Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[OH:4])[CH3:2].CC(C)([O-])C.[K+].[C:13]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([NH:21][C:22](=[O:25])[CH2:23][CH2:24][O:4][N:3]([CH2:5][CH3:6])[CH2:1][CH3:2])([CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:14])[CH3:15]
Reactant: C=CC(=O)NC(C)(C)CC(C)(C)C
Reactant: CCN(O)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)OCCC(=O)NC(C)(C)CC(C)(C)C

Procedure:
The procedure of Example I is repeated using diethylhydroxylamine, potassium-tert-butoxide and N-tert-octylacrylamide in tetrahydrofuran to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[N+](C1C=CC=CC=1)([O-])=O.C(Cl)(=O)C1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1.Cl.[OH-].[Na+]>>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccc2ncccc2c1
Solvent: O=[N+]([O-])c1ccccc1
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 200 °C

Procedure:
7.51 Parts of 2,5-di(p-chloroanilino)terephthalic acid obtained in Example 13, 79 parts of nitrobenzene, 6 parts of benzoyl chloride and 1.65 parts of quinoline were charged into a 200-ml flask of stainless steel, and maintained at 200° C. for 5 hours. When the mixture was temperature-increased up to about 180° C., hydrochloric acid gas was generated and the intramolecular-dehydration reaction was initiated. The reaction mixture was cooled to 110° C., and then 2.27 parts of 30% sodium hydroxide was dropwise added to decompose an excess of benzoyl chloride. Then, the reaction mixture was filtered while it was hot, washed with methanol, washed with water and dried to give 6.37 parts (92.8% of the theoretical yield) of 2,9-dichloroquinacridone.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Cl:25][CH2:26][CH2:27][CH2:28]Br>>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:28][CH2:27][CH2:26][Cl:25])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCCCBr
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(-c2nn(CCCCl)c3ncccc23)cc(C(C)(C)C)c1O

Procedure:
3-(3,5-Di-tertiary butyl-4-hydroxyphenyl)-1-(3-chloropropyl)-1H-pyrazolo[3,4-b]pyridine, melting at 107°-109° C. is prepared by reacting the compound of Example 1 with 3-chloropropyl bromide in a similar manner as Example 9, and recrystallizing from acetonitrile.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:4].CC(C)([O-])C.[K+]>C1COCC1>[O:4]=[C:3]1[NH:5][CH2:6][CH2:7][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[O:21][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCNC(=O)CCl)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCNC(=O)CO2)CC1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 4-(2-(2-chloroacetamido)ethyl)-4-hydroxypiperidine-1-carboxylate (example 89, step c) (0.3 g) in dry THF (18 mL) was added dropwise over 6 hours to a refluxing mixture of potassium tert-butoxide (1M in tert-butanol, 3 mL) and dry THF (60 mL). At the end of the addition the mixture was heated at reflux for a further 15 minutes and then cooled to room temperature. The mixture was partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. Trituration with diethylether afforded the subtitled compound. Yield 0.117 g.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[I-].[K+].[F:10][C:11]1[CH:48]=[CH:47][C:14]([C:15]([C:17]2[N:26]=[C:25](C3C(C(C)C)=C(S([O-])(=O)=O)C(C(C)C)=CC=3C(C)C)[C:24]3[C:19](=[CH:20][C:21]([CH3:46])=[CH:22][CH:23]=3)[N:18]=2)=[O:16])=[CH:13][CH:12]=1.O>CC(N(C)C)=O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([C:17]2[N:26]=[C:25]([NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[C:24]3[C:19](=[CH:20][C:21]([CH3:46])=[CH:22][CH:23]=3)[N:18]=2)=[O:16])=[CH:47][CH:48]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Cc1ccc2c(-c3c(C(C)C)cc(C(C)C)c(S(=O)(=O)[O-])c3C(C)C)nc(C(=O)c3ccc(F)cc3)nc2c1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc2c(Nc3cc(C)[nH]n3)nc(C(=O)c3ccc(F)cc3)nc2c1
Yield: 14.4 %

Procedure:
A solution of 5-methyl-1H-pyrazol-3-amine (225 mg, 2.31 mmol), potassium iodide (188 mg, 0.088 mmol), and 2-(4-fluorobenzoyl)-7-methylquinazolin-4-yl-2,4,6-triisopropylbenzenesulfonate (380 mg, 0.69 mmol) in DMA (2 mL) was stirred at 50° C. for 6 h, then water was added and the solution was filtered. The solid was then dried and triturated with acetonitrile to give (4-fluorophenyl)(7-methyl-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (36 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 2.50 (s, 3H), 6.53 (s, 1H), 7.38 (t, 2H), 7.51 (d, 2H), 7.66 (s, 1H), 8.08 (m, 2H), 8.62 (d, 1H), 10.57 (s, 1H), 12.18 (s, 1H); LC-MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:37]([O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:36][C:21]3[N:22]([CH3:35])[C:23]([NH:25][C:26]4[CH:31]=[C:30]([CH2:32][NH2:33])[CH:29]=[CH:28][C:27]=4[Cl:34])=[N:24][C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1.O>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:37]([O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:36][C:21]3[N:22]([CH3:35])[C:23]([NH:25][C:26]4[CH:31]=[C:30]([CH2:32][NH:33][C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[O:6])[CH:29]=[CH:28][C:27]=4[Cl:34])=[N:24][C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Solvent: O
Solvent: ClCCl
Product: Cn1c(Nc2cc(CNC(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Temperature: 25 °C

Procedure:
A solution of pivaloyl chloride (34 mg; 0.28 mmol) in DCM (1 mL) was added dropwise to a mixture of N-(4-bromo-phenyl)-2-(2-chloro-5-{[amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide ((see Example 72, step (d)) 150 mg; 0.27 mmol), TEA (41 mg; 0.41 mmol) and DCM (2 mL) at 0° C. The resulting mixture was stirred over night at rt, poured into water and extracted with DCM. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was recrystallized from EtOAc/petroleum ether to give the title compound.
Reaction SMILES: [OH-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.[C:13]([O:17][C:18](=[O:27])[CH2:19]SC1C=CC=CC=1)([CH3:16])([CH3:15])[CH3:14].C[S:29]([CH3:31])=O>>[N+:10]([C:7]1[C:6]([CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:27])=[N:5][C:4]([S:29][C:31]2[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(F)nc1
Reactant: CC(C)(C)OC(=O)CSc1ccccc1
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)Cc1nc(Sc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a mechanically stirred slurry of pulverized sodium hydroxide (16.0 g, 400 mmol) in DMSO (75 mL) was added dropwise a solution of 2-fluoro-5-nitropyridine (prepared as described by Finger and Starr, J. Am Chem. Soc., 81, 2674 (1959)) (5.7 g, 40 mmol) and t-butyl(phenylthio)acetate (9.0 g, 40 mmol) in DMSO (75 mL) while maintaining the temperature of the reaction mixture below 30° C. The mixture was allowed to stir at room temperature overnight and was then poured into ice/water. After adjustment of the pH to bout 2 with 1N HCl solution, the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The oily residue was subjected to flash chromatography on silica gel using 2:1 chloroform/hexane as eluant. Fractions containing the desired product were combined and concentrated to leave a yellow solid which was triturated with ether to leave t-butyl (3-nitro-6-phenylthio-2-pyridyl)acetate (1.5 g, 11%), m.p. 104°-107°.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH2:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1>[CH2:8]([NH:15][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCN
Reactant: O=C1CCCCO1
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)CCCCO
Temperature: 110 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Delta valerolactone (40 g, 0.4 mole) was added dropwise with stirring to n-heptylamine (50.6 g, 0.4 mole) so that the temperature of the mixture was maintained at 85° to 90° C. Heat was applied and the temperature raised to 110° C. over 20 minutes after which the temperature was maintained at 110° to 115° C. for a further 6 hours (after 3 hours N.M.R. indicated that the reaction was 90 to 95% complete). Toluene (200 ml, 173 g) was added and the solution cooled to 0° C. with stirring. After 1 hour at 0° C., the solid was collected and washed successively with ice cold toluene (50 ml, 43 g) and n-heptane (50 ml, 34 g). The material was dried at room temperature overnight to give the product. (81.6 g (95% yield) m.p. 53° to 54° C.).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:24])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:32][C:33]1([C:39]([Cl:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:24][C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:41]
Reactant: COc1ccccc1N1CCN(C[C@H](N)CC2CCCCC2)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](CC2CCCCC2)NC(=O)C2(C)CCCCC2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.30 g (0.91 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.16 g (1.00 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen at 0° C. for one hour, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the hydrochloride.hydrate salt of the title compound with ethanolic HCl to yield 0.30 g (63%) of a light yellow solid; mp=119-121° C.; MS(+)ESI m/z=456 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:33]([N:35]([CH2:36][CH3:37])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32])[CH3:34]
Reactant: CCNCC
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (50 mg), diethylamine (24 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the cooled reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (7 mg, yield 13%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]([NH:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[O:10]>C(O)C>[CH3:17][O:16][C:14]([C:13]1[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=1[NH:11][C:9](=[O:10])[CH2:8][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:15]
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccccc1NC(=O)CCl
Solvent: CCO
Product: COC(=O)c1ccccc1NC(=O)CN1CCNCC1

Procedure:
4.3 Grams of piperazine was added to 50 ml of ethanol, to this solution was added 2.3 g of methyl o-(α-chloroacetylamino)benzoate at a temperature of 40°-50° C. with stirring. The reaction mixture was stirred at the same temperature for 3 hours, then the reaction mixture was concentrated, to the obtained residue was added 20 ml of water, then saturated with sodium chloride, and extracted with chloroform. The chloroform layer was washed with a 10%-sodium hydroxide solution, then washed with a small amount of water and dried. After removal of the solvent by distillation, the residue obtained was purified by a silica gel column chromatography, and recrystallized from ether to obtain 2 g of o-methoxycarbonyl-α-(1-piperazinyl)-acetanilide in the form of colorless needle-like crystals. Melting point: 94°-96° C.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[NH:2][N:3]=[C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1)=[O:21])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
Hydrazine hydrate (0.27 mL, 2.76 mmol) was added to a stirred solution of 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (0.69 g, 2.76 mmol) in EtOH (3 mL). The mixture was stirred at 80° C. for 16 hours and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.66 g, 98% yield) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C:13]1[C:14]([NH:18][NH:19]C(OC(C)(C)C)=O)=[N:15][NH:16][CH:17]=1)=[O:12])[CH3:9].C1(C)C=CC=CC=1.[Cl:34]CCl>>[ClH:34].[ClH:34].[CH2:8]([O:10][C:11]([C:13]1[C:14]([NH:18][NH2:19])=[N:15][NH:16][CH:17]=1)=[O:12])[CH3:9]
Reactant: ClCCl
Reactant: CCOC(=O)c1c[nH]nc1NNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c[nH]nc1NN
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
After adding 25 ml of trifluoroacetic acid to a solution of 3.30 g of 3-(N′-t-butoxycarbonylhydrazino)-1H-pyrazole-4-carboxylic acid ethyl ester in 50 ml of dichloromethane, the mixture was stirred for 2 hours at room temperature. Next, 100 ml of toluene was added and the solvent was removed under reduced pressure. The residue was dissolved in a small amount of methanol, and after adding a 4N solution containing hydrochloric acid in ethyl acetate until the solution reached acidic, the solvent was removed under reduced pressure. The residue was treated with 50 ml of t-butyl methyl ether, and the solid was filtered off and dried under reduced pressure to give the title compound (3.30 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OS(C)(=O)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 96.4 %

Procedure:
N-Boc-L-tyrosine methyl ester 3 (29.5 g, 0.1 mol) and triethylamine (20.2 g, 0.2 mol) were dissolved in toluene (147.7 g) and then cooled to 0° C. To the mixture was added dropwise methanesulfonyl chloride (13.8 g, 0.12 mol) at 0° C. over 40 min. The mixture was further kept at 0° C. for 25 min. The reaction mass was washed with 5% hydrochloric acid (72.9 g) and 5% aqueous sodium bicarbonate (84.0 g), dried over magnesium sulfate, and then concentrated under reduced pressure with a rotary evaporator. After crystallization from the concentrate mass with n-hexane, precipitated crystals were collected by filtration and dried to give N-Boc-O-methanesulfonyl-L-tyrosine methyl ester 6 (36.0 g, yield 96%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:10]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([N:16]([CH2:15][C:11]1[CH:10]=[C:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CCc1ccc(NCc2cccc(-c3c(C)cccc3C)c2)cc1
Solvent: c1ccncc1
Product: COC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cccc3C)c2)C(C)=O)cc1
Yield: 97.6 %

Procedure:
A solution of methyl 3-(4-{[(2′,6′-dimethylbiphenyl-3-yl)methyl]amino}phenyl)propanoate (0.598 g, 1.60 mmol) and acetic anhydride (0.226 mL, 2.40 mmol) in pyridine (3 mL) was stirred at room temperature for 20 hr. The solvent was evaporated by concentration. The obtained residue was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-60% ethyl acetate/hexane) to give the title compound (0.649 g, yield 98%) as a colorless oil.
Reaction SMILES: OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C3C=2CN(C)C3=O)C=N1.Cl[C:51]1[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][N:54]=[C:53]([NH:61][C:62]2[CH:76]=[CH:75][C:65]([CH2:66][P:67](=[O:74])([O:71][CH2:72][CH3:73])[O:68][CH2:69][CH3:70])=[CH:64][C:63]=2[O:77][CH3:78])[N:52]=1.[NH2:79][C:80]1[CH:92]=[CH:91][C:90]([C:93]2[CH:94]=[N:95][N:96]([CH2:98][CH2:99][CH2:100][OH:101])[CH:97]=2)=[CH:89][C:81]=1[C:82]([N:84]([CH2:87][CH3:88])[CH2:85][CH3:86])=[O:83]>>[CH2:87]([N:84]([CH2:85][CH3:86])[C:82]([C:81]1[CH:89]=[C:90]([C:93]2[CH:94]=[N:95][N:96]([CH2:98][CH2:99][CH2:100][OH:101])[CH:97]=2)[CH:91]=[CH:92][C:80]=1[NH:79][C:51]1[C:56]([C:57]([F:59])([F:58])[F:60])=[CH:55][N:54]=[C:53]([NH:61][C:62]2[CH:76]=[CH:75][C:65]([CH2:66][P:67](=[O:74])([O:68][CH2:69][CH3:70])[O:71][CH2:72][CH3:73])=[CH:64][C:63]=2[O:77][CH3:78])[N:52]=1)=[O:83])[CH3:88]
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1)OCC
Yield: 50.1 %

Procedure:
Prepared analogously to Compound 1B using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1 E, 282.1 mg, 0.62 mmol) and 2-amino-N,N-diethyl-5-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]benzamide (Compound 3C, 196.7 mg, 0.62 mmol) to afford 228 mg of the title compound (50%). 1H NMR (400 MHz, CD3OD) δ 8.33 (br. s., 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.77 (dd, J=2.02, 8.34 Hz, 1H), 7.59-7.67 (m, 2H), 7.57 (d, J=8.08 Hz, 1H), 6.97 (br. s., 1H), 6.57 (br. s., 1H), 4.32 (t, J=6.95 Hz, 2H), 3.99 (quin, J=7.14 Hz, 4H), 3.89 (s, 3H), 3.59 (t, J=6.06 Hz, 2H), 3.43-3.52 (m, 2H), 3.08-3.22 (m, 4H), 2.11 (quin, J=6.57 Hz, 2H), 1.22 (t, J=7.07 Hz, 6H), 1.11 (t, J=6.95 Hz, 3H), 0.97 (br. s., 3H). MS (ESI): m/z 734.85 [M+H]+. UPLC: tR=1.22 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.S(Cl)([Cl:10])=O.[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:22]3[C:29]4[CH2:30][CH2:31][NH:32][CH2:33][C:28]=4[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH:16]=[CH:17][C:18]=1[Cl:19].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:10][CH2:2]/[CH:3]=[CH:4]/[C:5]([N:32]1[CH2:31][CH2:30][C:29]2[C:22]3[C:21]([NH:20][C:15]4[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=4)=[N:26][CH:25]=[N:24][C:23]=3[S:27][C:28]=2[CH2:33]1)=[O:7]
Reactant: O=C(O)/C=C/CBr
Reactant: O=S(Cl)Cl
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(/C=C/CCl)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
(2E)-4-Bromobut-2-enoic acid (1.33 g, 6.83 mmol) was dissolved in petroleum ether (25 mL). Thionylchloride (2.65 mL, 36.6 mmol) was added, and the mixture was heated to reflux for 4 h. The mixture was then concentrated in vacuo. Toluene was added and again removed in vacuo. The residue was dissolved in dichloromethane (14 mL). This solution was added to a solution of N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 15A (2.00 g, 5.69 mmol) and DIPEA (1.25 g, 9.68 mmol) in DMF (20 mL) at −10° C. The mixture was warmed to rt and stirred overnight. The precipitate was collected by suction filtration and washed with water to yield 1.52 g of a solid, which was used in the next step without further purification or separation.
Reaction SMILES: [CH3:1]N.[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][C:23]([N+:24]([O-])=O)=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[C:11]2=[O:27])[CH2:6][CH2:5]1>C(O)(C)C>[CH3:1][NH:24][C:23]1[CH:22]=[CH:21][C:18]2[C:19](=[O:20])[N:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)[C:11](=[O:27])[C:12]3[C:17]=2[C:16]=1[CH:15]=[CH:14][CH:13]=3
Reactant: CN1CCC(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)CC1
Reactant: CN
Solvent: CC(C)O
Product: CNc1ccc2c3c(cccc13)C(=O)N(C1CCN(C)CC1)C2=O

Procedure:
A mixture of 40% aqueous methylamine (2 mL) and 2,3-dihydro-2-(1-methylpiperidin-4-yl)-6-nitro-1H-benz[de]isoquinoline-1,3-dione (1.1 g; 3.14 mmol), prepared as in Example 3, in isopropanol (10 mL) was stirred at 65°-70° C. for six hours. Concentration of the solution followed by purification of the residue by column chromatography (silica-gel; 3% methanol in CH2Cl2 and approximately 1% aqueous NH4OH) gave 2,3-dihydro-6-methyamino-2-(1-methylpiperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione (0.63 g; 1.95 mmol) as a yellow precipitate, m.p. 251°-254° C.