Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[C:20]([Si:24]([CH3:37])([CH3:36])[O:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:30][CH:31]=1)([CH3:23])([CH3:22])[CH3:21].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:33](=[O:34])[CH2:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][Si:24]([C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:36])[CH3:37])[CH:27]=2)=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CC(=O)O)c1
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(NC(=O)Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)nc1C
Yield: 134.8 %

Procedure:
A solution of the 2-Amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (1 g, 5.37 mmole), triethylamine (2.9 mL, 20.81 mmol), [3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]acetic acid (0.55 g, 2.065 mmol), 1-propanephosphonic acid cyclic anhydride in 50% ethyl acetate (2.9 mL, 4.871 mmole) in anhydrous THF (50 mL) is heated at 60° C. for 1 h. The reaction was cooled, diluted with water, extracted with Methylene chloride (3×75 mL). The combined organic layers dried over MgSO4, filtered and evaporated. The solid residue was purified by flash column (10-40% EtOAc in hexane to give 2-{2-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-acetylamino}-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.21 g, 67.4%) as a white solid. MS m/e 435.2 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:7]([CH:18]2[O:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N#N.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:41])(=O)=O)=CC=1.[NH4+].[Cl-]>CCCCCC.C1COCC1.CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([F:41])[C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:7]([CH:18]2[O:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2C2OCCCO2)=N1
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)COC(c2c(F)cc(C(C)(C)C)cc2C2OCCCO2)=N1
Temperature: -78 °C
Yield: 36.2 %

Procedure:
A 200 mL round bottom flask containing 4.92 g (15.5 mmol) of vacuum-dried 2-(4-tert-butyl-2-1,3-dioxinan-2-yl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole was fitted with a stir bar, septum, and nitrogen inlet. Established and maintained N2 atmosphere. Added 100 mL of anhydrous THF. Cooled the solution to −78° C. Stirred rapidly and added 7.5 mL (19 mmol) of a 2.5 M solution of n-butyllithium in hexane dropwise over 5 minutes. Stirred the clear yellow solution at −17° C. for 3 hr. The solution became a deep red-orange color. Cooled the solution to −78° C. Stirred rapidly and added 5.89 g (18.7 mmol) of N-fluorobenzenesulfonimide dissolved in 30 mL anhydrous THF dropwise over 10 min. Stirred the reaction mixture at −78° C. for 5 min. Stirred at −20° C. for 30 min. Stirred at room temperature for 1 h. Poured the reaction mixture into 150 mL of 50% saturated aqueous NH4Cl and 300 mL Et2O. Separated phases and washed the organic phase with 150 mL water and 150 mL brine. Dried over Na2SO4 and removed the solvent on rotavap. Purified by silica gel flash chromatography using isocratic elution with 25% EtOAc/CH2Cl2. Recrystallized the isolated product from hexane to obtain 1.88 g of the title compound as light amber crystals. MS (ESI) 336 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pd]>[NH2:11][C:5]1[C:6]([C:8]([NH2:10])=[O:9])=[N:7][CH:2]=[CH:3][CH:4]=1
Reactant: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1ncccc1N

Procedure:
A solution of 6-chloro-3-nitropicolinamide (2.00 g, 9.91 mmol) in EtOAc/MeOH (1:1, 100 mL) is hydrogenated over 5% Pd-C (0.40 g) at 60 psi for 6 days, with additions of fresh catalyst after 2 and 4 days. After removal of the catalyst by filtration the solution is concentrated to dryness, to give 3-aminopicolinamide as an orange oil, which is used directly in the next step. The crude product is stirred under reflux with triethyl orthoformate (50 mL) for 42 h, during which time a tan precipitate forms. After cooling, the solid is filtered off, washed well with petroleum ether, and dried under vacuum to give 3H-pyrido[3,2-d]pyrimidin-4-one (1.27 g, 87a), mp 343-345° C. [Price, C. C. and Curtin, D. Y. J. Amer. Chem. Soc. 68, 914, 1946 report mp 346-347° C.].
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[C:8]([CH3:14])([CH3:13])[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[O:24][C:23](=[O:28])[CH:22]=[C:21]2OS(C(F)(F)F)(=O)=O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:21]2[C:20]3[C:25](=[CH:26][CH:27]=[C:18]([Cl:17])[CH:19]=3)[O:24][C:23](=[O:28])[CH:22]=2)[C:8]([CH3:13])([CH3:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2o1
Reactant: CCOC(=O)N1CCC(N)C(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2cc(=O)oc3ccc(Cl)cc23)C(C)(C)C1
Reaction time: 72 h
Yield: 60.5 %

Procedure:
To a solution of the 4-amino-3,3-dimethyl-piperidine-1-carboxylic acid ethyl ester (131 mg, 0.654 mmol) in DMF was added NaH (36.4 mg, 0.910 mmol) under nitrogen, and the mixture was stirred 10 min before trifluoro-methanesulfonic acid 6-chloro-2-oxo-2H-chromen-4-yl ester (prepared as before, 184 mg, 0.519 mmol) in DMF was added slowly, dropwise. The mixture was stirred 3 d before being concentrated with nitrogen flow to about half its original volume. The mixture was partitioned between EtOAc and H2O and the layers were separated. The aqueous was extracted with EtOAc (3×) and the combined organics were washed with H2O, saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography eluting with a gradient of 0 to 5% MeOH in CH2Cl2 afforded 119 mg (56%) of the title compound as a yellow solid. MS (ESI(+)Q1MS) m/z 379 (M+H)+; 1H NMR (300 MHz, DMSO) δ ppm 0.83-0.93 (m, 6H), 1.19 (t, 3H, J=7.0 Hz), 1.50-1.63 (m, 1H), 1.70-1.91 (m, 1H), 2.67-3.07 (m, 2H), 3.58-3.84 (m, 2H), 3.92-4.14 (m, 3H), 5.55 (s, 1H), 6.77-6.88 (m, 1H), 7.30-7.40 (m, 1H), 7.60-7.69 (m, 1H), 8.40-8.48 (m, 1H).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([OH:17])[CH:16]=1.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOCC.O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([CH:16]=1)[O:17][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COc1ccc(Br)cc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 47.2 %

Procedure:
Ethyldiisopropylamine (1.72 ml, 9.85 mmol) was added to a solution of 5-bromo-2-methoxy-phenol (0.80 g, 3.94 mmol) in DMF (10 ml) at rt. The clear, colorless solution was stirred for 5 min. followed by addition of tert-butylchlorodimethylsilane (0.71 g, 4.73 mmol). The reaction was complete in about two hours. Distilled water (˜6 ml) was added to the clear solution, stirred for 10 min., added ether (50 ml) and sat. NaHCO3 (10 ml), stirred for 30 min. The ether portion was separated and the aqueous phase was extracted with ether (2×50 ml). The combined ether phases were washed with water (100 ml), brine (60 ml), dried over MgSO4, filtered and concentrated to an oil, which was further purified by flash column chromatography [100% hexane with 0.5% triethylamine gradient to 30% EtOAc in hexane with 0.5% Et3N] to give (5-bromo-2-methoxy-phenoxy)-tert-butyl-dimethyl-silane as an oil (0.59 g, 99%), HPLC purity 99.5% at 1.43 min. (90/10 ACN/0.1% H3PO4): 1H NMR (DMSO-d6) δ 7.04-6.97(m, 2H, Ar), 6.71 (d, J=8 Hz, Ar), 3.78 (s, 3H, single OCH3), 0.99 (s, 9H, 3OCH3), 0.16 (s, 6H, 2OCH3). The product was carried over to the next step.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.C(O[CH2:22][C:23]([F:35])=[CH:24][C:25]1([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)(=O)C>O1CCCC1.O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2([CH:24]=[C:23]([F:35])[CH2:22][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:9]=3)[CH2:26][CH2:27]2)=[CH:33][CH:32]=1
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(Cl)cc2)CC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.33 g) in dry tetrahydrofuran (2 ml) and magnesium (30 mg) under nitrogen using iodine as an initiator at ca 40 C for 50 min, was cooled to room temperature then treated with cuprous bromide (ca 20 mg) for 10 min. After cooling to -78° C., a solution of 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-chlorophenyl)cyclopropane (Example 17) (0.32 g) in tetrahydrofuran was added slowly with stirring, then the mixture was allowed to warm to room temperature overnight. The mixture was treated with water (4 ml), then extracted with diethyl ether (3×20 ml). The combined organic extracts were washed with water (2×10 ml), dried, and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 8 ml/min) to afford 1-(4-chlorophenyl)-1-(2-fluoro-3-(3-phenoxyphenyl)prop-1-enyl)cyclopropane (98 mg, 22%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[CH:8][N:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2F)nc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccc(OCc2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
to a stirred solution of 6-(2-fluorobenzyloxy)nicotinic acid (0.89 g) in THF (10 ml) at 0° C. under Ar was added dropwise a solution of lithium aluminium hydride (1.0 M, 5.5 ml). The mixture was warmed to room temperature and stirred for 2 h. Saturated potassium sodium tartrate solution (1 ml) was added to the mixture followed by ethyl acetate (10 ml). The mixture was stirred for 30 min, filtered and concentrated in vacuo to give the product as a clear oil (0.63 g) which was used without further purification; δH (400 MHz, CDCl3) 8.14 (1H, d, J 1.5 Hz), 7.63 (1H, dd, J 8.5, 2.5 Hz), 7.49 (1H, dt, J 7.5, 1 Hz), 7.29 (1H, m), 7.13 (1H, dt, J 7.5, 1 Hz), 7.02 (1H, dt, J 10, 1 Hz), 6.81 (1H, d, J 8 Hz), 5.45 (2H, s) and 4.63 (2H, s); LC 73%, 2.24 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:19](O)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[OH:46][CH:47]1[CH2:50][NH:49][CH2:48]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:46][CH:47]1[CH2:50][N:49]([C:19]([C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:9]=2)=[O:20])[CH2:48]1
Reactant: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Reactant: OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)N2CC(O)C2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 5-(ethoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (2.0 g, 7.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.7 g, 14 mmol), 1-hydroxybenzotriazole hydrate (1.1 g, 7.0 mmol), and CH2Cl2 (50 mL) were added 3-hydroxyazetidine hydrochloride (1.2 g, 10 mmol) and N,N-diisopropylethylamine (3.7 mL, 21 mmol). The mixture was stirred at room temperature for 5 h, and then washed with brine and aq. Na2CO3 solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column (0-10% MeOH/CH2Cl2) to afford a syrup. LC-MS: 340.4 [M+1]+; 1H NMR (400 MHz, CDCl3): 8.34 (t, 1H, J=1.6 Hz), 8.19 (t, 1H, J=1.6 Hz), 8.04 (t, 1H, J=1.6 Hz), 7.52 (d, 2H, J=8.4 Hz), 7.28 (d, 2H, J=8.4 Hz), 4.75 (bs, 1H), 4.50 (m, 2H), 4.41 (q, 2H, J=7.2 Hz), 4.25 (bs, 1H), 4.10 (bs, 1H), 2.82 (bs, 1H), 2.41 (s, 3H), 1.42 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:6][N:5]([C:7]2[N:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[C:9]([CH3:16])[N:8]=2)[CH2:4][CH:3]1[CH2:17][OH:18].[C:25]([N:33]=[C:34]=[S:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[F:15][C:10]1[C:11]([O:13][CH3:14])=[N:12][C:7]([N:5]2[CH2:4][CH:3]([CH2:17][OH:18])[C:2]([NH:1][C:34]([NH:33][C:25](=[O:32])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[S:35])([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH2:6]2)=[N:8][C:9]=1[CH3:16]
Reactant: COc1nc(N2CC(CO)C(N)(c3cnccn3)C2)nc(C)c1F
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: COc1nc(N2CC(CO)C(NC(=S)NC(=O)c3ccccc3)(c3cnccn3)C2)nc(C)c1F
Yield: 95.4 %

Procedure:
To a stirred solution of [4-amino-1-(5-fluoro-4-methoxy-6-methyl-pyrimidin-2-yl)-4-pyrazin-2-yl-pyrrolidin-3-yl]methanol (930 mg, 2.78 mmol) in tetrahydrofuran (29 mL) under a nitrogen atmosphere is added benzoyl isothiocyanate (613 μL, 4.45 mmol). After stirring the reaction at room temperature for 1 hour the solvent is removed under reduced pressure. The resulting residue is purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (1.32 g, 95%). ES/MS (m/e): 498 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:21]([CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:19][CH3:20].C(OC)(OC)OC.[BH4-].[Na+]>CO.O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:27][CH2:28][CH3:29])[CH2:18][CH2:19][CH3:20])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: CCCN(CCC)CCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.4 %

Procedure:
The compound (225.3 mg) obtained in Example 103-3 was dissolved in methanol (6.76 ml). Then, the solution was added with the compound (165.0 mg) obtained in Example 1-2 and trimethyl orthoformate (304.8 mg), followed by stirring at room temperature for 18 hours. Sodium borohydride (108.7 mg) was added to the solution under ice-cooling, followed by stirring at room temperature for 0.5 hours. The reaction solution was added with water and subjected to separation/extraction with chloroform. Then, the extract was washed with saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (297.6 mg) as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH2:14]([NH2:17])[CH2:15][NH2:16]>C(Cl)Cl>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[NH:16][CH2:15][CH2:14][NH2:17]
Reactant: NCCN
Reactant: COc1ccc2nccc(Cl)c2n1
Solvent: ClCCl
Product: COc1ccc2nccc(NCCN)c2n1
Temperature: 100 °C
Yield: 51 %

Procedure:
A mixture of 8-chloro-2-methoxy-1,5-naphthyridine (1.71 g, 8.81 mmol) and ethylenediamine (1.18 mL, 2 eq.) was heated slowly to 80° C. over 1 h and subsequently up to 100° C. for 2 h. After cooling to rt, the yellow solution was taken in DCM and successively washed with NaHCO3. The aq. layer was back extracted with DCM (3 times) and the combined org. layers were concentrated to afford the title intermediate as a pale yellow oil (0.98 g, 51% yield).
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([OH:27])[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO.C(#N)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[C:16](=[O:18])[C:17]3[C:9]([OH:8])=[C:10]4[C:31](=[O:32])[N:30]([CH3:33])[CH2:29][CH2:28][N:11]4[C:12]=3[C:13]([OH:27])=[N:14]2)=[CH:21][CH:22]=1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(O)c32)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CN1CCn2c(c(O)c3c(=O)n(Cc4ccc(F)cc4)nc(O)c32)C1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 10-(benzyloxy)-2-(4-fluorobenzyl)-4-hydroxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]-pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (23 mg, 0.05 mmol) and Pearlman's catalyst [25 mg, 20% Pd(OH)2 on carbon] in methanol (10 mL) was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature for 45 minutes. The reaction mixture was diluted with acetonitrile and filtered. The filtrate was concentrated under vacuum, and the residue was subjected to purification on reverse phase HPLC. Collection and lyophilization of appropriate fractions provided the titled compound.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:8].[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:22][CH3:23])[C:16]=2[O:20][CH3:21])[C:11]1=[O:24].C([BH3-])#N.[Li+].O1CCOCC1.Cl>CO>[ClH:8].[CH:1]1([NH:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:22][CH3:23])[C:16]=3[O:20][CH3:21])[C:11]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: COc1ccc2c(c1OC)CCC(N)C2=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2c(c1OC)CCC(NC1CCCCC1)C2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a mixture of 200 volume parts of dry methanol and 200 volume parts of cyclohexanone is dissolved 10 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride and under nitrogen sparging and cooling at 0° C, there is added 9 parts of a molecular compound consisting of 1 mole lithium cyanoborohydride and 2 moles dioxane (LiBH3CN.2C4H8O2). At a constant temperature of 5° C, the reaction mixture is stirred for 2 hours. After the addition of dilute hydrochloric acid, the methanol is distilled off. The remaining mixture is washed with benzene and evaporated to dryness under reduced pressure. The residue is dissolved in ethanol, treated with activated carbon and recrystallized from a mixture of ethanol and ethyl ether. The procedure yields 9.65 parts of 2-cyclohexylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride as colorless crystals melting at 180°-190° C (decomposition).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[C:23]([CH:26]=O)[CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH3:36][O:37][CH2:38][CH2:39][NH2:40].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[C:23]([CH2:26][NH:40][CH2:39][CH2:38][O:37][CH3:36])[CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: COCCN
Reactant: COc1cc(-c2cc3c(C=O)cccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COCCNCc1cccc2c1cc(-c1cc(OC)c(OS(C)(=O)=O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 34.4 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-4-formylindol-2-yl]isoindolinone (0.252 g, 0.503 mmol) was dissolved in acetonitrile (15.0 mL), and the solution was treated with 2-methoxyethylamine (0.875 mL, 10.1 mmol), acetic acid (0.576 mL, 10.1 mmol) and sodium triacetoxyborohydride (0.533 g, 2.52 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=3/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-4-(2-methoxyethylaminomethyl)indol-2-yl]isoindolinone (0.0968 g, yield 34%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][OH:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(CO)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (78 mg, 92%), MS (ISP) m/z=341.5 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH:25][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1ccccn1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1F)c1ccccn1
Reaction time: 24 h
Yield: 75.7 %

Procedure:
Picolinic acid (10.0 g, 81 mmol) was added to a solution of 1,1'-carbonyldiimidazole (13,13 g, 81 mmol) in dimethylformamide (80 mL) and the reaction mixture was stirred for 1 hour before introduction of 2,4-difluoroaniline (9.06 mL, 89 mmol). After 24 hours, the reaction mixture was poured into saturated sodium bicarbonate solution, extracted into ether, dried, concentrated, and recrystallized using a mixture of ether and petroleum ether to yield N-(2,4-difluorophenyl)-2-pyridine-carboxamide as a white solid (14.37 g, 76.0%) m.p. 90.5°-95° C.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Cl>C(O)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:2][NH2:3]
Reactant: COc1cccc(CCl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cccc(CNN)c1
Reaction time: 0.5 h

Procedure:
While a solution of hydrazine monohydrate (10 g, 0.2 mol) in ethanol (35 ml) was heated under reflux, a solution of 3-methoxybenzyl chloride (5.0 g, 32 m mol) in ethanol (15 ml) was added drop-wise thereto over a period of 30 minutes. After this mixture was further refluxed for 2 hours, the solvent was distilled off under reduced pressure. The oily residue was extracted with ether (2×30 ml). After the extract was dried, the solvent was distilled off under reduced pressure. The resulting residue was subjected to chromatography on silica gel (40 g) using chloroform-methanol (20:1), so that there was obtained a crude fraction containing the desired compound. Then, this crude fraction was distilled (120-123° C./1-2 mmHg) to obtain the desired compound (2.9 g, 60%) as a colorless oily material.