Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH:4]([OH:7])[C:5]#[CH:6].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:17]([Si:14]([O:7][CH:4]([CH2:3][CH:2]([CH3:8])[CH3:1])[C:5]#[CH:6])([CH3:16])[CH3:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: C#CC(O)CC(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CC(CC(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
To a solution of 5-methyl-hex-1-yn-3-ol (5.0 g, 0.045 mol) in dry DMF (50 mL) were added imidazole (3.64 g, 0.054 mol) and tert-butyldimethylsilyl chloride (6.06 g, 0.054 mol). The resulting mixture was stirred at RT for 2.5 h and then treated with saturated NH4Cl (25 mL) and EtOAc (250 mL). The organic layer was washed with saturated NH4Cl (50 mL), water (4×100 mL), brine (2×100 mL), dried over sodium sulfate, and concentrated in vacuo to afford the crude product (9.84 g, 97.5%), as a yellow oil, which was used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.10 (s, 3H), 0.13 (s, 3H), 0.90-0.88 (m, 15H), 1.53-1.46 (m, 1H), 1.65-1.58 (m, 1H), 1.87-1.77 (septet, J=6.6 Hz, 1H), 2.36-2.35 (t, J=1.84 Hz, 1H), 4.39-4.37 (m, 1H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[C:12]([CH2:33][CH3:34])=[CH:13][C:14]4[C:26](=[O:27])[C:25]5[C:24]6[C:19](=[CH:20][C:21]([C:28]#[N:29])=[CH:22][CH:23]=6)[NH:18][C:17]=5[C:16]([CH3:31])([CH3:30])[C:15]=4[CH:32]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:33]([C:12]1[C:11]([N:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[CH:32][C:15]2[C:16]([CH3:31])([CH3:30])[C:17]3[NH:18][C:19]4[C:24]([C:25]=3[C:26](=[O:27])[C:14]=2[CH:13]=1)=[CH:23][CH:22]=[C:21]([C:28]#[N:29])[CH:20]=4)[CH3:34]
Reactant: CCc1cc2c(cc1N1CCC3(CC1)OCCO3)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2c(cc1N1CCC(=O)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Reaction time: 17 h
Yield: 64 %

Procedure:
8-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile, which had been prepared in Example 809, was dissolved in THF (10 ml), added with 5 N hydrochloric acid (50 ml), and the mixture was stirred for 17 hrs. The reaction mixture was neutralized with 5 N aqueous solution of sodium hydroxide and diluted with ethyl acetate (200 ml). The organic layer was washed with 10% brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (dichloromethane/methanol=99/1 to 90/10) to obtain the title compound (2.9 g, two step yield 64%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Br)n1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(Br)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
6-Bromo-pyridin-2-carbaldehyde (5.0 g, 26.9 mmol), malonic acid (6.3 g, 60.5 mmol), and piperidine (2.2 mL, 22.4 mmol) were added to pyridine (16.3 mL). The reaction mixture was stirred at 100° C. for 1 hour, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid was dried under reduced pressure to give 4.5 g of the titled compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:20][C:21]([NH:23][N:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:25]2[C:30]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:37])=[O:22])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:17]=1)[C:7]([O:9]N1C(=O)CCC1=O)=O.[CH3:46][NH:47][CH3:48]>C1COCC1>[Br:1][C:2]1[C:3]([CH2:20][C:21]([NH:23][N:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:25]2[C:30]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:37])=[O:22])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:17]=1)[C:7]([N:47]([CH3:48])[CH3:46])=[O:9]
Reactant: CNC
Reactant: COc1ccc(N(NC(=O)Cc2cc(OC)c(C(=O)ON3C(=O)CCC3=O)cc2Br)c2c(C)cccc2N2CCCCC2)cc1
Solvent: C1CCOC1
Product: COc1ccc(N(NC(=O)Cc2cc(OC)c(C(=O)N(C)C)cc2Br)c2c(C)cccc2N2CCCCC2)cc1
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of 85 mg of the compound obtained in stage 8 of Example 1 in 500 μL of THF are added at room temperature 2 mL (29 equivalents) of a 2 M dimethylamine solution in THF. The reaction medium is then stirred for 2 hours before being dry evaporated. The obtained white solid is taken up in 10 mL of ethyl acetate. The resulting organic phase is washed several times with water and then with a saturated NaCl solution, dried on sodium sulphate, dry evaporated. The raw product is chromatographed on silica gel (dichloromethane/methanol:98/2) in order to provide 45 mg of the expected compound as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][N:12]3[C:16](=[O:17])[CH2:15][CH2:14][C:13]3=[O:18])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][N:12]3[C:16](=[O:17])[CH2:15][CH2:14][C:13]3=[O:18])[N:10]=2)[CH2:3]1)(=[O:22])=[O:21]
Reactant: O=C1CCC(=O)N1Cc1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(CN3C(=O)CCC3=O)cs2)C1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 3-hydroxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (459 mg, 1.72 mmol) (obtained as described in Reference Example 69(2)) in methylene chloride (50 ml) were added methanesulfonyl chloride (0.16 ml, 2.06 mmol) and triethylamine (0.29 ml, 2.06 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-methanesulfonyloxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (515 mg, yield 87%) as a pale yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:8][C:7]=1[CH3:23])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[NH4+].[Cl-]>O1CCCC1>[CH3:23][C:7]1[N:8]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)[O:10][C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1oc(CCc2ccc(C(F)(F)F)cc2)nc1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
9.70 g 4-Methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazole-5-carboxylic acid ethyl ester were dissolved in 20 ml tetrahydrofuran and added to a ice cooled solution of 1.13 g lithium aluminium hydride in 10 ml tetrahydrofuran. The reaction mixture was stirred at 0° C. for one hour. Then 100 ml ethyl acetate and 50 ml saturated NH4Cl solution were added. The precipitate was filtered off through a celite pad and washed with ethyl acetate. The organic layer of the filtrate was separated. The aqueous layer of the filtrate was extracted two times with portions of 100 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was removed in vacuo and the residue purified by chromatography on silica gel with the eluent petroleum benzene:ethyl acetate=1:1 to obtain to 4.20 g {4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazol-5-yl}-methanol a yellow solid.
Reaction SMILES: NC1C=CC(C(O)=O)=CC=1.C1(C(Cl)=O)CCCCC1.CCN(CC)CC.[OH-].[Na+].[CH:29]1([C:35]([NH:37][C:38]2[CH:47]=[CH:46][C:41]([C:42]([O:44]C)=[O:43])=[CH:40][CH:39]=2)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[CH:29]1([C:35]([NH:37][C:38]2[CH:47]=[CH:46][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COC(=O)c1ccc(NC(=O)C2CCCCC2)cc1
Agent: Nc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C1CCCCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(NC(=O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 4-aminobenzoic acid 48a (1.98 mmol, 300 mg), cyclohexanecarbonyl chloride 48b (1.98 mmol, 291 mg), and Et3N (2.52 mmol, 0.43 mL) in 6 mL of THF was stirred at room temperature overnight. 1N aqueous NaOH (7.9 mmol, 7.9 mL) was added to the mixture (containing methyl 4-(cyclohexanecarboxamido)benzoate 48c) and the reaction mixture was stirred for 5 h at room temperature. The THF was removed by rotary evaporation and 1N aqueous HCl was added to precipitate the product, which was filtered to give 480 mg (92%) of 48d.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[CH2:14][OH:15])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[CH2:14][OH:15])[CH3:2]
Reactant: CCOc1ccc(C(=O)OC)cc1CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1ccc(C(=O)O)cc1CO
Temperature: 50 °C
Yield: 49.6 %

Procedure:
To a solution of methyl 4-ethoxy-3-(hydroxymethyl)benzoate (1.6 g, 7.61 mmol) in dioxane (10 mL) was added NaOH (6.0 g, 37.5 mmol) and the reaction mixture was heated at 50° C. for 2 hours. The reaction mixture was concentrated in vacuo to half-volume, acidified to pH 2 with aq. 6N HCl solution. The resulting suspension was filtered, the solid rinsed with water and acetonitrile, then dried in vacuo to give 4-ethoxy-3-(hydroxymethyl)benzoic acid (740 mg, 50%) as a white solid. 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 8.00 (s, 1H), 7.81 (dd, J=8.5, 2.2 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 5.13 (t, J=5.7 Hz, 1H), 4.50 (d, J=5.2 Hz, 2H), 4.11 (q, J=7.0 Hz, 2H), 1.34 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[NH2:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16]>O>[C:1]([NH:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)O

Procedure:
Benzoyl chloride (4.22 g, 0.030 mol) and 10% NaOH (12 ml, 0.030 mol) were added separately with vigorous stirring to a solution of L-leucine (3.94 g, 0.030 mol) in 150 ml of distilled water at ice bath temperature. The reaction was allowed to proceed at this temperature until the reaction mixture became clear (30 minutes); it was then extracted with ethyl acetate (2×100 ml). The aqueous layer was separated, acidified to pH 2 with 10% HCl, and extracted with ethyl acetate (3×50 ml). The ethyl acetate extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated in vacuo to yield quantitative amount of N-benzoyl-L-leucine as a semi-solid which was used directly for the following step.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[OH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29]1)=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:1]1[CH2:3][C@H:2]1[CH2:4][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29]1)=[O:27]
Reactant: O=C(Cc1ccccc1O)N1CC[C@H](O)C1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1OC[C@@H]1CO1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
A mixture of (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (228 mg, 0.88 mmol), (3S)-1-[(2-hydroxyphenyl)acetyl]pyrrolidin-3-ol (196 mg, 0.88 mmol) and Cs2CO3 (344 mg, 1.05 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography/(0-3% methanol in dichloromethane) to give the subtitled compound (35 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:9]=[C:8]([SH:10])[C:7]([CH3:11])=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][C:18]=1Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:2][C:3]1[CH:9]=[C:8]([S:10][C:18]2[CH:17]=[CH:16][C:15]([C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=2[Cl:12])[C:7]([CH3:11])=[CH:6][C:4]=1[NH2:5]
Reactant: Cc1cc(N)c(F)cc1S
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N)c(F)cc1Sc1ccc(C(F)(F)F)cc1Cl
Reaction time: 6 h
Yield: 73 %

Procedure:
1.00 Gram of 2-fluoro-5-methyl-4-mercaptoaniline hydrochloride, 2.24 g of 3,4-dichlorobenzotrifluoride and 1.59 g of potassium carbonate were dissolved in 10 ml of dimethylformamide, and the resulting solution was stirred for 6 hours at a temperature of from 110° to 120° C. in an oil bath. Thereafter, the reaction solution was poured into water and extracted with two 100-ml portions of diethyl ether. The extract obtained was washed with water, dried, filtered and concentrated. The residue obtained was subjected to chromatography on silica gel to obtain 1.27 g of 2-fluoro-5-methyl-4-[2-chloro-4-(trifluoromethyl)phenylthio]aniline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:18][CH:19]([CH:27]=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:8][C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:30][NH2:31].C1COCC1>ClCCl>[C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:18][CH:19]([CH2:27][NH:31][CH3:30])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:8][C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)C(C=O)C[C@H](NC(=O)Oc1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCC(C[C@H](NC(=O)Oc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 78 %

Procedure:
A stirred solution of 40 (6.1 g, 14.9 mmol) in dichloromethane (50 mL) was treated with 2 N methylamine-THF solution (10 mL) at 0° C. overnight. After removal of solvents, the residual oil was dissolved in methanol (80 mL) and placed in an ice-bath. To the above solution was added sodium borohydride in small portions over 30 min. The reaction solution was kept at 0° C. for 1 hour, and solvent was then evaporated. The residue was worked up with brine and dichloromethane. After separation, the organic phase was dried over anhydrous MgSO4, rotary evaporated and dried in vacuum. The crude amine 41 (5.4 g, 78%) was obtained as a light yellow glassy solid.
Reaction SMILES: [C:1](OC)#[N:2].N1C2C(=CC=CC=2)CC1.[C:14]([N:17]1[C:25]2[C:20](=[C:21]([CH3:36])[C:22]([CH2:34]Cl)=[C:23]([CH3:33])[C:24]=2[NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19][CH2:18]1)(=[O:16])[CH3:15].[C-]#N.[Na+]>CC#N.C1OCCOCCOCCOCCOCCOC1>[C:14]([N:17]1[C:25]2[C:20](=[C:21]([CH3:36])[C:22]([CH2:34][C:1]#[N:2])=[C:23]([CH3:33])[C:24]=2[NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCc2c(C)c(CCl)c(C)c(NC(=O)C(C)(C)C)c21
Reactant: COC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N1CCc2c(C)c(CC#N)c(C)c(NC(=O)C(C)(C)C)c21

Procedure:
1.27 (9H, S, C(CH3)3), 2.25 (3H, s, -CH3), 2.30 (6H, s, -CH3, >NCOCH3), 3.00 (2H, br, Indoline C3—H), 4.05 (2H, br, Indoline C2—H), 4.68 (2H, s, -CH2c l), 9.16 (1H, br, >NH). (3) N-(1-Acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (21 g) was suspended in CH3CN (150 ml), and NaCN (8.1 g) and 18-crown-6 (870 mg) were added, which was followed by refluxing for 15 hr. CH3CN was evaporated under reduced pressure and CHCl3 (300 ml) was added. The mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The obtained residue was washed with boiling MeOH to give 15.5 g of N-(1-acetyl-5-cyanomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:18]=[N:17][C:6]2[NH:7][C:8](=[O:16])[CH2:9][N:10]([CH2:12][C:13]([OH:15])=O)[CH2:11][C:5]=2[CH:4]=1.C(N(C(C)C)C(C)C)C.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Br:2][C:3]1[CH:18]=[N:17][C:6]2[NH:7][C:8](=[O:16])[CH2:9][N:10]([CH2:12][C:13]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[O:15])[CH2:11][C:5]=2[CH:4]=1
Reactant: O=C(O)CN1CC(=O)Nc2ncc(Br)cc2C1
Reactant: CN1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)CN2CC(=O)Nc3ncc(Br)cc3C2)CC1
Reaction time: 8 h
Yield: 83.5 %

Procedure:
A suspension of (7-bromo-2-oxo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-4-yl)acetic acid hydrochloride (1.66 g, 4.45 mmol) in CH2Cl2 (50 mL) was treated sequentially with (i-Pr)2EtN (3.1 mL, 18 mmol), N-methyl piperazine (0.54 mL, 4.87 mmol), HOBt (0.66 g, 4.88 mmol), and EDC (0.95 g, 4.96 mmol). After stirring overnight, the mixture was diluted with CH2Cl2 (100 mL) and then washed with H2O (100 mL). The aqueous layer was extracted with CH2Cl2 (4×100 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3 to 95:5) gave the title compound (1.42 g, 83%) as an off-white solid: MS (ESI) m/e 382 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)[CH:12]([CH3:14])[CH3:13]>>[Cl:10][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:21]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: CC(C)COc1cccc(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: CC(C)COc1cccc(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 68.8 %

Procedure:
The title compound (0.180 g) was prepared from 4-bromo-2-chloro-6-fluoroaniline (0.2 g, 0.89 mmol) and 3-isobutoxyphenylboronic acid (0.224 g, 1.16 mmol) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.44-7.41 (m, 2H), 7.27 (t, J 7.9, 1H), 7.17-7.10 (m, 2H), 6.84-6.81 (m, 1H), 5.50 (s, 2H), 3.83 (d, J 6.5, 2H), 2.07-1.97 (m, 1H), 1.00 (d, J 6.7, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12](Cl)=[N:13][OH:14].[Cl:16][C:17]1[CH:18]=[C:19]([C:23]#[C:24][C:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:26])[CH:20]=[CH:21][CH:22]=1.N1C=CC=C(C=O)C=1.I(C1C=CC=CC=1C(O)=O)=O.C(=O)(O)[O-].[Na+].[Cl-]>C(O)(C)C.CCOCC>[Cl:16][C:17]1[CH:18]=[C:19]([C:23]2[O:14][N:13]=[C:12]([C:3]3[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=3[F:1])[C:24]=2[C:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:26])[CH:20]=[CH:21][CH:22]=1
Reactant: ON=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: O=C(C#Cc1cccc(Cl)c1)c1cccnc1
Agent: O=C([O-])O
Agent: O=Cc1cccnc1
Agent: O=Ic1ccccc1C(=O)O
Solvent: CCOCC
Solvent: CC(C)O
Product: O=C(c1cccnc1)c1c(-c2cc(C(F)(F)F)ccc2F)noc1-c1cccc(Cl)c1
Temperature: 55 °C
Yield: 61.9 %

Procedure:
A mixture of 60 mg (0.25 mmol) of 2-fluoro-5-trifluoromethyl-N-hydroxybenzenecarbox-imidoyl chloride, 50 mg (0.21 mmol) of 3-(3-chlorophenyl) 1-(3-pyridyl)-2-propyn-1-one (prepared similarly to procedures noted above from lithio 3-chlorophenylacetylide and 3-pyridinecarboxaldehyde, followed by IBX oxidation), and 26 mg (0.36 mmol) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. overnight with shaking. An additional 30 mg of carboximidoyl chloride and 15 mg of sodium bicarbonate were added, and the reaction was heated for another 24 hrs. The mixture was cooled and diluted with ether. The ether fraction was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation. The residue was purified by prepTLC to give 56 mg (0.13 mmol) of 5-(3-chlorophenyl)-3-(2-fluoro-5-trifluoromethylphenyl)-4-[(3-pyridyl)carbonyl]isoxazole. 1H NMR (CDCl3): δ 7.10 (t, 1), 7.41 (m, 1), 7.52 (m, 1), 8.65 (br s, 1), and 8.86 ppm (br s, 1). MS m/z: 447.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([NH:12][C:13]2[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21](O)=[O:22])=[N:17][CH:18]=2)[CH2:7]1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([NH:12][C:13]2[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([NH:34][O:33][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][O:27]3)=[O:22])=[N:17][CH:18]=2)[CH2:7]1
Reactant: O=C(O)/C=C/c1cnc(N[C@@H]2CCCN(Cc3cccc(Cl)c3)C2)cn1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cnc(N[C@@H]2CCCN(Cc3cccc(Cl)c3)C2)cn1)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A mixture of (2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylic acid (218 mg, 0.59 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (82 mg, 0.70 mmol), HOBt (103 mg, 0.76 mmol) and EDCI (146 mg, 0.76 mmol) in DMF (6 mL) was stirred at 0° C. for 1 hr and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=95-5) to give (2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (251 mg, 91%) as an amorphous powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[N:11]([C:12]4[C@H:13]5[CH2:22][C@@H:16]([C:17]=4[CH:18]=3)[CH2:15][CH2:14]5)[CH2:10][CH2:9]2)[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:57][O:56][CH2:55]4)[CH2:50][C@@H:49]3[CH3:58])=[CH:44][N:43]=2)[C:27]1=[O:59].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].O.C(#N)C>[CH3:25][N:26]1[C:27](=[O:59])[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:55][O:56][CH2:57]4)[CH2:50][C@@H:49]3[CH3:58])=[CH:44][N:43]=2)=[CH:29][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[N:11]([C:12]5[C@H:13]6[CH2:22][C@@H:16]([C:17]=5[CH:18]=4)[CH2:15][CH2:14]6)[CH2:10][CH2:9]3)[C:3]=2[CH:23]=[O:24])=[CH:31]1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2[C@@H]2CC[C@H]3C2)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5[C@@H]5CC[C@H]6C5)C4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 43.6 %

Procedure:
A round-bottomed flask was charged with 4-chloro-2-[(1R,11S)-7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl]pyridine-3-carbaldehyde 170b (200 mg, 0.59 mmol), 1-methyl-3-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one 191j (400 mg, 0.88 mmol), PdCl2(dppf) (50 mg, 0.06 mmol), K3PO4 3 water (300 mg, 1.20 mmol), sodium acetate (100 mg, 1.20 mmol), acetonitrile (15 mL), and water (1.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified with silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 174a as a red solid (170 mg, 44%). MS-ESI: [M+H]+ 661.3