Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[C:5]([CH3:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:6]2[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[CH:13][CH:12]=1
Reactant: Cc1cnc(F)cc1I
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1cnc(F)cc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-fluoro-4-iodo-5-methylpyridine (1.9 g), 4-chlorophenylboronic acid (1.504 g), tetrakis(triphenylphosphine)palladium(0) (0.463 g), and sodium carbonate (2.55 g) in ethanol (20 mL), water (10 mL) and toluene (10 mL) was heated under reflux for 6 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layers were extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel using 5% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.CC(C)=O.O.CCOCC>[N:17]([CH:1]1[CH:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1)=[N+:18]=[N-:19]
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC1CN(C(=O)OCc2ccccc2)CC1O
Temperature: 80 °C
Reaction time: 24 h
Yield: 65.9 %

Procedure:
To a stirred mixture of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.2 g, 23.72 mmol) (Method 197) in DMF (30 mL) was added sodium azide (2.313 g, 35.58 mmol) in a mixture of acetone (20.00 mL) and water (10.00 mL). The resulting mixture was stirred at 80° C. for 24 h. The mixture was then diluted with water and ether, separated, and the organic layer was washed with brine, dried and conc. in vacuo. The resulting material was purified via silica gel chromatography (eluted with 15% to 35% ethyl acetate/hexane), yielding the title compound as a yellow solid (4.10 g, 65.9%). 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.50-7.25 (m, 5 H), 5.43-5.25 (m, 2 H), 4.31 (brs, 1 H), 4.00 (brs, 1 H), 3.77 (dd, 1 H), 3.69 (dd, 1 H), 3.53 (d, 1 H), 3.44 (dd, 1 H), 2.17 (brs, 1 H); m/z 263.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[F:16][C:17]1[N:22]=[C:21]([F:23])[C:20]([F:24])=[C:19](F)[C:18]=1[F:26].[F-].[Cs+].ClCCl>CN(C=O)C.[Cl-].[Na+].O>[F:23][C:21]1[C:20]([F:24])=[C:19]([C:3]#[C:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:18]([F:26])=[C:17]([F:16])[N:22]=1
Reactant: C[Si](C)(C)C#Cc1cccc([N+](=O)[O-])c1
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of trimethyl((3-nitrophenyl)ethynyl) silane, (11b) (1.45 g, 6.61 mmol) in DMF (10 mL) was added to the mixture of pentafluoropyridine (1.45 g, 8.59 mmol) and CsF(1.51 g, 9.92 mmol) in DMF (10 mL) slowly. The reaction mixture was stirred overnight. Brine (30 mL) and dichloromethane (60 mL) were added. Organic phase was separated and washed with water (30 mL×3). Solvent was evaporated by rotary evaporation and the residue was chromatographed (Hexane, then EtOAc:Hexane=1:30) to provide the desired product in 72% yield: 1H-NMR (300 MHz, CDCl3) δ 8.49 (dd, J=1.8, 1.8 Hz, 1H), 8.35 (ddd, J=8.4, 2.1, 0.9 Hz, 1H), 7.96 (ddd, J=7.8, 1.2, 1.2 Hz, 1H), 7.66 (dd, J=8.1, 8.1 Hz, 1 H); 13C-NMR (75 MHz, CDCl3) δ 148.2, 143.5 (dm, J=247.6 Hz), 141.9 (dm, J=264.0 Hz), 129.9, 127.0, 125.1, 122.2, 116.3 (tt, J=16.0, 4.4 Hz), 102.9 (t, J=3.5 Hz), 75.2 (t, J=4.2 Hz); HRMS (CI+): calcd for C13H5F4N2O2 [M+H]+ 297.02872, found 297.02908; m.p. 130-131° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[S:32](Cl)([CH3:35])(=[O:34])=[O:33]>ClCCl>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[S:32]([CH3:35])(=[O:34])=[O:33]
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)S(C)(=O)=O
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.60 mmol) and triethylamine (102 μL, 0.72 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of mesyl chloride (56 μL, 0.72 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, washed with water then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (175 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, 2H), 6.92-6.90 (d, 2H), 4.03 (t, 2H), 3.83-3.78 (m, 2H), 3.52 (t, 2H), 3.16 (s, 2H), 2.68 (s, 3H), 2.64 (t, 2H), 2.54 (m, 4H), 2.19-2.15 (m, 5H), 2.05-1.91 (m, 4H), 1.81-1.78 (m, 4H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:21](=[O:22])[C:20]4[C:19]([C:23](O)=[O:24])=[CH:18][CH:17]=[CH:16][C:15]=4[C@@H:14]3[CH3:26])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].OC1C2N=N[NH:34]C=2C=CC=1.C(N(CC)CC)C>O1CCCC1>[CH:1]1([N:7]2[CH2:8][CH2:9][CH:10]([N:13]3[C:21](=[O:22])[C:20]4[C:19]([C:23]([NH2:34])=[O:24])=[CH:18][CH:17]=[CH:16][C:15]=4[C@@H:14]3[CH3:26])[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1cccc2[nH]nnc12
Reactant: C[C@H]1c2cccc(C(=O)O)c2C(=O)N1C1CCN(C2CCCCC2)CC1
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1c2cccc(C(N)=O)c2C(=O)N1C1CCN(C2CCCCC2)CC1
Reaction time: 16 h
Yield: 40.2 %

Procedure:
(1S)-2-(1-Cyclohexylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (0.15 gr, 0.42 mmol), hydroxybenzotriazole ammonium salt (0.13 gr, 0.84 mmol) and 1-ethyl-3-(3′-dimethylamino) carbodiimide hydrochloric acid salt (0.16 gr, 0.84 mmol) were dissolved in a mixture of tetrahydrofuran (6 mL) and triethylamine (0.23 mL, 1.68 mmol) and stirred under nitrogen atmosphere for 16 hours. Volatiles were evaporated and the crude was dissolved in dichloromethane and washed with 15% ammonium hydroxide. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was purified by flash chromatography (dichloromethane/methanol/7N ammonia in methanol 100:3:1) to afford the title compound (0.060 g, 40%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2>C(O)C.[Ni]>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][CH2:6][NH:7]2
Reactant: Cc1ccc2nccnc2c1C
Agent: [Ni]
Solvent: CCO
Product: Cc1ccc2c(c1C)NCCN2
Reaction time: 2 h

Procedure:
5.3 g (0.034 mole) of 5,6-dimethylquinoxaline were dissolved in 200 ml of ethanol and, after the addition of 1 g of Raney nickel, the resulting solution was hydrogenated for 2 h at room temperature/normal pressure. After filtration, the product was concentrated to dryness and recrystallized from methyl-t-butyl ether.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)(=[O:26])=[O:25]>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([O:9][CH2:8][C:5]2[CH:6]=[N:7][C:2]([N:32]3[C:33]4[C:29](=[CH:28][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:35][CH:34]=4)[CH:30]=[CH:31]3)=[CH:3][CH:4]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccc(Cl)nc2)CC1
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following a procedure described in Intermediate-27 by using tert-butyl 4-((6-chloropyridin-3-yl)methoxy)piperidine-1-carboxylate and 5-(methylsulfonyl)-1H-indole (0.410 g, 27.70%); MS: 386.32 (M−100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[C:23]3=[N:24][S:25](=[O:29])(=[O:28])[CH2:26][CH2:27][N:22]3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]([C@@H:18]2[C:23]3=[N:24][S:25](=[O:29])(=[O:28])[CH2:26][CH2:27][N:22]3[CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: O=S1(=O)CCN2CCC[C@H](c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1cccc(Cl)c1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2CCC[C@H](c3ccc(Oc4cccc(Cl)c4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 3-chlorophenylboronic acid (167 mg), (9R)-9-(4-hydroxyphenyl)-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (100 mg), diacetoxycopper (130 mg), triethylamine (0.248 mL), and powdered 4A MS (1.50 g) in DMF (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (32.0 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][C@H:16]([C:19]([O:21]CC4C=CC=CC=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CC[C@H](N2CCN(c3ccc(F)cc3)CC2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](N2CCN(c3ccc(F)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 263.1 %

Procedure:
To a solution of (1S,3S)-benzyl 3-(4-(4-fluorophenyl)piperazin-1-yl)cyclopentanecarboxylate (0.6 g, 0.52 mmol) in methanol (15 ml) was added 10% palladium on charcoal (60 mg). The reaction mixture was stirred at room temperature under H2 atmosphere at atmospheric pressure for 2 h. Upon completion, the reaction mixture was filtered through a pad of celite, and washed with methanol (15 ml). The filtrate was concentrated under reduced pressure to afford the title compound (0.4 g, 87%), which was used further without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[C:3]=1[OH:11].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=S)=[CH:15][CH:14]=1.C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1.S([O-])([O-])(=O)=O.[Cu+2]>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[O:11][C:3]3[C:4]([CH:8]([CH3:9])[CH3:10])=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:15][CH:14]=1
Reactant: CC(C)c1cccc(N)c1O
Reactant: S=C=Nc1ccc(Br)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)c1cccc2nc(Nc3ccc(Br)cc3)oc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
A solution of 2-amino-6-isopropylphenol (0.354 g, 2.34 mmol) and 4-bromophenylisothiocyanate (0.500 g, 2.34 mmol) in tetrahydrofuran (35 mL) was stirred at room temperature for 3 h. Anhydrous copper (II) sulfate (3.361 g, 21.06 mmol), silica gel (3.361 g), and triethylamine (0.236 g, 0.33 mL, 2.34 mmol) were added, and the mixture stirred at room temperature for 18 h. The reaction mixture was filtered through a pad of Celite and the washed with diethyl ether (3×50 mL). The filtrate was concentrated to afford a brown solid. The solid material was applied to silica gel and passed through a pad a silica gel along with ethyl acetate (3×50 mL). The filtrate was concentrated to afford N2-(4-bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine (0.702 g, 91%). RP-HPLC Rt 18.066 min, 86% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 333 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH3:11])[C:5]=1[Cl:12].C(O[N:20]=O)CC(C)C>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([Cl:12])=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][N:20]=[CH:11]2)=[O:13]
Reactant: COC(=O)c1ccc(N)c(C)c1Cl
Reactant: CC(C)CCON=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]ncc2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 4-amino-2-chloro-3-methyl-benzoic acid methyl ester (5.29 g, 26.5 mmol) in acetic acid (100 mL) was added isoamylnitrite (3.9 mL, 29.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes then heated at reflux for 3 hours. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (2.26 g, 40%). 1H NMR (CDCl3, 400 MHz) 3.97 (3H, s), 7.42 (1H, d, J=8.8 Hz), 7.95 (1H, d, J=8.8 Hz), 8.29 (1H, s).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:5]=1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8].S(OC)(O[CH3:26])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:5]=1[N:6]([CH3:26])[S:7]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)(=[O:8])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cl)cc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a suspension of sodium hydride (60%, 0.07 g (1.75 mmol)) in DMF (2.0 ml), 2′,4′-dichloro-p-toluenesulfonanilide (0.50 g (1.58 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (0.17 ml (1.80 mmol)) was added dropwise. After 15 hours' stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The crystals separated were filtered and washed with diisopropyl ether to give 0.38 g (73%) of the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24](=[O:28])[C:25]([OH:27])=O)=[CH:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[C:37]([O:51][CH3:52])=[C:38]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:39]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:41]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:42]([C:40]1[CH:39]=[C:38]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[C:37]([O:51][CH3:52])=[C:36]([NH:35][C:25](=[O:27])[C:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([O:13][C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]=3)=[CH:15][CH:16]=2)=[O:28])[CH:41]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: O=C(O)C(=O)c1ccc(Oc2ccnc(N3CCOCC3)n2)c2ccccc12
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(NC(=O)C(=O)c2ccc(Oc3ccnc(N4CCOCC4)n3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
[4-(2-Morpholin-4-yl-pyrimidin-4-yl-oxy)-naphthalen-1-yl]-oxo-acetic acid (16) obtained above (36 mg, 0.095 mmol) was dissolved in 2 mL DCM and oxalyl chloride (0.08 mL, 0.949 mmol) was added, followed by catalytic DMF. The reaction mixture was stirred at rt, after which N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (14) (26 mg, 0.096 mmol) and DIEA (0.05 mL, 0.284 mmol) were added, and stirring was continued for 12 hr. The reaction mixture was concentrated in vacuo and the residue was purified by LC/MS (10-100% AcN/H2O over 8.5 min.) Calculated mass=444. Observed mass=444.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].N[CH2:12][C:13](=O)[CH2:14]CC(O)=O>C(O)CC.Cl>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH2:12][CH2:13][CH3:14])=[O:8]
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Solvent: CCCO
Product: CCCOC(=O)CCC(=O)CN
Reaction time: 20 h

Procedure:
0.5 g 5-aminolevulinic acid hydrochloride was dissolved in 100 ml dry n-propanol containing 1–2 drops of conc. hydrochloride in a 250 ml glass reactor equipped with a stirrer, reflux condenser and a thermometer. The reaction mixture was stirred at 70–80° C. for approx. 20 hours. After all the 5-aminolevulinic acid was converted to its n-propylester (followed by 1H-NMR), the excess propanol was removed, and the product dried under high vacuum (<1 mBar) at 40–50° C. The reaction gave 0.49 g propyl 5-aminolevulinate hydrochloride. The structure was confirmed by 1H-NMR in DMSO-d6.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)=[O:22]>>[CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]1([C:15]([NH:19][C@@H:20]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[CH:46][CH:45]=2)[C:21]([N:23]([CH2:35][CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)=[O:22])=[O:17])[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: O=C(NCc1ccccc1)NCC1(C(=O)O)CC1
Product: CCOC(CN(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C1(CNC(=O)NCc2ccccc2)CC1)OCC
Yield: 80.7 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 1-((3-benzylureido)methyl)cyclopropanecarboxylic acid (Compound VI-1) (154 mg, 0.62 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) (153 mg, 0.31 mmol) and the obtained residue was purified by Purif silica gel column chromatography (eluent: n-hexane:ethylacetate=50:50 to 0:100) to obtain the title compound (181 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][N:9]2[CH:13]([CH3:16])[CH2:14][OH:15])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:11]2=[C:10]3[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][N:9]3[CH:13]([CH3:16])[CH2:14][O:15]2)=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(C(C)CO)c2c(Cl)c(Cl)ncc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(Cl)ncc3c1=O)OCC2C
Temperature: 0 °C

Procedure:
2.42 g (0.007 mol) of ethyl 7,8-dichloro-1-(1-hydroxy-2-propyl)-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are heated with 1.15 g (0.0083 mol) of potassium carbonate in 14 ml of dimethylformamide at 80° C. for one hour. After addition of ice-water the precipitated product is isolated. The crude product is purified by column chromatography (eluent: dichloromethane/methanol 98:2).
Reaction SMILES: [Na].[CH3:2]CN(C(C)C)C(C)C.[OH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:47])=[C:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:34]=[C:35]4[CH2:46][CH2:45][NH:44][CH2:43][C:36]4=[N:37][C:38]=3[NH:39][CH:40]([CH3:42])[CH3:41])[CH2:29][CH2:28]2)=[O:26])[CH:24]=1.C=O>CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:47])=[C:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:34]=[C:35]4[CH2:46][CH2:45][N:44]([CH3:2])[CH2:43][C:36]4=[N:37][C:38]=3[NH:39][CH:40]([CH3:42])[CH3:41])[CH2:29][CH2:28]2)=[O:26])[CH:24]=1.[C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])=[O:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCNC2
Agent: C=O
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCN(C)C2
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyhydroborate (6.5 mg, 0.031 mmol) was added to a solution of DIPEA (5 μL, 0.031 mmol), (5-chloro-2-fluorophenyl)(1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone TFA salt (8.4 mg, 0.015 mmol) and formaldehyde (1.5 μL, 0.015 mmol) in MeOH (150 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (4.7 mg, 54.6%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.82-1.93 (m, 2H), 1.97-2.05 (m, 2H), 2.81-3.05 (m, 4H), 3.08 (s, 3H), 3.35-3.54 (m, 4H), 3.72-3.83 (m, 1H), 4.10-4.18 (m, 1H), 4.19-4.40 (m, 2H), 7.25-7.32 (m, 1H), 7.61 (ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.75 (dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 446.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[N:14]4[C@@H:15]([CH3:19])[CH2:16][O:17][CH2:18][C:13]4=[N:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH4+:31].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[N:14]4[C@@H:15]([CH3:19])[CH2:16][O:17][CH2:18][C:13]4=[N:12][C:7]=3[C:8]([NH2:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H]1COCc2nc3cnc4cc(Br)ccc4c3n21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C[C@H]1COCc2nc3c(N)nc4cc(Br)ccc4c3n21
Temperature: 25 °C

Procedure:
A 2-L, three-necked, Morton flask, equipped with mechanical stirrer, was charged with (11S)-3-bromo-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (9.12 g, 28.7 mmol) and CH2Cl2 (500 mL). The mixture was stirred at ambient temperature and MCPBA (10.35 g, 50% purity) was then added slowly in portions. The reaction was stirred at ambient temperature for 2 hours. Concentrated aqueous NH4OH solution (200 mL) was then slowly added to the reaction mixture followed by careful addition of p-toluenesulfonyl chloride (6.29 g, 33.0 mmol) in small portions. The reaction was stirred rapidly at ambient temperature overnight. The reaction was then treated with H2O (500 mL) and vigorous stirring was maintained for 2 hours. The layers were allowed to separate and a tan precipitate formed. The aqueous layer was removed and the organic layer, containing the precipitate, was filtered to give 6.0 g of (11S)-3-bromo-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a tan solid. The product was used in subsequent reactions without further purification.