Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4](N)=O.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[C:15]([NH:22][CH2:23][CH2:24][O:25][CH3:26])[N:14]=1.[CH2:27](N(CC)CC)C>C(#N)C>[CH2:26]([O:25][CH2:24][CH2:23][NH:22][C:15]1[N:14]=[C:13]([Cl:12])[CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18])[C:4]1[CH:3]=[CH:7][CH:8]=[CH:9][CH:27]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CCN(CC)CC
Reactant: COCCNc1nc(Cl)ccc1C(N)=O
Solvent: CC#N
Product: NC(=O)c1ccc(Cl)nc1NCCOCc1ccccc1
Temperature: 60 °C
Yield: 78.2 %

Procedure:
To a solution of 2,6-dichloro-nicotinamide (1) (12.6 g, 66.1 mmol) in acetonitrile (anhydrous, 200 mL) were added 2-benzyloxy-ethylamine (2) (10 g, 66.1 mmol) and triethylamine (11 mL, 79.3 mmol). The reaction was heated at 60° C. for 2 days. The solution was cooled to room temperature and the suspension was filtered. The filtrate was evaporated in vacuo. The residue was purified by Biotage with 25%-100% EtOAc/hexanes to afford 15.8 g (78.3% yield) of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH3:17][NH2:18]>C1COCC1.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH2:16])[N:9]=[C:10]([NH:18][CH3:17])[C:11]=1[I:12]
Reactant: CN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Solvent: CCO
Product: CNc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine and methylamine in THF/ethanol. ES-MS m/e (%): 317 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](O)=[O:33]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:32](=[O:33])[CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[CH:11][C:12]=1[F:17]
Reactant: O=C(O)Cc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Product: Cl
Product: O=C(Cc1ccccn1)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and (pyridin-2-yl)acetic acid, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[CH2:19][C:18]([N+:26]([O-:28])=[O:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:16][C:15]1=[O:29].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:40])(=O)=O)=CC=1>C1COCC1.CCCCCC>[F:40][CH:16]1[CH2:17][C:18]([N+:26]([O-:28])=[O:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][N:14]([CH3:13])[C:15]1=[O:29]
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CCC1=O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CN1CC(c2ccccc2)([N+](=O)[O-])CC(F)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
To a solution of 78.4 ul (0.555 mmol) diisopropylamine in 2 ml THF were added 347 ul (0.555 mmol) of a 1.6M n-BuLi solution in hexane at −5° C. The solution was stirred for 15 minutes at 0° C. and then cooled to −70° C. A solution of 100 mg (0.427 mmol) rac-1-methyl-5-nitro-5-phenyl-piperidin-2-one in 1 ml THF was added dropwise. The brown solution was stirred at −70° C. for 45 minutes. A solution of 180 mg (0.555 mmol) N-fluorobenzenesulphonimide in 1 ml THF was added dropwise. The mixture was stirred at −70° C. for 1.5 hour, quenched with 2 ml of a 20% NH4Cl solution and allowed to warm to room temperature. Water and ethyl acetate were added. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 58 mg (54%) of the title compound as a light yellow solid. MS (m/e): 253.2 (M+H).
Reaction SMILES: [CH2:1]([NH:4][C:5]([CH:7]([CH3:31])[CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=2[O:29][CH3:30])=[CH:11][CH:10]=1)=[O:6])[CH2:2][CH3:3].[C:32]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:30][O:29][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:20]=1[CH2:19][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:8][CH:7]([C:5](=[O:6])[NH:4][CH2:1][CH2:2][CH3:3])[CH3:31])[CH:18]=2)[CH:13]=[CH:14][CH:15]=1)[C:24]([NH:41][S:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:40])=[O:39])=[O:25]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CCCNC(=O)C(C)Cc1ccc2cccc(Cc3ccc(C(=O)O)cc3OC)c2c1
Product: CCCNC(=O)C(C)Cc1ccc2cccc(Cc3ccc(C(=O)NS(=O)(=O)c4ccccc4)cc3OC)c2c1

Procedure:
Using a similar procedure to that described in Example 2.h., except starting from 4-[7-[2-(propylcarbamoyl)propyl]naphth-1-ylmethyl]-3-methoxybenzoic acid and benzenesulfonamide, the title compound was obtained (83%) as a colorless solid; mp 214.0°-217.5° C., MS(CI), m/e=559(M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.Cl[C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:17].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:22][O:21][CH2:20][CH2:19][O:18][C:16]([N:5]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH2:4][CH2:3][N:2]([CH3:14])[CH3:1])=[O:17]
Reactant: CN(C)CCNc1ccc(C=O)cc1
Reactant: COCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COCCOC(=O)N(CCN(C)C)c1ccc(C=O)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
To a solution of 4-[[2-(dimethylamino)ethyl]amino]benzaldehyde (300 mg) in methylene chloride (4 mL) is added 2-methoxyethyl chloroformate (234 μL) and thereto is added dropwise pyridine (252 μL) under ice-cooling. The mixture is stirred at 50° C. for 2 days. The reaction mixture is diluted with chloroform (5 mL) and thereto is added a saturated sodium hydrogencarbonate solution (10 mL). After stirring, the organic layer is separated and concentrated. The residue is purified by column chromatography on silica gel (Solvent; chloroform:methanol=100:0→90:10) to give 4-[N-[(2-methoxyethoxy)carbonyl]-N-[2-(dimethylamino)ethyl]amino]benzaldehyde (290 mg, yield; 63%) as an amorphous powder. MS (APCI) m/z: 294 [M+H]+
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].CO>O1CCOCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:18][CH3:17])=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a stirred solution of 2-benzyl-4,5-dichloropyridazin-3(2H)-one (73.1 g, 286.6 mmol) in 1,4-dioxane (700 mL) was added 25 wt. % solution of NaOMe in MeOH (72.0 mL, 315 mmol) at RT under argon over 15 min. The resultant dark reaction mixture was stirred at RT for 1.5 h. The solvent was evaporated and to the resultant residue was added water (500 mL). The aqueous mixture was extracted with methylene chloride (4×120 mL). The combined organic layers were washed with water (2×300 mL) and then by saturated aqueous NaCl (2×150 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain the crude product. This crude product was purified by silica gel column chromatography eluting with 30% EtOAc/hexanes to give the title compound, 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (56.0 g, 78%) as pale yellow oil. HPLC: 3.19 min; MS, M+H=251. 1H NMR (DMSO-d6, 500 MHz): δ 8.05 (1H, s), 7.26-7.34 (5H, m), 5.24 (2H, s), 4.15 (3H, s).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](OC)=[C:4]([NH2:13])[CH:3]=1.[C:14]1(OB(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:24](=O)([O-])[O-:25].[K+].[K+].C(OCC)(=O)C>COCCOC.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>[NH2:13][C:4]1[CH:3]=[C:2]([O:25][CH3:24])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)Oc1ccccc1
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1N
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(N)c(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
2.02 g (0.01 mole) of 4-chloro-5-nitro-2-aminoanisole and 0.013 mole of phenylboric acid were dissolved in 70 mL of 1,2-dimethoxyethane under argon. Then, 0.5 g (0.0005 mole) of tetrakis(triphenylphosphine)palladium and 13 mL of 2 N potassium carbonate solution were added, and the reaction mixture was heated to 80° C. At the end of the reaction, the reaction mixture was poured into 100 mL of ethyl acetate. The organic phase was extracted with dilute sodium hydroxide solution and then dried over magnesium sulfate. The solvent was distilled off from a rotary evaporator, and the residue was purified [by column chromatography] on silica gel using hexane/ethyl acetate (8:1) [as the eluent].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22]C(=O)C)[CH:17]=1.[OH-].[Na+].O.C(OCC)(=O)C>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=1
Reactant: COCCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COCCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
N-(4-((6-(2-methoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide described in Production Example 20-5 (3.45 g, 10.1 mmol) was dissolved in methanol (50 mL), a 2 M sodium hydroxide solution (50 mL) was added at room temperature, and the mixture was heated and stirred at 70° C. for 3 hours. Water and ethyl acetate were added to the reaction mixture for partition. The aqueous layer was extracted with ethyl acetate three times and the combined organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under vacuum and the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=3:7-0:1-ethyl acetate:methanol=49:1-24:1). The target fraction and the mixture fraction were concentrated under vacuum separately from each other, the mixture fraction was purified again with silica gel column chromatography (ethyl acetate:methanol=1:0-9:1), and then the resultant was combined with the above-described target fraction to obtain the title compound (2.60 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:13]([CH3:23])[N:12]([CH2:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])[C:11]1=[O:33])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:19][CH2:18]2)=[C:13]([CH3:23])[N:12]([CH2:24][C:25]2[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=2[F:31])[C:11]1=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(N2CCNCC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(N2CCN(CCc3ccccc3)CC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 70.2 %

Procedure:
To a solution of {(R)-2-[3-(2,6-difluoro-benzyl)-4-methyl-2,6-dioxo-5-piperazin-1-yl-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (2-2) (30 mg, 0.054 mmol) in DMF (1 mL) were added potassium carbonate (15 mg, 0.108 mmol), KI (1.3 mg, 0.0081 mmol), and (2-bromo-ethyl)-benzene (11.0 mg, 0.059 mmol) in the order, followed by stirring at 80° C. for 4 hrs. The solution was diluted in dichloromethane and washed with distilled water. After concentration of the organic layer thus formed, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 1/1/1) and dried in a vacuum to afford 25 mg of the compound as a colorless oil (yield 70%). 1H NMR (300 MHz, CDCl3) δ 1.35 (9H, s), 2.22 (2H, m), 2.44 (3H, s), 2.49 (2H, m), 2.63 (2H, t), 2.82 (2H, t), 2.88 (2H, m), 3.62 (2H, m), 4.04 (1H, dd), 4.25 (1H, t), 5.01 (1H, m), 5.01-5.36 (2H, dd), 5.84 (1H, m), 6.89 (2H, t), 7.17-7.40 (11H, m)
Reaction SMILES: CN(C)C=O.[CH2:6]([N:8]([CH2:23][CH3:24])[CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=2)[C:14]([NH2:22])=[N:13]1)[CH3:7].Br.Br[CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:23]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=2)[C:14]([NH:22][CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[N:13]1)[CH3:24]
Reactant: CCN(CC)CCCBr
Reactant: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2cccc(Cl)c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 53 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 9.2 g of the 1-(3-diethylaminopropyl)-3-amino-4 -chloroindazole, 3-bromopropyldiethylamine hydrobromide and 7.9 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate and the alkali layer was extracted three times with chloroform. The chloroform layer was dried with anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 6.81 g of 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-4-chloroindazole having the following analytical values in a yield of 53%.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg+].[Br-]>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH3:27])[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: C[Mg+]
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cc2c(c(C)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reaction time: 24 h
Yield: 41.3 %

Procedure:
To a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) in THF (3mL) was added Ni(dppp)Cl2 (24 mg, 0.044 mmol) at room temperature. After stirring for a few minutes MeMgBr (3M, 0.59 mL, 1.76 mmol) was added and the mixture was allowed to stir for 24 h. The mixture was quenched with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-5,7-dimethyl-1-phenyl-1,6-naphthyridin-4(1H)-one (31 mg, 40%): LCMS RT: 1.51 min, MH+: 342.4.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>C1COCC1>[CH3:34][N:35]1[CH2:36][CH2:37][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:43][CH:42]=2)[CH2:39][CH2:40]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C(C)(C)C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 50, 70 mg, 0.157 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (36 mg, 0.1882 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 50% yield (0.051 g, 0.078 mmol).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[I-:29].[K+]>CC(C)=O>[I:29][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: [I-]
Reactant: CCOC(=O)C1=C(C)NC(CCl)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(CI)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
A mixture of 2-chlorometyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (0.5 g) and potassium iodide (1 g) in acetone (5 ml) is stirred at room temperature for 24 hours, then it is filtered, concentrated under reduced pressure and the residue purified by column chromatography on silica gel (20 g, eluent: hexane/AcOEt 80/20) to give 0.22 g of 2-iodomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](OC)=[C:6]([O:10]C)[C:5]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:15]=2[F:23])=[CH:4][C:3]=1[N:24]1[C:32](=[O:33])[NH:31][C:30]2[C:25]1=[N:26][C:27]([CH3:36])=[N:28][C:29]=2[O:34][CH3:35].CO.Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:10])[C:5]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:15]=2[F:23])=[CH:4][C:3]=1[N:24]1[C:32](=[O:33])[NH:31][C:30]2[C:25]1=[N:26][C:27]([CH3:36])=[N:28][C:29]=2[O:34][CH3:35]
Reactant: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(C)nc32)c(Cl)c(OC)c1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(C)nc32)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxy-methyloxyphenyl]-6-methoxy-2-methyl-7,9-dihydro-8H-purin-8-one (80 mg) in tetrahydrofuran (2 mL)-methanol (1 mL) was added concentrated hydrochloric acid (0.1 mL), and the mixture was stirred at room temperature for 2 hours, and then stirred at 60° C. for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/3) to give the title compound (22 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].Cl.[NH3:13]>>[NH2:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCCCCCCBr
Reactant: N
Agent: Cl
Product: NCCCCCCCC(=O)O
Temperature: 15 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
A 500-ml three-necked flask equipped with stirrer, thermometer and dropping funnel was charged with 400 ml of 25% aqueous ammonia, and the flask contents were maintained at 15° C. Thereto was added 50 g (0.22 mole) of molten 8-bromocaprylic acid over 30 minutes. After the addition, stirring was continued for further 10 hours. Thereafter, the ammonia was removed by warming the liquid reaction mixture. The mixture was then cooled and adjusted to pH 6.0 with 0.1N hydrochloric acid. The resulting crystalline precipitate was collected by filtration. The precipitate and the second crop obtained by concentration the mother liquor were combined and recrystallized from water to give 30 g of 8-aminocaprylic acid (m.p. 193°-195° C.). The yield was 86% based on the charged 8-bromocaprylic acid.
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:31])(=[O:30])[C:13]=2[CH:32]=1)=[O:8].O>C(O)=O>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:26]([CH:1]=[O:2])[CH2:27][CH2:28]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:31])[C:13]=2[CH:32]=1)=[O:8]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C=O)CC3)cc(Cl)c1O2
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Sodium formate (0.1 g, 1.37 mmol) was added to a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g, 0.68 mmol) in formic acid (85%, 5 mL), and stirred at 90° C. for 15 h. The reaction mixture was diluted using water (10 mL), extracted using ethyl acetate, washed with water and brine. Solvent was removed and the crude product was purified by column chromatography (silica gel, 1.5% methanol in chloroform) to obtain the title compound. Yield: 0.11 g, (35%); 1H NMR (DMSO-d6, 300 MHz): δ 2.62 (s, 3H, CH3), 3.17-3.24 (m, 4H, 2CH2), 3.47 (s, 4H, 2CH2), 3.85 (s, 3H, OCH3), 5.15 (s, 2H, CH2), 7.13 (s, 1H, Ar), 7.17 (s, 1H, Ar), 8.06 (s, 1H, CHO), 8.08 (t, 1H, Ar), 8.14 (d, 1H, Ar); MS: m/e (ES+) 465 (M+1); analysis: C21H21ClN2O6S.0.5H2O requires C, 53.23; H, 4.64; N, 5.91; Cl, 7.49; S, 6.75. found: C, 53.82; H, 4.48; N, 5.42; Cl, 8.07; S, 7.17%.