Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 25 mL rbf was added 0.4137 g (1.31 mmol) of 4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-nitro-phenylamine, 4 mL of THF/EtOH (1:1). Vacuum flushed 3×, then added 0.1655 g of PtO2 (40% by weight) as a slurry in 2 mL of THF/EtOH (1:1). Flushed with H2 3×. Allowed to stir at r.t. for 18 h. Added 10 ml DCM, and Celite let stir 1 h, then filtered over Celite pad, and rinsed with 20 mL DCM. Reduced in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.85 (br. s., 1.7 H) 5.31 (br. s., 1.7 H) 6.62 (d, J=8.08 Hz, 1 H) 7.19 (dd, J=8.08, 1.89 Hz, 1 H) 7.26 (d, J=2.02 Hz, 1 H) 7.66-7.70 (m, 2 H) 8.02-8.06 (m, 2 H). MS (m/z) 287.2 M (+1), tR=1.18, Meth 10
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2C(=O)C3=CC=CC=C3C2=O)[CH2:6][CH2:5]1)[CH3:2].O.NN.C(OCC)C>C(O)C.CO>[CH2:1]([O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH2:10])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCO[C@H]1CC[C@H](N)CC1

Procedure:
A solution of trans-N-(4-ethoxycyclohexyl)phthalimide (D64, 16.35 g), hydrazine hydrate (12 mL) in ethanol (300 mL) and methanol (200 mL) was stirred at reflux for 3 hours. The solvent was removed to give a slurry, which was treated with diethyl ether and filtered. The filtrate was evaporated to afford the title compound as a viscous oil contaminated with ether (8.16 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[NH2:8][C@@H:9]([CH3:22])[C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]2[CH2:20][O:19][CH2:18][O:17][C:16]=2[CH:21]=1)[OH:11].CN(C)CC(O)=O.I[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]1[CH:41]=[C:42]([CH:50]=[CH:51][CH:52]=1)[C:43]([O:45][CH2:46][CH:47]([CH3:49])[CH3:48])=[O:44])[N:35]=[CH:34]2>C(#N)CCC.[Cu]I>[NH2:8][C@@H:9]([CH3:22])[C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]2[CH2:20][O:19][CH2:18][O:17][C:16]=2[CH:21]=1)[O:11][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]1[CH:41]=[C:42]([CH:50]=[CH:51][CH:52]=1)[C:43]([O:45][CH2:46][CH:47]([CH3:48])[CH3:49])=[O:44])[N:35]=[CH:34]2
Reactant: C[C@H](N)[C@H](O)c1ccc2c(c1)OCOC2
Reactant: CC(C)COC(=O)c1cccc(-n2ncc3cc(I)ccc32)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CCCC#N
Product: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCOC5)[C@H](C)N)ccc32)c1
Temperature: 110 °C
Reaction time: 0.05 h
Yield: 33.9 %

Procedure:
A 250 mL one-neck round bottomed-flask with magnetic stirring and argon atmosphere was charged with cesium carbonate (30.3 g, 93.00 mmol), (1R,2S)-2-amino-1-(4H-benzo[d][1,3]dioxin-7-yl)propan-1-ol hydrochloride (I3) (7.37 g, 30.00 mmol), 2-(dimethylamino)acetic acid (1.547 g, 15.00 mmol), copper(I) iodide (1.428 g, 7.50 mmol) and butyronitrile (72 mL) and heated at 110° C. for 30 min. A solution of isobutyl 3-(5-iodo-1H-indazol-1-yl)benzoate (I1) (12.61 g, 30 mmol) in butyronitrile (12.00 mL) was generated by heating at 80° C. for 10 minutes. The solution was pumped to the above mixture within 3 minutes. The vessel was rinsed with further butyronitrile (6.00 mL) which also was added. The reaction mixture was sealed and stirred at 110° C. for 19 h. The reaction mixture was cooled and extracted between water and ethyl acetate (1 L). The organic phase was washed three times with water (3×500 mL), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica using ethyl acetate:heptane 1:1 with 2% TEA followed by ethyl acetate:heptane 3:1 with 2% TEA and finally with ethyl acetate with 2% TEA. This gave the title compound (5.1 g, 34%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:13])=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]#[C:23][CH3:24]>CC(C)=O>[CH2:21]([O:13][C:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:12][C:8]2[CH2:9][CH2:10][O:11][C:7]=2[CH:6]=1)[C:22]#[C:23][CH3:24]
Reactant: CCCc1cc2c(cc1O)OCC2
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1cc2c(cc1CCC)CCO2
Temperature: 25 °C

Procedure:
Following the same procedure as in Example 3 c), a mixture of 5.0 g (0.026 moles) of 5-propyl-6-hydroxy-2,3-dihydrobenzofuran (title 93.5%), 3.9 g (0.028 moles) of anhydrous potassium carbonate in ml 30 of acetone was added with 3.7 g (0.028 moles) of 1-bromo-2-butyne: the mixture was heated to reflux for 6 hrs. After cooling to room temperature, the mixture was filtered and the filtrate evaporated u.v (20° C./21 mbar). The residue so obtained was purified by chromatography on silica column (eluant n-hexane/ethyl acetate 3/1 (v/v)). A liquid product (3.8 g, purity 96%) was obtained, whose NMR and MS analyses corresponded to those of the aforementioned compound.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:34])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[O:30][CH:31]=[CH:32][N:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:34][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[O:30][CH:31]=[CH:32][N:33]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ncco5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ncco5)cc4)CC3)n2CCS1
Yield: 86.5 %

Procedure:
A solution of the compound (260 mg, 0.52 mmol) obtained in Example 84-1) and 4 M hydrochloric acid (1,4-dioxane solution, 3 mL) in methanol (6 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, a 5 M aqueous sodium hydroxide solution (10 mL) was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=20:80) to obtain the title compound (172 mg, 87%) as a colorless solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1.C(Br)(Br)(Br)[Br:49].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.O1CCCC1>[Br:49][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCO)c5)c4)cc23)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCBr)c5)c4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
A suspension of Intermediate 77 (0.65 g, 1.0 mmol) and carbon tetrabromide (1.0 g, 3.0 mmol) in dichloromethane (14 mL) was sonicated for 5 minutes and then cooled in an ice-water bath. Following the addition, via syringe, of a triphenylphosphine (0.52 g, 2.0 mmol) solution in tetrahydrofuran, the cooling bath was removed, allowing the mixture to stir overnight at room temperature. The mixture was quenched with ethanol and concentrated to foam under reduced pressure. The foam was taken up in tetrahydrofuran (15 mL) and treated as before with carbon tetrabromide (3.0 mmol) and triphenylphosphine (2.0 mmol). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The crude material was again taken up in tetrahydrofuran (15 mL) and treated as before with carbon tetrabromide (3.0 mmol) and triphenylphosphine (2.0 mmol). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The residue was taken up a suspension in acetone and filtered. The concentrated filtrate was purified via automated flash silica gel chromatography, using a 40 g Silicycle SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound as straw-colored foam (0.35 g, 48%). ES/MS calcd. for C36H32BrN4O5S+ 711.1. Found m/z=711.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.Cl.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[C:29]2[CH:28]=[N:27]1)[CH3:20].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C.C(Cl)Cl>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34]([N:35]3[CH2:36][CH2:37][N:38]([C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][N:3]([CH3:2])[CH3:16])=[CH:15][CH:14]=4)[CH2:39][CH2:40]3)=[C:29]2[CH:28]=[N:27]1)[CH3:20]
Reactant: CCOc1cccc(Cn2ncc3c(N4CCNCC4)ncnc32)c1
Reactant: CN(C)CCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOc1cccc(Cn2ncc3c(N4CCN(C(=O)c5ccc(OCCN(C)C)cc5)CC4)ncnc32)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
To 4-[2-(dimethylamino)ethoxy]benzoic acid hydrochloride (66 mg, compound obtained in Reference example 78(2)) is added successively methylene chloride (2 mL), 1-(3-ethoxybenzyl)-4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride (100 mg), 1-hydroxybenzotriazole (49.3 mg), triethylamine (118.6 μL) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (70 mg) and the mixture is stirred at room temperature for 17 hours. The reaction mixture is diluted with chloroform (5 mL) and thereto is added a saturated sodium hydrogencarbonate solution (10 mL). After stirring, the organic layer is separated and concentrated. The resultant crude product is purified by flash column chromatography on NH-silica gel (Solvent; ethyl acetate:chloroform=1:0→0:1) to give 1-(3-ethoxybenzyl)-4-[4-[4-[2-(dimethylamino)ethoxy]benzoyl]piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine (103 mg, yield; 69%) as an amorphous powder. MS (APCI) m/z: 530 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4](B2OC(C)(C)C(C)(C)O2)=[N:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(#N)C.Br[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=1[O:38][CH2:39][CH3:40]>O>[CH2:39]([O:38][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:28]=1[C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[C:32]([O:34][CH3:35])=[O:33])[CH3:40]
Reactant: CCOc1cc(C(=O)OC)ccc1Br
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOc1cc(C(=O)OC)ccc1-c1cnn(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-Methyl-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (183 mg, 0.88 mmol), potassium phosphate (374 mg, 1.76 mmol) and dichloro(1,1-bis(diphenylphosphino)-ferrocene)palladium(II) dichloromethane adduct (9.6 mg, 0.012 mmol) were added to an acetonitrile solution (3 mL) of methyl 4-bromo-3-ethoxybenzoate (152 mg, 0.59 mmol), and stirred overnight at 100° C. The reaction liquid was cooled to room temperature, and water was added to it. This was extracted with ethyl acetate, washed with saturated saline water, and dried with magnesium sulfate. The solution was filtered, and concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=50/50) to obtain the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1)[CH3:2].C(O)(=O)C.[CH:17](=O)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[C:20]1([CH2:19][CH2:18][CH:17]=[N:10][NH:9][C:7](=[O:8])[C:6]2[CH:11]=[CH:12][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=CCCc1ccccc1
Reactant: CCc1ccc(C(=O)NN)cc1
Solvent: CC(=O)O
Solvent: CO
Product: CCc1ccc(C(=O)NN=CCCc2ccccc2)cc1

Procedure:
4-ethyl-benzoic acid hydrazide (10 g, 60.9 mmoles) was dissolved in 32 mL of methanol. Acetic acid (1 mL) was added, the mixture was brought to reflux, and hydrocinnamaldehyde (5.77 g, 67 mmoles) was then slowly added. The reaction mixture was refluxed for 10 h and monitored by TLC. The precipitates were collected via filtration and washed with hexanes. 4-Ethyl-benzoic acid (3-phenyl-propylidene)-hydrazide was obtained as a white solid (9.34 g, 54.7% yield). Rf=0.36 (1:1 EtOAc:n-hexane); 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.72-7.24 (m, 10H), 2.87 (t, J=15.2 Hz, 2H), 2.79-2.57 (m, 4H), 1.24 (t, J=8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].O=[C:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH2:24][CH:25]=2)[N:17]=[C:16]2[N:26]([CH:29]([CH3:31])[CH3:30])[N:27]=[CH:28][C:15]=12)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCN(C(=O)OC(C)(C)C)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.8 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 g, 2.38 mmol) in methanol (15 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (1.18 g, 5.95 mmol) and acetic acid (0.17 g, 2.85 mmol) stirred it at room temperature for 2 days. Then NaBH3CN (0.224 g, 3.57 mmol) was added to it resulting reaction mixture was stirred at room temperature for 8 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (0.5 g, 34.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N:12]2[C@H:16]([CH3:17])[CH2:15][O:14][C:13]2=[O:18])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[ClH:19].[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[ClH:19].[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:5]([C:4]3[CH:8]=[CH:9][C:10]([N:12]4[C@H:16]([CH3:17])[CH2:15][O:14][C:13]4=[O:18])=[CH:11][C:3]=3[O:2][CH3:1])=[O:7])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COc1cc(N2C(=O)OC[C@H]2C)ccc1C(=O)O
Agent: Cl
Product: COc1cc(N2C(=O)OC[C@H]2C)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Yield: 37.8 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-2-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (1.1 g) described in Preparation Example 45 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (956 mg) described in Preparation Example 64, the title compound (731 mg) was obtained.
Reaction SMILES: [I:1]C1C=CC2C3(C)CCN(C(OC(C)(C)C)=O)CC3OC=2C=1.O[C:24]1[CH:25]=[CH:26][C:27]2[O:43][CH:31]3[CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35][C:30]3([CH3:44])[C:28]=2[CH:29]=1>>[I:1][C:24]1[CH:25]=[CH:26][C:27]2[O:43][CH:31]3[CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35][C:30]3([CH3:44])[C:28]=2[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3cc(O)ccc3OC2C1
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(I)cc3OC2C1
Product: CC(C)(C)OC(=O)N1CCC2(C)c3cc(I)ccc3OC2C1

Procedure:
Synthesized as described for tert-butyl 7-iodo-4a-methyl-3,4,4a,9a tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from tert-butyl 6-hydroxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate. MS m/z 360 [M-tBu+H]+
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.C(N(CC)CC)C.[CH2:22]([O:29][C:30](ON1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:23]1([CH2:22][O:29][C:30]([NH:1][CH2:2][C@@H:3]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of (S)-3-(aminomethyl)-1-N-Boc-pyrrolidine (3.0 g, 14.98 mmole) in DMF (40 mL) was added triethylamine (2.5 mL, 17.94 mmole) and N-(benzyloxycarbonyloxy)succinimide (4.46 g, 17.90 mmole). After 18 hours, the reaction solution was concentrated under vacuum and redissolved in diethyl ether (250 mL). The organic solution was washed with H2O (2×150 mL), brine (100 mL) and dried over Na2SO4 and concentrated. The remaining residue was purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to give the title compound (4.46 g, 91%) as a light yellow oil: LC-MS (ES) m/e 335 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:25]#[C:26][Si](C)(C)C)[CH:23]=[CH:24][C:18]=2[N:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:25]#[CH:26])[CH:23]=[CH:24][C:18]=2[N:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc2ccc(C#C[Si](C)(C)C)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2nc([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)[nH]c2c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of [(S)-2-Phenyl-1-(6-trimethylsilanylethynyl-1H-benzoimidazol-2-yl)-ethyl]-carbamic acid tert-butyl ester (90 mg, 0.208 mmol) in methanol (10 mL) at room temperature, was added finely powdered anhydrous potassium carbonate (258 mg, 1.87 mmol). The resulting heterogenous mixture was stirred at room temperature until LC/MS indicated the reaction was complete. The solvent was then allowed to evaporate and resulting residue was partitioned in 1:1 v/v water/ethyl acetate (50 mL total volume) and the aqueous layer was separated and extracted twice with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The yellowish colored residue was applied to a silica gel column using dichloromethane (10 mL) and gradient eluted from 10 to 75% v/v ethyl acetate in hexanes to give [(S)-1-(6-ethynyl-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (54 mg, 72%)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][O:13][C:12]3=[O:23])=[N:7][C:6]=12.[F:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:26]=1[C:40]1[N:44]=[CH:43][N:42]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[N:41]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOC(C)=O.O1CCOCC1>[Cl:22][C:18]1[CH:17]=[C:16]([C@H:15]2[CH2:14][O:13][C:12](=[O:23])[N:11]2[C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[CH:3][C:2]([C:29]4[CH:28]=[CH:27][C:26]([C:40]5[N:44]=[CH:43][N:42]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:51])([CH3:50])[CH3:52])[N:41]=5)=[C:25]([F:24])[CH:30]=4)=[C:6]3[N:7]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3ncn(COCC[Si](C)(C)C)n3)c(F)c2)OC1(C)C
Reactant: O=C1OC[C@H](c2cccc(Cl)c2)N1c1ccn2ncc(Br)c2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5cccc(Cl)c5)nc34)cc2F)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(3-chlorophenyl)oxazolidin-2-one (100 mg, 0.254 mmol) were added 3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (139 mg, 0.330 mmol), Pd2 dba3 (11.6 mg, 0.0127 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (14.7 mg, 0.0254 mmol), dioxane (1.2 mL) and 2M Na2CO3 (0.2 mL). The reaction was stirred for 2 hours at 80° C. in a sealed tube. After cooling, EtOAc and water were added. The organic phase was washed with brine and dried over MgSO4. The residue was purified by reverse phase chromatography (SP4, 12M, water/CH3CN 90:10 to 0:100, 20 column volumes) to yield (S)-4-(3-chlorophenyl)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (67 mg, 43.5% yield) as a pale yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5]
Reactant: CN
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Product: CNC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Yield: 17 %

Procedure:
As described for example 69, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.29 mmol) was converted, using methylamine (2 M solution in THF) instead of isopropylamine, to the title compound (16 mg, 17%) which was obtained as a white solid. MS: m/e=326.1 [M+H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=O)[CH2:10]N(C)C)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH2:16][C:17]([NH2:19])=[NH2+:18].[O-]CC.[Na+].Cl>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][N:16]=[C:17]([NH2:19])[N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC(=O)Cc1cccc(Br)c1
Reactant: NC(N)=[NH2+]
Agent: CC[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: Nc1nccc(-c2cccc(Br)c2)n1
Temperature: 25 °C
Yield: 31.5 %

Procedure:
Combine 1-(3-bromo-phenyl)-3-dimethylamino-propanone (3.00 g, 11.8 mmol) and guanidinium chloride (1.12 g, 11.8 mmol), sodium ethoxide (5 mL, 21% wt solution in ethanol), absolute EtOH (24 mL) and heat to reflux overnight. Cool to room temperature and pour into 1% hydrochloric acid (200 mL). Extract with ethyl acetate, dry over sodium sulfate and condense to afford 4-(3-bromo-phenyl)-pyrimidin-2-ylamine (930 mg, 3.72 mmol) as a white solid. MS (m/z): 250.2 (M).