Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: OCc1cnc(-c2ccccc2)nc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1cnc(-c2ccccc2)nc1Cl
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a stirred (4-chloro-2-phenylpyrimidin-5-yl)methanol (242 mg, 1.10 mmol) in CH2Cl2 (11 mL) was added Dess-Martin periodinane (553 mg, 1.43 mmol). The reaction was kept for 2 hrs and was diluted with EtOAc (10 mL).The organic layer was washed with saturated NaHCO3 solution (10 mL), and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the crude product as a white solid (250 mg). The crude product was purified by flash chromatography (silica gel, 20% EtOAc/hexane) to give 4-chloro-2-phenylpyrimidine-5-carbaldehyde (205 mg, 82% for 2 steps) as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.C(OC(Cl)=O)C(C)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](=[NH:44])[NH:42]O)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]2[N:44]=[C:10]([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:12][N:42]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Agent: CC(C)COC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2noc(COCc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of benzyloxy-acetic acid (5 g, 30 mmol), NEt3 (3.6 g, 36 mmol) in toluene (150 mL) was added isobutylchloroformate (4.1 g, 30 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 hours. 4-(N-hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (7.3 g, 30 mmol) was added to the mixture. The mixture was heated under reflux overnight, cooled and the mixture was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.4˜7.3 (5H, m), 4.7 (2H, s), 4.69 (2H, s), 4.2˜4.04 (2H, m), 3.02˜2.84 (3H, m), 2.04˜4.94 (2H, m), 1.84˜4.7 (2H, m), 1.46 (9H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(C)C=CC=CC=1>C1C=CC=CC=1>[C:13]([N:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: C1=CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)N1CC=CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
83.1 g (1 mol) of 1,2,5,6-tetrahydropyridine are dissolved in 300 ml of benzene. 83 g of sodium bicarbonate are introduced into this solution and the mixture is cooled to 0° under a nitrogen atmosphere and, at this temperature, treated dropwise in the course of one hour with 332 ml of a 50% strength solution of benzyl chloroformate in toluene (1 mol). The reaction mixture is stirred at 0° for a further 21/2 hours and then poured into 1.5 liters of ice-water. The benzene phase is separated off and the aqueous phase is extracted by shaking 3 times with 250 ml of methylene chloride; subsequently the combined organic phases are washed with 1 N hydrochloric acid and then with a saturated solution of sodium chloride, dried over sodium sulphate and evaporated under a water pump vacuum. The oily residue is distilled under a high vacuum and gives 1-carbobenzyloxy-1,2,5,6-tetrahydropyridine with a boiling point of 102°-113°/0.01 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22]B(O)O.[F-].[K+].O1CCCC1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CB(O)O
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Yield: 78.2 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (25 g), methylboronic acid (8.4 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (1:1, 2.9 g) and potassium fluoride (16 g) was added tetrahydrofuran (140 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (16 g). The obtained 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (16 g) was dissolved in chloroform (100 mL), 4N hydrogen chloride/ethyl acetate (50 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (200 mL), and the precipitate was collected by filtration to give the title compound (10 g).
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH3:28])[CH:3]=1.[N:29]#[C:30]Br>C(Cl)Cl>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([C:30]#[N:29])[CH2:21][CH2:22]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH3:28])[CH:3]=1
Reactant: N#CBr
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCNCC2)CCO1
Solvent: ClCCl
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCN(C#N)CC2)CCO1
Reaction time: 4 h
Yield: 66 %

Procedure:
To a solution of 4-amino-5-chloro-2-ethoxy-N-[{4-(4-piperidinylmethyl)-2-morpholinyl}-methyl]benzamide (Example 22) (1.0 g) and TEA (0.41 ml) in methylene chloride (10 ml) was added cyanogen bromide (0.27 g) at room temperature, and then the mixture was stirred for 4 hours, washed with water, then brine and dried over anhydrous magnesium sulfate. Then, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (0.7 g) as a white solid. Melting point 197° C. (degradation, recrystallized from E)
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH2:16]([NH2:22])[C@H:17]1[O:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>>[CH2:16]([NH:22][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[C@H:17]1[O:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: NC[C@@H]1CCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@@H]2CCCO2)c1Cl
Yield: 98.5 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.01 g, 3.44 mmol), (2S)-tetrahydrofurfurylamine (0.33 mL, 3.20 mmol) and triethylamine (0.72 mL, 5.17 mmol) were reacted to form the desired product (1.12 g, 99%). EI-MS m/z 353(M-H)−.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:8])[O:4][C:5](=[O:7])[CH:6]=1.[Al](Br)(Br)[Br:10].BrBr>C(OCC)(=O)C>[Br:10][C:6]1[C:5](=[O:7])[O:4][C:3](=[O:8])[C:2]=1[CH3:1]
Reactant: Br[Al](Br)Br
Reactant: CC1=CC(=O)OC1=O
Agent: BrBr
Solvent: CCOC(C)=O
Product: CC1=C(Br)C(=O)OC1=O
Temperature: 120 °C
Yield: 9023.2 %

Procedure:
A mixture of 3-methyl-2,5-furandione (citraconic anhydride, 1 g), AlBr3 (26 mg) and Br2 (0.46 mL) was heated at 120° C. overnight. Ethyl acetate was then added and the organic phase was washed with HCl 0.1% and then with brine. The organic phase was dried and concentrated in vacuo to give the crude product (1.680 g) that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH2:21][CH2:22][C:23](=O)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][C:23]1[N:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH3:11])[C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1)[CH3:30]
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(OC)cc1
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(C(=O)O)cc1C
Temperature: 140 °C
Yield: 50.4 %

Procedure:
4-Amino-3-methylbenzoic acid (0.322 g) was mixed with ethyl 7-(4-methoxyphenyl)-4,7-dioxoheptanoate (25C, see scheme 25) (0.498 g) and p-toluensulfonic acid (49 mg) in dioxane (3 mL). The mixture was heated at 140° C. via microwave over 2 hours. The resultant solution was diluted with EtOAc (20 mL) and washed with 0.5 N HCl (8 mL), Brine (8 mL) and dried over anhydrous Na2SO4. After removal of solvents under reduced pressure, the residue was purified by flash silica gel column chromatography, eluted with 10% MeOH in DCM, to afford 4-(2-(3-ethoxy-3-oxopropyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid (0.35 g) as a light yellow solid.
Reaction SMILES: O.O[CH:3]1[C:20]2[CH:19]3[CH2:21][CH2:22][CH:16]([CH:17]=[CH:18]3)[C:15]=2[CH:14](O)[C:13]2[C:4]1=[CH:5][C:6]1[S:10][C:9](=[S:11])[S:8][C:7]=1[CH:12]=2>N1C=CC=CC=1>[S:8]1[C:7]2[CH:12]=[C:13]3[C:4](=[CH:5][C:6]=2[S:10][C:9]1=[S:11])[CH:3]=[C:20]1[C:15]([CH:16]2[CH2:22][CH2:21][CH:19]1[CH:18]=[CH:17]2)=[CH:14]3
Reactant: OC1C2=C(C3C=CC2CC3)C(O)c2cc3sc(=S)sc3cc21
Solvent: O
Solvent: c1ccncc1
Product: S=c1sc2cc3cc4c(cc3cc2s1)C1C=CC4CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In pyridine (30 mL), the 5,10-dihydroxy-5,10-dihydro-6,9-dihydro-6,9-ethanoanthra[2,3-d] [1,3]dithiol-2-thione: 1-6 (1.03 g) was dissolved, and cooled to 0° C. in an ice bath. Thereafter, phosphonyl chloride (0.81 mL) was added in the cooled mixture, and stirred for 2 hours. After completion of the reaction, the mixture was poured into iced water, and then the obtained precipitate was recovered through filtration.
Reaction SMILES: C[O-].[Na+].[C:4](O)(=[O:6])C.C(O)(=O)C.IC1C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1.Cl>CO>[CH3:4][O:6][CH:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Ic1ccccc1
Solvent: CO
Product: COC(=O)C(OC)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 15.6 %

Procedure:
A 28% solution of sodium methoxide in methanol (12.8 g) and iodobenzene diacetate (7.15 g) were added to a solution of methyl 4-methoxyphenylacetate (4.0 g) in methanol (60 mL), and the reaction solution was stirred at room temperature for five days. 1 N hydrochloric acid (67 ml) was added dropwise to the reaction solution under ice-cooling, and methanol was evaporated from the reaction solution under reduced pressure. Ethyl acetate was added to the remaining aqueous layer, and the organic layer was separated. The resulting organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) to obtain 725 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([OH:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:31][C:32]1[C:37]([F:38])=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][C:33]=1[F:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([O:22][CH2:31][C:32]3[C:33]([F:41])=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[C:37]=3[F:38])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(F)c(CCl)c1F
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(O)cc(C)cc12)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(OC)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 80 mg (0.20 mmol) of rac-(1-{[(7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl)carbonyl]amino}-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 141A and 38 mg (0.20 mmol) of 2-(chloromethyl)-1,3-difluoro-4-methoxybenzene from Example 133A in 2 ml of DMF was admixed with 129 mg (0.396 mmol) of caesium carbonate. The resulting suspension was stirred at RT for 72 h. The reaction mixture was diluted with dichloromethane (15 ml) and extracted with saturated aqueous sodium hydrogencarbonate solution (10 ml). The organic phase was concentrated under reduced pressure, which gave a crude material that contained the target compound in a multicomponent mixture (30% pure). The crude material was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:24][CH3:25])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:21]C)[N:11]2[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([NH2:23])[N:6]=1.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:23][C:7]1[N:6]=[C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:24][CH3:25])[N:13]=[C:12]2[C:8]=1[NH:9][C:10](=[O:21])[N:11]2[CH2:14][CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CCC(C)COc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCC(C)COc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
To a solution of 2-[(2-methylbutyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (41 mg) in dry MeOH (4.5 mL) was added 4N HCl in 1,4-dioxane (0.766 mL) and the reaction mixture was stirred at room temperature for 3 h. The reaction was neutralised with 2M sodium hydroxide solution and concentrated in vacuo. The resulting white residue was taken up in water (20 mL) and was filtered under reduced pressure to give the title compound as an off-white solid (20 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8])=[O:4].[N:27]1([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]([CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8])=[O:4]
Reactant: COC(=O)CNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: COC(=O)CNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(methoxycarbonyl-methyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][CH2:18][C:17]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)#[CH:25].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[CH2:1]([C:8]1[C:13]([C:25]#[C:24][C@:26]2([OH:34])[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][CH2:18][C:17]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc(N2CCC3(C2)OCCO3)nc1Cc1ccccc1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O[C@]1(C#Cc2ccc(N3CCC4(C3)OCCO4)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of 3.0 g of 2-benzyl-3-iodo-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine, 1.07 g of (3R)-3-ethynyl-3-quinuclidinol, 82 mg of tetrakis(triphenylphosphine)palladium (0), 68 mg of cuprous iodide, 2.0 ml of triethylamine and 7 ml of methanol was stirred at room temperature overnight in a nitrogen atmosphere. The reaction solution was partitioned between aqueous dilute ammonia-ethyl acetate, washed with washed with water, dried over anhydrous magnesium sulfate and then concentrated. 10 ml of tetrahydrofuran was added to the residue to dissolve under heating, and to the mixture was added 15 ml of ethyl acetate. The mixture was filtered through 10 g of NH-silica gel, washed with ethyl acetate, and concentrated. The residue was crystallized from ethyl acetate, to give 2.79 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1COCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[CH:6][C:7]=1[C:8]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:10]
Reactant: O=C(O)c1cnccc1Cl
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1cnccc1Cl)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
Combine 4-chloronicotinic acid (0.10 g, 6.0 mmol) and 1,1′-carbonyldiimidazole (0.97 g, 6.0 mmol) in dry THF (15 mL). Stir at room temperature under nitrogen for 90 min. Add morpholine (1.58 mL, 18.0 mmol) and stir at room temperature under nitrogen for 15 hours. Dilute with dichloromethane, wash with saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride. Separate the layers and dry the organic layer over magnesium sulfate. Concentrate in vacuo. Purify the crude residue by column chromatography [5% to 25% (10% 2 M ammonia/methanol solution in dichloromethane)/dichloromethane] to give the title compound (1.17 g, 86%). MS (ES) m/z 227 [M+1]+.
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]3[N:25]([CH3:26])[CH:24]=[CH:23][C:10]3=[N:11][C:12]=2[C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH2:3]1.[C:27]1(=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[NH:28]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:37]=[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[N:28]1[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]3[N:25]([CH3:26])[CH:24]=[CH:23][C:10]3=[N:11][C:12]=2[C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH3:14])[CH2:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1N1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1N1CCC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Yield: 58.9 %

Procedure:
A mixture of tert-butyl ((1S)-1-(6-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (250 mg, 0.694 mmol), isoindoline-1,3-dione (153 mg, 1.04 mmol) and PPh3 (328 g, 1.25 mmol) in THF (2 mL) was stirred at 0° C. Next, diethyl azodicarboxylate (217 mg, 1.25 mmol) was added dropwise at 0° C. and the mixture was stirred at 20° C. for 16 hours. The solvent was evaporated in vacuo, and the residue was purified by preparative TLC to give the title compound as a white solid (200 mg, 42.3%). ESI-MS m/z [M+H]+ calc'd for C22H31N5O4, 490. found 490.
Reaction SMILES: Cl[C:2]1[C:3]([CH:16]=O)=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH2:19][SH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[CH2:9]([O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]2[S:20][C:19]([C:18]([O:22][CH3:23])=[O:21])=[CH:16][C:3]=12)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CS
Reactant: O=Cc1c(Cl)cncc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(OCc3ccccc3)cncc2s1
Temperature: 25 °C
Yield: 55 %

Procedure:
To an ice cold solution of Example 236B (4.2 g, 17 mmol) in anhydrous tetrahydrofuran (42 mL) under nitrogen atmosphere was added methyl thioglycolate (1.83 mL, 20.4 mmol) followed by powdered cesium carbonate (6.65 g, 20.4 mmol). Then the reaction mixture was allowed to warm to room temperature with stirring under nitrogen. After 30 minutes the reaction was refluxed for 15 minutes and cooled to room temperature. The reaction mixture was quenched with ice (50 mL) and partitioned with ethyl acetate (250 mL). The organic layer separated was washed with an ice cold solution of saturated NaCl (3×60 mL), dried (Na2SO4), and concentrated under reduced pressure to obtain the crude product which was recrystallized from methanol. The mother liquor was purified by flash chromatography on silica gel eluting with 7% acetone-hexane. The combined fractions gave the title compound in 55% yield (3.07 g). MS (APCI) m/e: 300 (M+H)+; 1H NMR (300 MHz, DMSO-d6) d: 3.92 (s, 3H), 5.42 (s, 2H), 7.35-7.47 (m, 3H), 7.52-7.57 (m, 2H, Ar—CH), 8.12 (s, 1H,), 8.36 (s, 1H), 8.98 (s, 1H).
Reaction SMILES: [NH2:1][OH:2].Cl.C([O-])([O-])=O.[K+].[K+].[O:10]1[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH:12]=[C:11]1[C:19]#[N:20]>O.CCO>[OH:2][NH:1][C:19]([C:11]1[O:10][C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH:12]=1)=[NH:20]
Reactant: NO
Reactant: N#Cc1cc2cnccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1cc2cnccc2o1
Temperature: 70 °C

Procedure:
A solution of NH2OH.HCl (1.22 g, 17.5 mmol) and K2CO3 (1.21 g, 8.75 mmol) in H2O (3 mL) was added to a stirred solution of furo[3,2-c]pyridine-2-carbonitrile (1.26 g, 8.75 mmol) in EtOH (6 mL). The reaction was heated to 70° C. for 2 h, before being concentrated in vacuo. The remainder was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc (8×), then the combined organic extracts were washed with brine, back-extracting with EtOAc (4×). The combined organic extracts were dried (MgSO4), filtered, and concentrated to give the title compound: m/z (ES+)=178.0 [M+H]+.