Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[O:20][N:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[O:20][N:19]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=7.8 Hz, 1H), 8.24 (s, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.96 (d, J=1.0 Hz, 1H), 7.89-7.80 (m, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.5, 1.5 Hz, 1H), 5.84 (s, 2H), 2.91 (t, J=7.6 Hz, 2H), 1.76-1.47 (m, 2H), 0.92 (t, J=7.3 Hz, 3H); MS (ES) m/z 445 (M+1).
Reaction SMILES: N.F[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]([CH3:27])([CH3:26])[O:17][C:16]3=[O:28])[CH2:11][CH:10]=2)=[CH:5][C:4]=1[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.FC1[N:41]=CC(C2CC[C@@H](N3C(C4C=CC=CC=4)C(C)(C)OC3=O)CC=2)=CC=1C1N=CC=CN=1>CC(O)C.CS(C)=O>[NH2:41][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]([CH3:27])([CH3:26])[O:17][C:16]3=[O:28])[CH2:11][CH:10]=2)=[CH:5][C:4]=1[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: CC1(C)OC(=O)N([C@@H]2CC=C(c3cnc(F)c(-c4ncccn4)c3)CC2)C1c1ccccc1
Reactant: CC1(C)OC(=O)N([C@H]2CC=C(c3cnc(F)c(-c4ncccn4)c3)CC2)C1c1ccccc1
Agent: N
Solvent: CC(C)O
Solvent: CS(C)=O
Product: CC1(C)OC(=O)N(C2CC=C(c3cnc(N)c(-c4ncccn4)c3)CC2)C1c1ccccc1
Temperature: 130 °C

Procedure:
A 2-mL glass microwave reaction vessel was charged with ammonia, (2 M solution in 2-propanol) (1.806 mL, 83 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) and a mixture of 3-((S)-4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one and 3-((R)-4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (370 mg, 0.832 mmol) in DMSO (8.324 mL). The reaction mixture was stirred and heated at 130° C. for 3 days. LC-MS indicated clean and good conversion to the desired product with a small amount of starting material present. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with water and brine and dried over MgSO4. The solution was filtered and concentrated under reduced pressure. The material thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in heptane, to provide Example 131 (3-(4-(6-amino-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one) (210 mg, 0.476 mmol, 57.1% yield) as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.87-8.92 (m, 4H), 8.60-8.64 (m, 2H), 8.20 (d, J=2.56 Hz, 1H), 8.17 (d, J=2.46 Hz, 1H), 7.34-7.46 (m, 9H), 7.25-7.34 (m, 4H), 5.95-5.98 (m, 1H), 5.83-5.89 (m, 1H), 4.70 (s, 1H), 4.67 (s, 1H), 3.59-3.77 (m, 2H), 2.60-2.75 (m, 1H), 1.90-2.43 (m, 8H), 1.71-1.80 (m, 1H), 1.47-1.53 (m, 8H), 0.78-0.87 (m, 6H). m/z (ESI) 442.2 (M+H)+.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH2:11][CH3:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14][CH:15]([N:17]1[C:21]([NH2:22])=[CH:20][CH:19]=[N:18]1)[CH3:16]>C1C=CC=CC=1>[CH3:14][CH:15]([N:17]1[C:21]2[N:22]=[C:9]([CH2:10][CH2:11][CH3:12])[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:20]=2[CH:19]=[N:18]1)[CH3:16]
Reactant: CCCC(=O)CC(=O)C(=O)OCC
Reactant: CC(C)n1nccc1N
Solvent: c1ccccc1
Product: CCCc1cc(C(=O)OCC)c2cnn(C(C)C)c2n1
Temperature: 62 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
To a solution of ethyl 2,4-dioxoheptanoate (446 mg, 2.397 mmol) in benzene (5 mL) was added 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and the mixture was stirred at 62° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (Silica gel, gradient of 0 to 100% EtOAc/hexanes) to give 370 mg (56%) of product. LCMS E-S (M+H)=276.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99-1.12 (m, 3 H), 1.46-1.54 (m, 3 H), 1.58-1.70 (m, 6 H), 1.82-1.96 (m, 2 H), 2.91-3.02 (m, 2 H), 4.51 (q, J=7.2 Hz, 2 H), 5.28-5.44 (m, 1 H), 7.58-7.68 (s, 1 H), 8.27-8.40 (s, 1 H)
Reaction SMILES: [ClH:1].C1(C)C=CC=C[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14]N.Cl.O.[NH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.Cl>CCO>[ClH:1].[CH3:3][C:8]1[C:9]2[NH:14][C:22]3[CH2:21][CH2:20][NH:19][CH2:24][C:23]=3[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCNCC1
Reactant: Cc1ccccc1-c1ccccc1NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cccc2c3c([nH]c12)CCNC3
Temperature: 25 °C
Yield: 89 %

Procedure:
o-Tolylphenylhydrazine hydrogen chloride (25 g, 158.6 mmol) and 4-piperidone monohydrate hydrogen chloride (24.4 g, 158.6 mmol) were suspended in EtOH (310 mL). Concentrated aqueous HCl (26 g, 317 mmol) was then added. The mixture was refluxed for 3 h, and then the reaction was cooled to rt. The ppt was filtered and washed with cold EtOH. The white solid was air-dried for 18 h. 6-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (36.6 g, 141.2 mmol, 89%) was isolated and a white powder. 1H NMR (CD3OD, 300 MHz) δ 7.22–7.25 (1H, m), 6.89–6.96 (2H, m), 4.40 (2H, m), 3.60 (2H, t, 6.2 Hz), 3.16 (2H, t, 6.2 Hz), 2.45 (3H, s) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]#[N:5].OO.CS(C)=[O:18].[OH-].[K+]>CO.O>[CH3:10][C:8]1[CH:9]=[C:2]([CH3:1])[C:3]([C:4]([NH2:5])=[O:18])=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=1
Reactant: CS(C)=O
Reactant: Cc1cc(C)c(C#N)c([N+](=O)[O-])c1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(C(N)=O)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
To a solution of 4,6-dimethyl-2-nitroaniline (3 g, 18.07 mmol) in acetic acid (20 mL) and 6 N HCl (60 mL) at 0° C. was added a solution of sodium nitrite (2.18 g, 31.62 mmol) in water (5 mL). The reaction mixture was stirred at 0° C. for 30 min after completion of addition and copper (I) cyanide (3.24 g, 3 mmol) was added pinch by pinch. The resulting mixture was stirred at 0° C. for 5 h and at room temperature for an additional 2 h. The mixture was passed through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=7:1) to yield 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 81%) as a light yellow solid. A solution of 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 15.7 mmol) and copper (I) cyanide (7.05 g, 78.3 mmol) in DMAC (20 mL) was stirred at reflux for 14 h. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), filtered through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=6:1) to yield 0.64 g of 2,4-dimethyl-6-nitro-benzonitrile (23%). A solution of 2,4-dimethyl-6-nitro-benzonitrile (1.1 g, 6.24 mmol) in MeOH (20 mL) and water (10 mL) was mixed with hydrogen peroxide (10 mL), DMSO (10 mL) and potassium hydroxide (0.636 g, 11.36 mmol). The reaction mixture was stirred at 60° C. for 3 h, diluted with water (100 mL), extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford 4,6-dimethyl-2-nitrobenzamide (0.52 g, 43%). A solution of 4,6-dimethyl-2-nitrobenzamide (0.52 g, 2.68 mmol) in MeOH (30 mL) was mixed with palladium carbon (0.25 g). The resulting suspension was stirred at room temperature under hydrogen for 14 h. The mixture was passed through a Celite pad, concentrated using a rotary evaporator to afford 2-amino-4,6-dimethyl benzamide (0.42 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:14]([C@@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH3:16])[C:13](=[O:24])[C:12]3[CH:25]=[C:26](I)[CH:27]=[CH:28][C:11]=3[NH:10][C:9]2=[O:30])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:14]([C@@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH3:16])[C:13](=[O:24])[C:12]3[CH:25]=[C:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH3:31])[CH:27]=[CH:28][C:11]=3[NH:10][C:9]2=[O:30])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2NC(=O)[C@@H]1c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccccc1-c1ccc2c(c1)C(=O)N([C@H](C)c1ccc(Cl)cc1)[C@@H](c1ccc(Cl)cc1)C(=O)N2
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of (3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-iodo-1,4-benzodiazepine-2,5-dione (120 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol), 2-methylbenzene boronic acid (35 mg, 0.26 mmol) and sodium carbonate (220 μL, 2M in H2O) in ethanol (300 μL) and toluene (5 mL) was heated under argon, at 90° C., for 10 h. After the mixture was cooled at room temperature, the solvent was evaporated in vacuo. The residue was partitioned between AcOEt (20 mL) and water (15 mL), dried (Na2SO4) and evaporated. Chromatography on silica (AcOEt/hexanes/CH2Cl2, 1:6:3) afforded the title compound (92 mg, 68%) as a colorless powder: 1H NMR (400 MHz, CDCl3) δ 1.78 (d, J=7.2 Hz, 3H, CH3), 1.99 (s, 3H, CH3), 5.29 (s, 1H, CH), 6.51 (q, J=7.2 Hz, 1H, CH), 6.64–6.67 (m, 2H, ArH, 6.71 (d, J=8.4 Hz, 1H, ArH), 6.93 (d, J=8.4 Hz, 2H, ArH), 7.05–7.11 (m, 1H, ArH), 7.15 (dd, J=8.0 Hz, J=2.0 Hz, 1H, ArH), 7.20–7.26 (m, 3H, ArH), 7.35 (d, J=8.4 Hz, 2H, ArH), 7.56 (d, J=8.4 Hz, 2H, ArH), 7.61 (d, J=2.0 Hz, 1H, ArH), 7.91 (br s, 1H, NH). Mass spectrum (LCMS, ESI pos.): Calcd for C30H24Cl2N2O2: 514.0; found: 515.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=O.[NH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:15][CH:14]=[CH:13][CH:12]=2>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[N:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:17]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cccnc12
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCc1nc2cnc3cccnc3c2n1CCNC(=O)OC(C)(C)C

Procedure:
Methoxyacetyl chloride (5.9 g, 54 mmol) was added dropwise to a chilled (ice bath) solution of tert-butyl N-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate (15.0 g, 49.5 mmol, U.S. Pat. No. 6,194,425, Example 87) in anhydrous pyridine (100 mL). The reaction mixture was heated at reflux until analysis by liquid chromatography/mass spectroscopy (LCMS) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethanol (100 mL), combined with potassium carbonate solution (200 mL of 2 M), and heated at reflux for 4 hours. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 14 g of tert-butyl N-[2-(2-methoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamate.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13]C)[CH:10]=[CH:9][C:8]=1[O:15]C.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].O>O1CCCC1>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[C:10]3[CH:9]=[C:8]([OH:15])[CH:7]=[CH:12][C:11]=3[O:13][C:27]2([CH3:29])[CH3:28])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: COc1ccc(OC)c(Br)c1
Reactant: CC(C)C(=O)c1ccc(C(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(C2c3cc(O)ccc3OC2(C)C)cc1
Reaction time: 0.33 h
Yield: 24.8 %

Procedure:
n-Butyllithium (1.6 M, 20.8 mL, 33.2 mmol) was added to a solution of 1-bromo-2,5-dimethoxybenzene (7.2 g, 33.2 mmol) in tetrahydrofuran (20 mL) at −78° C., and the mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 1-(4-isopropylphenyl)-2-methylpropan-1-one (5.70 g, 30.0 mmol), and the mixture was stirred for 30 minutes at room temperature. Water (30 mL) was poured into the reaction mixture, which was then extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. A mixture of the residue and 48% hydrobromic acid (30 mL) was heated under reflux for 24 hours in an argon atmosphere. After cooling, water (30 mL) was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to obtain the title compound (2.1 g, yield 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:7]=12.CN(C=O)C.Cl[C:20]1[N:25]=[CH:24][C:23]([N:26]2[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[NH:28][C:27]2=[O:34])=[CH:22][N:21]=1>>[CH3:32][C:29]1([CH3:33])[NH:28][C:27](=[O:34])[N:26]([C:23]2[CH:24]=[N:25][C:20]([O:13][C:5]3[C:6]4[C:10]5([CH2:9][O:8][C:7]=4[C:2]([CH3:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]5)=[N:21][CH:22]=2)[C:30]1=[O:31]
Reactant: CC1(C)NC(=O)N(c2cnc(Cl)nc2)C1=O
Reactant: Cc1ccc(O)c2c1OCC21CC1
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ncc(N3C(=O)NC(C)(C)C3=O)cn2)c2c1OCC21CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol (Intermediate 13, 18 mg, 0.1 mmol) in dry DMF (1 ml) potassium carbonate (27.6 mg, 0.2 mmol) and then 3-(2-chloropyrimidin-5-yl)-5,5-dimethyl-imidazolidine-2,4-dione (Intermediate 23, 20 mg, 0.083 mmol) were added and the reaction mixture was stirred for 2 hours at 80° C. After cooling the reaction mixture was quenched with water (1 ml), diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried over sodium sulfate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 7:3 to cyclohexane/ethyl acetate 3:7 as eluents affording the title compound (18 mg) as a light beige solid.
Reaction SMILES: [CH2:1]([C:5]1([CH2:32][CH2:33][CH2:34][CH3:35])[C:17]2[CH:16]=[C:15]([N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[B:41](OC)([O:44]C)[O:42]C.Cl>O.C1COCC1>[CH2:1]([C:5]1([CH2:32][CH2:33][CH2:34][CH3:35])[C:17]2[CH:16]=[C:15]([N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([B:41]([OH:44])[OH:42])=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: COB(OC)OC
Reactant: CCCCC1(CCCC)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC1(CCCC)c2cc(B(O)O)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Temperature: -30 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a dry 100 mL two-neck flask containing 1.3 g (2.47 mmol) of compound 2 and 30 mL of dry THF was dropwise added 2.3 mL (3.71 mmol) of 1.6 M of n-butyl lithium under N2 at −78° C. while maintaining a good stirring. After stirring for 1 h, trimethyl borate (0.4 mL, 3.71 mmol) was added in one portion. The reaction mixture was then stirred for 1 h at −78° C. When the mixture was naturally warmed to −30° C., water and HCl (3 M) were added. Then the solution mixture was poured into water wad extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness under 35° C. The crude product was purified by silica gel column chromatography using dichloromethane and petroleum ether/ethyl acetate as eluent affording a light-yellow solid (0.96 g, 79%). 1H NMR (400 MHz, DMSO-d6, δ) 8.02 (s, 2H), 7.80 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.08 (d, J=1.6 Hz, 1H), 6.93-7.01 (m, 6H), 6.91 (d, J=2.0 Hz, 1H), 1.79-1.88 (m, 4H), 0.95-1.04 (m, 4H), 0.65 (t, J=7.4 Hz, 6H), 0.50-0.58 (m, 4H). 13C NMR (100 MHz, DMSO-d6, δ) 152.1, 148.9, 147.4, 146.8, 142.1, 136.1, 133.1, 129.4, 129.3, 128.2, 123.3, 122.7, 121.1, 119.1, 118.3, 54.3, 39.2, 25.8, 22.4, 13.8. MS (FAB) m/z 489.7 (M+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15])=[C:7]2[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:29][CH:28]=1.Cl[C:39](OCC)=[O:40].O>CN(C=O)C>[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][C:8]3[C:14](=[O:15])[N:16]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)[C:39](=[O:40])[N:26]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([CH3:34])([CH3:35])[C:36]#[N:37])=[CH:31][CH:32]=4)[C:7]=3[C:6]=2[N:5]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(CNC(=O)c2cnc3ccc(Cl)nc3c2Nc2ccc(C(C)(C)C#N)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)c3cnc4ccc(Cl)nc4c3n(-c3ccc(C(C)(C)C#N)cc3)c2=O)cc1
Temperature: 60 °C
Yield: 46.9 %

Procedure:
Sodium hydride (1.0 g, 25 mmol) was suspended in 25 mL DMF. To the resulting mixture was slowly added dropwise a solution of 6-chloro-4-((4-(2-cyanoprop-2-yl)phenyl)amino)-N-(4-methoxybenzyl)-1,5-naphthyridine-3-carboxamide (2.43 g, 5 mmol) in DMF (25 mL) at room temperature. After the completion of the dropwise addition, the resulting mixture was warmed up to 60° C. and reacted for 1 hr. To the reaction mixture was slowly added dropwise ethyl chloroformate (1.36 g, 12.5 mmol) under an ice bath. After the completion of the dropwise addition, the resulting mixture was warmed up to 60° C. and reacted for 16 hrs. The reaction was cooled to room temperature, then slowly poured into water, and extracted with ethyl acetate (3×150 mL). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was separated by silicagel column chromatography (EtOAc/PE=0-1/5) to produce a pale yellow solid (1.2 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[N:3]=1.Cl.[CH:18]1([N:22]([CH3:29])[CH2:23]/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH2:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:26](=[O:27])/[CH:25]=[CH:24]/[CH2:23][N:22]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[CH3:29])[CH2:13]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2c1c(I)nn2[C@@H]1CCNC1
Reactant: CN(C/C=C/C(=O)O)C1CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2nc(I)c3c(N)ncnc32)C1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.4 %

Procedure:
To a cooled solution of (R)-3-iodo-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4) (990 mg, 3.0 mmol), (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acid (21) (871 mg, 3.0 mmol) and DIPEA (3.1 mL, 18 mmol) in DMF (15 mL) was added HBTU (1.74 g, 4.5 mmol). The resulting solution was stirred at RT overnight, then quenched with water. The layers were separated and the aqueous layer was extracted with 85% DCM/IPA(3×). The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to provided (R,E)-1-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one (22) (1.71 g, quant. yield) as a white solid. LC-MS (ESI): m/z (M+1) 482.0.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6].[C:9](#N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Br-].[Zn+2].[Br-]>[CH3:6][S:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:1]1
Reactant: N#Cc1ccccc1
Reactant: CSCC[C@@H](N)CO
Agent: [Br-]
Agent: [Zn+2]
Product: CSCC[C@@H]1COC(c2ccccc2)=N1
Temperature: 120 °C
Reaction time: 90 h
Yield: 48.6 %

Procedure:
A mixture of (R)-methioninol (4.95 g), benzonitrile (8.3 mL) and zinc bromide (250 mg) was stirred at 120° C. for 90 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was washed with water and brine, dried over magnesium sulfate and filtered again. The filtrate was concentrated in vacuo, and the resultant crude product was purified by column chromatography on silica gel (solvent; hexane/ethyl acetate=5/1 to 3/1) to give (R)-4-(2-methylthioethyl)-2-phenyl-4,5-dihydrooxazole (3.94 g, yield: 48.6%) as a colorless oil.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13]Br.[CH2:16]([O:18][C:19](=[O:30])[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH3:17].NC1C=CC=CC=1>>[CH2:16]([O:18][C:19](=[O:30])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:13][C:5]3[C:4](=[CH:9][CH:8]=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=3)[C:3]2=[O:15])=[CH:27][CH:28]=1)[CH3:17]
Reactant: CCOC(=O)CCCc1ccc(N)cc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Solvent: Nc1ccccc1
Product: CCOC(=O)CCCc1ccc(N2Cc3cc([N+](=O)[O-])ccc3C2=O)cc1

Procedure:
By using 2-bromomethyl-4-nitrobenzoic acid methyl ester and 4-(4-aminophenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester.