Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]2)[CH:26]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]([NH:22][NH2:23])=O)=[CH:10][CH:9]=1)=[O:6].[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>O1CCCC1>[CH2:34]([N:36]1[C:37](=[O:38])[NH:23][N:22]=[C:20]1[CH2:19][O:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]3)[CH:26]=[C:2]([F:1])[CH:3]=2)=[CH:9][CH:10]=1)[CH3:35]
Reactant: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCC(=O)NN)c4ccccc34)c2)CC1
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCn1c(COc2ccc(NC(=O)c3cc(F)cc(N4CCC(C)CC4)c3)c3ccccc23)n[nH]c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.7 %

Procedure:
To a solution of 3-fluoro-N-(4-hydrazinocarbonylmethoxy-naphthalen-1-yl)-5-(4-methyl-piperidin-1-yl)-benzamide (0.35 g, 0.77 mmol) in tetrahydrofuran (10 ml) is added ethylisocyanate (60 mg, 1.1 eq). The mixture is stirred at room temperature for 15 hours before being evaporated to dryness to give the urea intermediate as a solid (0.34 g). MS: 522 (M+1). Urea intermediate (0.1 g, 0.19 mmol) in 5% NaOH (2 ml) is heated at 100° C. for five hours. The mixture is then extracted with ethyl acetate, washed with water, dried over Na2SO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with ethyl acetate then ethyl acetate containing a few drops of ammonium hydroxide to give N-[4-(4-ethyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethoxy)-naphthalen-1-yl]-3-fluoro-5-(4-methyl-piperidin-1-yl)-benzamide as a white solid (21 mg). Mp: 240-241° C. 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.27 (s, 1H), 8.16 (d, J=5.1 Hz, 1H), 7.88 (d, J=4.5 Hz, 1H), 7.57-6.95 (m, 7H), 5.27 (s, 2H), 3.78 (m, 4H), 2.77 (t, J=11.4 Hz, 2H) 1.68 (m, 3H), 1.20 (brs, 6H), 0.95 (brs, 3H). MS: 504 (M+1).
Reaction SMILES: [NH2:1][C:2]1([C:10]#[N:11])[CH2:7][CH2:6][N:5]([O:8][CH3:9])[CH2:4][CH2:3]1.[CH2:12](ON1CCC(=O)CC1)C>>[NH2:1][C:2]1([C:10]#[N:11])[CH2:3][CH2:4][N:5]([O:8][CH2:9][CH3:12])[CH2:6][CH2:7]1
Reactant: CON1CCC(N)(C#N)CC1
Reactant: CCON1CCC(=O)CC1
Product: CCON1CCC(N)(C#N)CC1

Procedure:
4-Amino-1-ethoxy-piperidine-4-carbonitrile was prepared analogously to the synthesis of 4-amino-1-methoxy-piperidine-4-carbonitrile (preparation example P1, step P1.1) starting from N-ethoxy-4-piperidone (Journal of Organic Chemistry (1961), 26, 1867-74).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][SH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][N:16]=1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: Clc1cc(-c2ccccc2)on1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSc1cc(-c2ccccc2)on1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 24.3 %

Procedure:
2-(N-tert-Butoxycarbonylamino)ethanethiol (300 mg) was dissolved in dimethylformamide (3.0 ml), and the mixture was cooled to 5° C., followed by addition of sodium hydride [>55% (oil), 73 mg]. The resulting mixture was stirred at the same temperature for 30 minutes. Then, 3-chloro-5-phenylisoxazole (300 mg) was added to the reaction mixture, followed by stirring of the mixture at the same temperature for 30 minutes and further at room temperature for 3 days. At the end of this time, the reaction mixture was added to ice-cold water (40 ml) and extracted with ethyl acetate (40 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the title compound (130 mg, 24%) as colorless crystals.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11](Br)[CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:29]1([N:28]([C:4]2[CH:5]=[CH:6][C:1]3[N:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:16]4[C:17]([C:2]=3[CH:3]=2)=[CH:18][C:19]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:14][CH:15]=4)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2-c1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Product: c1ccc(N(c2ccccc2)c2ccc3c(c2)c2cc(N(c4ccccc4)c4ccccc4)ccc2n3-c2ccccc2)cc1

Procedure:
In the present embodiment, raw materials, 12.03 g (30 mmol) of N-phenyl-3,6-dibromocarbazole and 12.18 g (72 mmol) of diphenylamine are used to obtain 3,6-bis(N,N-diphenylamino)-9-phenylcarbazole (hereinafter, referred to as PhCzP2), that is the carbazole derivative represented by the above structural formula (76), in the same way as in Embodiment 2 described above. The obtained PhCzP2 is purified by sublimation at a higher temperature of 270° C. and a lower temperature of 175° C. The yield after the sublimation purification is approximately 50%. FIG. 21 shows a 1H NMR spectrum of the obtained PhCzP2, FIG. 22 shows a 13C NMR spectrum of the obtained PhCzP2, and FIG. 23 shows an enlarged view of a region (A) surrounded by a dashed line in FIG. 22. In FIGS. 21 to 23, a longitudinal axis indicates relative intensity of signals, and a lateral axis indicates the dimensionless value δ which is the difference of resonant frequency between a sample and an authentic sample divided by frequency of an oscillator. Data of 1H NMR and 13C NMR of the obtained PhCzP2 is as follows:
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:21])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[N:13][NH:14][C:15]2=S)([CH3:4])([CH3:3])[CH3:2].O.[NH2:23][NH2:24]>C(O)C>[C:1]([NH:5][CH2:6][CH:7]([OH:21])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[N:13][N:14]=[C:15]2[NH:23][NH2:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NCC(O)COc1cccc2c(=S)[nH]ncc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1cccc2c(NN)nncc12
Yield: 100 %

Procedure:
A stirred mixture of 5-(3-t-butylamino-2-hydroxypropoxy)-1(2H)-phthalazinthione (0.5 g), ethanol (50 ml) and hydrazine hydrate (15 ml) was heated under reflux for 21 hours. Ethanol and excess of hydrazine were removed by evaporation under reduced pressure to give 5-(3-t-butylamino-2-hydroxypropoxy)-1-hydrazinophthalazine (0.5 g, 100%) which was treated with 1.0N sulphuric acid (3.26 ml). Evaporation under reduced pressure gave the crude salt which was crystallised from aqueous methanol to give 5-(3-t-butylamino-2-hydroxypropoxy)-1-hydrazinophthalazine sulphate hydrate (0.45 g, 65%, m.p. 274°-276°, decomposition).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(C#N)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(C#N)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 124.4 %

Procedure:
To a solution of methyl 3-tert-butyl-5-cyanobenzoate (8.8 g, 0.0360 mol) in MeOH (76 mL) was added a solution of NaOH (2.0 g, 0.050 mol) in water (15 mL). The mixture was allowed to stir at rt for 2.5 h and then acidified with 1N HCl. The mixture was concentrated to remove methanol and the residue was extracted with EtOAc. The organic solutions were combined, washed with 1NHCl and brine, dried over Na2SO4, filtered, and concentrated to a small volume. Hexane was added and the product precipitated. The solid was filtered, washed with hexanes and dried to give 3-tert-butyl-5-cyanobenzoic acid (9.1 g, 73%). 1H NMR (400 MHz, d6-DMSO) δ: 8.19 (m, 1H), 8.13 (m, 1H), 8.10 (m, 1H), and 1.32 (s, 9H). LCMS: ES− 202.2.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[C:10]([CH2:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:9][NH:8][C:6]=2[N:7]=1.[OH-].[Na+:24].Cl>O>[Na+:24].[NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[C:10]([CH2:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([O-:19])=[O:18])=[CH:15][CH:14]=3)=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)O)cc3)c2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2[nH]cc(CCc3ccc(C(=O)[O-])cc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask was charged with 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoic acid (5.0 g; 93.85% purity HPLC) and water (30 ml), the pH was corrected to about 13 with a 2M sodium hydroxide solution in water, and complete dissolution was observed. The pH was then corrected to about 9 with a 1M hydrochloric acid solution in water, and abundant solid formation was observed. The resulting suspension was stirred at about 25° C. for 1 hour, the solid was collected by filtration and dried in an oven under vacuum to afford 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoic acid sodium salt as a white solid in 99.6% purity (HPLC).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:18][CH3:19])=[C:9]([O:16][CH3:17])[C:10]=2[O:14][CH3:15])[CH:5]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>N1C=CC=CC=1>[CH3:20][S:21]([O:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:18][CH3:19])=[C:9]([O:16][CH3:17])[C:10]=2[O:14][CH3:15])[CH:5]=1)(=[O:23])=[O:22]
Reactant: COc1cc2cc(CCO)ccc2c(OC)c1OC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2cc(CCOS(C)(=O)=O)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2-Hydroxyethyl)-5,6,7-trimethoxynaphthalene (1.26 g) was dissolved in pyridine (5 mL), methanesulfonyl chloride (715 mg) was added at 0° C. to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The resultant extract was washed with water and saturated brine. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:5) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]([N:12]=[C:13]=S)=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[CH2:15]([NH2:18])[CH2:16][NH2:17]>C1C=CC=CC=1>[Br:1][C:2]1[C:11]([NH:12][C:13]2[NH:17][CH2:16][CH2:15][N:18]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2
Reactant: NCCN
Reactant: S=C=Nc1ccc2nccnc2c1Br
Solvent: c1ccccc1
Product: Brc1c(NC2=NCCN2)ccc2nccnc12
Reaction time: 2 h

Procedure:
The 5-bromo-6-isothiocyanato-quinoxaline (3.5 g.) is directly dissolved in benzene (400 ml) and added dropwise to a well-stirred solution of ethylene diamine (15 g.) in benzene (50 ml). During a period of about two hours, an oil separates as a lower layer. The upper benzene layer is poured off and the oil is washed with diethyl ether and then dissolved in methanol (500 ml). The methanolic solution is refluxed until hydrogen sulfide evolution ceases. The methanolic solution is concentrated in vacuo to a volume of approximately 100 ml upon which a yellow solid precipitates. The precipitate is collected by filtration and recrystallized from methanol to afford of (5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine: m.p. 250-251 C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11]([Cl:23])=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3ccc(Br)cc3)n[nH]c(=O)c2c1
Product: COc1ccc2c(-c3ccc(Br)cc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(4-bromophenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:20]=1[N+:27]([O-:29])=[O:28]>CN(C=O)C>[C:14]([O:13][C:3](=[O:12])[CH:4]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:20]=1[N+:27]([O-:29])=[O:28])[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)cc(F)c1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (54.6 g, 60%, 1.365 mol) in 600 mL of DMF was added di-t-Butyl malonate (118 g, 0.546 mol) at 0° C. and stirred for 30 min. 2,4,6 trifluoronitrobenzene was added as a solution in 400 mL of DMF (75 g, 0.42 mol) over 3 hours and the solution stirred at ambient temperature for 12 hours. The reaction mixture was extracted with ethyl acetate (3×'s). The ethyl acetate was washed with water (3×'s) and with brine and dried over MgSO4 and concentrated to give 62 g of crude product. LCMS [M+Na]−396; 1H NMR (500 MHz, DMSO) δ 7.81 (m, 1H), 7.27 (m, 1H), 5.00 (s, 1H), 1.41 (m, 18H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:8]([OH:12])=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:3]1.CS(O[CH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[S:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[CH2:19][CH2:18][N:1]([C@H:2]1[CH2:11][CH2:10][C:9]2[C:8]([OH:12])=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:3]1)[CH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)OCCc1cccs1
Reactant: N[C@H]1CCc2c(O)cccc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Oc1cccc2c1CC[C@H](N(CCc1cccs1)CCc1cccs1)C2
Temperature: 25 °C
Yield: 63.6 %

Procedure:
5.0 g of (S)-5,6,7,8-tetrahydro-6-amino-1-naphthol, 2.2 g of 2-(2-thienyl)ethyl methane-sulfonate, 4.8 g of sodium carbonate and 100 ml of xylene were mixed to form a mixture, and the mixture was refluxed for 48 h to 50 h. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography to obtain 1.3 g of (S)-5,6,7,8-tetrahydro-6-[N,N-bis[(2-thienyl)ethyl]]amino-1-naphthol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:13]=[C:14]([N:18]([CH3:30])[C:19](=[O:29])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH:25]4[CH2:28][CH2:27][CH2:26]4)[CH3:24])[CH:15]=[CH:16][CH:17]=3)[N:9]=[C:10](I)[C:3]=12.[CH3:31][O:32][C:33]1[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=[CH:37][C:38]=1[CH3:39]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:13]=[C:14]([N:18]([CH3:30])[C:19](=[O:29])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH:25]4[CH2:28][CH2:27][CH2:26]4)[CH3:24])[CH:15]=[CH:16][CH:17]=3)[N:9]=[C:10]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[C:33]([O:32][CH3:31])[CH:34]=3)[C:3]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C
Reactant: CN(C(=O)/C=C/CN(C)C1CCC1)c1cccc(-n2nc(I)c3c(N)ncnc32)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nn(-c3cccc(N(C)C(=O)/C=C/CN(C)C4CCC4)c3)c3ncnc(N)c23)ccc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
To a stirred solution of (E)-N-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-4-(cyclobutyl(methyl)amino)-N-methylbut-2-enamide (52) (222 mg, 0.4 mmol) and 2-(3-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (119 mg, 0.48 mmol) in DMF/H2O (4 mL/1 mL) were added Pd(dppf)Cl2 (16 mg, 0.02 mmol) and K3PO4.3H2O (320 mg, 1.2 mmol). The resulting mixture was purged with N2 (3×) and stirred at 80° C. overnight. Solvents were removed in vacuo. The residue was pre-purified by flash chromatography (silica gel, 0 to 10% MeOH in DCM with 0.3% TEA) followed by a prep HPLC to provide (E)-N-(3-(4-amino-3-(3-methoxy-4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-4-(cyclobutyl(methyl)amino)-N-methylbut-2-enamide (53) (29 mg, 14%) as a white solid. LC-MS (ESI): m/z (M+1) 512.3. 1H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 8.29 (d, J=9.4 Hz, 1H), 8.19 (t, J=2.0 Hz, 1H), 7.65 (t, J=8.1 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.32-7.22 (m, 3H), 6.72-6.61 (m, 1H), 5.99 (d, J=13.0 Hz, 1H), 3.89 (s, 3H), 2.98-2.78 (m, 2H), 2.77-2.62 (m, 1H), 2.25 (s, 3H), 1.87 (s, 3H), 1.83-1.71 (m, 2H), 1.71-1.54 (m, 2H), 1.50-1.32 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[N:22]=[N:21][N:20]=2)[CH2:8][C@H:7]1[CH2:39][CH3:40])=[O:5])[CH3:2].[CH3:41][O:42][C:43](=[O:49])[C:44]([CH3:48])([CH3:47])[CH2:45]O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[C:27]([C:35]([F:36])([F:38])[F:37])[CH:26]=3)[N:22]([CH2:45][C:44]([C:43]([O:42][CH3:41])=[O:49])([CH3:48])[CH3:47])[NH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:39][CH3:40])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nnnn2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Reactant: COC(=O)C(C)(C)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC2=NNN(CC(C)(C)C(=O)OC)N2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 19 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(tetrazol-5-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (230 mg) is dissolved in tetrahydrofuran (3 ml), and thereto are added 3-hydroxy-2,2-dimethylpropionic acid methyl ester (58 μl), a solution (0.18 ml) of 40% diethyl azodicarboxylate in toluene and triphenylphosphine (121 mg). The mixture is stirred at room temperature for 19 hours, and partitioned by adding water and diethyl ether. The organic layer is washed with saturated brine, then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[2-(2-methoxycarbonyl-2-methylpropyl)-2H-tetrazol-5-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (243 mg). MS (m/z): 688 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.O1CCOCC1.[ClH:28]>C(O)(C)C>[ClH:28].[ClH:28].[CH3:19][C:4]([CH3:20])([CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[C:3]([O:2][CH3:1])=[O:21]
Reactant: COC(=O)C(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COC(=O)C(C)(C)CN1CCNCC1
Temperature: 55 °C
Yield: 58.8 %

Procedure:
To a solution of tert-butyl 4-(3-methoxy-2,2-dimethyl-3-oxopropyl)piperazine-1-carboxylate (58.0 g, 193.08 mmoles) in isopropyl alcohol (150 mL) add a 4M dioxane solution of hydrogen chloride ((4 equiv); 193.08 mL, 772.31 mmoles) over 15 minutes, observing gas evolution and a fine precipitate. Heat at 55° C. for 3 h to give a white precipitate. Cool to 10° C. and collect the white solid by filtration, wash with further isopropyl alcohol (30 mL), then EtOAc. Dry in a vacuum oven at 45° C. for 1 h to give methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate dihydrochloride (31 g, 59% yield). MS (m/z): =201.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]2[S:16][CH:17]=[C:18]([C:19]([CH3:21])=[CH2:20])[C:4]=2[O:3]1>C1COCC1.CO.[Pd]>[CH3:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:6][C:5]2[S:16][CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[C:4]=2[O:3]1
Reactant: C=C(C)c1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CN(C(=O)OC(C)(C)C)Cc2scc(C(C)C)c2O1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of tert-butyl 2-methyl-8-(1-methylethenyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (269 mg) in THF-MeOH (2:1, 15 ml) was added 10% palladium on carbon (30 mg), and the mixture was stirred for 2 hr under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (243 mg, 90%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28](C)(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O
Reactant: N
Product: CC(C)(O)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 459, substituting 2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 479) in place of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone. mp 176-178° C., 1H NMR (300 MHz, CDCl3) δ 1.00 (s, 6H), 4.19 (s, 2H), 4.54 (s, 1H), 7.49 (s, 2H), 7.62 (t, 1H, J=9 Hz), 7.66 (ddd, 1H, J=2,5,9 Hz), 7.92 (s, 4.5H), 7.94 (d, 0.5H, J=2 Hz), 8.20 (s, 1H); MS (DCI/NH3) m/z 468 (M+H)+; 1 Cl, 490 (M+Na)+;1 Cl; Anal. Calcd for C20H19ClFN2O5S: C, 51.34; H, 4.09; N, 8.98. Found: C, 51.33; H, 4.23; N, 8.76.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2](=[O:4])[C:1]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:6])=[CH:16][CH:15]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of 20 g (123 mmol) isatoic anhydride (formed by treating anthranilic acid with phosgene) and 15.64 g (123 mmol) 4-chloroaniline was heated at 120° C. for 2 hours. The reaction was cooled to room temperature, mixed with CH2Cl2 and filtered.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])([CH3:3])[CH3:2].[Cl:12][CH2:13][C:14](O)=O.N>Cl>[CH:1]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]=[C:14]1[CH2:13][Cl:12])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccccc1N
Reactant: O=C(O)CCl
Agent: Cl
Agent: N
Product: CC(C)n1c(CCl)nc2ccccc21
Yield: 64.5 %

Procedure:
N-isopropyl-o-phenylenediamine (2.8 g, 18.6 mmol), which is a known compound, was reacted with monochloroacetic acid (2.64 g, 28 mmol) in hydrochloric acid. The reaction mixture was made to weak by alkaline alkali with aqueous ammonia and the obtained oily material was refined in a usual manner to give the title intermediate (2.5 g, 12 mmol).