Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(O)(C)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH:16][C:20]3[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc(OC)c1OC
Temperature: 110 °C
Yield: 79 %

Procedure:
A mixture of 6-t-Butoxycarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamine, Intermediate 3 (500 mg, 2.0 mmol), 5-bromo-1,2,3-trimethoxybenzene (494 mg, 2.0 mmol), Cl-BrettPhos-Pd precatalyst/BrettPhos admixture (53 mg, 0.040 mmol (1:1 mol: mol)) and cesium carbonate (912 mg, 2.80 mmol) in t-BuOH (15 mL) was heated at 110° C. for 16 hours. Upon cooling, the reaction mixture was diluted with EtOAc and the insolubles were filtered off (celite). The filtrate was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 2:3 hexanes:EtOAc) to obtain a clear glass (659 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=2[O:31][CH3:32])[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:36]1C=C(S(Cl)(=O)=O)C=C(Cl)[CH:41]=1>>[CH2:36]([O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:13]([NH:12][S:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)(=[O:11])=[O:10])[CH:14]=2)=[CH:27][CH:26]=1)[CH3:41]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(NS(=O)(=O)c2cc(Cl)cc(Cl)c2)c1OC
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c(OC)c(OC)c2)cc1

Procedure:
4-[3-(3,5-Dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, MS (ISP): m/e=523.1 (M−H), was prepared in analogy to example 31, steps A to D. Step C was performed using 3,5-dichloro-benzenesulfonyl chloride and yielded 4-[3-(3,5-dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[Cl:20][C:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:13])[O:12]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Product: O=C1OC(Cl)(c2ccccc2)c2ccccc21
Reaction time: 0.25 h

Procedure:
Over a period of 15 minutes, 22.5 parts of 2-benzoylbenzoic acid are added, in small portions, while stirring, to 40 parts of thionyl chloride. The reaction mixture is then brought slowly to reflux and this is maintained for 90 minutes. The excess thionyl chloride is removed in vacuo and the residue is taken up in 50 parts of anhydrous benzene and the whole is then evaporated to dryness in vacuo. The operation is repeated a second time and then the residue is taken up in 80 parts of anhydrous tetrahydrofuran. This solution is used in that form in the stage described below.
Reaction SMILES: C([O:8][C:9](=[O:33])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:32])[C@@H:16]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:17][S:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:19])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[CH2:21]([S:18]([NH:17][C@@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:33])=[O:8])=[O:32])[CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:20])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)C[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 101 %

Procedure:
N-benzylsulfonyl-D-leucyl-L-proline benzyl ester (1.2 g) was dissolved in methanol (20 ml), and 10% palladium-carbon (120 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a white foam-like solid (981 mg, 97%), which was directly used for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][C@H:35]1[O:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:37]5[CH2:38][CH2:39][O:40][C@H:35]([CH2:34][O:33][CH3:32])[CH2:36]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COC[C@@H]1CNCCO1
Product: COC[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2S)-2-Methoxymethyl-morpholine following General Procedure C.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:6]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[NH4+].[Cl-]>C1COCC1>[C:24]([O:23][C:21]([NH:6][C@@H:7]([CH2:10][C:11]1[CH:12]=[N:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1)[CH2:8][CH2:9][C:5]([NH:2][NH2:3])=[O:4])=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1Cc1ccc(C(F)(F)F)nc1
Reactant: NN
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)NN)Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Hydrazine monohydrate (0.93 mL, 18.6 mmol) was added to a solution of (R)-tert-butyl 2-oxo-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidine-1-carboxylate (1.6 g, 4.65 mmol) in THF (23 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous NH4Cl (20 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting off-white solid was purified by recrystallization from EtOAc to provide (R)-4-(tert-butoxycarbonylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pentanehydrazide (1.40 g, 80%) as a white solid. LCMS (API-ES) m/z: 399.1 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1.[OH-].[Li+].CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(CC2CCc3[nH]c(C(=O)O)cc32)c1

Procedure:
The title compound was synthesized from methyl 4-(3-methoxybenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (116 mg, 0.40 mmol) and lithium hydroxide (167 mg, 4.00 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc to afford the title compound. 74, mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.09-2.18 (m, 1H), 2.53-2.65 (m, 1H), 2.65-2.73 (m, 2H), 2.74-2.85 (m, 2H), 3.28-3.37 (m, 1H), 3.81 (s, 3H), 6.56 (d, J=1.46 Hz, 1H), 6.73-6.83 (m, 3H), 7.22 (t, J=7.81 Hz, 1H), 8.85 (br. s, 1H). LCMS m/e 272 (M+H). Purity 99% (HPLC).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[NH:28][CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:51][N:52]=[C:53]=[O:54]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:53](=[O:54])[NH:52][CH3:51])[CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
A solution containing 35 (228 mg, 0.4 mmol), DIPEA (104 mg, 0.8 mmol) in DCM (5 mL) was cooled to 0° C. Methyl isocyanate (35 mg, 0.6 mmol) was added. After 3 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with saturated aqueous NaHCO3, 1N HCl, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude 40 (230 mg) which was used without further purification. Mass spectrum, m/z [630.1] (M+H)+.
Reaction SMILES: [N:1]1[C:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]=2[S:3][C:2]=1[NH2:14])=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:15](Cl)(=[O:18])[CH2:16][CH3:17].O>N1C=CC=CC=1>[N:1]1[C:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]=2[S:3][C:2]=1[NH:14][C:15](=[O:18])[CH2:16][CH3:17])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCC(=O)Cl
Reactant: Nc1nc2c(s1)CCc1ccccc1-2
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc2c(s1)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Under ice-cooling, to a solution of 4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-amine (1.50 g, 7.4 mmol) in pyridine (20 mL) was added propionyl chloride (1.03 g, 11 mmol), and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to give the title compound (1.75 g, yield 91%) as a powder.
Reaction SMILES: [C:1](F)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[CH:12]([NH:19][CH3:20])[CH2:13][N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:18][CH:16]1[CH2:15][N:14]([CH2:13][CH:12]([NH:19][CH3:20])[C:11]([F:10])([F:21])[F:22])[CH2:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(F)c1ccccc1
Reactant: CNC(CN1CC(O)C1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(CN1CC(OC(=O)c2ccccc2)C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 44.3 %

Procedure:
A solution of benzoyl fluoride (1.37 mL, 12.6 mmol) in DCM (5 mL) was added dropwise under argon to an ice cooled solution of 1-(3,3,3-trifluoro-2-(methylamino)propyl)azetidin-3-ol (Compound C3.1) (2.28 g, 11.5 mmol) and TEA (3.21 mL, 23 mmol) in DCM (45 mL). The stirring was continued at rt for 2.5 h. NaHCO3 (saturated, 20 mL) was added and the mixture was stirred vigorously for 40 min. The layers were separated, the aqueous layer was extracted with DCM, and the combined organic layers were washed with NaHCO3 (saturated), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC. After concentrating the fractions to approximately 30 mL the aqueous emulsion was extracted DCM (×2). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the title product (1.54 g, 44%.) as a colourless oil. 1H NMR (500 MHz, DMSO-d6) δ 7.97 (2H), 7.67 (1H), 7.53 (2H), 5.16 (1H), 3.7-3.79 (2H), 3.25 (1H), 3.18 (1H), 2.92-3.02 (1H), 2.66 (1H), 2.59 (1H), 2.38 (3H), 1.99-2.06 (1H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11]1([CH3:20])[C:12]([C:17](Cl)=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.C1(C)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:11]1([CH3:20])[C:12]([C:17]([NH:1][C:2]2[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=2)=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1ccccc1C(=O)Nc1nc(C(Cl)(Cl)Cl)ns1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A solution of 22.0 g (0.1 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 16.0 g (0.1 mole) 2-toluoyl chloride in 250 ml xylene was heated at reflux for 20 hours. The reaction mixture was cooled to room temperature and the resulting precipitate removed by filtration. Following recrystallization for toluene, 11.8 g (35% yield) of pure product was otained; m.p. 170° C.
Reaction SMILES: [C:1]([C:3]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([NH:9][C:3]2([C:1]#[CH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: C#CC1(N)CCCCC1
Solvent: CCN(CC)CC
Product: C#CC1(NS(=O)(=O)c2cccc(Cl)c2)CCCCC1
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of 1-ethynylcyclohexanamine (40 mg, 0.32 mmol) in CH2C2 was added triethylamine (68 mL, 0.48 mmol), followed by 3-chlorobenzenesulfonyl chloride (68.2 mg, 0.32 mmol). After 30 min, the mixture was partitioned between ethyl acetate and 3N aq. HCl. The organic layer was washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated in vacuuo to give the title compound as a white solid (90 mg, 93% yield);
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:32]=[CH:31][C:11]([O:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].C([O-])(O)=O.[Na+].Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>C(Cl)Cl>[CH2:42]([O:41][C:39]([NH:7][C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:31][CH:32]=1)=[NH:6])=[O:40])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CCOc1cc(C(Oc2ccc(C(=N)N)cc2)C(=O)OC)ccc1OC(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1cc(C(Oc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)OC)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a suspension of 9C (570 mg, 1.12 mmol) in CH2Cl2 (12 mL) was added 1.0 M NaHCO3 (11.2 mL, 11.2 mmol), followed by benzyl chloroformate (0.22 mL, 1.5 mmol) in CH2Cl2 (3.0 mL). The mixture was stirred at rt for 30 min. TLC indicated some 9C still present. Another portion of benzyl chloroformate (0.1 mL, 0.84 mmol) in CH2Cl2 (3.0 mL) was added. After stirring at rt for 1.0 h, the reaction was quenched with ammonium hydroxide (0.65 mL), and extracted with CH2Cl2. The organic extract was washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (1:1) to give 9D (570 mg, 73% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (d, J=6.16 Hz, 6H) 1.38 (t, J=7.03 Hz, 3H) 3.71 (s, 3H) 4.04 (q, J=7.03 Hz, 2H) 4.46 (m, 1H) 5.18 (s, 2H) 5.58 (s, 1H) 6.85 (d, J=8.8 Hz, 1H) 6.90 (d, J=8.35 Hz, 2H) 7.09 (m, 2H) 7.20-7.40 (m, 6H), 7.82 (d, J=9.20 Hz, 2H).
Reaction SMILES: CN(C=O)C.[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8].Br[C:13]1[C:17]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[S:15][C:14]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[N+:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:13]([C:11]#[C:10][Si:7]([CH3:9])([CH3:8])[CH3:6])=[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:15][C:16]=2[CH:21]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)c1sc2cc([N+](=O)[O-])ccc2c1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc([N+](=O)[O-])ccc2c1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
DMF (20 ml), (trimethylsilyl)acetylene (5 ml), triethylamine (10 ml) and bis(triphenylphosphine)palladium (II) dichloride (420 mg, 0.6 mmol) were added to ethyl 3-bromo-6-nitro-1-benzothiophene-2-carboxylate obtained in Example (183b) (794 mg, 2.41 mmol) and copper (I) iodide (12 mg, 0.63 mmol), and the mixture was stirred at 80° C. for one hour. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with dilute hydrochloric acid and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10) and recrystallized from an ethyl acetate/hexane solvent, to obtain 110 mg of the title compound as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[F:31].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41]([NH:40][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=4)=[O:42])=[C:3]([F:31])[CH:4]=3)[C:16]=12
Reactant: COc1cccc(N=C=O)c1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(N)c(F)c4)c4c(N)ncnc43)CC2)CC1
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)Nc2ccc(-c3nn([C@H]4CC[C@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2F)c1
Reaction time: 19 h

Procedure:
trans-3-(4-Amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (77 mg, 0.182 mmol) was suspended in pyridine (1 mL). A solution of 3-methoxyphenylisocyanate (30 mg, 0.200 mmol) in pyridine (1 mL) was added to the reaction mixture and stirring was continued for 19 hours. The reaction mixture was concentrated under reduced pressure to yield the crude product as a pale yellow oil (149 mg). The crude material was purified on RP-HPLC (Waters PrepLC 4000, flow rate: 10 mL/min. λ=254 nm Gradient: 10% to 30% acetonitrile/0.1M aqueous ammonium acetate gradient over 40 minutes; Deltapak C18, 300A, 15 μm, 40×100 mm column) to afford trans-N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N′-(3-methoxyphenyl)urea as a white solid (76 mg, 0.133 mmol). HPLC-RT: 12.33 min. (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300A, 5 μm, 150×3.9 mm column); m/z (MH+)=574.2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([O:8][C:9](=[O:31])[N:10]([C:20]1[CH:25]=[C:24](Br)[N:23]=[C:22]([NH2:27])[C:21]=1[N+:28]([O-:30])=[O:29])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[CH3:7]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:6]([O:8][C:9](=[O:31])[N:10]([C:20]1[CH:25]=[C:24]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[N:23]=[C:22]([NH2:27])[C:21]=1[N+:28]([O-:30])=[O:29])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[CH3:7]
Reactant: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: c1cocn1
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(-c2ncco2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using oxazole (33 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(3-cyano-benzyl)-carbamic acid ethyl ester (100 mg) and palladium bis(triphenylphosphine)dichloride (33 mg), giving the product (67 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH3:17].[CH3:18][S:19]([N:22]([CH3:46])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:37]2[C:32]([CH:33]=[N:34][C:35](OS(C(F)(F)F)(=O)=O)=[N:36]2)=[CH:31][CH:30]=1)(=[O:21])=[O:20].C(N(CC)C(C)C)(C)C.COCC(O)C>>[OH:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:35]3[N:34]=[CH:33][C:32]4=[CH:31][CH:30]=[C:29]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]([CH3:46])[S:19]([CH3:18])(=[O:21])=[O:20])[N:37]4[N:36]=3)=[C:3]([O:16][CH3:17])[CH:4]=2)[CH2:8][CH2:9]1
Reactant: COc1cc(CN2CCC(O)CC2)ccc1N
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc(CN2CCC(O)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 120 °C

Procedure:
Into an 8-dram vial, [1-(4-Amino-3-methoxy-benzyl)-piperidin-4-ol (0.102 g, 0.430 mmol), Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (88.0 mg, 0.195 mmol), N,N-Diisopropylethylamine (0.0749 mL, 0.430 mmol), and 1-Methoxy-2-propanol (0.70 mL, 7.2 mmol) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-(2-{2-[4-(4-Hydroxy-piperidin-1-ylmethyl)-2-methoxy-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide a yellow solid (92 mg, 72%). LCMS (E/I+) 537.11 (M+H). NMR 1H (DMSO-d6)-9.16 (bs, 1H), 9.00 (s, 1H), 8.07-8.12 (m, 1H), 7.95-8.01 (m, 1H), 7.86 (s, 1H), 7.64-7.70 (m, 1H), 7.52-7.58 (m, 1H), 7.19 (d, 1H, J=9.96 Hz), 7.03 (d, 1H, J=4.60 Hz), 7.01 (d, 1H, J=4.60 Hz), 6.90-7.00 (m, 1H), 4.24 (dd, 2H, J=4.64, 16.65 Hz), 2.80-4.00 (m, 15H), 1.40-2.00 (m, 4H).