Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 100 °C

Procedure:
To a 150 mL pressure vessel was added ethyl 2-chloronicotinate (3.1 g, 17 mmol), 4-(pyridin-2-ylamino)phenol (3.14 g, 17 mmol), and cesium carbonate (5.8 g, 18 mmol) followed by DMSO. The solution was sealed and heated to 100° C. for 20 h. It was cooled and diluted with water and extracted five times with ethyl acetate. The combined organic were washed with brine, dried over sodium sulfate, filtered, and concentrated to a dark brown residue. The residue was taken up in dichlormethane and adsorbed onto silica gel before being purified with flash chromatography (0 to 50% ethyl acetate:hexanes), affording the product as a pale orange solid. MS (ESI, pos. ion) m/z: 336.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](Br)[C:6]([CH:10]2[CH2:12][CH2:11]2)=[C:5]([F:13])[C:3]=1[NH2:4].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:14])[C:6]([CH:10]2[CH2:12][CH2:11]2)=[C:5]([F:13])[C:3]=1[NH2:4]
Reactant: CB1OB(C)OB(C)O1
Reactant: Nc1c(Cl)cc(Br)c(C2CC2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(Cl)c(N)c(F)c1C1CC1
Temperature: 25 °C

Procedure:
2-Chloro-4-bromo-5-cyclopropyl-6-fluoroaniline (14.0 g, 53 mmol), trimethylboroxine (13.4 g of 50% solution in THF, 53 mmol), tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.2 mmol) and potassium carbonate (14.0 g, 101 mmol) are combined and stirred in 250 mL of a 4:1 DME/water solution. The mixture is degassed by repeated alternating application of vacuum and positive nitrogen pressure (10×). The mixture is heated to reflux temperature for 2 days and then cooled to room temperature. Most of the DME is removed by rotary evaporator and the residual mixture is partitioned between Et2O (500 mL) and water (500 mL). The organic phase is washed with brine (3×250 mL), dried (MgSO4) and concentrated by rotary evaporator. The crude product is purified using flash chromatography (5% CH2Cl2/hexanes) to give 2-chloro-4-methyl-5-cyclopropyl-6-fluoroaniline a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH:4]=[CH:3]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][CH:5]1[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: CC1(C)C=CC(=O)CC1
Product: CC1(C)C=CC(NCc2ccccc2)CC1

Procedure:
Using the procedure outlined in Example 1, 4,4-dimethyl-2-cyclohexen-1-one and benzylamine were converted to the title compound: RT=2.39 min; m/z (ES+)=216.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Br:22][CH2:23][C:24](Br)=[O:25].C(OCC)(=O)C>ClCCl.O>[Br:22][CH2:23][C:24]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:25]
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)CCCN1C(=O)CBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of diethyl 2,2-pyrrolidinedicarboxylate (D63, 900 mg) in dichloromethane (9 mL) at 0° C., potassium carbonate (0.5M solution, 12.5 mL) and bromoacetyl bromide (0.55 mL) were added. The resulting mixture was stirred at 0° C. for 2 hours. The mixture was then diluted with water and then allowed to reach r.t. Ethyl acetate (15 mL) was added and phases were separated. The aqueous phase was then extracted with ethyl acetate (2×10 mL) and washed with brine (20 mL). The organic phase was dried and concentrated in vacuo to give the desired compound (1.06 g) as orange oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+:15]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH2:8][CH:9]([C:1]3[CH:6]=[CH:5][N:15]=[CH:3][CH:2]=3)[C:10](=[O:13])[NH:11][N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1NN=C(c2ccccc2)CC1c1ccncc1
Reaction time: 8 h
Yield: 50 %

Procedure:
To a 200 ml, three-necked, round-bottomed flask equipped with a magnetic stir bar, 150 ml pressure-equalizing addition funnel, reflux condenser and a glass stopper, was added 21 g (135 mmole) of 4-bromopyridine and 70 of anhydrous THF. The system was oven-dried and flushed with argon before use. 135 ml (135 mmole) of THF solution of phenylmagnesium bromide (1M) was placed in the pressure-equalizing addition funnel. Then, the grignard solution was added dropwise over a period of 10 minutes. After the addition, the reaction was stirred for 15 minutes for completion. The solution of Grignard reagent was then obtained. A solution of 4-pyridylmagnesium bromide obtained above was added to a hot suspension of 6-phenylpyridazinone compound 7.8 g (45 mmole) in dry toluene (50 ml). The mixture was refluxed for 8 h, left overnight at ambient temperature, then decomposed with a saturated solution of ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with 100 ml of ethyl acetate. The solvent was removed and the residue was crystallized from ethanol. The crystals were collected by filtering and dried over a medium frit sintered glass funnel in vacuo to give 5.6 g of white crystals. Yield was 50%, confirmed by ESI-MS. ESI-MS: m/z 252.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2.[Cl:19][CH2:20][C:21]1[O:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:24][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[ClH:19].[C:26]1([C:23]2[O:22][C:21]([CH2:20][O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH2:8][CH:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:6][CH2:5]4)=[N:25][N:24]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClCc1nnc(-c2ccccc2)o1
Reactant: Oc1ccc2c(c1)CCC(CN1CCCCC1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cl
Product: c1ccc(-c2nnc(COc3ccc4c(c3)CCC(CN3CCCCC3)C4)o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.2 %

Procedure:
To a solution of 6-hydroxy-2-piperidinomethyltetralin (141 mg, free form of Reference Example 19) and 2-chloromethyl-5-phenyl-1,3,4-oxadiazole (148 mg) in DMF (3 ml) was added potassium carbonate (143 mg) and the reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent:ethyl acetate:methanol=10:1) and alumina column chromatography (eluent:ethyl acetate:hexane=1:4), and then converted into its hydrochloride, which was further recrystallized from methanol-diethyl ether to obtain the titled compound (175 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=2.C[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].FC1C=[N+]([O-])C2C(C=1[N+]([O-])=O)=CC=CC=2>>[Cl:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([O:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=3)[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(O)cc1
Reactant: Clc1ccc2cc(Br)cnc2c1
Reactant: CCOC(=O)C(C)Br
Agent: O=[N+]([O-])c1c(F)c[n+]([O-])c2ccccc12
Product: CCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1

Procedure:
Ethyl 2-{4-[(7-chloroquinolin-3-yl)oxy]phenoxy}propionate (5) was prepared from 3-bromo-7-chloroquinoline, 4-methoxyphenol and ethyl 2-bromopropionate following essentially the same procedure as that described in Example 1 parts (a), (b) and (c). The product, a pale yellow oil, was characterized by its proton magnetic resonance spectrum. Pmr spectrum (CDCl3 ; δ in ppm): 9.75 (1H, d); 8.06 (1H, bs); 7.41 (3H, m); 7.00 (4H, s); 4.75 (1H, q); 4.21 (2H, q); 1.62 (3H, d); 1.27 (3H, t).
Reaction SMILES: [N:1]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:2]1[C:3]([N:5]([CH2:14][CH3:15])[CH2:6][C:7]([O:9]C(C)(C)C)=[O:8])=[O:4].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:2]1[C:3]([N:5]([CH2:14][CH3:15])[CH2:6][C:7]([OH:9])=[O:8])=[O:4]
Reactant: CCN(CC(=O)OC(C)(C)C)C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC(=O)O)C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 106.5 %

Procedure:
To a solution of Cbz-D-hPro-N(Et)Gly-O-t-Bu (5 g, 12.4 mmol) in dichloromethane (50 mL) was added anisole (2.5 mL) and trifluoroacetic acid (50 mL). The mixture was allowed to stir for several hours at room temperature. The solvents were removed in vacuo and the resulting oil was partitioned between saturated aqueous NaHCO3 and diethyl ether. The layers were separated and the organic phase was extracted once with saturated aqueous NaHCO3. The combined aqueous phase was adjusted to pH 2 with 5N aqueous HCl and extracted three times with ethyl acetate (150 mL). The combined ethyl acetate extracts were dried with MgSO4, filtered, and concentrated to give a colorless oil (4.6 g, 106%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][CH2:26][C@H:13]4[C:12]=23)[O:5][N:4]=1.C(N(C(C)C)[CH:30]([CH3:32])[CH3:31])C.[CH2:36](Br)[CH:37]=[CH2:38]>CN(C)C=O>[CH2:32]([N:1]([CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][CH2:26][C@H:13]4[C:12]=23)[O:5][N:4]=1)[CH2:38][CH:37]=[CH2:36])[CH:30]=[CH2:31]
Reactant: C=CCBr
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCN(CC=C)Cc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Yield: 74.5 %

Procedure:
2 g (5.95 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, 30 ml of N,N-dimethylformamide, 3.1 ml (17.8 mmol) of N-ethyldiisopropylamine and 1.1 ml (13.1 mmol) of allyl bromide were stirred at room temperature for 1.5 hours. The reaction solution was chromatographed on 250 g of silica gel while eluting with methylene chloride/ethyl acetate 7/3. There were obtained 2 g (81%) of (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 175°-177°.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]=[CH:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](I)[CH3:22].O>CN(C)C=O>[CH2:21]([N:16]1[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12][C:11]1=[N:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH3:22]
Reactant: CC(C)c1ccccc1N=C1N=CC(C)(C)CS1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CC(C)(C)CSC1=Nc1ccccc1C(C)C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g) in N,N-dimethylformamide (2 ml) was added under ice-cooling 60% sodium hydride (0.05 g). The mixture was stirred for 30 minutes. Ethyliodide (0.17 g) was added thereto. The mixture was stirred at room temperature for 2 hours. To a reaction mixture was added water (30 ml), extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 3-ethyl-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.21 g, yield: 71%) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:18]=[C:17]([C:19]([O:21][CH3:22])=O)[CH:16]=[CH:15][CH:14]=1)[C:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6]2.[OH2:29].[NH2:30][NH2:31]>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:18]=[C:17]([C:19]3[O:21][C:22](=[O:29])[NH:31][N:30]=3)[CH:16]=[CH:15][CH:14]=1)[C:7]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:6]2
Reactant: O
Reactant: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(OC)ccc32)n1
Reactant: NN
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(-c2n[nH]c(=O)o2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-(5-methoxy-2-phenylindol-1-ylmethyl)pyridine-2-carboxylate (70 mg) in methanol (1.2 mL) and tetrahydrofuran (0.4 mL) was added hydrazine monohydrate (0.091 mL). This mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (1 mL), and then 1,1′-carbonyldiimidazole (46 mg) was added thereto at room temperature. The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (48 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 5.52 (2H, s), 6.62 (1H, s), 6.65-6.80 (2H, m), 7.13 (1H, d, J=2.5 Hz), 7.25 (1H, d, J=8.9 Hz), 7.35-7.50 (3H, m), 7.55-7.65 (2H, m), 7.75 (1H, d, J=7.9 Hz), 7.85 (1H, t, J=7.9 Hz), 12.78 (1H, br s). ESI-MS (m/z): 399 (M+H)+
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:15][CH2:14][S:13][C:9]=3[C:10](=O)[O:11][C:6]=2[CH:5]=[C:4]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[CH:3]=1.[CH2:25]([Mg]Br)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:25]([C:10]1([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]2[S:13][CH2:14][CH2:15][C:8]=2[C:7]2[C:2]([OH:1])=[CH:3][C:4]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[CH:5][C:6]=2[O:11]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCC[Mg]Br
Reactant: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3
Product: CCCCCCC1(CCCCCC)Oc2cc(C(C)C(C)CCCCC)cc(O)c2C2=C1SCC2

Procedure:
By reacting 1,2-dihydro-9-hydroxy-7-(3-methyl-2-octyl)-4-oxo-4H-thieno[2,3-c][1]benzopyran with n-hexylmagnesium bromide, using the manipulative procedure described in Example 8, there is obtained 4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=[C:21]3[NH:22][C:29]2=[O:30])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc(Nc2ccc(OCc3ccccc3)cc2)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cnc2c(c1)[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Yield: 93.6 %

Procedure:
A solution of N2-[4-(benzyloxy)phenyl]-5-methylpyridine-2,3-diamine (0.63 g) and CDI (0.67 g) in THF (20 mL) was refluxed overnight. The mixture was concentrated in vacuo. The residual solid was washed with AcOEt to give 3-[4-(benzyloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.64 g) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.[C:22](#[N:25])[CH:23]=[CH2:24]>CC(O)C>[OH2:7].[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:24][CH2:23][C:22]#[N:25])[CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: C=CC#N
Solvent: CC(C)O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCC#N)C[C@H]1OC
Product: O
Yield: 100 %

Procedure:
To a stirred and refluxed solution of 103 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide in 640 parts of 2-propanol were added 19.7 parts of 2-propenenitrile. The mixture was stirred overnight at reflux temperature and then over weekend at room temperature. Another portion of 3 parts of propenenitrile was added to the mixture at reflux. After stirring for 3 hours at reflux temperature, the reaction mixture was evaporated, yielding 121 parts (100%) of cis-4-amino-5-chloro-N-[1-(2-cyanoethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate (interm. 1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][S:15][CH3:16].OOS([O-])=O.[K+].[OH2:31].C[OH:33]>>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:14][S:15]([CH3:16])(=[O:33])=[O:31]
Reactant: CSCC(CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Reactant: O
Reactant: CO
Agent: O=S([O-])OO
Agent: [K+]
Product: CC(C)(C)OC(=O)NC(CN1C(=O)c2ccccc2C1=O)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl [1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(methylsulfanyl)propan-2-yl]carbamate (10.0 g, 28.6 mmol) in methanol (100 mL) was added Oxone (53.1 g, 85.7 mmol) and water (100 mL). The reaction mixture was stirred at ambient temperature for 3 hours and then quenched with 20% aqueous sodium bisulfite solution, diluted with water, and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl [1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(methylsulfonyl)propan-2-yl]carbamate which was used without further purification. MS ESI calc'd. for C17H22N2O6SNa [M+H]+ 405. found 405. 1H NMR (400 MHz, CD3OD) δ 7.89-7.81 (m, 4H), 4.51-4.48 (m, 1H), 3.88-3.82 (m, 2H), 3.44-3.40 (m, 2H), 3.01 (s, 3H), 1.26 (s, 9H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([NH:23][C@H:24]([C:31]([OH:33])=O)[CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>C(OCC)(=O)C.C(O)(=O)C>[C:34]([O:38][C:39](=[O:42])[CH2:40][NH:41][C:31](=[O:33])[C@H:24]([CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)[NH:23][C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CNC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.2 %

Procedure:
Dicyclohexyl carbodiimide (226 mg) was added to a solution of 273 mg of Nα -t-butoxycarbonyl-β-(4-thiazolyl)-L-alanine and 132 mg of glycine t-butylester in 5 ml of ethyl acetate at 0° C. The reaction solution was stirred at 0° C. for 0.5 hour, then at ambient temperature for 18 hours. 4 drops of glacial acetic acid was then added to the reaction mixture and the mixture filtered. The filtrate was concentrated under vacuum to provide 426 mg of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 4-aminophenylboronic acid pinacol ester with reaction time of 24 h. Chromatography (hexane/ethyl acetate 6:4) gave the title compound as a yellow solid.
Reaction SMILES: C[O-].[Na+].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:13]([O:12][C:4](=[O:11])[CH:5]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:14]
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Yield: 66.6 %

Procedure:
In 200 ml of ethanol, 16.2 g of sodium methoxide were dissolved. Into this solution, 49.5 g of diethyl malonate were dropped and gently refluxed. 37.98 g of benzyl chloride were dropped into the mixture over one hour and the mixture was refluxed for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and water was added to the residue. After extraction with ethyl acetate, the ethyl acetate was dried with sodium sulfate anhydride. After removing the solvent under reduced pressure, followed by purification with distillation, 50 g of 2-benzylmalonic acid diethyl ester were obtained.
Reaction SMILES: [C:1]([NH:5][CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:11]=O.CO.[C:15](=[O:18])([O-])[O-].[K+].[K+]>O>[C:1]([N:5]([CH2:11][O:18][CH3:15])[CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)(C)NC[Si](C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCN(C[Si](C)(C)C)C(C)(C)C
Reaction time: 0.75 h

Procedure:
N-tert-Butyl-N-(trimethylsilylmethyl)amine (N-1) (8.47 g, 53.1 mmol) was added dropwise, over approximately 30 min, via a pressure equalizing addition funnel to a stirred solution of aqueous formaldehyde (5.98 mL of a 37 wt. % solution in water, 79.7 mmol) at 0° C. (ice cooling). After 45 min, methanol (6.45 mL, 159.3 mmol) was added and the resulting solution was saturated with potassium carbonate. After stirring vigorously for approximately 5 h, the aqueous phase was removed. The organic phase was saturated with potassium carbonate and stirred overnight. The reaction mixture was poured into water and extracted three times with diethyl ether. The combined organic extracts were washed with brine, dried (MgSO4) and the volatiles evaporated in vacuo. Distillation (high vacuum; ˜70° C.) of the residual liquid afforded the title compound as a colorless liquid (3.50 g).