc(Br)cc2Cl)cc1
Product: ON=Cc1ccc(Oc2ccc(Br)cc2C(F)(F)F)cc1

Procedure:
Prepared analogously to 78b) starting from 4-(4-bromo-2-trifluoromethyl-phenoxy)-benzaldehyde, it was further reacted directly without chromatographic purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([C:37]4[CH:36]=[N:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(-c3cnn(CCO)c3)nn12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Stage 182.1, 620 mg, 1.529 mmol) was dissolved in DME (5 mL) in a microwave reactor with 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 493 mg, 1.529 mmol) and a solution of 2 M Na2CO3 (2.75 mL). Then tetrakis(triphenylphosphine)-palladium (88 mg) was added and the RM was heated at 150° C. for 15 min under microwave irradiations. It was then taken up with EtOAc and washed with 10% Na2CO3 sol. and brine. The organic layer was dried over Na2SO4 and the solvent was removed. It was then dissolved in DCM (18 mL) and HCl in dioxane (4 N, 1.146 mL) was added. It was stirred at rt for 2 h. The solvent was removed and it was taken up in EtOAc/MeOH (9:1) and washed with water and brine. The organic layer was dried over Na2SO4 and the solvent was removed. The residue was triturated with Et2O and the solid was filtered off. The yellow solid obtained was the pure racemate of the title compound (tR 1.1 min (conditions 2), MH+=421)
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:44])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:18][C:19]([F:43])([F:44])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCCBr)c2ccccc2-c2ccccc21
Product: CCOC(=O)c1ccc(N2CCN(CCCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 and the compound prepared in step (a) of Example 94 were used as the starting compounds. Thus, ethyl 4-[4-[5-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]pentyl]-piperazin-1-yl]benzoate was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH2:30]([O:32][CH2:33][CH2:34][NH2:35])[CH3:31].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:30]([O:32][CH2:33][CH2:34][NH:35][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:28])([F:29])[F:27])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14])[CH3:31]
Reactant: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCOCCN
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CC
Yield: 51.4 %

Procedure:
1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (60.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-ethoxy-ethylamine (30.0 mg), DPPA (85.0 mg), and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 495; and 1H NMR (CD3OD, 400 MHz): δ 7.96 (1H, d), 7.77-7.75 (2H, m), 7.65 (1H, d), 7.43-7.41 (1H, m), 7.26-7.24 (1H, m), 4.27-4.26 (2H, q), 3.66-3.64 (2H, m), 3.59-3.55 (4H, m), 1.43-1.39 (3H, t), 1.23-1.20 (3H, t), 2 —NH proton signals were not observed.