Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N:7]([CH2:13][C:14]#[N:15])[C:8](=[O:12])[O:9][CH2:10][CH3:11])([O-])=O.CO.C(Cl)Cl>C(O)(=O)C.[Fe]>[CH2:10]([O:9][C:8]([N:7]1[CH2:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:1]=[C:14]([NH2:15])[CH2:13]1)=[O:12])[CH3:11]
Reactant: CCOC(=O)N(CC#N)Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)N1CC(N)=Nc2ccccc2C1
Temperature: 90 °C
Yield: 25.9 %

Procedure:
To a solution of ethyl-2-nitrobenzyl-(cyanomethyl)carbamate (2) (227 mg, 0.862 mmol) dissolved in acetic acid (5 mL) under a nitrogen atmosphere was added Fe (289 mg, 5.17 mmol). The reaction mixture was heated to 90° C. for 4 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting brown oil was diluted with EtOAc (20 mL) and filtered over GF/F paper (rinsing with 10 mL of EtOAc). The organic phase was washed with saturated Na2CO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated. The resulting brown oil was purified by column chromatography (5% MeOH/CH2Cl2, then 20% MeOH/CH2Cl2) to provide 52 mg (0.223 mmol, 26% yield) of (E)-ethyl-2-amino-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate (3) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.17-1.25 (m, 3H), 3.81 (s, 2H), 4.02-4.12 (m, 2H), 4.23 (s, 2H), 6.79 (br s, 1H), 6.85-6.92 (m, 2H), 7.18-7.24 (m, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:10][C@@H:9]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:36]=2)[N:31]([CH2:47][O:48][CH:49]([Si:51]([CH3:54])([CH3:53])[CH3:52])[CH3:50])[N:30]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.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:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH2:47][O:48][CH:49]([Si:51]([CH3:52])([CH3:54])[CH3:53])[CH3:50])[N:30]=[C:29]4[CH3:28])[N:15]=2)[CH2:10][C@@H:9]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)C[C@@H]1Cc1ccccc1
Reactant: Cc1nn(COC(C)[Si](C)(C)C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1nn(COC(C)[Si](C)(C)C)c2ccc(-c3cncc(N4CCN(C(=O)OC(C)(C)C)[C@@H](Cc5ccccc5)C4)n3)cc12
Temperature: 140 °C
Yield: 72.5 %

Procedure:
To a solution of 2-[(S)-4-Boc-3-benzylpiperazinyl]-6-chloropyrazine 115 (0.10 g, 0.258 mmol) and [3-methyl-1-(trimethylsilyl)ethoxymethy-1H-indazol-5-yl]boronic acid pinacol ester 117 (0.10 g, 0.258 mmol) in 1,2-dimethoxyethane (5 mL) was added saturated sodium carbonate solution (0.5 mL) and Pd(dppf)Cl2 (0.019 g, 0.026 mmol). The reaction mixture was heated in a microwave reactor at 140° C. for 15 minutes. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 2-[(S)-4-Boc-3-benzylpiperazinyl]-6-[3-methyl-1-(trimethylsilyl)ethoxymethyl-1 H-indazol-5-yl]pyrazine 118 (0.115 g, 0.187 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.Br.Br.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[OH:31])[N:24]=[C:23]2[CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[OH:31])[N:24]=[C:23]2[CH2:32][CH:33]2[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=3)[CH2:37][CH2:38]2)=[CH:17][CH:16]=1
Reactant: Oc1ncnc2nc(CC3CCNCC3)n(Cc3ccc(F)cc3)c12
Reactant: COc1ccc(CCCl)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(CCN2CCC(Cc3nc4ncnc(O)c4n3Cc3ccc(F)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of 1.9 parts of 1-(2-chloroethyl)-4-methoxybenzene, 5 parts of 7-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-7H-purin-6-ol dihydrobromide, 4 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 70° C. After cooling, the reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.2 parts (46%) of 7-[(4-fluorophenyl)methyl]-8-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methyl]-7H-purin-6-ol; mp. 122.2° C. (compound 62).
Reaction SMILES: [NH2:1][C:2]([CH3:13])([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].S([O-])([O-])(=O)=O.[Na+].[Na+].[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(=O)C1C=CC=CC=1>[CH:27](=[N:1]/[C:2]([CH3:13])([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O=Cc1ccccc1
Product: CC(C)(CNC(=O)OC(C)(C)C)/N=C/c1ccccc1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a suspension of tert-butyl (2-amino-2-methylpropyl)carbamate (1.98 g) and anhydrous sodium sulfate (3.00 g) in toluene (5 mL), benzaldehyde (1.07 mL) was added at room temperature, and the mixture was stirred for 11 hours under reflux by heating. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure to obtain (E)-tert-butyl (2-(benzylideneamino)-2-methylpropyl)carbamate (G8).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.C(N(CC)CC)C.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[N:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ccncc2)CC1

Procedure:
4.0 g (26.6 mmol) of 4-chloropyridine hydrochloride, 4.2 g (26.6 mmol) of ethyl piperidine-4-carboxylate and 7.4 ml (53.2 mmol) of triethylamine were stirred in 100 ml of xylene at 130° C. for 24 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[CH2:10]2)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.O>O1CCCC1>[F:29][CH:27]([F:28])[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]([N:11]2[C:12](=[O:14])[C:13]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=3[NH:4][C:1](=[O:3])[CH3:2])[CH2:10]2)[CH2:16][C:17]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:18])=[CH:21][C:22]=1[O:30][CH2:31][CH3:32]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N2CCOCC2)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (300 mg, 0.67 mmol) in tetrahydrofurane was added carbonyldiimidazole (130 mg, 0.80 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added morpholine (0.1 ml, 1.0 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give N-{2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-3-morpholin-4-yl-3-oxo-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (250 mg, 72%): mp, 164-166° C.; 1H NMR (CDCl3): 1.43 (t, J=7.5 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 3.04 (dd, J=6, 10 Hz, 1H, CHHCO), 3.54-3.72 (m, 9H, morpholine ring+CHHCO), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.27 (d, J=17 Hz, 1H, CHHN), 4.44 (d, J=17 Hz, 1H, CHHN), 5.54-5.59 (m, 1H, CHN), 6.85 (t, JH-F=75 Hz, 1H, OCF2H), 6.94-7.16 (m, 3H, Ar), 7.14 (d, J=8 Hz, 1H, Ar), 7.46 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=7.5 Hz, 1H, Ar), 10.60 (s, 1H, NHCO). 13C NMR (CDCl3): 15.3, 25.6, 36.5, 42.8, 46.9, 49.8, 54.7, 65.5, 67.2, 67.4, 112.6, 114.1, 116.7, 117.6, 118.3, 118.4, 119.9, 120.8, 123.5, 133.9, 138.5, 140.5, 142.2, 151.5, 166.7, 169.7, 170.4; Anal. Calcd. for C26H29F2N3O6: C, 60.34; H, 5.65; N, 8.12; Found: C, 60.04; H, 5.71; N, 8.19.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[CH3:22][C:23]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:31]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([CH3:22])[CH:32]=2)[CH2:8][CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1C
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a flask containing 1,1-dimethylethyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (3.80 g, 11.5 mmol, prepared according to Heterocycles, 1996, 43, 2131-2138) were added the title compound from Example 3 Step A (3.80 g, 13.8 mmol) and trans-dichlorobis(triphenylphosphine)palladium (II) (804 mg, 1.15 mmol). Acetonitrile (57 mL) and sodium carbonate (28.7 mL, 1.0 M aqueous, 28.7 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70° C. for 3 h, then was allowed to cool to ambient temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 10% EtOAc in hexanes, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 276.0 [M-C4H9]+; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=9.0 Hz, 1H), 7.24-7.22 (m, 2H), 6.12 (br s, 1H), 4.09 (br m, 2H), 3.88 (s, 3H), 3.65-3.62 (m, 2H), 2.61 (s, 3H), 2.52 (br m, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC.O>COCCOC>[CH3:13][N:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:9]([F:12])([F:10])[F:11])=[CH:5][C:6]1=[O:8]
Reactant: Cc1cc(C(F)(F)F)cc(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CI
Product: Cc1cc(C(F)(F)F)cc(=O)n1C
Temperature: 25 °C
Yield: 97.7 %

Procedure:
To a suspension of 6-methyl-4-(trifluoromethyl)-1H-2-pyridone (2 g, 11.25 mmol) and potassium carbonate (4.68 g, 33.9 mmol) in DME (25 mL) was added iodomethane (9.62 g, 67.8 mmol) at room temperature and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine solution (200 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography on a Biotage (40 m) column to obtain 2.1 g (97% yield) of 1,6-dimethyl-4-(trifluoromethyl)-2-pyridone as a white solid: mp 80-82° C. EI-HRMS m/e calcd for C8H8F3NO (M+) 191.0558, found 191.0559.
Reaction SMILES: O1CCCC1.[C:6]1([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[C:6]1([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:22][N:21]=3)=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ON=C(Cl)Cc1ccc(Nc2ccccc2)cc1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2ccc(Nc3ccccc3)cc2)no1
Temperature: 50 °C
Reaction time: 7 h
Yield: 38.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenylamino-phenyl)-acetohydroximoyl chloride (150 mg, 0.576 mmol) described in Manufacturing Example 69-1-4 and 3-ethynyl-pyridin-2-ylamine (43 mg, 0.367 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (201 μL, 1.44 mmol) at room temperature, which was stirred for 7 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (48 mg, 24%).
Reaction SMILES: [CH:1]([N:4](C(C)C)CC)(C)[CH3:2].BrCC#N.[F:14][C:15]1[C:16]([OH:28])=[N:17][CH:18]=[C:19]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:20]=1>C(Cl)Cl>[C:1]([CH2:2][N:17]1[CH:18]=[C:19]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:20]=[C:15]([F:14])[C:16]1=[O:28])#[N:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: Oc1ncc(OC(F)(F)C(F)F)cc1F
Agent: N#CCBr
Solvent: ClCCl
Product: N#CCn1cc(OC(F)(F)C(F)F)cc(F)c1=O

Procedure:
Diisopropylethylamine (0.82 ml, 4.7 mmol) and 0.30 ml (4.3 mmol) of bromoacetonitrile were added consecutively with stirring at ambient temperature to 3-fluoro-5-(1,1.2,2-tetrafluoroethoxy)-2-pyridinol (0.90 g, 3.98 mmol) in 5 ml of methylene chloride and the mixture allowed to react overnight. It was then diluted with 25 ml of methylene chloride, extracted with 25 ml of water and with dilute aqueous sodium carbonate, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain the title compound as a solid. This was recrystallized from toluene to obtain 0.92 g (86 percent of theory) of purified material melting at 75.5-77° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3C[CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])(C)C)=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].Cl[C:38]1[N:39]=[C:40](N2CCOC[C@@H]2C)[C:41]2CN(C(OCC)=O)CC=2N=1.N1C=CC=C(NC(NC2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)C=1>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]>[CH3:35][C@@H:30]1[N:29]([C:14]2[C:15]3[CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:28])=[O:23])[CH2:18][C:16]=3[N:17]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:4]([NH:3][C:1]4[CH:38]=[N:39][CH:40]=[CH:41][CH:2]=4)=[O:36])=[CH:7][CH:8]=3)[N:13]=2)[CH2:34][CH2:33][O:32][CH2:31]1
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccnc3)cc2)OC1(C)C
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)Nc4cccnc4)cc3)nc(N3CCOC[C@@H]3C)c2C1

Procedure:
Method as described for intermediate 5 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 1-(pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as catalyst. The reaction mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and reduced in vacuo. The residue was purified first by flash chromatography using a gradient of 0-40% DCM/MeOH, then triturating with a mixture of petrol ether/ethyl acetate (9:1) affording the title compound after filtration and drying of the solid obtained (23 mg, 0.05 mmol, 30%).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]3=[N:14][O:15][N:16]=[C:12]3[CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:19]1([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH2:30][C:29](=O)[CH2:28][CH2:27]3)[CH:23]=[N:22][N:21]=[N:20]1.C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[N:19]1([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH:29]([N:5]2[CH2:6][CH2:7][N:2]([CH2:8][CH2:9][C:10]4[CH:18]=[CH:17][C:13]5=[N:14][O:15][N:16]=[C:12]5[CH:11]=4)[CH2:3][CH2:4]2)[CH2:28][CH2:27]3)[CH:23]=[N:22][N:21]=[N:20]1
Reactant: O=C1CCc2cc(-n3cnnn3)ccc2C1
Reactant: c1cc2nonc2cc1CCN1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Product: c1cc2nonc2cc1CCN1CCN(C2CCc3cc(-n4cnnn4)ccc3C2)CC1
Reaction time: 3 h

Procedure:
To a flask charged with 5-(2-piperazin-1-ylethyl)-2,1,3-benzoxadiazole hydrochloride (25 mg, 0.093 mmol) and a stir bar was added 6-(1H-tetrazol-1-yl)-3,4-dihydronaphthalen-2(1H)-one (30 mg, 0.14 mmol), Titanium (IV) isopropoxide (0.27 mL, 0.93 mmol), and sodium cyanoborohydride (29 mg, 0.46 mmol). The mixture was allowed to stir for 3 hours. LC showed formation of the desired product. The reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated and purified by mass-directed HPLC (0.1% TFA in water and acetonitrile). LC-MS (IE, m/z): 431 [M+1]+. (0.98 μM)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16](=O)[CH3:17])[CH:5]=[CH:4][C:3]=1[C:19](=[CH:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21].[CH3:26][O:27][NH2:28]>CO>[CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:16][CH:17]=[N:28][O:27][CH3:26])[CH:5]=[CH:4][C:3]=1[C:19](=[CH:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21]
Reactant: CC=C(C(=O)OC)c1ccc(C(C)=O)c(COc2ccccc2)c1C
Reactant: CON
Solvent: CO
Product: CC=C(C(=O)OC)c1ccc(CC=NOC)c(COc2ccccc2)c1C
Temperature: 25 °C
Yield: 72.7 %

Procedure:
22 g (67.4 mmol) of methyl α-[2-methyl-4-acetylphenyloxymethylphenyl]-β-methylacrylate and 11.3 g (0.135 mol) of O-methylhydroxylamine hydrochloric were refluxed in 600 ml of methanol for 6 hours. The mixture was allowed to cool to about 25° C., was hydrolyzed and extracted with ice water. The organic phases were washed with water, dried and evaporated down. There was obtained 18 g of the title compound in the form of pale yellow crystals (mp.: 55°-60° C.).
Reaction SMILES: [NH3:1].F[B-](F)(F)F.C(O[C:10](=[N+:18]1[CH2:26][CH:25]2[CH:20]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][CH2:23][C:24]2=[O:27])[CH2:19]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH:1]=[C:10]([N:18]1[CH2:26][CH:25]2[CH:20]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][CH2:23][C:24]2=[O:27])[CH2:19]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(Cc1ccccc1)=[N+]1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reactant: N
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N=C(Cc1ccccc1)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 5 h

Procedure:
A 0.8N solution (8.8 cc) of ammonia in dichloromethane is added to a stirred suspension, cooled to -20° C., of (3aRS,7aRS)-2-(1-ethoxy-2-phenylethylidene)-4-oxo-7,7-diphenylperhydroisoindolium tetrafluoroborate (3.75 g) in anhydrous dichloromethane (30 cc). The reaction mixture is allowed to return to room temperature and stirring is continued for 5 hours. The reaction mixture is treated with 10% strength aqueous potassium carbonate solution (30 cc). The precipitate present is removed by filtration and the organic phase is then washed with distilled water (15 cc) and with saturated aqueous sodium chloride solution (15 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in acetonitrile (22 cc). The crystals obtained are drained and dried. (3aRS,7aRS)-2-(α-Iminophenethyl)-7,7-diphenylperhydro-4-isoindolone (1.3 g), m.p. 202° C., is obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1CCNC1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(Cl)c2c(c1)O[C@@H](CN1CCCC1)CO2

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), pyrrolidine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 331 (M+, 0.4), 110 (4), 85 (8), 84 (bp), 63 (2), 55 (5).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH3:11])[C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23]Br>CN(C)C=O>[CH3:11][N:8]1[C:6]2[N:7]=[C:2]3[N:3]([C:4](=[O:12])[C:5]=2[CH:10]=[N:9]1)[CH2:23][CH2:22][CH2:21][CH2:20][S:1]3
Reactant: Cn1ncc2c(=O)[nH]c(S)nc21
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(=O)n3c(nc21)SCCCC3
Temperature: 80 °C
Reaction time: 6 h
Yield: 22 %

Procedure:
In 120 ml of dimethylformamide was dissolved 6.0 g (32.9 mmol) of 4,5-dihydro-6-mercapto-1-methylpyrazolo[3,4-d]pyrimidin-4(1H)-one [Helv. Chim. Acta, 42, 349 (1959)], and 13.7 g (98.8 mmol) of potassium carbonate and 5.90 ml (49.4 mmol) of 1,4-dibromobutane were added to the solution, followed by stirring at 80° C. for 6 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform to give 1.71 g (22%) of Compound 45. The compound was recrystallized from ethanol for purification.
Reaction SMILES: Cl.C[O:3][C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:8][CH:7]=[CH:6][C:5]=1[C:18]([CH3:22])([CH3:21])[C:19]#N.C(O)(=[O:25])C>>[CH3:21][C:18]1([CH3:19])[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[C:4]=2[O:3][C:22]1=[O:25]
Reactant: CC(=O)O
Reactant: COc1c(Oc2ccccc2C)cccc1C(C)(C)C#N
Agent: Cl
Product: Cc1ccccc1Oc1cccc2c1OC(=O)C2(C)C

Procedure:
Conc. hydrochloric acid (20 ml) and acetic acid (60 ml) were added to 2-[2-methoxy-3-(o-tolyloxy)phenyl]-2,2-dimethylacetonitrile (5.7 g), and the mixture was refluxed under heating for 48 hours. After cooling, the reaction mixture was evaporated. Saturated aqueous solution of sodium bicarbonate (100 ml) was added to the oily residue and warmed. After cooling, the mixture was extracted with ethyl acetate, and the extract was washed with water, dried and evaporated. The solid residue was purified by recrystallization from a mixture of ethanol and n-hexane to give 3,3-dimethyl-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (2.5 g). mp 115°-117° C.