Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[B:27](OCCCC)([O:33]CCCC)[O:28]CCCC.Cl>CCCCCC.C1COCC1.O>[C:21]1([C:7]([B:27]([OH:33])[OH:28])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: OB(O)C(=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium in hexane (2.5 M, 15 mL) was added slowly under nitrogen to a stirred solution of (2-bromoethene-1,1,2-triyl)tribenzene (5.00 g, 14.9 mmol) in THF (50 mL) at −78° C. and then the mixture was stirred further for 1 h. Tributyl borate (11.0 mL, 40.8 mmol) was added at −78° C. before the mixture was warmed slowly to room temperature and stirred for 8 hours. Water (100 mL) was added, followed by conc. HCl (100 mL) to acidify the mixture, which was then stirred for 2 hours. The reaction mixture was extracted with EtOAc and the combined organic phases were dried over MgSO4. Concentration under reduced pressure gave 1,2,2-triphenylvinylboronic acid, which, without further purification, was reacted with pinacol (1.73 g, 14.6 mmol) in toluene under reflux for 2 hours to effect condensation by the azeotropic removal of the water formed. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (hexanes/EtOAc=20/1) to afford D (2.41 g, 65%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CC1(C)NC(=O)CCc2cc(N)ccc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(=O)NC3(C)C)ncc1Cl

Procedure:
Following a procedure analogous to Example 1826d, 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one and 2-(2,5-dichloropyrimidin-4-ylamino)-N-methylbenzamide were converted to 2-(5-chloro-2-(1,1-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)-N-methylbenzamide, TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.55 (d, 1H), 8.25 (s, 1H), 7.9 (dd, 1H), 7.6 (d, 1H), 7.5 (t, 1H), 7.5-7.45 (m, 2H), 7.4 (td, 1H), 3.2 (m, 2H), 3.1 (s, 3H), 2.8 (m, 2H), 2.0 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1([C:11]([OH:13])=O)[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:4][NH:3]1.C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:23]>ClCCl>[Cl:1][C:2]1([C:11]([F:23])=[O:13])[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:4][NH:3]1
Reactant: CCNC1=NC(Cl)(C(=O)O)NC=C1
Reactant: Fc1nc(F)nc(F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC1=NC(Cl)(C(=O)F)NC=C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution containing 7.0 g (34.72 mmol) of acid prepared in step 2.4 and 5.32 mL (38.19 mmol) of triethylamine in 98 mL of dichloromethane are added 5.89 mL (69.79 mmol) of cyanuric fluoride. The mixture is stirred for 3 hours and the solution is diluted with 590 mL of CH2Cl2 and 190 mL of ice-cold aqueous NaHCO3. The organic phase is washed twice with 190 mL of ice-cold aqueous NaHCO3 and dried over MgSO4. The solvent is then evaporated off under reduced pressure. 7.0 g of expected product are obtained in the form of a red oil that solidifies slowly, and that is used as obtained in the following step. Quantitative yield.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][C:7](=[O:9])[O:6][C:5](=[O:10])[CH2:4]2)[CH2:2]1.[CH3:11][Mg]Br.CC1CCCO1.Cl>O1CCCC1.[Cu]Cl.C(OC)(C)(C)C.O>[O:9]=[C:7]([CH3:11])[CH2:8][C:3]1([CH2:4][C:5]([OH:6])=[O:10])[CH2:2][CH2:1]1
Reactant: C[Mg]Br
Reactant: O=C1CC2(CC2)CC(=O)O1
Agent: Cl[Cu]
Agent: Cl
Solvent: CC1CCCO1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CC1(CC(=O)O)CC1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a solution of 4.4 g 6-oxa-spiro[2.5]octane-5,7-dione (31 mmole) in 66 ml tetrahydrofuran are added 600 mg copper(I)chloride (6 mmole, 0.2 eq). The mixture is cooled to −20° C. and 9.8 ml of methylmagnesium bromide in 2-methyl tetrahydrofuran (3.2 M solution in 2-methyl tetrahydrofuran, 31 mmole, 1.0 eq) are added dropwise over 0.5 hours. The mixture is warmed to room temperature and stirred for 2 hours. 66 ml of water are added and the mixture is acidified to pH 3.0 by addition of 20.4 g of 2 M hydrochloric acid. 50 ml of methyl tert-butyl ether are added and the phases are separated. The aqueous phase is extracted again with 50 ml of methyl tert-butyl ether and the combined organic phases are washed with 20 ml of brine and concentrated to dryness. The resulting crude product is directly used in the next step (esterification to [1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCCl.ClCCl.O>[CH2:26]([O:13][C:12](=[O:14])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: OCc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(CC(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.1 %

Procedure:
To a stirred mixture of commercially available 3,4-dimethoxyphenylacetic acid (100.0 g, 510 mmol) in anhydrous 1,2-dichloroethane (500 cm3) at ambient temperature under an atmosphere of dry nitrogen was added thionyl chloride (112 cm3, 1.53 mol) portionwise over 20 minutes. The resulting solution was heated to reflux for 16 hours. The brown solution was cooled to ambient temperature and the volatile fractions removed in vacuo. Residual thionyl chloride was removed by an azeotrope with toluene (3×200 cm3) to afford a crude brown oil. The crude oil was dissolved in anhydrous dichloromethane (400 cm3) and cooled to 0° C. in an ice bath. To the cooled solution was added triethylamine (75 cm3, 535 mmol) dropwise over 10 minutes followed by a solution of benzyl alcohol (50 cm3, 485 mmol) dissolved in anhydrous dichloromethane (200 cm3). The mixture was stirred for 20 hours and warmed to ambient temperature. Water was added to the mixture (700 cm3) and the aqueous extracted with dichloromethane (2×100 cm3). The combined dichloromethane extracts were dried over sodium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to afford a crude brown oil. The crude product was purified by column chromatography (silica, eluting with hexane-ethyl acetate 1:0 to 1:1) to afford the title compound as a pale yellow viscous oil (83.4 g, 57.2%) with a positive ion ESI (M−1H)+287.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>CO>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([OH:4])=[O:2])[CH:12]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)C(OCc2ccc3ccccc3c2)C1
Yield: 75 %

Procedure:
A solution of 60 mg (0.13 mmol) of tert-butyl (3RS,4RS)-4-(3-methoxycarbonyl-phenyl)-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate (Example 26(e)] and 0.26 ml (0.26 mmol) of 1N sodium hydroxide solution in 2 ml of methanol was stirred at 30° C. for 18 hours. For the working-up, the reaction mixture was neutralized with 1N hydrochloric acid and extracted twice with 10 ml of methylene chloride each time. The organic phases were combined, dried over sodium sulphate and evaporated under reduced pressure. The residue was crystallized from a mixture of hexane and diethyl ether. There were obtained 45 mg (75% of theory) of (3RS,4RS)-3-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzoic acid as colourless crystals; MS: 462 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH2:22])[CH:10]=2)=[CH:5][CH:4]=1.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28].CCN(CC)CC.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccccc1Oc1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC(=O)Nc1ccccc1Oc1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Reaction time: 0.5 h

Procedure:
To a mixture of 2-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-phenylamine, (Example 26), (0.33 g, 1.0 mmol), butyryl chloride (0.15 mL, 1.5 mmol, Aldrich), and 4-dimethylaminopyridine (0.006 g, 0.05 mmol, Aldrich) in CH2Cl2 (5 mL) was added Et3N (0.21 mL, 1.5 mmol, Aldrich). The mixture was stirred for 30 min, diluted with hexanes (10 ml) and treated with H2O (2 mL). The resulting solids were filtered, washed with H2O and hexanes, and dried in vacuum for 16 h at room temperature to give the title compound as a white powder. Mp: 112° C., MS (ESI, pos. ion) m/z: 402 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:23]1(C)[CH:28]=CC=C[CH:24]=1.CC1(C)C(C)(C)OB(C(C)=C)O1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[C:8]1([C:5]2[CH:4]=[CH:3][C:2]([C:23]([CH3:28])=[CH2:24])=[CH:7][N:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccccc1
Reactant: Clc1ccc(-c2ccccc2)nc1
Agent: [Pd]
Agent: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: C=C(C)c1ccc(-c2ccccc2)nc1

Procedure:
To a 1 L round bottom flask was added 5-chloro-2-phenylpyridine (10.15 g, 53.5 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.8 g, 4.3 mmol), potassium phosphate tribasic monohydrate (37.0 g, 161 mmol) with toluene (200 mL) and water (20 mL). The reaction mixture was degassed with nitrogen for 20 mins. 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (12.07 mL, 64.2 mmol) and Pd2(dba)3 (0.980 g, 1.070 mmol) were added and the reaction mixture was refluxed for 18 h. The aqueous layer was removed and the organic layer was concentrated to dryness. The crude product was chromatographed on silica gel with 0-20% EtOAc in hexane to yield 11 g of the desired product (HPLC purity: 95%). The product was confirmed by GC/MS.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.ClCCl.[OH-].[Na+].[CH2:25](Br)[C:26]#[CH:27]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl.CO>[CH2:27]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:3]1[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=[C:2]1[CH3:1])[C:26]#[CH:25]
Reactant: Cc1nc2cnc3ccccc3c2n1CCCCO
Reactant: C#CCBr
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C#CCOCCCCn1c(C)nc2cnc3ccccc3c21
Reaction time: 18 h

Procedure:
To 4-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-butanol (1 g, 3.917 mmol), dichloromethane (14 mL), sodium hydroxide (14 mL of 50%), and benzyltrimethylammonium chloride (0.15 g, 0.783 mmol) were combined with stirring. Propargyl bromide (1.3 mL of 80% in toluene, 11.75 mmol) was added to the resulting mixture at ambient temperature. After the resulting reaction mixture was allowed to stir at ambient temperature for 1 hour, TLC analysis using 9/1 dichloromethane/methanol indicated incomplete reaction. After 18 hours HPLC monitoring indicated complete reaction. The two reaction layers were separated. The organic layer was washed with water (3×100 mL). All aqueous layers were combined and extracted with dichloromethane (3×100 mL). All organic layers were combined and washed with brine (3×100 mL). The brine layers were combined and extracted with dichloromethane (3×100 ML). All resulting organic layers were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure. HNMR analysis of the resulting dark oil was consistent with the desired product and some residual solvent. HPLC and LC/MS were consistent with the desired product (1.1 g) that was of sufficient purity for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:16]C(=O)C.O.S(=O)(=O)(O)O>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:16]
Reactant: CC(=O)Nc1ccc2ccc(C(F)(F)F)cc2c1Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Nc1ccc2ccc(C(F)(F)F)cc2c1Cl
Temperature: 25 °C

Procedure:
A mixture of 1-chloro-7-trifluoromethyl-2-acetamidonaphthalene (700 mg, 2.43 mmol), water (3 mL) and concentrated sulfuric acid (3 mL in ethanol (6 mL) is heated to reflux temperature under a N2 atmosphere for 1 hour. After cooling to room temperature, the mixture is extracted with EtOAc. The extracts are washed with water, brine, dried (Na2SO4) and concentrated. Flash chromatography on silica gel (3:1 hexanes/EtOAc) gives 1-chloro-7-trifluoromethyl-2-aminonaphthalene as a white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:27])C=1.O>ClCCl>[N:1]1([C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[O:8])[CH2:2][CH2:3][S:4](=[O:27])[CH2:5][CH2:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCSCC1
Solvent: O
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCS(=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13.1 g (49.0 mmol) of 4-nitrophenyl thiomorpholine-4-carboxylate were initially charged in 135 ml of dichloromethane and admixed at 0° C. with 7.6 g (44.1 mmol) of m-chloroperbenzoic acid in portions. The mixture was stirred at RT for two hours, water was added and the organic phase was removed. The organic phase was washed rapidly with saturated aqueous sodium hydrogencarbonate solution, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 7.8 g (56% of theory)
Reaction SMILES: Br[C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:3](=[O:13])[C:4]3[C:9]([C:10](=[O:12])[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C1C=C(Br)C(=O)c2ccccc21
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(c2ccc(O)cc2)C(=O)c2ccccc21
Temperature: 100 °C
Yield: 45.5 %

Procedure:
To a mixture of 2-bromo-1,4-naphthoquinone (1.0 g, 4.22 mmol), 4-hydroxyphenylboronic acid (640 mg, 4.64 mmol), potassium phosphate (3.135 g, 14.76 mmol), tricyclohexylphosphine (118 mg, 0.422 mmol), toluene (20 mL) and water (1 mL) was added palladium acetate (47 mg, 0.21 mmol) under N2. The reaction mixture was heated to 100° C. for 3 h. The reaction was cooled to rt and water was added. The mixture was extracted with EtOAc, and the combined organic extracts were washed with water and brine. The organic phase was separated, dried and concentrated to give crude product. Purification by column chromatography, using 10% EtOAc in hexane, gave 480 mg of 2-(4-hydroxy-phenyl)-[1,4]naphthoquinone (45%). MS (ES) m/z: 251.03 (M+1).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[O:17]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1>O1CCCC1>[CH3:6][O:7][C:8]1[C:16]2[O:15][C:14]([C:19]3([OH:22])[CH2:20][CH2:21][O:17][CH2:18]3)=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCOC1
Reactant: COc1cccc2ccoc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2cc(C3(O)CCOC3)oc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
Methyl sulfoxide (1.16 ml) was added dropwise to a stirred solution of oxalyl chloride (0.71 ml) in dry dichloromethane (15 ml) at −60° C. under an inert atmosphere. After stirring at this temperature for 30 minutes a solution of 3-hydroxytetrahydrofuran (0.55 ml) in dry dichloromethane was added carefully. After a further 30 minutes triethylamine was added dropwise and the reaction allowed to warm to room temperature. The reaction was poured onto water (40 ml) and extracted with dichloromethane (30 ml). The organic phase was washed with water (50 ml), brine (2×50 ml) and saturated aqueous sodium hydrogen carbonate solution (2×50 ml). After drying over magnesium sulphate the solvent was removed in vacuo to afford tetrahydro-furan-3 -one as a yellow gum (0.19 g). n-Butyllithium (0.72 ml, 1.6M in hexanes) was added dropwise to a stirred solution of 7-methoxybenzofuran (0.15 g) in dry tetrahydrofuran (5 ml) at −78° C. under a dry nitrogen atmosphere. After stirring for 20 minutes a solution of tetrahydrofuran-3 -one (90 mg) in dry tetrahydrofuran (2 ml) was added carefully. After stirring for a further 15 minutes at −78° C. the reaction was allowed to warm to room temperature. The reaction was carefully quenched with water and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (2×15 ml) and water (15 ml). The combined organic extracts were dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 50% ethyl acetate in hexane to give the title compound as an orange gum (64 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[CH3:2].[CH2:25](O)[CH3:26].C([O-])([O-])=O.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([C:26]1[CH:25]=[CH:16][C:11]([N:10]([CH3:22])[CH3:9])=[CH:12][CH:13]=1)[CH:15]=2)[CH3:2]
Reactant: CCOC(=O)CCCCCn1c2c(c3cc(Br)ccc31)CCCC2
Reactant: CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCn1c2c(c3cc(-c4ccc(N(C)C)cc4)ccc31)CCCC2

Procedure:
4-Dimethylamino boronic acid (0.221 g, 1.34 mmol), tetrabutylammonium bromide (TBAB) (0.049 g, 1.25 mmol), palladium acetate (Pd(OAc)2 (0.017 g, 0.08 mmol), triorthotoluene phosphine (P(o-toluene)3 (0.035 g, 0.12 mmol), and 6-(6-bromo-1,2,3,4-tetrahydro-carbazol-9-yl)-hexanoic acid ethyl ester (compound 4)(0.300 g, 0.76 mmol) were added to a flask, dissolved in toluene (3 mL), ethanol (2 mL), and 2M Na2CO3 (1 mL), and stirred overnight at 70° C. Compound 32 was purified by column chromatography to give 310 mg of the product as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl[P:24]1(=[O:29])[O:28][CH2:27][CH2:26][O:25]1>C(OCC)C>[O:29]=[P:24]1([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][CH:9]=2)[O:28][CH2:27][CH2:26][O:25]1
Reactant: C=Cc1ccc(COCCCCO)cc1
Reactant: O=P1(Cl)OCCO1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=Cc1ccc(COCCCCOP2(=O)OCCO2)cc1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
4-Hydroxy-1(4′-vinylbenzyloxy)butane (5) (10.03 g; 48.69 mmol) and dried triethylamine (4.92 g, 48.69 mmol) were dissolved in dry diethyl ether (150 ml) and the resulting solution placed in a rigorously dried flask. The solution was cooled to −30° and 2-chloro-2-oxo-1,3,2-dioxaphospholane (6.94 g; 48.69 mmol) added dropwise over 30 minutes, the temperature being held at −30°. The reaction mixture was then stirred for a further 2 hours, during which time the temperature was allowed to rise to 100. The mixture was filtered and the precipitate washed with dry ether. The filtrate was evaporated (20°/21 mm) to give a cloudy oil. The residue was shaken with 50 ml of dry ether and refiltered. Evaporation of the filtrate gave the product as a viscous yellow oil (13.73 g; 90.4%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]([C:27]([NH2:29])=[O:28])[NH2:26].N1C2C(=CC(CC3N4N=C(/C(=N/NC(N)=O)/C)C=CC4=NN=3)=CC=2)C=CC=1>>[CH3:24][N:25]([C:27]([NH2:29])=[O:28])/[N:26]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:13][N:14]=2)[N:17]=1)\[CH3:22]
Reactant: CN(N)C(N)=O
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: C/C(=N\NC(N)=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Product: C/C(=N\N(C)C(N)=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 54.6 %

Procedure:
The title compound (27 mg, 55%) was synthesized from 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (40 mg, 0.132 mmol) and 1-methylhydrazine-carboxamide (23.5 mg, 0.264 mmol) using the same procedure as described in the synthesis of 37. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.06 (d, 1H), 8.73 (d, 1H), 8.17 (m, 4H), 8.00 (d, 1H), 7.79 (m, 1H), 6.69 (s, 2H), 4.82 (s, 2H), 3.27 (s, 3H), 2.32 (s, 3H). LCMS (method A): [MH]+=375.0, tR=3.79 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.CCN=C=NCCCN(C)C.[C:32]([NH:39][NH2:40])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].CCOC(C)=O>C(Cl)Cl.CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:40][NH:39][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A mixture of 4-(6-hydroxyquinolin-2-yl)benzoic acid (Compound 3, Example 3) (200 mg, 0.754 mmol), EDCI (145 mg, 0.754 mmol) and BocNHNH2 (100 mg, 0.754 mmol) in DCM (10 mL) and DMF (10 mL) was stirred at 25° C. overnight, followed by an aqueous/EtOAc workup. The crude was purified by column chromatography on silica gel (PE/EtOAc=1/1) to give the product (200 mg, yield 70%) as a yellow solid.