Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1COCC1.C([Li])CCC.[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([Cl:23])[N:16]=1)([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[C:11]([C:15]1[N:16]=[C:17]([Cl:23])[C:18]([CH:19]=[CH2:1])=[CH:21][CH:22]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1ccc(C=O)c(Cl)n1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=Cc1ccc(C(C)(C)C)nc1Cl
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a diethyl ether (17 ml) solution of 6-tert-butyl-2-chloronicotinonitrile (Tetrahedron 1965, 21, 2453-2467, 1.0 g, 5.4 mmol) was added 0.94 M diisobutylaluminum hydride in toluene solution (8.6 ml, 8.0 mmol) at −78° C. and the reaction was allowed to warm to room temperature over 2 hours with stirring. Then the reaction was quenched with 10% potassium sodium tartrate tetrahydrate aqueous solution and the whole was extracted with EtOAc, and washed with 2M sodium hydroxide aqueous solution and brine. The organic layer was evaporated and purified by silica gel column chromatography, eluting with hexane/EtOAc (5:1), to give 6-tert-butyl-2-chloronicotinaldehyde (1.0 g, 95%). To a THF (24 ml) suspension of methyltriphenylphosphonium bromide (5.3 g, 14.8 mmol) was added 1.60 M n-butyllithium (9.3 ml, 14.8 mmol) in hexane solution at 0° C. and the reaction was stirred for 30 minutes. Then to this mixture was added a THF (5 ml) solution of the 6-tert-butyl-2-chloronicotinaldehyde (1.0 g, 5.2 mmol) at 0° C., and the reaction was stirred for 2 hours at room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution, and the whole was extracted with EtOAc, and dried over magnesium sulfate. The organic layer was evaporated and purified by silica gel column chromatography, eluting with hexane/EtOAc (10:1), to give the title compound (735 mg, 71%).
Reaction SMILES: [N:1]1([C:6]2[C:11]([F:12])=[CH:10][C:9]([N:13]3[CH2:17][C@H:16]([C:18]([O:20]C)=O)[O:15][C:14]3=[O:22])=[CH:8][C:7]=2[F:23])[CH2:5][CH:4]=[CH:3][CH2:2]1.[NH3:24]>CO>[N:1]1([C:6]2[C:11]([F:12])=[CH:10][C:9]([N:13]3[CH2:17][C@H:16]([C:18]([NH2:24])=[O:20])[O:15][C:14]3=[O:22])=[CH:8][C:7]=2[F:23])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: COC(=O)[C@H]1CN(c2cc(F)c(N3CC=CC3)c(F)c2)C(=O)O1
Reactant: N
Solvent: CO
Product: NC(=O)[C@H]1CN(c2cc(F)c(N3CC=CC3)c(F)c2)C(=O)O1
Yield: 58 %

Procedure:
A solution of methyl (5R)-3-[4-(2,5-dihydro-1H-pyrrol-1-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidine-5-carboxylate (Step 4, 0.09 g, 0.28 mmol) in 2.0M ammonia in MeOH (2.8 mL) is heated to 55° C. for 4 h. The reaction mixture is cooled, concentrated and the residue purified by pTLC (5% MeOH/CH2Cl2) to give the title compound (50 mg, 58%); MS for C14H13F2N3O3MS m/z 310.5 (M+H)+; 1H NMR (300 MHz, d6-DMSO): δ 3.93-3.98 (m, 1H), 4.17-4.25 (m, 5H), 4.97-5.02 (m, 1H), 5.93 (s, 2H), 7.27 (d, 2H), 7.61 (s, 1H), 7.85 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:15](=[O:16])[N:14]([CH3:17])[C:13]3[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:12]=3[S:11]2(=[O:26])=[O:25])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:22]([C:20]1[CH:19]=[CH:18][C:13]2[N:14]([CH3:17])[C:15](=[O:16])[N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:28][CH:27]=3)[S:11](=[O:25])(=[O:26])[C:12]=2[CH:21]=1)=[O:24])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN1C(=O)N(Cc2ccc(S(C)(=O)=O)cc2)S(=O)(=O)c2cc(C(=O)O)ccc21
Reactant: NCc1ccccc1
Product: CN1C(=O)N(Cc2ccc(S(C)(=O)=O)cc2)S(=O)(=O)c2cc(C(=O)NCc3ccccc3)ccc21

Procedure:
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[1,2,4]thiadiazine-7-carboxylic acid was coupled with benzyl amine according to the procedure of Example 2 to give the title compound. 1H-NMR (CDCl3); δ 8.19 (s, 1H), 8.01 (d, 1H), 7.74 (d, 2H), 7.45 (d, 2H), 7.34 (m, 6H), 6.67 (bs, 1H), 4.62 (t, 2H), 3.76 (bs, 2H), 3.22 (s, 3H) and 2.98 (s, 3H) ppm. Anal. (C24H23N3O6S2.0.5C4H10O.0.66H2O) C,H,N. MS: M++1=514.1 Da
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH3:44][S:45](Cl)(=[O:47])=[O:46].N1C=CC=CC=1.Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:38]=[CH:39][C:40]([NH:43][S:45]([CH3:44])(=[O:47])=[O:46])=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(NS(C)(=O)=O)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 108.7 %

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene (126 mg) obtained in Example 197-(1) was dissolved in dichloromethane (3 ml) and added thereto were methanesulfonyl chloride (48 mg) and pyridine (48 mg). The mixture was stirred at room temperature for 3.5 hours. To the mixture was added 2N hydrochloric acid aqueous solution at 0° C. and extracted with ethyl acetate. The organic layer was washed with water, aqueous sodium hydrogen carbonate solution and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-1:2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylsulfonylaminophenyl)-2-thienylmethyl)benzene (154 mg) as yellow caramel. ESI-Mass m/Z 706/708 (M−H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[N:3]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[C:4]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(-c2ccsc2)[nH]c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(-c2ccsc2)n(S(=O)(=O)c2ccccc2)c1C
Yield: 40 %

Procedure:
Using ethyl 2-methyl-5-(3-thienyl)-1H-pyrrole-3-carboxylate (1.25 g), sodium hydride (60% in oil, 255 mg) and benzenesulfonyl chloride (1.22 mL), a procedure as in Reference Example 4 was performed to give the title compound as white crystals (yield 0.80 g, 40%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[O:16][CH2:15][C:14](=O)[N:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:12]1)(C(C)(C)C)(C)C>O1CCCC1>[Cl:25][C:20]1[CH:19]=[C:18]([N:13]2[CH2:14][CH2:15][O:16][C@H:11]([CH2:10][CH2:9][OH:8])[CH2:12]2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CN(c2ccc(Cl)c(Cl)c2)C(=O)CO1
Solvent: C1CCOC1
Product: OCC[C@@H]1CN(c2ccc(Cl)c(Cl)c2)CCO1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
580 mg (1.43 mmole) of 2-[(2R)-(3,4-dichlorophenyl)-5-oxomorpholin-2-yl]ethanol t-butyldimethylsilyl ether [prepared as described in step (b) above] were dissolved in 6 ml of anhydrous tetrahydrofuran. The solution was then heated under reflux under a stream of nitrogen and 0.60 ml (6.0 mmole) of a 10 M boranedimethyl sulfide complex was added dropwise. The mixture was then stirred for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and 5 ml of 1 N aqueous hydrochloric acid were added. The mixture was then stirred at 100° C. for 1 hour. The reaction mixture was air-cooled, made basic by the addition of a 1 N aqueous solution of sodium hydroxide, diluted with a saturated aqueous solution of sodium chloride and then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of methylene chloride and methanol ranging from 9:1 to 17:3 by volume as the eluent, to obtain 360 mg of the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]([C:10]1[S:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:9])[CH3:6]>>[CH2:5]([O:7][C:8]([C:10]1[S:11][C:12]([Cl:15])=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=1)=[O:9])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(Cl)s1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A solution of fuming nitric acid (75 mL) was cooled to 10° C. followed by the addition of 5-chloro-thiophene-2-carboxylic acid ethyl ester (15 g, 78.7 mmol). The resulting mixture was stirred for 30 minutes at 10° C. followed by the addition of ice water. The solution was then extracted with ethyl acetate and dried, then concentrated under vacuum and purified by column chromatography using silica gel to provide 10.29 g (55%) of the title product.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:2]1.[CH3:12][C:13]([NH2:24])([CH3:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:2][NH:24][C:13]([CH3:23])([CH3:12])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: C=CCCCCCCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: C=CCCCCCCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 24 %

Procedure:
Using the method of Example 5, supra, 1,2-epoxy-9-decene (202 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)-ethylamine (197 mg, 1.1 mmol) were used to prepare 80 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 334 (M+1, 0.02), 318 (0.7), 212 (100), 194 (13), 163 (11), 121 (23); 1H-NMR (CDCl3) δ 7.06 (2H, d, J=8.6), 6.80 (2H, d, J=8.6), 5.79 (1H, dddd, J=23.1, 10.2, 6.6 and 6.6), 4.95 (2H, m), 3.77 (3H, s), 3.52 (1H, m), 2.76 (1H, dd, J=11.7 and 3.0), 2.64 (1H, s), 2.39 (1H, dd, J=11.6 and 9.4), 2.03 (2H, m), 1.33 (10H, m), 1.05 (6H, s): 13C-NMR (CDCl3) δ 158.1, 139.1, 131.4, 129.8, 114.1, 113.4, 69.8, 55.2, 53.7, 47.8, 46.5, 35.1, 33.8, 29.6, 29.0, 28.8, 26.6, 26.4, 25.7; FT-IR (film) cm−1 3387 (broad, s), 1612, 1512, 1246, 1038, 910, 760.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C:21]4[C:26]5[C:27](=[O:35])[N:28]6[C@H:32]([CH2:33][O:34][C:25]=5[CH:24]=[CH:23][CH:22]=4)[CH2:31][CH2:30][CH2:29]6)[C:17]([C:36]([F:39])([F:38])[F:37])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:42](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH3:42][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C:21]4[C:26]5[C:27](=[O:35])[N:28]6[C@H:32]([CH2:33][O:34][C:25]=5[CH:24]=[CH:23][CH:22]=4)[CH2:31][CH2:30][CH2:29]6)[C:17]([C:36]([F:37])([F:38])[F:39])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)O
Reactant: O=C1c2c(Nc3nc(Nc4ccc(N5CCNCC5)cc4)ncc3C(F)(F)F)cccc2OC[C@@H]2CCCN12
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Nc4cccc5c4C(=O)N4CCC[C@H]4CO5)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.077 mmol) 2-(4-piperazin-1-yl-phenylamino)-4-((S)-4-oxo-2,3,10,10a-tetrahydro-1H.4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino)-5-trifluoromethyl-pyrimidine are dissolved in 0.5 mL dimethylformamide and combined with 12 μL (0.154 mmol) formaldehyde and 2 μL (0.039 mmol) acetic acid. 86 mg (0.385 mmol) of sodium triacetoxyborohydride are metered into this mixture and it is stirred for 16 h at ambient temperature. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which at the starting point consists of 95% water and 5% acetonitrile and at the end point consists of 5% water and 95% acetonitrile. 0.2% Formic acid is added to the two eluants. The suitable fractions are combined with 1 N aqueous hydrochloric acid and freeze-dried.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=4[F:28])[CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=4[F:28])[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Nc1ccc(Oc2ccnc3cc(C4=CCC5(CC4)OCCO5)sc23)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccnc3cc(C4CCC5(CC4)OCCO5)sc23)c(F)c1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
A round-bottomed flask was charged with 4-(2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (Example 161, Step A, 50.0 mg, 0.125 mmol), palladium on carbon (44.6 mg, 0.0376 mmol, 10%) and MeOH (10 mL). The air was exchanged with nitrogen three times and then was exchanged with hydrogen another three times. Then the reaction mixture was stirred under hydrogen at room temperature until the starting material had been consumed (overnight). The mixture was filtrated to remove the palladium on carbon and then the solvent was removed under reduced pressure to afford crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (12.8 mg, 25.5%). LRMS (APCI pos): m/e 401 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.40 (m, 1H), 7.25 (s, 1H), 7.02 (t, 1H), 6.42-6.60 (m, 3H), 4.00 (s, 4H), 3.81 (br s, 2H), 2.89 (m, 1H), 2.14 (m, 2H), 1.90 (m, 4H), 1.72 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7](=[O:12])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[CH:15][N:16]([CH3:18])[CH3:17])[C:7](=[O:12])[NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Br)cc2CN1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)NCc2cc(Br)ccc21
Temperature: 100 °C
Yield: 63.3 %

Procedure:
To a suspension of 7-bromo-1,4-dihydro-2H-isoquinolin-3-one (450 mg, 2 mmol) in 1 mL of N,N-dimethylformamide is added N,N-dimethylformamide dimethylacetal (954 mg, 8 mmol). The reaction mixture is heated in a microwave at 100° C. for 10 min. The reaction mixture is then filtered and washed with N,N-dimethylformamide to give 356 mg of 7-bromo-4-dimethylaminomethylene-1,4-dihydro-2H-isoquinolin-3-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([OH:24])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2CCCN(C(=O)OCc3ccccc3)C2)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a solution of 3-(3-hydroxy-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester (Example 11; 2.08 g, 6.39 mmol) in 15 mL dimethylformamide was added cesium carbonate (4.17 g, 12.78 mmol) and ethyl bromoacetate (1.42 mL, 12.78 mmol). The mixture was heated to 60° C. under N2 with stirring for 3 h and cooled to ambient temperature. The resultant brown suspension was diluted with 300 mL water and extracted with diethyl ether (2×200 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 15% ethyl acetate/hexanes to yield 1.42 g (54%) of the desired 3-(3-ethoxycarbonylmethoxy-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[Cl:9].[N+:10]([O-])([OH:12])=[O:11]>>[Cl:9][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([Cl:8])=[CH:7][C:2]=1[Br:1]
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc(Cl)c(Br)c1
Product: O=[N+]([O-])c1cc(Cl)c(Br)cc1Cl
Temperature: 0 °C

Procedure:
A solution of 2-bromo-1,4-dichlorobenzene (1.000 g, 4.443 mmol, Aldrich, used as received) in fuming HNO3 (7.0 mL) was stirred at 50° C. for 1.5 h and poured into ice (80 g). Yellowish white solid was filtered, washed with water (10 mL), and dried under vacuum to obtain 1.14 g (95%) of pure (1H NMR) title compound as a yellowish white powder; m.p. 50-53° C. (lit m.p. 57-58° C.; Fox, D. L. and Turner, E. E., J. Chem. Soc. 1859 (1930)); 1H NMR (CDCl3): δ 7.863 (s, 1H), 8.030 (s, 1H). This material was used as such for the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36](B(O)O)[CH:37]=1>COCCOC>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([O:41][CH3:42])=[C:34]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:33]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(Cl)cc1-c1ccccc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 37.5 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 5-chloro-2-methoxy-phenylboronic acid (48 mg, 0.26 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (22 mg, 38%). LC-MS m/e 451.31 (M+H+)
Reaction SMILES: [CH:1]12[CH2:7][CH:5]([O:6]1)[CH2:4][N:3]([C:8]1[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:21][CH2:20]3)[CH:9]=1)[CH2:2]2.O.NN>CCO>[CH:5]12[CH2:7][CH:1]([O:6]1)[CH2:2][N:3]([C:8]1[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH:19]3[CH2:20][CH2:21][CH:22]([NH2:25])[CH2:23][CH2:24]3)[CH:9]=1)[CH2:4]2
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(Oc2cc(N3CC4CC(C3)O4)cc3nccnc23)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC1CCC(Oc2cc(N3CC4CC(C3)O4)cc3nccnc23)CC1
Yield: 77.8 %

Procedure:
To a solution of 2-[4-[7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoxalin-5-yl]oxycyclohexyl]isoindoline-1,3-dione (800 mg, 1.700 mmol) in EtOH (10 mL) was added hydrazine monohydrate (85.10 mg, 83.35 μL, 1.700 mmol) and the reaction was stirred at reflux overnight, then concentrated, diluted with DCM, and filtered. The filtrate was concentrated, and purified on a 40 g silica gel cartridge with 0-50% (20% NH3/MeOH) to yield 4-[7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoxalin-5-yl]oxycyclohexanamine (450 mg, 77.8%) as a yellow solid. 1H NMR (300 MHz, Chloroform-d) ∂ 8.65 (d, J=1.9 Hz, 1H), 8.53 (d, J=1.9 Hz, 1H), 6.83 (q, J=2.6 Hz, 2H), 4.83 (t, J=6.0 Hz, 4H), 3.87-3.60 (m, 5H), 3.34 (dt, J=8.7, 6.6 Hz, 1H), 3.01-2.83 (m, 1H), 2.23 (dq, J=11.3, 5.8, 4.8 Hz, 2H), 2.07 (d, J=8.7 Hz, 1H), 1.92-1.62 (m, 6H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:20]=[CH:19][C:18]2[C:9]3[NH:10][C:11](=[O:17])[C:12]4[N:13]([CH:14]=[CH:15][N:16]=4)[C:8]=3[C:7](=[CH:21][C:22]([OH:24])=[O:23])[C:6]=2[CH:5]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38]=[C:39]=[O:40]>CN(C)C=O>[C:22]([CH:21]=[C:7]1[C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[C:11](=[O:17])[NH:10][C:9]=2[C:18]2[CH:19]=[CH:20][C:4]([NH:3][C:39]([NH:38][CH3:37])=[O:40])=[CH:5][C:6]1=2)([OH:24])=[O:23]
Reactant: CN=C=O
Reactant: Nc1ccc2c(c1)c(=CC(=O)O)c1c2[nH]c(=O)c2nccn21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc2c(c1)c(=CC(=O)O)c1c2[nH]c(=O)c2nccn21
Reaction time: 30 h

Procedure:
To 11 g of 8-amino-10-(carboxymethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one dihydrochloride dissolved in 110 ml of dimethylformamide and 110 ml of dioxane at a temperature in the region of 20° C. are added 12.42 g of potassium carbonate, followed by dropwise addition of 5.3 ml of methyl isocyanate. The stirring is continued for 30 hours at the same temperature. The reaction medium is then filtered. The solid recovered is dried under reduced pressure (15 mmHg; 2 kPa). The residue is taken up in 50 ml of water and the precipitate is filtered off. The solid is acidified with 2 ml of concentrated hydrochloric acid in 50 ml of water and then filtered and dried under reduced pressure (15 mmHg; 2 kPa). The insoluble product thus formed is taken up in 700 ml of dimethylformamide and brought to 50° C. in the presence of 1 g of animal black. The solution is filtered on Celite and the filtrate is concentrated on a rotary evaporator at 40° C. under reduced pressure (15 mmHg; 2 kPa). (1 mmHg; 0.13 kPa). The residue is taken up in 200 ml of ethyl ether and then filtered and dried for 8 hours at 50° C. under reduced pressure (1 mmHg; 0.13 kPa). 3.67 g of 10-(carboxymethylene)-8-(3-methylureido)-5H,10H-imidazo(1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of an orange-coloured powder, the melting point of which is greater than 260° C. (Analysis, C17 H13N5O4.0.9 DMF.0.9 H2O, % calculated C: 58.12; H: 3.73; N: 19.93, % found C: 58.1; H: 3.4; N: 19.6).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:21][N:20]=1>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:22]2[O:21][N:20]=[C:19]([CH2:18][N:3]3[C:4]4[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=4)[CH:10]=[C:2]3[CH3:1])[CH:23]=2)=[CH:29][CH:28]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: Fc1ccc(-c2cc(CCl)no2)cc1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(-c2ccc(F)cc2)on1

Procedure:
Synthesized in a manner similar to Example 23 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(4-fluorophenyl)isoxazole: MS (ES) m/z 400 (M+1).
Reaction SMILES: Br[N:2]1[C:6]2=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=[C:5]2[NH:4][CH:3]1[CH2:12][CH2:13][CH2:14][CH3:15].[CH:16](OB(O)O)=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:12]([C:3]1[NH:4][C:5]2[C:6]([N:2]=1)=[N:7][C:8]([CH3:11])=[C:9]([CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:10]=2)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1Nc2ccc(C)nc2N1Br
Reactant: OB(O)OC=Cc1ccccc1
Product: CCCCc1nc2nc(C)c(C=Cc3ccccc3)cc2[nH]1
Yield: 103.2 %

Procedure:
The same procedure as in step 8 of Example 1 was repeated using 4.0 g(0.0133 mole) of the compound obtained in step 4 of Example 1 and 3.0 g(0.0203 mole) of styrylboric acid to obtain 4.0 g of the title compound(yield 93%).