Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:36])=[C:25]([CH:27]=[N:28][C:29]([O:31][Si](C)(C)C)=[CH2:30])[CH:26]=1>C1(C)C=CC=CC=1>[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[CH2:30][C:29](=[O:31])[NH:28][CH:27]([C:25]3[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[CH3:36])[C:6]32[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][C:7]3=[O:11])[CH:18]=[CH:17][CH:16]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: O=C1Nc2cc(F)ccc2/C1=C/c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(F)ccc12

Procedure:
In a manner similar to the method described in example 1c, E/Z-6-fluoro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 167b was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a, in toluene to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.1 g). The racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione was separated by chiral column chromatography to give the titled compounds as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[N:21]1[C:30]2[C:25](=[CH:26][C:27]([C:31](O)=[O:32])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:31]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:21]=[CH:22][CH:23]=[N:24]3)=[O:32])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc2nccnc2c1
Agent: Cl
Product: O=C(CNC(=O)c1ccc2nccnc2c1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and quinoxaline-6-carboxylic acid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]=[C:20]([C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[N:52]1([C:58]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])=[O:59])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CN(C=O)C.O>[O:29]=[C:27]([N:55]1[CH2:56][CH2:57][N:52]([C:58](=[O:59])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:67])[F:68])[CH2:53][CH2:54]1)[CH2:26][NH:25][C:23]([C:20]1[CH:19]=[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH3:10])[NH:22][N:21]=1)=[O:24]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: COc1ccccc1-c1cc(C(=O)NCC(=O)O)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1cc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)n[nH]1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 37 %

Procedure:
DIPEA (99 mg, 0.13 mL, 0.76 mmol) was added to a stirred solution of {[5-(2-methoxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (60 mg, 0.21 mmol) in DMF (2 mL). HOBT (34 mg, 0.25 mmol) and EDCI (49 mg, 0.25 mmol) were then added at room temperature. After 2 minutes, piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride salt (64.3 mg, 0.21 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated to afford 40 mg (35.7% yield) of 5-(2-methoxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 97.45%. 1H NMR (DMSO-d6): δ 13.5 (s, 1H), 8.0 (m, 1H), 7.62 (m, 4H), 7.5 (m, 1H), 7.3 (m, 1H), 7.16 (m, 1H), 7.01 (m, 2H), 4.1 (d, 2H), 3.84 (s, 3H), 3.6 (m, 2H), 3.56 (m, 2H), 3.36 (m, 2H), 3.1 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25](O)=[O:26])([O-])=O.CCOC(C)=O.O>CN(C=O)C>[NH2:15][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([NH:14][CH2:13][CH:10]1[CH2:9][CH2:8][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:12][CH2:11]1)=[O:26]
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccccc1CC(=O)NCC1CCN(c2ccncc2)CC1
Reaction time: 2.5 h
Yield: 59.8 %

Procedure:
A solution of 1-(4-pyridyl)piperidine-4-methylamine (156 mg, 0.817 mmol), 2-nitrophenylacetic acid (159 mg, 0.875 mmol), and 1-[3-(dimethylaminopropyl]-3-ethylcarbodiimide hydrochloride (168 mg, 0.875 mmol) in DMF was stirred 16 h; and the mixture was poured into EtOAc and H2O. The aqueous layer was washed with EtOAc (2×) and the combined extracts were dried (K2CO3) and concentrated. The under an atmosphere of hydrogen gas. After 2.5 h, the mixture was filtered and the filtrate concentrated. The residue was dissolved in 5% HOAc in MeOH and loaded onto a SCX Column (Varian). The column was eluted with MeOH followed by 2 M NH3 in MeOH. The latter fractions were concentrated yielding 158.6 mg (60%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][CH2:25][C:26]([NH:28][CH3:29])=[O:27].C(N(C(C)C)CC)(C)C>C(#N)C.Cl.C(OCC)(=O)C>[ClH:24].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][N:17]([CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccc(CCNCc3ccco3)c2)cc1
Reactant: CNC(=O)CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CNC(=O)CN(CCc1cccc(OCc2ccccc2)c1)Cc1ccco1
Yield: 65.4 %

Procedure:
A solution of 3.0 g (9.8 mmol) of [2-(3-benzyloxy-phenyl)-ethyl]-(furan-2-ylmethyl)amine, 15.0 g (10.7 mmol) of 2-chloro-N-methyl-acetamide and 1.87 ml (10.7 mmol) of diisopropylethylamine in 50 ml of acetonitrile was stirred under reflux for 24 hours. The solvent was removed under reduced pressure and the crude reaction mixture was purified by flash chromatography (ethyl acetate/hexane 1:1 v:v). The product isolated was dissolved in anhydrous hydrochloric acid in ethyl acetate. The solvent was removed under vacuum and the residue was triturated with diethyl ether. 2.66 g (65% yield) of the title compound were isolated as a hygroscopic solid.
Reaction SMILES: ClC(OCC)=O.CC[N:9](CC)CC.[OH:14][B:15]1[C:19]2[C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]([CH2:31][N+:32]([O-:34])=[O:33])[O:16]1.[NH4+].[OH-]>C1COCC1>[OH:14][B:15]1[C:19]2[C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28]([NH2:9])=[O:29])=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]([CH2:31][N+:32]([O-:34])=[O:33])[O:16]1
Reactant: O=C(O)CCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Ethyl chloroformate (80 μL, 0.83 mmol) was added dropwise to a solution of Et3N (0.35 mL, 4.7 mmol) and 4-(1-hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid (111 mg, 0.38 mmol) in THF (4 mL) at 0° C. (bath temp). The mixture was stirred at 0° C. (bath temp) for 15 min and then 28% NH4OH (0.5 mL) was added dropwise at 0° C. (bath temp). The mixture was allowed to warm to rt over 20 min. The precipitate was isolated by filtration and washed with THF and H2O to give the title compound as a light yellow solid: yield 52 mg (45%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:24][CH:25]([F:27])[F:26])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[Cl:28]CCl>CN(C=O)C.Cl[Cu]>[Cl:28][C:2]1[CH:3]=[C:4]([O:24][CH:25]([F:27])[F:26])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: O=C1c2c(I)cc(OC(F)F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: ClCCl
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cc(OC(F)F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
A solution of the 7-iodo-5-difluoromethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindolone (0.082 g, 0.16 mmol) in DMF (5 mL) was treated with CuCl (0.064 g, 0.65 mmol) and stirred at 140° C. for 1-2 h. After this time, the reaction mixture was diluted with dichloromethane (15 mL) and the solids removed by filtration. The filtrate was concentrated. Silica gel column chromatography using, typically 30% ethyl acetate in hexane, afforded 7-Chloro-2-(4-trifluoromethoxy-benzyl)-5-difluoromethoxy-2,3-dihydro-isoindolone (0.02 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.08 (s, 2H), 4.58 (s, 2H), 6.37 (t, 1H), 6.87 (s, 1H), 7.01 (m, 3H), 7.17 (d, 2H). GC-MS: m/z 407 (M)+, 322 (M−85)+.
Reaction SMILES: [CH3:1][S-:2].[Na+].CC(N(C)C)=O.[Br:10][C:11]1[C:12]([CH3:25])=[C:13]([CH3:24])[C:14]2[O:18][C:17]([CH2:20]I)([CH3:19])[CH2:16][C:15]=2[C:22]=1[CH3:23].O>C(OCC)(=O)C>[Br:10][C:11]1[C:12]([CH3:25])=[C:13]([CH3:24])[C:14]2[O:18][C:17]([CH3:19])([CH2:20][S:2][CH3:1])[CH2:16][C:15]=2[C:22]=1[CH3:23]
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CI)O2
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSCC1(C)Cc2c(C)c(Br)c(C)c(C)c2O1
Temperature: 140 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
Sodium thiomethoxide (213 mg, 3.03 mmol) was added to a solution of DMA (3 mL) containing 5-bromo-2-(iodomethyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (270 mg, 0.683 mmol) synthesized in Reference Example 133, and the mixture was stirred at 140° C. for 4 hours. The reaction solution was cooled to room temperature, and water and ethyl acetate were added thereto to separate an organic layer. The organic layer was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 100:0-90:10) to give 130 mg of the title compound (yield: 68%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][CH2:21][NH2:22]>CCO>[N+:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:22][CH2:21][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH3:14])([O-:13])=[O:12]
Reactant: CN1CCCC1CCN
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: CN1CCCC1CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
Chloro-2,4-dinitrobenzene 1 (1.00 g, 4.937 mmol) was dissolved in anhydrous EtOH (20 mL) in a small argon purged flask and warmed in an oil bath to 40° C. Addition of 2-(1-methylpyrrolidin-2-yl)ethanamine 30 (0.696 g, 5.431 mmol) occurred dropwise. The reaction was stirred at 65-70° C. for 24 hours. After cooling to room temperature the solvent was removed under reduced pressure and the resulting residue partitioned between H2O and ethyl acetate and 1M ammonium hydroxide solution added to adjust pH to 10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with H2O, brine (twice), dried over magnesium sulphate, filtered and then concentrated. Recrystallization of the crude solid from EtOH yielded a yellow powder 31 (2,4-Dinitro-phenyl)-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine Yield: 0.979 grams (67.4%). 1H NMR (DMSO) 8-1.51-1.71 (m, 3H), 1.78-1.96 (2×m, 3H), 2.06-2.14 (m, 1H), 2.26 (s, 3H), 2.26-2.36 (m, 1H), 2.93-3.03 (m, 1H), 3.48-3.53 (m, 2H), 7.18 (d, 1H, J=9.6), 8.27 (dd, 1H, J=9.7, 2.7), 8.86 (d, 1H, J=2.8), 9.50 (br s, 1H); MS (ESI): 295 (MH+, 100%)
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([C:21]([O:23]C)=[O:22])=[CH:16][N:15]=2)=[N:6]1.[OH-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([C:21]([OH:23])=[O:22])=[CH:16][N:15]=2)=[N:6]1
Reactant: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
830 mg (2.20 mmol) of the compound from example 44A were initially charged in tetrahydrofuran (10 ml), 4.40 ml (4.40 mmol) of aqueous lithium hydroxide solution (1.0 M) were added and the suspension was stirred at RT for 90 min Subsequently, the now clear solution was concentrated and the residue was partitioned between ethyl acetate and water. The aqueous phase was adjusted to pH<7 with 1M hydrochloric acid, and a solid precipitated out. This was filtered off, washed with water and tert-butyl methyl ether, and dried under high vacuum. This gave 710 mg (89% of theory) of the title compound in solid form.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:8]2[C:7]([CH3:11])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=2)=[CH:15][C:14]=1[C:20]([F:21])([F:22])[F:23]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1cc(C=O)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(C=O)c(F)cc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 48.8 %

Procedure:
To a solution of 2,4-difluoro-5-methylbenzaldehyde (100 mg, 0.64 mmol) and 4-chloro-3-trifluoromethylphenol (126 mg, 0.64 mmol) in DMSO was added potassium carbonate. The reaction was stirred at room temperature for 36 hours. The reaction was diluted with ethyl acetate (30 mL) and washed with water (2×50 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with acetonitrile:water (plus 0.1% aqueous formic acid) 5:95 to 100:0 to furnish the title compound as a white solid 104 mg, 49%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH:13][C:14]3[C:15](=[O:30])[N:16]([CH3:29])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[CH:12]=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([N:38]2[CH2:49][CH2:48][C:47]3[C:46]4[CH2:45][C:44]([CH3:51])([CH3:50])[CH2:43][C:42]=4[S:41][C:40]=3[C:39]2=[O:52])[C:33]=1[CH:53]=[O:54].[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].C(#N)C.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH:13][C:14]3[C:15](=[O:30])[N:16]([CH3:29])[CH:17]=[C:18]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([N:38]5[CH2:49][CH2:48][C:47]6[C:46]7[CH2:45][C:44]([CH3:50])([CH3:51])[CH2:43][C:42]=7[S:41][C:40]=6[C:39]5=[O:52])[C:33]=4[CH:53]=[O:54])[CH:19]=3)[CH:12]=[C:6]2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Reactant: CC1(C)Cc2sc3c(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCn2nc(Nc3cc(-c4ccnc(N5CCc6c(sc7c6CC(C)(C)C7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 116.8 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 3-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-amino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 209d (344 mg, 0.83 mmol), 4-chloro-2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}pyridine-3-carbaldehyde 109a (202 mg, 0.56 mmol), Pd(dppf)Cl2 (20 mg, 0.028 mmol), K3PO4 (235 mg, 1.11 mmol), sodium acetate (91 mg, 1.11 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The mixture was cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford 254a (400 mg, crude), which was directly used in next step without further purification. MS-ESI: [M+H]+ 612.3
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][S:5][C:6]1[NH:7][CH:8]=[CH:9][N:10]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][S:5]([C:6]1[NH:10][CH:9]=[CH:8][N:7]=1)=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ccccc1CSc1ncc[nH]1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1ccccc1CS(=O)c1ncc[nH]1
Temperature: 0 °C
Yield: 12.7 %

Procedure:
To a solution of 2.5 g of 2-(2-aminobenzylthio)imidazole in a mixture of 25 ml of chloroform and 10 ml of methanol was dropwise added under stirring and under chilling with ice 2.6 g (12.1 mmol) of m-chloroperbenzoic acid. The mixture was further stirred for 15 min. Thus precipitated crystalline product was collected by filtration, washed twice with water and placed in 40 ml of saturated aqueous sodium hydrogencarbonate. The aqueous mixture was stirred, and then the crystalline product was collected by filtration. The obtained solid product was stirred in a mixture of 30 ml of chloroform and 10 ml of 1N aqueous NaOH. The aqueous portion was taken out and made ammonia-alkaline by addition of 20% aqueous ammonium chloride. The mixture was chilled after addition of sodium chloride, to give a crystalline precipitate. The precipitate was collected by filtration, washed successively with two portions of water and one portion of acetone, and dried under reduced pressure to give 340 mg of the desired compound as a pale brown crystalline powder, yield 12.7%.
Reaction SMILES: [NH:1]([C:3]([NH:5][C:6]1[S:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([CH3:16])[CH:7]=1)=[O:4])[NH2:2].[CH:17](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:16][C:8]1[CH:7]=[C:6]([N:5]2[C:3](=[O:4])[NH:1][N:2]=[CH:17]2)[S:10][C:9]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1sc(NC(=O)NN)cc1C
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(-n2cn[nH]c2=O)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of ethyl 5-(hydrazinecarboxamido)-3-methylthiophene-2-carboxylate (12.80 g, 52.61 mmol), trimethyl orthoformate (6.33 mL, 57.86 mmol) and p-toluenesulfonic acid monohydrate (0.260 g, 1.367 mmol) in ethanol (130 mL) was stirred at reflux for 30 minutes. The reaction mixture was allowed to cool to ambient temperature, and kept at +5° C. for 16 h. The resulting solid was filtered and washed with ethyl acetate. The filtrate was concentrated, and the residue was triturated with ethanol. The combined material was dried to afford the title compound as a cream solid in 70% yield (9.37 g): 1H NMR (300 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.66 (s, 1H), 7.27 (s, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.47 (s, 3H), 1.29 (t, J=7.1 Hz, 3H); MS (ES+) m/z 254.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:15]=2[N:14]=[N:13]1>>[NH:12]1[C:16]2[CH:17]=[CH:18][C:19](/[CH:21]=[C:6]3/[C:7](=[O:11])[NH:8][C:9]4[C:5]/3=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccc2[nH]nnc2c1
Product: O=C1Nc2cc(Cl)ccc2/C1=C\c1ccc2[nH]nnc2c1

Procedure:
The title compound was synthesized according to the method described for Example A1 except reacting 6-chlorooxindole (36 mg, 0.216 mmol) with 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (35 mg, 0.238 mmol) to obtain 32 mg, 51%. 1H NMR (400 MHz, d6-DMSO) δ 15.95 (s, 1H), 10.81 (s, 1H), 8.27 (bs, 1H), 8.04 (bs, 1H), 7.85 (s, 1H), 7.76 (bs, 1H), 7.49 (d, J=8.8 Hz, 1H), 6.91 (bs, 2H); MS ESI 297.0 [M+H]+, calcd for [C15H9ClN4O+H]+ 297.05.
Reaction SMILES: F[C:2]1[C:3]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([CH3:15])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>ClCCl>[CH3:15][C:10]1[C:11]([CH:13]=[O:14])=[CH:12][N:8]([C:3]2[C:2]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: Cc1nn(-c2ncccc2F)cc1C=O
Reactant: C1COCCN1
Solvent: ClCCl
Product: Cc1nn(-c2ncccc2N2CCOCC2)cc1C=O
Temperature: 160 °C
Yield: 72 %

Procedure:
A mixture of 1-(3-fluoro-2-pyridyl)-3-methyl-pyrazole-4-carbaldehyde (230 mg, 1.12 mmol) and morpholine (2 mL, 22.93 mmol) is heated under microwave irradiation (temperature 160° C., ramp time: 2 min, hold time: 10 min, potency: 250 W). The excess of morpholine is eliminated in vacuo and the residue is diluted in dichloromethane and washed in saturated aqueous solution of sodium bicarbonate. The organic layer is separated, dried over magnesium sulfate and the solvent evaporated in vacuo. The residue is purified by normal phase Isco chromatography using hexane/ethyl acetate as eluent (from 50 to 100% in ethyl acetate) to yield 72% of the title compound. MS (m/z): 273 (M+1).
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][CH:20]3[O:24]C(=O)[N:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21]3)[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3.C1COCC1>O>[Br:18][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:19][CH:20]([OH:24])[CH2:21][NH:22][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:8]3[C:16]([C:15]=2[CH:14]=1)=[CH:17][C:5]([Br:4])=[CH:6][CH:7]=3
Reactant: O=C1OC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CN1c1ccccn1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: OC(CNc1ccccn1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 168 h
Yield: 82.1 %

Procedure:
LiOH.H2O (0.0076 g, 0.182 mmol, 10 equiv) was added to 5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(pyridin-2-yl)oxazolidin-2-one (0.0091 g, 0.0182 mmol) in a mixture of 208 μL, THF and 23 μL, H2O (v/v=9:1). The mixture was stirred at room temperature for 7 days. The reaction mixture was purified by silica gel chromatography using CH2Cl2/EtOAc as elute to afford 0.0071 g white solid as product, yield 41.0%.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[CH:4][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C(OCC)C.O>[CH2:15]([NH:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:22])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCCCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A solution of hexanoic acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide (740 mg, 2.46 mmole) in 20 mL diethyl ether (ether) was treated with 400 mg of lithium aluminium hydride (LAH) and the mixture was heated to reflux for 90 minutes. After cooling to 0° C., 0.4 mL of water, 0.4 mL of 15% aqueous sodium hydroxide solution and 1.2 mL of water were successively added and the reaction mixture was stirred at room temperature for 30 minutes. MgSO4 was added and the mixture was filtered and concentrated in vacuo to provide a pale yellow oil. The product was purified by flash chromatography SiO2, 5% ethyl acetate/hexanes) to yield 635 mg (81%) of hexyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (17) as a colorless oil.