Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.Cl.[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][C:38](=[O:40])[NH2:39])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O>[ClH:7].[ClH:7].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:32]2[CH:31]=[CH:30][C:29]3[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=3)[C:33]=2[CH2:37][C:38](=[O:40])[NH2:39])=[O:19])=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc(NC2=NCCN2)cc1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(NC4=NCCN4)cc3)ccc2c1
Reaction time: 2 h

Procedure:
45 Milliliters of 20% hydrous pyridine was added to 2.85 g of 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoic acid.hydrochloride, 3 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 2.65 g of N,N'-dicyclohexylcarbodiimide (hereinafter referred to as "DCC") and 131 mg of 4-dimethylaminopyridine (hereinafter referred to as "DMAP"), followed by stirring for 2 hours under cooling with ice and 3 days under cooling with water. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of N,N-dimethylformamide (hereinafter referred to as "DMF"), and a small amount of the insoluble matter was filtered off. The filtrate was added dropwise to 500 ml of a mixed liquid of ether and acetone (10:1) and this was stirred for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH2:22][CH:23]([F:25])[F:24])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)C(C)C)(C)C.Br[CH2:36][CH:37]=[CH:38][C:39](Cl)=[O:40].[NH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH2:22][CH:23]([F:25])[F:24])=[C:17]([NH:20][C:39](=[O:40])[CH:38]=[CH:37][CH2:36][N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC(F)F
Reactant: C1CCNCC1
Reactant: O=C(Cl)C=CCBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(C=CCN1CCCCC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.5 g N4-(3-Chloro-4-fluoro-phenyl)-7-(2,2-difluoro-ethoxy)-quinazoline-4,6-diamine was dissolved in 10 ml THF and 1.2 ml N,N-Diisopropyl-ethylamine (DIEA) and 0.48 g 4-Bromo-but-2-enoyl chloride were added and the mixture was stirred at room temperature for 2 hours. 0.27 ml piperidine was added and stirred at room temperature overnight. An additional 0.7 ml piperidine was added and the mixture heated to 70° C. After 3 hours the reaction mixture was poured into water, the solids were extracted with ethyl acetate, washed with water and brine, dried over NaSO4 and flash chromatographed under 0-4% methanol in chloroform to yield 0.2 g 4-Piperidine-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-(2,2-difluoro-ethoxy)-quinazolin-6-yl]-amide.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[S-:4].[K+].Cl[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:15]#[N:16]>CO.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[S:4][C:18]1[CH:17]=[C:14]([CH:13]=[CH:12][C:19]=1[N+:20]([O-:22])=[O:21])[C:15]#[N:16]
Reactant: Fc1ccc([S-])c(F)c1
Reactant: N#Cc1ccc([N+](=O)[O-])c(Cl)c1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#Cc1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
A solution of potassium 2,4-difluorothiophenoxide (6.1 g) in methanol (30 ml) was added dropwise to a solution of 3-chloro-4-nitrobenzonitrile (5 g) in toluene (50 ml). The mixture was stirred for 5 hours at room temperature, washed with water, and concentrated to dryness. The oily residue was crystallized from a mixture of ethanol and hexane to give crystals of 3-(2,4-difluorophenylthio)-4-nitrobenzonitrile (3.6 g).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14]C)=O)(=[O:4])=[O:3].O.[NH2:17][NH2:18]>C(O)C>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:17][NH2:18])=[O:14])(=[O:4])=[O:3]
Reactant: COC(=O)Cc1ccccc1S(N)(=O)=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1ccccc1S(N)(=O)=O
Yield: 76.7 %

Procedure:
To a suspension of 30 g of methyl 2-(aminosulfonyl)benzeneacetate in 125 ml of absolute ethanol was added 7.8 g of hydrazine monohydrate. The suspension was heated at reflux for about 16 hours, then cooled in an ice-water bath. A viscous oil formed which solidified on continued stirring and cooling. The suspension was filtered and suction-dried to give 23 g of the subject compound; m.p. 116°-125° C. Anal. Calc. for: C8H11N3O3S; C,41.9; H,4.8; N,18.3. Found: C,41.5; H,4.9; N,18.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14]Cl)[CH:7]=[C:6]([Br:17])[CH:5]=1.[H-].[Na+].O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:7]=[C:6]([Br:17])[CH:5]=1
Reactant: COC(=O)c1cc(Br)cc(NC(=O)CCCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of 3-bromo-5-(4-chloro-butanoylamino)-benzoic acid methyl ester (D13) (530 mg, 1.6 mmol, 1 equiv) in THF (5 ml) at room temperature was added NaH (60% in mineral oil, 64 mg, 1.7 mmol, 1.1 equiv) and the resulting mixture was stirred at room temperature for 2 h. H2O was then added and the resulting mixture was diluted with AcOEt. The two layers were separated and the organic phase dried over MgSO4 and concentrated in vacuo to give 3-bromo-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D9a) (361 mg, 76%) as a yellow solid. [M−H]-296.3, RT=2.49.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O-]CC.[Na+].[CH3:18][O:19][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22]>C(O)C>[CH3:18][O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH2:22][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: C=C(C)C(=O)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C(C)CN1CCN(c2ccc(Cl)cc2)CC1
Yield: 99 %

Procedure:
1-(4-Chloro-phenyl)-piperazine (392 mg; 2.0 mmol) and sodium ethoxide (150 mg; 2.21 mmol) are dissolved in ethanol (2 mL) and irradiated for 5 minutes in a mono-mode microwave oven at 60° C. 2-Methyl-acrylic acid methyl ester (400 μL; 4.0 mmol) is then added and the resulting mixture is irradiated for 50 minutes in a mono-mode microwave oven at 100° C. The reaction is concentrated under reduced pressure, diluted in ethylacetate (10 mL) and extracted with water (2×5 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired product (586 mg; 1.98 mmol).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][OH:19])[C:13]=1[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH:18]=[O:19])[C:13]=1[CH3:20]
Reactant: Cc1c(Br)ccnc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c(Br)ccnc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
To a stirred and cooled (−78° C.) solution of oxalyl chloride (2.82 mL, 33.37 mmol) in DCM (70 mL) under nitrogen was added dropwise a solution of dimethyl sulfoxide (5.17 mL, 72.81 mmol) in DCM (10 mL). Stirring was continued for 10 minutes. A solution of (4-bromo-3-methyl-2-pyridyl)methanol (which may be prepared as described in Description 6) (6130 mg, 30.34 mmol) in DCM (35 mL) was then added dropwise over 20 minutes. The reaction was then allowed to stir for 1 hour. Triethylamine (18.98 mL, 136.53 mmol) was then added dropwise and the reaction was allowed to warm to room temperature over 1.5 hours. The reaction was then quenched by addition of water (approximately 100 mL). The organics were separated and washed with additional water (150 mL). The organics were dried using a hydrophobic frit and concentrated in vacuo to give 4-bromo-3-methyl-pyridine-2-carbaldehyde (D7) (5.709 g, 28.541 mmol, 94.1% yield) as a brown oil which crystallised on standing.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Cl:11])=[N:4][CH:3]=1.[CH3:12][NH2:13].[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1>>[Cl:11][C:5]1[N:4]=[CH:3][C:2]2[N:1]=[C:29]([C:28]3[CH:31]=[CH:32][C:25]([O:24][CH:21]4[CH2:22][CH2:23][N:18]([CH:14]5[CH2:17][CH2:16][CH2:15]5)[CH2:19][CH2:20]4)=[CH:26][CH:27]=3)[N:13]([CH3:12])[C:8](=[O:10])[C:7]=2[CH:6]=1
Reactant: Nc1cnc(Cl)cc1C(=O)O
Reactant: O=Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: CN
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2cnc(Cl)cc2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 5-amino-2-chloroisonicotinic acid, methylamine and 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C@H:5]([OH:21])[C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8].N1C(C)=CC=CC=1C.O([Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C@H:5]([O:21][Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])[C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)C[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of the crude alcohol 12 (2.7 g, 9.1 mmol) in CH2Cl2 (10 mL) under argon, cooled to 0° C., 2,6-lutidine (2.6 mL, 22.7 mmol) and triisopropylsilyl triflate (3.6 mL, 13.6 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h and diluted with CH2Cl2 (25 mL). The organic layer was separated and washed with 10% HCl (50 mL), NaHCO3 (50 mL, sat) and NaCl (50 mL, sat), dried (Na2SO4), filtered and concentrated. The crude oil was purified by column chromatography (silica gel, diethyl ether/hexanes 2:98 to 15:85) to yield 13 (2.9 g, 70%) as colorless oil. 1H-NMR (500 MHz, CDCl3): 0.88 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.7 Hz, 3H), 1.01-1.07 (m, 2H), 1.97-2.04 (m, 1H), 2.53 (dd, J=15.3 and 4.7 Hz, 1H), 2.60 (dd, J=15.2 and 7.5 Hz, 1H), 3.57 (s, 3H), 3.59-3.65 (m, 1H), 4.34-4.40 (m, 1H), 4.78 (d, J=10.3 Hz, 1H), 5.06-5.09 (m, 2H), 7.27-7.35 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]([N:17]1[CH:21]=[CH:20]N=[CH:18]1)(N1C=CN=C1)=[O:11].Cl.O.N1CC[C:27](=[O:30])[CH2:26]C1>CN(C=O)C.CCOC(C)=O>[O:30]=[C:27]1[CH2:26][CH2:18][N:17]([C:10]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:11])[CH2:21][CH2:20]1
Reactant: Cc1ccc(CO)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(COC(=O)N2CCC(=O)CC2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
4-Methylbenzyl alcohol (37.6 g, 308 mmol) was added to a solution of 1,1′-carbonyldiimidazole (50.0 g, 308 mmol) in DMF at RT and stirred for 1 h. 4-Piperidone hydrate hydrochloride (commercially available from Sigma-Aldrich, 47.0 g, 308 mmol) was added, resulting in a reaction mixture that was then heated to 50° C. and stirred for 15 h. The reaction mixture was diluted with EtOAc and washed with 0.1 M HCl, H2O (four times), and brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (step gradient elution: 10%, 25%, 50% EtOAc in hexanes) produced the title compound (42.4 g, 85% yield) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:22]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=3)[C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)C(NCCN1CCOCC1)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C(c2ccc(Br)cc2)N(CCN2CCOCC2)C(c2ccccc2)N1c1ccc(C(F)(F)F)cc1
Yield: 69.1 %

Procedure:
To a solution of 2-(4-bromo-phenyl)-2-(2-morpholin-4-yl-ethylamino)-N-(4-trifluoromethyl-phenyl)-acetamide (2.90 g, 6.00 mmol) in anhydrous MeOH (20 mL) was added benzaldehyde (633 mg, 6.00 mmol), followed by para-toluenesulfonic acid (229 mg, 1.20 mmol) and sodium sulfate (8.98 g, 63.2 mmol). The reaction was refluxed overnight, filtered, and directly purified by flash column chromatography eluting with ethyl acetate: petroleum ether gradient (10%-25%) to afford the product as a yellow solid (2.38 g, 69.2%).
Reaction SMILES: [CH3:1][C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11](S(O)(=O)=O)=[CH:10][CH:9]=1.[BH3-]C#N.[Na+].C[C:24]1[C:29](Br)=[C:28](O)[C:27](Br)=[CH:26][C:25]=1[C:33]1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)[C:39]2[CH:38]=CC=C[C:34]1=2.[ClH:54]>CCO.O.C1(C)C=CC=CC=1>[ClH:54].[CH:10]1[C:11]2=[C:12]3[C:33]([C:25]4[C:26]2=[CH:27][CH:28]=[CH:29][CH:24]=4)=[CH:34][CH:39]=[CH:38][C:13]3=[C:8]([CH2:18][NH:7][C:2]([CH3:1])([CH2:5][OH:6])[CH2:3][OH:4])[CH:9]=1
Reactant: CC(N)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(CO)(CO)NCc1ccc2c3c(cccc13)-c1ccccc1-2
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
To a 2 L Erlenmeyer flask was added 3-fluoroanthenecarbaldehyde (11.51 g, 50 mmol) 2-methyl-2-amino-1,3-propanediol (Aldrich, 5.52 g, 52.5 mmol), p-toluenesulfonic acid.H2O (Eastman Kodak Co., Rochester, NY, 14650, 0.1 g, 0.5 mmol), and PhCH3 (500 mL). The mixture was warmed to reflux for a few minutes and H2O (2-3 mL) was driven off. The resulting golden colored solution was allowed to cool to RT, diluted with abs. EtOH (500 mL) and stirred overnight. NaBH3CN (Aldrich, 95%, 1.57 g, 25 mmol) was added to the reaction. After the NaBH3CN dissolved, an indicator (bromocresol green, Eastman, 5 mg) was added. To the resulting added. To the resulting blue solution was added 5 drops of 1M solution of HCl gas in abs.olute EtOH every 15 minutes. After 3 days the indicator turned green then yellow and voluminous white precipitate was present in the flask. To the flask was then added 1M HCl gas (10 mL) in abs. EtOH, and H2O (10 mL). The liquid was then removed by rotary evaporation to give a yellow solid. The solid was shaken with 20% HCl solution (500 mL) and collected by filtration. The resulting solid was washed with additional 20% HCl solution (250 mL) and then with CH2Cl2 (4×250 mL), pressed and then sucked dry. The slightly yellow solid was then recrystallized from CH3OH/Et2O to give 11.80 g (66%) of 2-((3-fluoranthenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride mp 262°-265° (dec), (C, H, Cl, N).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([C:12]1[N:17]=[C:16]([C:18](=O)[CH3:19])[CH:15]=[CH:14][CH:13]=1)[CH3:11].[CH2:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31])[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH2:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:18]([C:16]1[N:17]=[C:12]([C:10](=[N:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH3:11])[CH:13]=[CH:14][CH:15]=1)[CH3:19])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1ccccc1N
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C)n1
Solvent: Cc1ccccc1
Product: CCCCc1ccccc1N=C(C)c1cccc(C(C)=Nc2c(C)cccc2C)n1

Procedure:
1-{6-[1-(2,6-Dimethyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 1 (2.3 g, 0.0088 mol), 1.68 g (0.0244 mol) of 2-n-Butyl-phenylamine 12, 100 g of fresh molecular sieves, and 100 ml of toluene were kept at 100° C. for 3 days under the flow of nitrogen. The solvent was removed in a rotary evaporator and the residue was recrystallized from 5 ml of ethanol. The yield of (1-{6-[1-(2-n-butyl-phenylimino)-ethyl]-pyridin-2-yl}-ethylidene)-(2,6-dimethyl-phenyl)-amine 11 was 2.60 g (76%) as a yellow solid. 13C NMR (500 MHz, CD2Cl2, TMS (selected signals)): δ 166.8 (C═N), 166.1 (C═N).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]([CH3:11])(OC(=O)C)[CH:5]=[CH2:6]>[Cu]Cl>[C:3]([O:12][CH2:6][CH:5]=[C:4]([CH3:11])[CH:3]([O:2][CH3:1])[O:12][CH3:13])(=[O:2])[CH3:4]
Reactant: C=CC(C)(OC(C)=O)C(OC)OC
Agent: Cl[Cu]
Product: COC(OC)C(C)=CCOC(C)=O
Temperature: 160 °C
Yield: 81.9 %

Procedure:
564 g of 1,1-dimethoxy-2-methyl-2-acetoxy-but-3-ene and 0.3 g of copper (I) chloride were heated, with stirring, at 160° C. in a reaction vessel equipped with a stirrer, an internal thermometer and a descending condenser. Over the entire reaction time of 5 hours, a stream of nitrogen (90 liters/hour) was passed continuously through the reaction vessel. Subsequent working up of the reaction mixture by distillation gave 462 parts of 4,4-dimethoxy-3-methyl-crotyl acetate, corresponding to a yield of 81.9% of theory.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[O:10][C:11]=1[CH3:12].[CH3:18]B1OB(C)OB(C)O1>CN(C)C=O.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]>[CH3:17][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[O:10][C:11]=2[CH3:12])=[C:2]([CH3:18])[CH:3]=[N:4]1
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)o1
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2c(C)cnn2C)c(C)o1

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (130 mg, 0.43 mmol) potassium carbonate (300 mg, 2.17 mmol), PdCl2(dppf) (15.9 mg, 0.02 mmol) and trimethylboroxine (0.12 ml, 0.87 mmol) in N,N-Dimethylformamide (3.5 ml) was stirred at 110° C. in a sealed tube for 2 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (60 mg, 0.26 mmol, 59° A yield) as a yellow oil: LCMS (ES) m/z=235 (M+H)+.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13][CH:14]3[C:23]4[N:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC([N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[CH2:40]Cl)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.[I-].[K+]>CC#N>[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[CH2:40][N:13]([C@H:10]1[CH2:9][CH2:8][C@@H:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:12][CH2:11]1)[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1
Reactant: c1cnc2c(c1)CCCC2N[C@H]1CC[C@@H](N2CCOCC2)CC1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc2c(c1)CCCC2N(Cc1nc2ccccc2[nH]1)[C@H]1CC[C@@H](N2CCOCC2)CC1
Temperature: 25 °C

Procedure:
The above amine (69.0-mg, 0.22 mmol), 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (70.0 mg, 0.26 mmol), N,N-diisopropylethylamine (50 μL, 0.28 mmol), and potassium iodide (3.7 mg, 0.02 mmol) in CH3CN (1.5 mL) were stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Purification of the crude material by radial chromatography on silica gel (1 mm plate, NH4OH/MeOH/CH2Cl2, 1:1:98 then 1:2:97) afforded the desired compound (56.8 mg, 47%) as a pale yellow solid. 1H NMR (CDCl3) δ 1.30-1.34 (m, 2H), 1.45-1.66 (m, 11H), 1.88-2.01 (m, 4H), 2.05-2.16 (m, 4H), 2.40 (br m, 4H), 2.54 (t, 1H, J=4.4 Hz), 2.59 (t, 1H, J=3.9 Hz), 2.68-2.73 (m, 1H), 3.04-3.11 (m, 1H), 3.61-3.71 (m, 4H), 4.29 (dd, 1H, J=8.7, 5.7 Hz), 4.43 (s, 2H), 6.829 (dd, 1H, J=7.5, 4.8 Hz), 7.07 (d, 1H, J=6.9 Hz), 7.22-7.28 (m, 2H), 7.61-7.70 (m, 1H), 7.73-7.79 (m, 1H), 8.32 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: [CH2:1]([S:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(O)(=O)C.O>[Br:11][C:8]1[S:7][C:6]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=1
Reactant: CCCCSc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCCSc1ccc(Br)s1
Reaction time: 0.5 h

Procedure:
A solution of compound 6 (5.18 g, 0.030 mol) and N-bromosuccinimide (5.34 g, 0.030 mol) in chloroform (80 ml) and glacial acetic acid (80 ml) was gently heated under reflux (with stirring) for 0.5 h (glc analysis revealed a complete reaction). The reaction mixture was diluted with water and washed with dichloromethane (2×100 ml); the combined organic extracts were washed successively with water (300 ml) and aqueous potassium hydroxide (5%, 300 ml) before being dried (MgSO4). The solvent was removed in vacuo and the residue was distilled to give a colourless liquid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14]CC)=[O:13])[CH2:6]2.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6]2
Reactant: CCOC(=O)C1Cc2ccc(OC)cc2C1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C1Cc2ccc(O)cc2C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
50 g (0.23 mol) of the compound from Example 13 are initially introduced in 780 ml of absolute CH2Cl2 at -78° C. 114 ml (1.2 mol) of boron tribromide in 360 ml of absolute CH2Cl2 are then added dropwise and the mixture is stirred at -78° C. for 30 minutes. It is then stirred at 0° C. for 2.5 h, subsequently cooled to -78° C. again and 690 ml of absolute MeOH are added cautiously. After 15 minutes, the mixture is evaporated, the residue is dissolved in 818 ml of MeOH, 272 ml of 2N NaOH solution are added and the mixture is stirred at 20° C. for 2 h. The methanol is evaporated in vacuo, the aqueous phase is washed with 200 ml of ethyl acetate and then acidified to pH 1-2 using concentrated hydrochloric acid with ice cooling. The aqueous phase is shaken twice with 100 ml of ethyl acetate each time, and the combined ethyl acetate phases are dried over Na2SO4 and evaporated. The residue is recrystallized from toluene.