Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([O:21][CH3:22])=[O:20]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 72.4 %

Procedure:
To a mixture of 4-nitrophenol (100 g, 719 mmol) and anhydrous K2CO3 (400 gm, 2.894 mol) in anhydrous acetone (950 ml) was added methyl chloroacetate (114 g, 1.050 moles) and refluxed for 12 hours. Acetone was distilled off and water (1500 ml) was added. Crude 7 was filtered, dried and recrystallised from a mixture of ethyl acetate:hexane (1:5) to give pure 7 (110 g, 72.5%) as a white fluffy powder with an m.p between 97-98.4° C.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[CH3:26]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]([O:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])=[CH:19][C:18]=1[CH3:26]
Reactant: O=C(O)c1cnc(OC2CCC2)c(Br)c1
Reactant: Cc1cc(B(O)O)ccc1Cl
Product: Cc1cc(-c2cc(C(=O)O)cnc2OC2CCC2)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-cyclobutoxy-nicotinic acid (example BY) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; MS (ESI): 316.2 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([Cl:22])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[Cl:22][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:29]1[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 90 °C
Yield: 89.6 %

Procedure:
A vial was charged with (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (546.36 mg, 1.435 mmol), 2-fluoropyridin-3-ylboronic acid (303 mg, 2.153 mmol), potassium phosphate (914 mg, 4.31 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (50.8 mg, 0.072 mmol). The vial was flushed with Ar (g), then dioxane (5383 μL) and water (1794 μL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 20 min at 90° C. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (0-100% EtOAc/Hexane) to give (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (510.4 mg) as an off-white solid containing ca. 5% of the bis-coupled byproduct.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH2:12][CH2:13]O)[CH:9]=[CH:10][CH:11]=1.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][CH2:13][Br:16]
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1cccc(-c2ccco2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1cccc(-c2ccco2)c1

Procedure:
A solution of 2-(3-furan-2-yl-phenyl)ethanol and carbon tetrabromide in DCM was treated with triphenylphosphine at 0° C. The resultant mixture was stirred at room temperature for one hr. The volatiles were removed under reduced pressure. Purification by column chromatography (5% ethyl acetate/hexanes) gave 3-(2-furyl)phenethyl bromide. 1H NMR (CDCl3) δ 7.57 (d, J=1.6, 1H), 7.55 (s, 1H), 7.47 (s, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.66 (m, 1H), 6.47 (m, 1H), 3.60 (t, J=7.2 Hz, 2H), 3.20 (t, J=7.2 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[Cl:16])[C:5]([CH3:7])=O.[C:18]1(=[O:37])[N:22]([CH2:23][CH2:24][O:25][C:26](=[O:31])/[CH:27]=[C:28](\[NH2:30])/[CH3:29])[C:21](=[O:32])[C:20]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:19]12>>[CH3:7][C:5]1[NH:30][C:28]([CH3:29])=[C:27]([C:26]([O:25][CH2:24][CH2:23][N:22]2[C:21](=[O:32])[C:20]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:19]3[C:18]2=[O:37])=[O:31])[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[C:4]=1[C:3]([O:2][CH3:1])=[O:17]
Reactant: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Reactant: C/C(N)=C/C(=O)OCCN1C(=O)c2ccccc2C1=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc(Cl)c1Cl

Procedure:
Prepared by a method analogous to that of Example 1(a) from 13.0 g (48 mmol) of 2-(2,3-dichlorobenzylidene)-acetoacetic acid methyl ester and 13.1 g (48 mmol) of 3-amino-crotonic acid-(2-phthalimido ethyl)ester. 14.2 g (57%) of pale yellow crystals melting at 195°-196° C.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][N:6]=1.[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>CN(C)C=O>[O:21]1[CH2:20][CH:19]1[CH2:17][O:4][C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:7][N:6]=1
Reactant: Cc1c(O)noc1-c1ccccc1
Reactant: BrCC1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(OCC2CO2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
7.32 g of sodium methoxide were added to a solution of 6.00 g of 3-hydroxy-4-methyl-5-phenylisoxazole in 500 ml of dimethylformamide, and the mixture was stirred at room temperature for 10 minutes. 10.4 g of epibromohydrin were then added dropwise at room temperature to the mixture, and the mixture was stirred at room temperature for 48 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, eluted with a 2:1 by volume mixture of cyclohexane and ethyl acetate, to give 5.60 g of the title compound as colorless cotton-like crystals, melting at 87°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=2[F:22])[N:15]=[CH:14][N:13]=1>O1CCOCC1.CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=3[F:22])[N:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Fc1cc(F)c2c(Cl)ncnc2c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Fc1cc(F)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 71.4 %

Procedure:
3-Chloro-4-fluoroaniline (12 g) and 1N HCl in dioxane (40 ml) were added sequentially, each in one portion, to a mixture of 4-chloro-5,7-difluoroquinazoline (16.5 g) in IPA (250 ml) and the mixture was stirred at 80° C. under a nitrogen atmosphere for 17 hours. The reaction mixture was cooled to 0° C. and the precipitated solid was filtered and dried to leave N-(3-chloro-4-fluorophenyl)-5,7-difluoroquinazolin-4-amine as a green solid (18.2 g, 71%); Mass spectrum MH+ 310.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([C:11](OC)=[O:12])[CH2:10][CH2:9]1)=[O:7].[BH4-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([CH2:11][OH:12])[CH2:9][CH2:10]1)=[O:7]
Reactant: COC(=O)C1(C(=O)NCc2ccccc2Cl)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1ccccc1Cl)C1(CO)CC1
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of methyl 1-(2-chlorobenzylcarbamoyl)cyclopropanecarboxylate (330 mg, 1.2 mmol) in THF (5 mL) and CH3OH (5 mL) was added sodium borohydride (93 mg, 2.4 mmol, 2 equiv.). The reaction mixture was stirred for 3 h and quenched with diluted AcOH. The reaction mixture was concentrated and dissolved in EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4, and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give N-(2-chlorobenzyl)-1-(hydroxymethyl)cyclopropanecarboxamide (164 mg, 55%). LRMS (M+H+) m/z 240.0.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]2=[O:16])(C)(C)C.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[NH2:7][CH:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]2=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CC2CCC1CC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CC2CCC1CC2=O
Temperature: 25 °C
Yield: 91.5 %

Procedure:
(5-Oxo-bicyclo[2.2.2]oct-2-yl)-carbamic acid tert-butyl ester (Preparation 75, 279 g, 1.17 mol, 10 eq) was taken up in DCM (450 mL). TFA (416 mL, 5.60 mol, 4.8 eq) was added dropwise. On addition, the reaction warms to reflux while much gas evolves. The reaction mixture was kept at reflux temperature for 1 hour after which it was allowed to cool to room temperature overnight. The mixture was concentrated and the residue was taken up in DCM (50 mL) and then tert-butyl methyl ether (1.3 L) was added which resulted in a brown suspension. The solids were collected by filtration (P3) and were washed with tert-butyl methyl ether. The latter was dried in vacuo (40° C.) to furnish title compound as an off-white solid (272 g, 1.07 mol, 92%).
Reaction SMILES: [Si]([O:8][CH:9]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:36]=[CH:35][C:26]([CH2:27][NH:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:25]([CH3:37])[CH:24]=2)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:38])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH2:19]([C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH:9]([OH:8])[C:39]([CH3:40])([CH3:42])[CH3:41])=[C:13]([CH3:38])[CH:14]=1)([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][NH:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:25]([CH3:37])[CH:24]=1)[CH2:21][CH3:22])[CH3:20]
Reactant: CCC(CC)(c1ccc(CNCCS(C)(=O)=O)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)(c1ccc(CNCCS(C)(=O)=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
To a mixture of [4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzyl]-(2-methanesulfonylethyl)amine (1.47 g, 2.43 mmol) in THF (30 mL) is added 1M TBAF (2.7 mL, 2.7 mmol), and refluxed for 2 h. After cooling to RT, the mixture is diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers are MgSO4 dried, concentrated, and chromatographed (80% EtOAc/Hex) to give the title compound (0.97 g, 1.93 mmol, 79%).
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[CH2:53][C:54]([NH:56][C@H:57]2[CH2:61]CN[CH2:58]2)=O)=O)=CC=1)([O-])=O>C(#N)C>[CH:3]([N:56]([CH2:54][CH3:53])[CH:57]([CH3:58])[CH3:61])([CH3:31])[CH3:4]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(CNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (5.38 g) in anhydrous acetonitrile (70 ml), N,N'-carbonyldiimidazole (2.04 g) was added, followed by stirring at room temperature for one hour. To the reaction mixture, N,N-diisopropylethylamine (2.0 ml) and a solution of the compound (11.00 g), which had been obtained in (2), in anhydrous acetonitrile (35 ml) were added and the mixture was reacted overnight at room temperature. The reaction mixture was concentrated by evaporation under reduced pressure. Ethyl acetate was added to the residue. The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography (ethyl acetate-methanol) through a silica gel column, whereby the title target compound (10.09 g) was obtained as an amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:36]=[CH:35][C:29](/[C:30](=[N:33]/[H])/[NH:31]O)=[CH:28][CH:27]=1.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[Br:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]2[N:33]=[C:14]([CH2:13][N:10]3[CH2:11][CH2:12][C:8]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:9]3=[O:17])[O:15][N:31]=2)=[CH:28][CH:27]=1
Reactant: [H]/N=C(\NO)c1ccc(Br)cc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(Br)cc3)no2)CCC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 85 °C

Procedure:
2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.300 g, 0.905 mmol; Example 58D), (Z)-4-bromo-N-hydroxybenzimidamide (0.214 g, 0.996 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.211 g, 1.358 mmol) were stirred together in dichloroethane (5 mL) at room temperature for 3 hours. The reaction was then heated to 85° C. for 18 hours. The reaction was cooled, loaded onto a GraceResolv 80 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=8.6, 2H), 7.62 (d, J=8.6, 2H), 7.38-7.30 (m, 4H), 7.07-6.97 (m, 4H), 4.87 (s, 2H), 3.56 (t, J=6.5, 2H), 2.83 (t, J=6.4, 2H); MS (ESI+) m/z 512.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.CS(O[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=1)(=O)=O.C(N(CC)CC)C>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:24][CH:25]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Yield: 20.8 %

Procedure:
A solution of 1-(4-pyridinyl)piperazine (1.63 g), N-[4-(2-methylsulphonyloxyethyl)phenyl]methanesulphonamide (2.93 g) and triethylamine (1.01 g) in ethanol (25 ml) was heated under reflux for 18 hours and then evaporated. The resulting oil was partitioned between dichloromethane and water (some insoluble material remained in the aqueous layer). The aqueous layer was washed with dichloromethane and the organic layers were combined, washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed in silica gel. Elution with dichloromethane/methanol (19:1) first gave some impurity followed by a solid which was crystallised from methanol/ethyl acetate to give the title compound (0.75 g), m.p. 208°-210° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:28]([NH:30][C:31](=[N:39][CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH:45]=1)OC1C=CC=CC=1)#[N:29]>>[C:28]([NH:30][C:31]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:25])=[N:39][CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:51]2[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]2)[CH:45]=1)#[N:29]
Reactant: CN(CCCCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: CN(CCCCCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.48 g (1.3 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,7-heptanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Chromatographic working-up analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=671 ([M+H]+, 3), 229 (100); IR (KBr): 2164 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanol/ether; m.p.: 96°-98° C. (isopropanol/ether).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][C:9](=[O:20])[CH:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH3:11].C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]([F:41])([F:40])[C:33]1[CH:38]=[CH:37][C:36](Cl)=[CH:35][CH:34]=1>CN(C)C=O>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][C:9](=[O:20])[CH:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:36]2[CH:37]=[CH:38][C:33]([C:32]([F:41])([F:40])[F:31])=[CH:34][CH:35]=2)=[CH:17][CH:18]=1)[CH3:11]
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: CC(Oc1ccc(O)cc1)C(=O)OCCOCc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCCOCc1ccccc1F
Temperature: 95 °C

Procedure:
33.4 g of 2-(2-fluorobenzyloxy)ethyl-2-(4-hydroxyphenoxy)propionate was dissolved in 120 ml of dimethylformamide, 15.2 g of potassium carbonate were added thereto, then the mixture was heated at 95° C. for one hour with stirring. 27.1 g of 4-trifluoromethyl chlorobenzene were added to the solution which was then heated to 95° to 100° C. for five hours. After cooling the reaction solution to room temperature, it was poured into ice-water, then extracted with toluene. The toluene layer was washed successively with 1% strength by weight sodium hydroxide solution and water, and was dried and filtered. The toluene was distilled off under reduced pressure, and further volatile by-products were removed at 100° C./0.1 mmHg. The end product of 2-(2-fluorobenzyloxy)ethyl-2-[4-(4-trifluoromethylphenoxy)phenoxy]propionate was obtained in a yield of 20.7 g. (nD20 1.5235)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:19])[C:3]=1[NH:20][CH3:21].[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][C:26]=1[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:20]([C:3]2[C:4]([CH3:19])=[CH:5][C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])=[CH:7][C:2]=2[F:1])[CH3:21])=[CH:27][C:26]=1[CH3:33]
Reactant: COC(=O)c1ccc(C=O)cc1C
Reactant: CNc1c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN(C)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2F)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
A mixture of (2-fluoro-6-methyl-4-triisopropylsilanyloxy-phenyl)-methyl-amine (326 mg, 1.05 mmol) and 4-formyl-2-methyl-benzoic acid methyl ester (320 mg, 1.80 mmol) in 4 mL acetic acid is stirred for 2.5 hours at room temperature. Sodium triacetoxyborohydride (773 mg, 3.65 mmol) is added and stirred. Upon completion of the reaction, the mixture is concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer is extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4) and concentrated. The residue is purified on 40 g silica with ethyl acetate in heptane gradient (10% to 20%) to provide 457 mg (92%) of the titled compound as an oil. MS (ES) m/z 475.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH2:21][CH2:22][N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: CN1CCNCC1
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Solvent: CCN(CC)CC
Product: CN1CCN(CCc2ccc3c(n2)COC3=C2C(=O)Nc3ccc(F)cc32)CC1
Temperature: 100 °C
Yield: 101.4 %

Procedure:
Following the method described in Example 19, 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (60 mg, 0.20 mmol) and N-methylpiperazine (300 mg, 3.00 mmol) are heated 100° C. for 2 h. The reaction mixture is cooled and treated with triethylamine (10 drops). The reaction mixture is loaded onto silica gel and purified by chromatography (silica gel, gradient elution, 2% MeOH/Chloroform to 20% MeOH/chloroform ) to provide the title compound (80 mg, 100%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([C:10]#[N:11])[NH:6][C:7](=O)[CH3:8])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:22]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:6]=[C:7]([CH3:8])[S:22][C:10]=1[NH2:11])=[O:12])[CH3:2]
Reactant: CCOC(=O)C(C#N)NC(C)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(C)sc1N
Temperature: 110 °C
Reaction time: 22 h
Yield: 100.9 %

Procedure:
A suspension of 2-acetylamino-cyanoacetic acid ethyl ester (1.70 g, 10.00 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (2.02 g, 5.00 mmol) in toluene (25.00 ml) was heated under argon to 110° C. and stirred for 22 h. The solvent was then evaporated, and the residue purified by flash chromatography (heptane/ethyl acetate 1:1) to yield 5-amino-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.94 g, 50.5%) as a yellow solid, MS (ISP): m/e=187.3 (M+H+).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Br)([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=O)C.C1COCC1.[NH3:23]>C(O)C>[NH2:23][C:11]([C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1)([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(C)(Br)c1ccc(OC(C)=O)cc1
Reactant: N
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)C(C)(N)c1ccc(O)cc1
Temperature: 25 °C

Procedure:
10 g of methyl 2-(4-acetoxyphenyl)-2-bromopropionate, 50 mL of THF and 30 mL of ethanol are introduced into a Woulff bottle at ambient temperature. The mixture is saturated with gaseous ammonia and stirred for one night at ambient temperature. The insoluble matter is filtered and purified over a silica column with 90/10 dichloromethane/methanol to yield the product (5 g; Yd=77%).