Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@@:8]1([CH2:15][N+:16]([O-])=O)[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[CH:11][CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][C:6](=[O:19])[CH2:7][C@@:8]1([CH2:15][NH2:16])[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[CH:11][CH2:12]2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CC=C[C@H]21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@]1(CN)C[C@H]2CC=C[C@H]21
Reaction time: 6.5 h

Procedure:
Tert-butyl[(1R,5S,6S)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (peak 2, 20.7 g, 77.4 mmol) was dissolved in ethanol (200 mL) and water (100 mL). To the solution, iron powder (34.69 g, 619.5 mmol) and ammonium chloride (2.09 g, 38.72 mmol) were added, and the mixture was stirred for 6.5 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain a mixture of the compound of interest and the starting material at almost 1:1 ratio (20.18 g, estimated by 1H-NMR). This mixture was dissolved again in ethanol (200 mL) and water (100 mL). To the solution, iron powder (40.36 g, 720.7 mmol) and ammonium chloride (4.18 g, 78.1 mmol) were added, and the mixture was stirred for 9 hours under heating to reflux while iron powder (32.73 g, 584.5 mmol) was further added thereto in three portions. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (17.53 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nccc(O)c2cc1OC
Solvent: CC#N
Product: COc1cc2nccc(Cl)c2cc1OC
Temperature: 65 °C
Yield: 73.4 %

Procedure:
A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (1 L, 10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65° C. and phosphorus oxychloride (POCl3, 50.0 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 80° C. The reaction was deemed complete (approximately 9.0 hours) when <2% of the starting material remained (in process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 10° C. and then quenched into a chilled solution of dichloromethane (DCM, 238.0 kg), 30% NH4OH (135.0 kg), and ice (440.0 kg). The resulting mixture was warmed to approximately 14° C., and phases were separated. The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation with the removal of solvent (approximately 190.0 kg). Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and the mixture was cooled to approximately 10° C., during which time the product crystallized out. The solids were recovered by centrifugation, washed with n-heptane (20.0 kg), and dried at approximately 40° C. to afford the title compound (8.0 kg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl.[C:11]([OH:15])(=[O:14])[CH:12]=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[N:9]=[CH:12]/[C:11]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)/C=N/Nc1ccc(F)cc1

Procedure:
To a solution of 4-fluorophenyl hydrazine 1.32 g (0.011 mol) in water (30 mL) at room temperature was added HCl (1.32 g, 0.014 mol) followed by the drop-wise addition of glyoxylic acid (50%, 1.71 g, 0.012 mol) over 20 minutes. The thick suspension was stirred for 30 m. The product was isolated by filtration, washed with water and then dissolved in ethyl acetate (40 mL), dried over magnesium sulfate, filtered and the product isolated as a solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH2:13][C@@H:14]([CH:23]([CH3:25])[CH3:24])[CH2:15]/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])[O:11][C:10]([CH3:27])([CH3:26])[N:9]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].S([O-])(O)(=O)=O.[K+].S([O-])([O-])(=O)=O.[K+].[K+]>O1CCOCC1>[C:31]([O:30][C:28]([N:9]1[C@@H:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C@H:12]([CH2:13][C@@H:14]([CH:23]([CH3:24])[CH3:25])[CH2:15]/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[O:11][C:10]1([CH3:26])[CH3:27])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)/C=C/C[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(C)C
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)[C@@H](C/C=C/C(=O)O)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
1.7 g (3.5 mmol) of t-butyl (4S,5S)-4-(cyclohexylmethyl)-5-[(S,E)-5-(ethoxycarbonyl)-2-isopropyl-4-pentenyl]-2,2-dimethy--3-oxazolidinecarboxylate are dissolved in 20 ml of dioxan and treated with 7 ml (7.0 mmol) of 1N sodium hydroxide solution. Thereafter, the reaction mixture is stirred at 90° for 2.5 hours, cooled and poured into ice-water. Then, the reaction mixture is adjusted to pH 3 with a pH 2 buffer of potassium hydrogen sulphate and potassium sulphate and extracted with methylene chloride. The methylene chloride extracts are dried over magnesium sulphate and evaporated under reduced pressure. Chromatography of the residue on 18 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent yields 1.28 g of (E,S)-5-[[(4S,5S)-3-(t-butoxycarbonyl)-4-(cyclohexylmethyl)-2,2-dimethyl-5-oxazolidinyl]methyl]-6-methyl-2-heptenoic acid as an oil, MS: 436 (M-CH3)+.
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[CH:8]=[O:9].[F:13][C:14]([F:24])([F:23])[C:15]1[S:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:13][C:14]([F:24])([F:23])[C:15]1[S:19][C:18]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=2)[CH:8]=[O:9])=[CH:17][CH:16]=1
Reactant: O=Cc1ccnc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)s1
Agent: OBO
Product: O=Cc1ccnc(-c2ccc(C(F)(F)F)s2)c1

Procedure:
2-(5-(trifluoromethyl)thiophen-2-yl)isonicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and (5-(trifluoromethyl)thiophen-2-yl)boronic acid (29.4 mg, 62.3 mg theoretical, 47.2%). LC-MS m/z 258.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[S:9](Cl)([C:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:17]([N:18]([CH3:20])[CH3:19])[C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10]>CN(C)C=O>[S:9]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])([C:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:17]([N:18]([CH3:20])[CH3:19])[C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: NCCCCCCN
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: CN(C)C=O
Product: CN(C)c1cccc2c(S(=O)(=O)NCCCCCCN)cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.2 %

Procedure:
Hexamethylenediamine (5.39 g, 45.9 mmol) was combined with dimethylformamide (15 ml), and a solution of dansyl chloride (2.40 g, 8.7 mmol) in dimethylformamide (10 ml) was dropwise added thereto, followed by stirring at room temperature for 4 hours. Insoluble materials were removed by filtration, and the filtrate was stirred at room temperature overnight. After concentration, water and ethyl acetate were added to thereto, and 1 N hydrochloric acid was added thereto to adjust the aqueous layer to pH 4. The aqueous layer was washed with ethyl acetate three times, adjusted to pH 11 with potassium carbonate and extracted with ethyl acetate twice. The extracts were collected, washed with water three times, dried over anhydrous sodium sulfate and concentrated to give Compound (4) (1.04 g) as an oil. Yield, 34%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH:11]=[N:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[C:4]([O:30]C)[C:3]=1[F:32].B(Br)(Br)Br.C(=O)(O)[O-:38].[Na+].C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:28])([CH3:29])[CH2:9][C:10]([OH:27])([C:23]([F:24])([F:25])[F:26])[CH:11]2[NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][NH:17][C:18]3=[O:38])=[C:4]([OH:30])[C:3]=1[F:32]
Reactant: O=C([O-])O
Reactant: COc1c(C(C)(C)CC(O)(C=Nc2cccc3cnccc23)C(F)(F)F)ccc(Cl)c1F
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c(=O)[nH]ccc23)c2cc(Cl)c(F)c(O)c21
Temperature: 25 °C
Yield: 31.6 %

Procedure:
80.3 mg (0.166 mmol) of (rac.) 5-{[4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}isoquinolin-[1(2H)-one is mixed at room temperature with 1.7 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for two and one-half hours at room temperature. The reaction mixture is mixed with ice, and then saturated sodium bicarbonate solution is added in drops (pH 8). After the ethyl acetate is added and after ten minutes of vigorous stirring at room temperature, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with water and with brine, dried, and the residue is chromatographed on a Flashmaster after the solvent is spun off. 24.6 mg (31.6%) of the desired compound is isolated.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[CH2:34]([NH2:37])[CH:35]=[CH2:36]>CO>[OH:1][CH:2]([CH2:3][NH:37][CH2:34][CH:35]=[CH2:36])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(c1ccc(OCCCCC2CO2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: C=CCN
Solvent: CO
Product: C=CCNCC(O)CCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reaction time: 8 h

Procedure:
1-{1-[4-(4-Oxiranylbutoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (4.6 g) is dissolved in methanol (100 ml), and thereto is added allylamine (10 ml), and the mixture is stirred overnight. The reaction mixture is concentrated and purified by silica gel column chromatography (eluent; dichloromethane: methanol=10:1) to give 1-{1-[4-(5-hydroxy-6-allylaminohexyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2.5 g) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:7])[C:5]2=[CH:15][CH:16]=1.O>CO.[BH4-].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:15][CH:16]=1)[C:6](=[O:7])[N:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH:9]2[OH:10]
Reactant: CC(C)CN1C(=O)c2ccc(Cl)cc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)CN1C(=O)c2ccc(Cl)cc2C1O
Temperature: 20 °C
Reaction time: 20 h

Procedure:
5-Chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-chloro-3-hydroxy-2isobutyl-2,3-dihydroinsoindol-1-one are prepared as described in Example 1, starting with 12 g of 4-chloro-N-isobutylphthalimide in 100 cm3 of methanol and 3 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and 100 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C. The aqueous phase is extracted twice with 150 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 12 g of 5-chloro-3-hydroxy-2-isobutyl-2,3-dihydroinsoindol-1-one and 6-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder. (Rf=0.15, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.O[CH2:74][CH2:75][CH2:76][N:77]1[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]1>C1COCC1>[CH3:83][N:80]1[CH2:81][CH2:82][N:77]([CH2:76][CH2:75][CH2:74][O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])[CH2:78][CH2:79]1
Reactant: CN1CCN(CCCO)CC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN1CCN(CCCOc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)CC1
Yield: 57.9 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0817 g, 0.177 mmol) was dissolved in THF (4.0 mL), and the solution was treated with triphenylphosphine (0.0930 g, 0.354 mmol), 40% DEAD-toluene solution (0.161 mL, 0.354 mmol) and 1-(3-hydroxypropyl)-4-methylpiperazine (0.140 g, 0.855 mmol), followed by purification by flash column chromatography (chloroform/methanol=7/3) to obtain 4-[3-(4-methylpiperazin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0617 g, yield 58%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6]1[N:11](C(OC(C)(C)C)=O)[C:10]2[CH:19]=[CH:20][C:21]([N:23]([S:31]([CH3:34])(=[O:33])=[O:32])C(OC(C)(C)C)=O)=[CH:22][C:9]=2[S:8](=[O:36])(=[O:35])[CH:7]=1)[CH3:2].ClCCl.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6]1[NH:11][C:10]2[CH:19]=[CH:20][C:21]([NH:23][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:22][C:9]=2[S:8](=[O:36])(=[O:35])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC1=CS(=O)(=O)c2cc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)ccc2N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1=CS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Yield: 87 %

Procedure:
A solution of [7-(methanesulfonyl-tert-butyloxycarbonyl-amino)-4-tert-butyloxycarbonyl-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl]-acetic acid ethyl ester (Example 8f, 0.30 g, 0.54 mmol) in 1:1 dichloromethane/trifluoroacetic acid was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate solution and brine solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (0.17 g, 0.47 mmol, 86% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.32 (t, 3H, J=6.9 Hz), 3.03 (s, 3H), 4.02 (s, 2H), 4.21 (q, 2H, J=7.0 Hz), 5.02 (s, 1H), 6.96 (s, 1H), 7.02 (d, 1H, J=8.4 Hz), 7.53 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 7.65 (d, 1H, J=2.2 Hz), 10.73 (s, 1H). LC-MS (ESI) calcd for C13H16N2O6S2 [M+H+] 361.04. found 361.18 [M+H+].
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24](O)=[O:25])=[N:16]1.Cl.[CH3:28][NH:29][O:30][CH3:31].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:5]=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24]([N:29]([O:30][CH3:31])[CH3:28])=[O:25])=[N:16]1
Reactant: CNOC
Reactant: COc1cn(-c2ccc(N3CCOCC3)c(F)c2F)nc(C(=O)O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cn(-c2ccc(N3CCOCC3)c(F)c2F)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A mixture of 1-(2,3-difluoro-4-morpholin-4-ylphenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (3.8 g, 10 mmol), N,O-dimethylhydroxylamine hydrochloride (1.1 g, 11 mmol), HOBt (1.5 g, 11 mmol), triethylamine (2.9 mL, 21 mmol) and WSC (2.2 g, 11 mmol) in DMF (20 mL) was stirred at room temperature overnight. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound (3.3 g, 77% yield) as a brown solid: NMR (300 MHz, DMSO-d6): δ ppm 3.05-3.18 (4H, m), 3.24 (3H, s), 3.57 (3H, s), 3.68-4.02 (7H, m), 7.03 (1H, td, J=8.8, 2.1 Hz), 7.27-7.81 (1H, m), 8.50 (1H, s).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:40])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[N:37][C:36]([CH3:39])=[N:35]1.[CH2:41]([C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50](Cl)[N:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:41]([C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50]([NH:40][C:30]2[CH:31]=[CH:32][C:33]([N:34]3[CH:38]=[N:37][C:36]([CH3:39])=[N:35]3)=[C:28]([O:27][CH3:26])[CH:29]=2)[N:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 29.8 %

Procedure:
Palladium(II) acetate (5.9 mg, 0.026 mmol) and 2-(dicyclohexylphosphino)biphenyl (19 mg, 0.052 mmol) were dissolved under an atmosphere of nitrogen in dioxane (2 mL). The reaction was stirred for 25 minutes at room temperature. Sodium tert.-butylate (48 mg, 0.49 mmol), 3-methoxy-4-(3-methyl-[1,2,4]triazol-1-yl)-phenylamine (67 mg, 0.33 mmol) dissolved in dioxane (1.5 mL) and 4-benzyl-2-chloro-6-methyl-pyrimidine (79 mg, 0.36 mmol) were added. The reaction was heated three times for 30 minutes to 200° C. in a microwave oven. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylenechloride/methanol (19:1 v/v) as eluent to yield the title compound as a yellow gum (38 mg, 30%). MS ISP (m/e): 387.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.49 (s, 1H), 7.97 (s, 1H), 7.56 (d, 1H), 7.26-7.33 (m, 5H), 6.98 (d, 1H), 6.51 (s, 1H), 3.97 (s, 2H), 3.83 (s, 3H), 2.48 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[N:10]=[C:11]([CH3:24])[N:12]=[C:13]([NH:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:8]=2[N:7]=[N:6]1.[H-].[Na+].[CH2:27](I)[CH3:28]>CN(C)C=O.O>[CH2:27]([N:14]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[C:13]1[C:8]2[N:7]=[N:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:9]=2[N:10]=[C:11]([CH3:24])[N:12]=1)[CH3:28]
Reactant: CCI
Reactant: COCCn1nnc2c(Nc3c(C)cc(C)cc3C)nc(C)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1c(C)cc(C)cc1C)c1nc(C)nc2c1nnn2CCOC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from Example 38, Part B (150 mg, 0.46 mmol) was treated with sodium hydride (17 mg, 0.55 mmol, 80%) and ethyl iodide (55 ml, 0.69 mmol) in dry dimethylformamide (3 ml) and stirred at room temperature for 48 h. The reaction was diluted with 50 ml water, and extracted with 4-30 ml methylene chloride. The combined organic extracts were dried over anydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (50 g, 1/1 hexanes/ethyl acetate) afforded the desired product, 144 mg (88%) as a clear viscous oil. CI-HRMS calcd. for C19H27N6O1 (M+H): 355.2246. Found: 355.2240.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[C:33]=1[OH:41]>ClCCl.O>[OH:41][C:33]1[C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=[CH:37][C:32]=1[NH:31][C:16](=[O:18])[CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: Nc1cccc([N+](=O)[O-])c1O
Reactant: COc1ccc(CC(=O)O)cc1OC1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2cccc([N+](=O)[O-])c2O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A suspension of 3-cyclopentyloxy-4-methoxyphenylacetic acid (1.00 g) and 1,1'-carbonyldiimidazole (821 mg) in dichloromethane (5 ml) was stirred at room temperature, under argon, for 2 hours. The resulting solution was added to a stirred solution of 2-amino-6-nitrophenol (723 mg) in dichloromethane (10 ml) and the mixture stirred at room temperature, under argon, overnight. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were washed with water (100 ml), 1N HCl (50 ml) and brine (50 ml), dried over CaSO4 and evaporated in-vacuo to yield the title compound (1.05 g, 68%) as an orange solid. δH (250 MHz;d6DMSO), 1.58-1.97 (8H,m,4 ×CH2), 3.73 (2H,s,CH2), 3.87 (3H,s,OMe), 4.79 (1H,m,CH), 6.78-6.93 (3H,m,ArH), 6.98 (1H,t,ArH), 7.78 (1H,dd,ArH), 7.95 (1H,bs,CONH), 8.71 (1H,dd,ArH), 10.5 (1H,bs,ArOH).