Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.CCCCCC.[C:12]([C:14]1([OH:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1)#[CH:13].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:27][CH:26]=1>C1COCC1>[OH:32][C:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[C:13]#[C:12][C:14]1([OH:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1
Reactant: COc1ccc(C(=O)c2cccs2)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)(C#CC2(O)CN3CCC2CC3)c2cccs2)cc1
Reaction time: 0.5 h

Procedure:
A 1.6 N solution of BuLi in hexane (1.12 ml, 1.79 mmol) was added dropwise to a solution of 3-ethynyl-1-azabicyclo[2.2.2]octan-3-ol 47 (123 mg, 0.81 mmol) in THF (5 ml) at room temperature. After stirring for 30 minutes, (4-methoxyphenyl)(2-thienyl)methanone (231 mg, 1.06 mmol, commercial) in THF (1 ml) was added slowly. After 2 hours, the reaction was quenched by addition of saturated aqueous NH4Cl solution and diluted with AcOEt. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The yellowish oil was purified by chromatography on silica gel (CH2Cl2/MeOH 85/15) and 3-[3-hydroxy-3-(4-methoxyphenyl)-3-(2-thienyl)-1-propynyl]quinuclidin-3-ol 152 was obtained as a white solid (41 mg, 14%, mixture of diastereomers).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([O-:10])=O)[CH2:7][CH2:6]1)=[O:4].[K+].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34]>C1COCC1.C(OCC)(=O)C.CN(C=O)C>[OH:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[NH:27][C:8]([C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]1)=[O:10]
Reactant: Nc1ccccc1O
Reactant: COC(=O)C1(C(=O)[O-])CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)Nc2ccccc2O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a stirred suspension of potassium 1-(methoxycarbonyl)cyclopropanecarboxylate (182 mg, 1 mmol) in 3 mL THF at room temperature under nitrogen was added 15 μL of DMF. Oxalyl chloride (87 μL, 1 mmol) was then added neat dropwise by syringe. After stirring at ambient temperature for 2 hours, the reaction was cooled to 0° C. and treated with DIEA (0.497 ml, 2.85 mmol) followed by 2-aminophenol (104 mg, 0.951 mmol) neat as a solid. The cooling bath was allowed to melt and the reaction was then stirred at ambient temperature overnight. The reaction was diluted to 30 mL with ethyl acetate and washed with 2N HCl, water, saturated sodium bicarbonate and brine. The organics were dried (MgSO4), filtered and concentrated to a yellow solid (147 mg, 68% yield).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CC[CH2:11][CH2:10]1>>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:10][CH3:11]
Reactant: O=Cc1ccccc1
Reactant: C1CCOC1
Product: CCC(=O)c1ccccc1
Temperature: 180 °C
Reaction time: 14 h
Yield: 45 %

Procedure:
Into a stainless steel autoclave with a glass liner was placed 1.5 g. of the 3-methyl-2-aminopyridyl aldimine of benzaldehyde, 75 ml of tetrahydrofuran and 0.2 g. of RhCl(PPh3)3. The autoclave was flushed with ethylene, to remove any air, then pressurized with ethylene to 150 psi, followed by heating to 180 degrees C. for 14 hours. Upon cooling the resulting dark red liquid was concentrated to one-fourth its original volume and stirred with moist silica gel in 20 ml of CH2Cl2 for 1 hour. Solvent was removed on the rotary evaporator and the product propiophenone was obtained by heating the silica gel at 130 degrees and 50 mm and collecting the distillate. The yield of propiophenone, as a clear oil, was 0.45 g., 45% yield based on starting aldimine and 1800% yield based on the rhodium catalyst.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[C:6]([O:14][CH3:15])=[N:5]2.[C:16](OCC)(OCC)(OCC)[CH2:17][CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:16]([CH2:17][CH3:18])=[N:13][N:12]=[C:7]1[C:6]([O:14][CH3:15])=[N:5]2
Reactant: COc1nc2cc(Cl)ccc2nc1NN
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2c(OC)nc3cc(Cl)ccc3n12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 5.1 g. (0.022 mole) of 6-chloro-2-hydrazino-3-methoxyquinoxaline, the product of Preparation C(d), and 60 ml. of triethyl orthopropionate was heated with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting mixture was then cooled to room temperature (~20° C.), and the precipitate which formed was subsequently collected by means of suction filtration and washed with diethyl ether to ultimately afford 4.3 g. (75%) of pure 7-chloro-1-ethyl-4-methoxy-[1,2,4[4,3-a]quinoxaline, m.p. 221°-223° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH2:24][CH2:25][OH:26])[CH2:22][O:21][C:20]1([CH3:28])[CH3:27])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:12]([O:16][C:17]([N:19]1[CH:23]([CH2:24][CH2:25][O:26][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:22][O:21][C:20]1([CH3:28])[CH3:27])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCO)COC1(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Yield: 90.6 %

Procedure:
Dry, freshly crystallised p-toluenesulphonyl chloride (1.86 g, 9.8 mmol) and 4-dimethylaminopyridine (10 mg, 0.082 mmol) were added to a solution of alcohol 5 (2.00 g, 8.15 mmol) and triethylamine (2.6 ml, 18.75 mmol) in dichloromethane (20 ml) at 5° C. with stirring. The resulting solution was protected from moisture and kept at 5° C. until all the starting material 5 had reacted (33 h, TLC). A colourless solid, presumably triethylamine hydrochloride, crystallised out of the reaction, and was filtered away. The filtrate was diluted with dichloromethane to a volume of 90 ml, and washed with water (2×20 ml), brine (20 ml), dried over Na2SO4, and concentrated to give the crude tosylate 7 as white solid. This material was purified by dissolving in ether (ca. 330 ml), filtering through celite 545 on a wad of cotton wool to give 2.95 g (90%) of 7. 1H NMR (200 MHz, CDCl3) 7.78 (m, 2H), 7.35 (d, 2H), 4.09 (m, 2H), 4.09 (m, 2H), 3.90 (m, 2H), 3.73 (m, 1H), 2.95 (m, 2H), 1.51 (s, 6H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]1[CH2:23][O:22][C:10]2=[CH:11][CH:12]=[C:13]3[C:17]([N:16]([CH2:18][C@@H:19](O)[CH3:20])[N:15]=[CH:14]3)=[C:9]2[CH2:8]1)[CH3:5])[CH3:2].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>C1COCC1>[N:40]([C@H:19]([CH3:20])[CH2:18][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]3[O:22][CH2:23][CH:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[CH2:8][C:9]3=2)[CH:14]=[N:15]1)=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(C)OC1COc2ccc3cnn(C[C@H](C)O)c3c2C1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(C)OC1COc2ccc3cnn(C[C@@H](C)N=[N+]=[N-])c3c2C1
Temperature: 95 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of the product from Step G (0.35 g, 1.09 mmol) and triethylamine (0.55 g, 5.47 mmol) in anhydrous THF (50 ml) at 0° C. was added methanesulfonic anhydride (0.47 g, 2.73 mmol). The mixture was stirred for 1 h and sodium azide (0.71 g, 10.9 mmol) was added. The reaction mixture was evaporated to a residue that was dissolved in anhydrous DMF (80 mL) and heated at 95° C. for 3 h. The mixture was cooled, poured into a saturated solution of sodium bicarbonate (80 mL), and extracted with EtOAc (3×80 mL). The combined extracts were dried (MgSO4) and evaporated to a residue that was purified by chromatography (silica, 10% EtOAc/hexane) to give an oil (0.30 g, 80%): LC/MS (+APCI) m/z 346 (M+H).
Reaction SMILES: [Cl:1]Cl.[CH3:3][C:4]([CH3:45])([CH3:44])[C:5](=[O:43])[CH:6]([N:20]1[CH:23](SC)[CH:22]([CH:26]([O:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[CH3:27])[C:21]1=[O:42])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8].[N+](C1C=CC(C([O-])=O)=CC=1)([O-])=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][CH:23]1[N:20]([CH:6]([C:5](=[O:43])[C:4]([CH3:45])([CH3:44])[CH3:3])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:21](=[O:42])[CH:22]1[CH:26]([O:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30])[CH3:27]
Reactant: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Reactant: ClCl
Agent: O=C([O-])c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)C(C)(C)C)C1Cl
Temperature: -60 °C
Reaction time: 2 h

Procedure:
660 μl of a solution of chlorine in carbon tetrachloride containing 850 mg in 10 ml are added at -60° C. to a solution of 244 mg (0.395 mmol) of p-nitrobenzyl 4,4-dimethyl-2-[4-methylthio-3-(1-(p-nitrobenzyloxycarbonyloxy)-ethyl)-2-oxoazetidinyl]-3-oxo-pentanoate-p-nitrobenzoate in 16 ml of methylene chloride. The weakly yellow solution is stirred at -60° C. during the course of 2 hours and the solvent is removed in vacuo, 236 mg of a colorless non-crystalline solid being obtained. IR spectrum in CH2Cl2 : 2930, 2850, 1795, 1765, 1725, 1620, 1530, 1355 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12]C)=[O:5].C(=O)(O)[O-].[Na+]>Br>[NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5]
Reactant: COc1ccccc1C(=O)c1cc(Cl)ccc1N
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(Cl)cc1C(=O)c1ccccc1O
Yield: 93.4 %

Procedure:
A mixture of 2.15 g of 2-amino-5-chloro-2'-methoxybenzophenone and 20 ml of 47% hydrogen bromide was heated for 1 hour under reflux. The solution was rendered neutral with sodium bicarbonate, and subjected to extraction with 100 ml of ethyl acetate. The extract solution was washed with water and dried over anhydrous magnesium sulfate; the solvent was then distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography (eluent, hexane:ethyl acetate=10:1) to yield 1.9 g of 2-amino-5-chloro-2'-hydroxybenzophenone as needles, m.p. 51° to 52° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:5])[CH3:2].C(OC([C@@H]1CCC[C@H]1NCCC(C)C)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)C
Agent: CCOC(=O)[C@@H]1CCC[C@H]1NCCC(C)C
Product: CCOC(=O)C1CCCC1NCCC(C)C

Procedure:
To a solution of 2-(3-methylbutylamino)-cyclopent-1-enecarboxylic acid ethyl ester (6.84 g, 30.4 mmol) in acetic acid (100 mL) was added a 8.0 M solution of borane in pyridine (4.6 mL, 36.8 mmol) at 25° C. After stirring for 15 min, the reaction mixture was concentrated in vacuo. The crude material was triturated with 1.0 M aqueous hydrochloric acid solution (25 mL) and stirred for 0.5 h (until the gas evolution ceased). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-10% methanol in dichloromethane) to afford cis-2-(3-methylbutylamino)-cyclopentanecarboxylic acid ethyl ester (2.37 g, 10.4 mmol, 34%) as a colorless oil and trans-2-(3-methylbutylamino)-cyclopentanecarboxylic acid ethyl ester (1.18 g, 5.2 mmol, 17%) as a white solid. cis-2-(3-Methylbutylamino)-cyclopentanecarboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ 0.90 (6H, d, J=6.3 Hz), 1.26 (3H, t, J=7.0 Hz), 1.34-1.46 (3H, m), 1.57-1.74 (4H, m), 1.81-1.90 (1H, m), 1.94-2.04 (2H, m), 2.53 (1H, q, J=8.1 Hz), 2.59 (2H, t, J=7.5 Hz), 3.27 (1H, q, J=7.6 Hz), 4.11-4.17 (2H, m). trans-2-(3-Methylbutylamino)-cyclopentanecarboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ: 0.92 (6H, d, J=6.8 Hz), 1.28 (3H, t, J=7.3 Hz), 1.41-1.47 (2H, m), 1.51-1.90 (5H, m), 2.00-2.09 (3H, m), 2.62-2.74 (3H, m), 3.38 (1H, q, J=7.2 Hz), 4.16 (2H, q, J=7.0 Hz). LC-MS (ESI) calcd for C13H25NO2 227.19, found 228.3 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: COc1ccccc1B(O)O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 74.2 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.31 mmol) with 2-methoxyphenylboronic acid (0.297 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 gave 0.399 g (74%) of (±)-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a tan solid. mp 100-103° C.; Anal. calcd. for C23H22O5S: C, 67.3; H, 5.4. Found: C, 66.95; H, 5.43.
Reaction SMILES: CC(=CC)C.Cl[O-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[O:29])[S:20][CH:21]=2)=[CH:13][CH:12]=1.P([O-])(O)(O)=[O:31].[K+]>C(OCC)(=O)C.O.C(O)CCC>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:31])=[O:29])[S:20][CH:21]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2csc(CCCCCCC=O)n2)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2csc(CCCCCCC(=O)O)n2)cc1
Reaction time: 0.67 h
Yield: 92.4 %

Procedure:
Add 2-methyl-2-butene (7.0 mL) and sodium hypochlorite (2.51 g, 27.75 mmol) to a solution of 7-[4-(4-methoxyphenyl)thiazol-2-yl]heptanal (4.02 g, 13.25 mmol) and potassium dihydrogen phosphate (3.10 g, 22.78 mmol) in tent-butanol (60 mL) and water (12 mL) at room temperature. Stir the mixture for 40 minutes, dilute with ethyl acetate (500 mL) and wash with brine (3×200 mL). Dry the combined organic extracts over sodium sulfate and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1:19), and triturate the residue with hexanes/methylene chloride to afford 7-[4-(4-methoxyphenyl)thiazol-2-yl]heptanoic acid (3.91 g, 88%): APCI MS m/z 320 [C17H21NO3S+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:22][N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17].[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:22][N:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc(Br)cc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3ccc(Br)cc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(5-bromo-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.015 g, 0.027 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in methylene chloride and thereby washed to obtain (Z)-2-[(5-bromo-1H-indol-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.012 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])[CH:3]=1.Cl.I([O-])(=O)(=O)=[O:27].[Na+].[OH-].[Na+]>O>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:27])[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCSC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCS(C)=O
Reaction time: 2.5 h
Yield: 49.4 %

Procedure:
To a stirred solution of product from Example 49 (1.496 g, 4 mmoles) in 2N hydrochloric acid (5.0 ml, 10 mmoles) and water (20 ml) was added sodium periodate (856 mg, 4.0 mmoles) and the mixture stirred for 2.5 hours. It was then basified with 4N sodium hydroxide (3 ml) and extracted with methylene chloride (3×30 ml). The extract was concentrated in vacuo and the residue flash-chromatographed on deactivated silica column using methylene chloride:methanol:ammonia (100:3.5:0.5) solvent system. The appropriate fractions were combined and concentrated to give a yellow oil which crystallized from methylene chloride-ether to give 770 mg of the title product as a light yellow solid, mp. 116°-117° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH:29]1([C:32]2[NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[N:33]=2)[CH2:31][CH2:30]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:29]1([C:32]2[N:33]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[C:7]([CH2:12][N:13]5[CH2:18][CH2:17][CH:16]([CH:19]6[CH2:22][O:21][CH2:20]6)[CH2:15][CH2:14]5)[N:8]4[CH3:11])=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:3]=3)[C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)[CH2:31][CH2:30]1
Reactant: c1ccc2[nH]c(C3CC3)nc2c1
Reactant: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-(4-oxetan-3-ylpiperidin-1-ylmethyl)-9H-purine (100 mg, 0.25 mmol), 2-cyclopropyl-1H-benzoimidazole (47 mg, 0.30 mmol), Pd2dba3 (6 mg, 0.006 mmol), Xphos (12 mg, 0.025 mmol) and cesium carbonate (121 mg, 0.37 mmol) in DMF (2 mL) was purged with argon gas then subjected to microwave irradiation at 145° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH 100:0 to 99:1 to 98:2 to 95:5) to afford 450 as a pale purple foam (60 mg, 46 LCMS (Method I): RT=2.63 min, M+H+=529. 1H NMR (CDCl3, 400 MHz) δ 7.94 (dd, J=7.1, 2.0 Hz, 1 H); 7.68 (d, J=7.4 Hz, 1 H); 7.27-7.19 (m, 2 H); 4.76 (dd, J=7.8, 6.1 Hz, 2 H); 4.46 (t, J=6.1 Hz, 2 H); 4.35 (m, 4 H); 3.89-3.82 (m, 7 H); 3.76 (s, 2 H); 2.91-2.81 (m, 3 H); 2.79-2.70 (m, 1 H); 2.18 (m, 2 H); 1.62 (m, 5 H); 1.36 (m, 2 H) and 1.08-1.01 (m, 2 H)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:3]=1.[F-:24].[Cs+].CS(C)=O>CCOC(C)=O>[F:24][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: [F-]
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3ncccn3)n2)cc1
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2cc(F)cc(-c3ncccn3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 2 dram vial equipped with a stir bar and charged with 2-(4-chloro-6-(4-isopropoxyphenyl)pyridin-2-yl)pyrimidine (all material from step 1) was added CsF (200 mg, 1.32 mmol) and DMSO (0.7 mL). The vial was sealed with a septum cap and then placed in a 140° C. heating block with stirring for 18 hours. The reaction mixture was allowed to cool to room temperature and then was transfered to a 125 mL separatory funnel. The mixture was diluted with EtOAc (50 mL) and twice washed with water:brine (25 mL:25 mL). The organic solution was dried over MgSO4; filtered; then concentrated in vacuo to afford a solid amber residue. This material was subjected to silica gel purification (hexanes:EtOAc) to afford 2-(4-fluoro-6-(4-isopropoxyphenyl)pyridin-2-yl)pyrimidine as a white solid (15 mg, 27% over two steps). 1H-NMR (400 MHz, CDCl3) δ 8.96 (d, J=5.0 Hz, 2H), 8.12 (dd, J=9.5, 2.3 Hz, 1H), 8.09-8.04 (m, 2H), 7.50 (dd, J=9.8, 2.3 Hz, 1H), 7.36 (t, J=4.9 Hz, 1H), 7.02-6.97 (m, 2H), 4.65 (spt, J=6.0 Hz, 1H), 1.38 (d, J=6.0 Hz, 6H); MS: MS m/z 310.2 (M++1).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@H:4]([C:5]3[CH:16]=[N:15][NH:14][C:6]=3[C@H:7]2[C:10]([O:12][CH3:13])=[O:11])[N:3]1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CCN(C(C)C)C(C)C>C(#N)C>[CH3:13][O:12][C:10]([C@@H:7]1[C:6]2[N:14]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:15]=[CH:16][C:5]=2[C@H:4]2[CH2:9][N:8]1[C:2](=[O:1])[N:3]2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:11]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)[C@@H]1c2[nH]ncc2[C@H]2CN1C(=O)N2OCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1ncc2c1[C@@H](C(=O)OC)N1C[C@H]2N(OCc2ccccc2)C1=O
Temperature: 50 °C
Yield: 11.8 %

Procedure:
0.2 g of the product obtained in Stage K of Example 1 is dissolved in 2 ml of acetonitrile, in a round-bottomed flask. 0.150 μl of ethyl bromoacetate and 240 μl of DIEA are added. The medium is heated at 50° C. for 24 hours and then the reaction medium is extracted with ethyl acetate, the organic phase is washed with an aqueous tartaric acid solution at 10% and then with an aqueous NaCl solution. The organic phase is dried over magnesium sulfate, filtered off and the solvent is evaporated off under reduced pressure. 266 mg of the crude product are obtained which are purified by chromatography on silica, eluting with a methylene chloride/acetone/triethylamine, 95/0.5/0.1%, mixture. 37 mg of the isomer A, ethyl trans-4,5,6,8-tetrahydro-8-(methoxycarbonyl)-6-oxo-5-(phenylmethoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-1-acetate having the empirical formula C20H22N4O6 are obtained (M=414.42 g).