Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH:36](Br)([CH3:38])[CH3:37]>>[CH:36]([O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])([CH3:38])[CH3:37]
Reactant: CC(C)Br
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC(C)C)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with isopropyl bromide
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].CN(C=O)C.[OH:10][C:11]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>O>[I:21][C:19]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:10][CH:2]([CH3:4])[CH3:3])[CH:20]=1
Reactant: CC(C)Br
Reactant: COC(=O)c1ccc(I)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(I)cc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromopropane (6.49 mL) was added to a DMF (70 mL) suspension of methyl 2-hydroxy-4-iodobenzoate (12.8 g) and potassium carbonate (12.7 g), and the mixture was stirred at 60 C for 2 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to obtain the title compound (14.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl>[C:21]([O:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:24])[CH:22]=[CH2:23]
Reactant: CS(=O)(=O)NCc1ccc(O)cc1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(CNS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 20.1 g (0.10 mol) of N-(4-hydroxybenzyl)methanesulfonamide, 10.1 g (0.10 mol) of triethylamine and 100 ml of methylene chloride cooled to approximately 0° C. was added a solution of 9.0 g (0.10 mol) of acryloyl chloride in 50 ml of methylene chloride over a 10-minute period. Stirring was continued for 30 minutes, and the mixture was filtered. The filtrate was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator. The residue was recrystallized from 100 ml of 1:1 hexane:1,2-dichloroethane. The yield of N-(4-acryloyloxybenzyl)methanesulfonamide was 8.2 g (32.1 percent of theory), m.p.=112° to 115° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:29]3[CH:28]=[C:27]([O:30][CH3:31])[CH:26]=[CH:25][C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Reactant: COc1ccc(O)c(B(O)O)c1
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cccc(OC)c4O)n3)n2)c1
Yield: 16 %

Procedure:
6-(2-Hydroxy-3-methoxyphenyl)-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-5-methoxyphenylboronic acid in 16% yield using method F; δH [2H6]-DMSO 13.72,(1H, b), 12.48,(1H, b), 8.39,(1H, d), 8.32,(1H, d), 8.27-8.14,(4H, m), 7.72,(1H, d), 7.67,(1H, s), 7.09,(1H, d), 7.04-6.90,(3H, m), 3.86,(6H, s); MS 401 (MH)+; HPLC retention time (system 1) 3.98 minutes.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][CH2:2]1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1.[BH4-].[Na+]>C(O)(=O)C.CO>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=1
Reactant: O=Cc1cccnc1
Reactant: c1ccc2c(c1)NCCCN2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1cncc(CN2CCCNc3ccccc32)c1
Temperature: 25 °C

Procedure:
To solution of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine from Example 15A (0.50 g, 3.38 mmol) in 1% acetic acid/methanol (25 ml), at room temperature, was added pyridine-3-carboxaldehyde (0.35 ml, 03.72 mmol). The mixture was stirred at reflux for 18 h and then allowed to cool to room temperature. Sodium borohydride (0.050 g, 0.80 mmol) was added. The mixture was stirred for 2 h and then evaporated in vacuo. The residue was partitioned between EtOAc and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacua. The residue was purified by flash chromatography on silica (eluant EtOAc) to give a white solid; yield 0.386 g (40%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9]([N:11]([CH2:13][CH2:14][OH:15])[CH3:12])=[O:10])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:15][CH2:14][CH2:13][N:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH3:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)N(C)CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(C)CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
1.65 g of methanesulfonyl chloride was added dropwise, with stirring, to a solution of 1.66 g of 2-(N-ethoxycarbonyl-N-methylamino)ethanol and 1.65 g of triethylamine in 20 ml of methylene chloride, whilst ice-cooling, and the solution was then stirred at the same temperature for 30 minutes. At the end of this time, the mixture was poured into ice-water and extracted with methylene chloride. The extracts were combined and washed with water, after which they were dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave a residue which was purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 2.62 g (yield 81%) of the title compound as an oil.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16](=[O:22])[CH2:17][O:18][CH2:19][CH:20]=[CH2:21])[CH3:14].[CH:23]([CH:25]=[CH2:26])=[O:24]>C1COCC1>[CH2:13]([O:15][C:16](=[O:22])[CH:17]([O:18][CH2:19][CH:20]=[CH2:21])[CH:23]([OH:24])[CH:25]=[CH2:26])[CH3:14]
Reactant: C=CC=O
Reactant: C=CCOCC(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCOC(C(=O)OCC)C(O)C=C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under an atmosphere of argon, n-BuLi (3 mmol, 1.2 ml, 2.5 M in hexane) was added dropwise to a solution of diisopropylamine (281 mg, 2.78 mmol) in dry THF (20 ml) at −78° C. After stirring for 20-30 min, a solution of allyloxy-acetic acid ethyl ester (200 mg, 1.38 mmol) in THF (4 ml) was added and the mixture was stirred at −78° C. for 10 min. Acrolein (79 mg, 1.38 mmol) was added into the reaction mixture and stirring was maintained until all starting materials were consumed. The reaction was quenched by addition of EtOH (2 ml) and warmed to room temperature. The solution was diluted with EtOAc (60 ml), washed with H2O (20 ml×2), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.F[C:26]1[C:35]([O:36][CH3:37])=[C:34]2[C:29]([C:30](=[O:45])[C:31]([C:42]([OH:44])=[O:43])=[CH:32][N:33]2[C@@H:38]2[CH2:40][C@@H:39]2[F:41])=[CH:28][CH:27]=1>CS(C)=O>[F:41][C@H:39]1[CH2:40][C@H:38]1[N:33]1[C:34]2[C:29](=[CH:28][CH:27]=[C:26]([N:15]3[CH2:16][CH2:17][C@@H:13]([C:10]4([NH:8][CH3:9])[CH2:11][CH2:12]4)[CH2:14]3)[C:35]=2[O:36][CH3:37])[C:30](=[O:45])[C:31]([C:42]([OH:44])=[O:43])=[CH:32]1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3OC)C2)CC1
Temperature: 100 °C
Yield: 49.7 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (102 mg, 379 μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (1 ml, 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (112 mg, 379 μmol) was added thereto and stirred while heating in an oil bath of 100° C. for 15 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (2 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (2 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×4), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by a preparative chromatography (developed into the lower layer of a 7:3:1 mixture of chloroform:methanol:water), purified further by recrystallization from ethanol, and then dried under a reduced pressure. 78.3 mg (50%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [C:1]([C:3]1([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[CH2:21][CH3:22])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)#[N:2].C(O)(=[O:25])C.S(=O)(=O)(O)O>O>[CH2:21]([C:13]1[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[C:3]1([C:1]([NH2:2])=[O:25])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:22]
Reactant: CC(=O)O
Reactant: CCc1ccc([N+](=O)[O-])cc1C1(C#N)Cc2ccccc2C1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1ccc([N+](=O)[O-])cc1C1(C(N)=O)Cc2ccccc2C1
Temperature: 0 °C
Yield: 71 %

Procedure:
To a mixture of the compound (1.16 g) obtained in Example 25b and acetic acid (10 ml), water (2 ml) and concentrated sulfuric acid (20 ml) were added sequentially. The reaction mixture was heated under reflux for 13 h, cooled, put into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (870 mg) (yield, 71%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C2CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Nc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(6-amino-pyridin-3-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][OH:13].O=[CH:15][C:16]([Cl:19])([Cl:18])[Cl:17]>C(OCC)(=O)C>[Cl:17][C:16]([Cl:19])([Cl:18])[CH:15]1[NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH2:12][O:13]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(N)c(CO)c1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)COC(C(Cl)(Cl)Cl)N2
Reaction time: 0.08 h

Procedure:
Methyl 4-amino-3-hydroxymethylbenzoate (1 g.) and anhydrous chloral (1 ml.) were mixed together, initially with external ice-cooling, and then on a steam bath for 5 minutes. The product was dissolved in ethyl acetate (100 ml.) and the solution was washed with water (50 ml.), then dried. The solvent was evaporated, and the residue was crystallized from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80 C.) to give methyl 1,2-dihydro-2-trichloromethyl-4H-benzo[d]-[1,3]-oxazine-6-carboxylate, m.p. 178°-179° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16].[H-].[Na+]>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C(Cl)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1N1CCCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A solution of 3-bromo-2-methylaniline (1 g, 5.37 mmol) in DCM (15 mL) was treated with TEA (0.749 mL, 5.37 mmol) and then dropwise with a solution of 5-bromopentanoyl chloride (1.072 g, 5.37 mmol) in DCM (4 mL). The mixture was stirred at rt for 30 min, then was diluted with DCM, washed with water and brine, and dried and concentrated. The residue was dissolved in THF (100 mL) and added to a suspension of sodium hydride (60% oil dispersion, pre-washed with hexane, 0.430 g, 10.75 mmol) in THF (50 mL). The resulting mixture was stirred overnight at rt. The mixture was concentrated and the residue was acidified with 1 M hydrochloric acid. The mixture was extracted with DCM and the organic phase was washed with water, dried and concentrated to give 1-(3-bromo-2-methylphenyl)piperidin-2-one as a tan oil (1.4 g, 97%). 1H NMR (400 MHz, chloroform-d) δ 7.49-7.54 (1H, m), 7.07-7.13 (2H, m), 3.38-3.60 (2H, m), 2.54-2.59 (2H, m), 2.26 (3H, s), 1.91-2.02 (4H, m). Mass spectrum m/z 268, 270 (M+H)+.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[SH:48]>[Cu]I>[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1S
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CN(C)C=O
Product: COc1ccccc1Sc1ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12
Temperature: 120 °C

Procedure:
Into a sealed tube was added (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.320 g, 0.826 mmol), Sodium tert-butoxide (238 mg, 2.48 mmol), Copper(I) iodide (16 mg, 0.083 mmol), 1,2-Ethanediol (92.6 uL, 1.66 mmol), N,N-Dimethylformamide (12 mL, 150 mmol), and finally 2-Methoxy-benzenethiol (0.174 g, 1.24 mmol). The reaction was heated at 120° C. overnight. The reaction was partitioned with DCM and water. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded [7-(2-Methoxy-phenylsulfanyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine an orange solid (9 mg, 2.5%). MP 171-172° C. LCMS (E/I+) 447.24 (M+H). NMR 1H (DSMO-d6)-9.27 (s, 1H), 8.97 (s, 1H), 7.35 (d, 2H, J=9.00 Hz), 7.08-7.20 (m, 2H), 6.97 (d, 1H, J=4.68 Hz), 6.92 (d, 1H, J=4.57 Hz), 6.75 (t, 1H, J=6.72 Hz), 6.68 (d, 2H, J=9.08 Hz), 6.36 (dd, 1H, JJ=1.40, 6.41 Hz), 3.91 (s, 3H), 3.01 (t, 4H, J=4.72 Hz), 2.43 (t, 4H, J=4.68 Hz), 2.21 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:60].Cl>>[ClH:1].[ClH:30].[ClH:60].[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:18][CH:17]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Yield: 93 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[(4-methylpiperazin-1-yl)methyl]phenyl amino}-1,5-naphthyridin-3-yl)ethanone (74 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.27 mmol) followed by formation of the dihydrochloride salt to afford the desired product (96 mg, 93%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.32 (s, 1H), 8.44 (d, J=9.1 Hz, 1H), 8.34 (d, J=9.1 Hz, 1H), 7.65 (d, J=7.6 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.31 (br s, 1H), 7.12 (br s, 1H), 4.26 (br s, 2H), 3.45 (br s, 8H), 2.97 (s, 3H), 2.80 (s, 3H); ESI MS m/z 520 [M+H]+; HPLC>99% (AUC), tR=9.37 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([SH:17])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][C:26](=[O:27])[NH:25][C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Reactant: Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cnc2c(SC(=O)Nc3ccc(C)cc3)cccn2c1=O

Procedure:
To a suspension of 0.4 g of 3-ethoxycarbonyl-9-mercapto-4H-pyrido[1,2-a]pyrimidin-4-one II-1 in 10 ml of dry CH2Cl2 is added 0.35 g of 4-methylphenyl isocyanate III-1, and the resultant mixture is stirred at room temperature for 4 hours. At this time the reaction mixture is crystallized again after it is once dissolved.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[CH3:6][O:7][C:8](=[O:12])[CH2:9][C:10]#[N:11].[OH-].[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8](=[O:12])[C:9]([C:10]#[N:11])=[CH:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: COC(=O)CC#N
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)=CC(C)C
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A solution of isobutyraldehyde (30.0 g, 416 mmol), methyl-cyano-acetate (20.6 g, 208 mmol), ammonium hydroxide (3.2 g, 41.6 mmol) and acetic acid (5.0 g, 83.2 mmol) in 500 mL of toluene is warmed to reflux under a Dean-Stark trap for 12 hours. The mixture is cooled to room temperature and extracted with saturated NaHSO3 (3×100 mL), saturated NaHCO3 (3×100 mL), and 100 mL of brine. The organic layer is dried over Na2SO4, and the solvent is evaporated. The remaining oil is distilled under high vacuum (0.5 mm Hg, B.P.=115-120° C.) to give 28.8 g of 2-cyano-4-methyl-2-pentenoic acid methyl ester 61 as an oil (90% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=1.[Na+].[I-:16]>O1CCOCC1.[Cu]I>[I:16][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)Cc1ccc(Br)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)NC(C)Cc1ccc(I)cc1
Temperature: 120 °C
Reaction time: 70 h

Procedure:
To 6.00 g (23.4 mmol) N-(1-(4-bromophenyl)propan-2-yl)acetamide (II.1) in 65 mL dioxan are added 0.45 g (2.34 mmol) CuI, 0.50 mL (4.70 mmol) N,N″-dimethyl-ethylendiamine and 7.02 g (46.9 mmol) NaI. The reaction mixture is stirred at 120° C. for 70 h. The mixture is allowed to cool to r.t. and half of the solvent is removed in vacuo. EtOAc and diluted aq. ammonia solution are added and the layers are separated. The aq. layer is once more extracted with EtOAc. The organic layers are combined, dried with Na2SO4, filtered and the solvent is removed in vacuo. The crude product is triturated with diethylether and dried at 50° C. in vacuo.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:10])C1C=CC=CC=1.CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[CH2:30]([O:29][C:12]1[C:13]2[C:18](=[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[C:9]([OH:10])=[O:8])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(OCc1ccccc1)c1ccc2c(OCc3ccccc3)cccc2c1OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(OCc3ccccc3)cccc2c1OCc1ccccc1
Yield: 92 %

Procedure:
1,5-Bis-benzyloxy-naphthalene-2-carboxylic acid benzyl ester (0.556 g, 1.17 mmol), MeOH (6.4 mL) and NaOH (1.25 mL), H2O (65.0 mL) and citric acid (0.28 g, 1.5 mmol) Yield: 0.507 g creamy white solid (92% yield). 1H NMR (400 MHz CDCl3) δ 5.23 (s, 2H), δ 5.28 (s, 2H), δ 7.06 (d, J=7.3 Hz, 1H), δ 7.38-7.55 (m, 11H), δ 7.83 (d, J=8.7 Hz, 1H), δ 8.08 (d, J=8.7 Hz, 1H), δ 8.26 (d, J=8.7 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1[O:18][C:17]([CH:19]([CH3:23])[CH2:20][CH:21]=O)=[CH:16][CH:15]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:21][CH2:20][CH:19]([C:17]2[O:18][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH3:23])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(C)CC=O)o1
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(C)CCNCc2ccc(C(C)(C)C)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
0.26 ml of 4-tert-butylbenzylamine (1.5 mmol) and 346 mg of [rac]-3-(5-methyl-furan-2-yl)-butyraldehyde (2.25 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 68 mg (1.8 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was then refluxed for 2¼ h. After cooling down to rt again 68 mg of sodium borohydride were added and the mixture was again refluxed for additional 18 h. After cooling down to rt, the reaction mixture was treated with 3 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 328 mg light yellow oil (73%). MS (ISP) 300.4 (M+H)+.