Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:42])[C@H:3]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[C:27]([C:38]([F:41])([F:40])[F:39])[CH:26]=3)[O:22][N:21]=2)=[CH:16][CH:15]=1)[C:4]([O:6]C(C)(C)C)=[O:5].Cl>O1CCOCC1>[CH3:1][CH:2]([CH3:42])[C@H:3]([NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[C:27]([C:38]([F:40])([F:39])[F:41])[CH:26]=3)[O:22][N:21]=2)=[CH:18][CH:19]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(CCN[C@H](C(=O)OC(C)(C)C)C(C)C)cc3)no2)cc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(CCN[C@H](C(=O)O)C(C)C)cc3)no2)cc1C(F)(F)F
Temperature: 70 °C

Procedure:
To (2S)-tert-butyl 3-methyl-2-(4-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)phenethylamino)butanoate (86 mg; 0.15 mmol) was added 4M HCl in dioxan and the mixture was heated in a tube at 70° C. for 3 hours. The solvent was then removed in vacuo and the residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.56 (1H, s), 8.50 (1H, d, J=8.1 Hz), 8.08 (2H, d, J=7.8 Hz), 7.65 (1H, d, J=8.1 Hz), 7.51 (2H, d, J=8.0 Hz), 7.40-7.38 (2H, m), 7.31 (1H, td, J=7.0, 2.3 Hz), 7.18 (1H, d, J=7.6 Hz), 3.09-2.80 (5H, m), 2.16 (3H, s), 1.99-1.90 (1H, m), 0.96 (6H, dd, J=6.8, 2.1 Hz). LC/MS (Method B): 524 (M+H)+. HPLC (Method H) Rt 9.20 min (Purity: 97.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][CH:16]=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>C(NCC)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:26]=[C:25]([CH2:24][OH:27])[N:12]4[CH:11]=2)[CH:15]=[CH:16][CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CO)cc3cccc(c1=O)c32
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-3-quinolinecarboxamide (prepared according to the general procedure in WO 9932450, 0.53 g), copper iodide (0.11 g), bis(triphenylphosphine)palladium(II) chloride (0.043 g) and propargyl alcohol (0.085 mL) in 20 mL diethylamine is stirred at room temperature for 18 h. The solid in the reaction mixture is filtered, washed with hexanes and dried. The solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (gradient from CH2Cl2 to 3% MeOH/CH2Cl2) affords N-(4-chlorobenzyl)-2-(hydroxymethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a white solid (0.23 g, 52%), m.p. 211-213° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]2[C:7]=1[O:6][C@@H:5]([CH2:4][NH2:1])[CH2:14][CH2:13]2
Reactant: [N-]=[N+]=NC[C@H]1CCc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H]1CCc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (R)-2-(azidomethyl)-8-(2,6-dichlorophenyl)-6-fluorochroman (0.26 g, 0.73 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.74 g, 2.2 mmol) and the reaction mixture stirred at room temperature for 2 days. The brown suspension was then filtered through celite, the filter cake washed with ethyl acetate (50 mL) and the combined filtrates concentrated under vacuum. The solvent was removed under vacuum. Chromatography with 0–10% methanol in methylene chloride plus 1% NH4OH afforded {[(R)-8-(2,6-dichlorophenyl)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]methyl}amine as a colorless oil. The colorless oil was dissolved in ethyl acetate and made into its hydrochloride salt (0.18 g, 67%) as a white crystalline solid using excess ethereal hydrochloric acid, mp 190–192° C.; MS (ES) m/z 326.0 ([M+H]+); [α]D25=−4.39° (c 1% solution in MeOH).
Reaction SMILES: C(O[C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)C.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C1COCC1>[C:11]1([C:4]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC1=CC(=O)CCC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1C=C(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., 3-ethoxycyclohex-2-enone (2 g, 14.3 mmol) in THF (2 mL) was added phenylmagnesium bromide (1.0 M solution in THF, 15.0 mL) slowly. After the addition, the reaction mixture was warmed up to room temperature and stirred for 1 hr. Then 1N HCl solution (15.16 mL) was added to quench the reaction and the organic layer was separated. The aqueous layer was extracted with dichloromethane 3 times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the title compound as yellow solid (quantitative yield). 1H NMR (400 MHz, CDCl3) δ 2.16 (2H, dt, J=4, 12 Hz), 2.48 (2H, t, J=8 Hz), 2.77 (2H, dt, J=2, 6 Hz), 6.41 (1H, t, J=2 Hz), 7.39-7.41 (3H, m), 7.52-7.54 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][NH:10]1.F[C:21](F)(F)S(OC)(=O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]1[CH3:21]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1c[nH]n(-c2ccccc2OC)c1=O
Product: CCOC(=O)c1cn(C)n(-c2ccccc2OC)c1=O
Yield: 66 %

Procedure:
In the same manner as in Reference Example 64 and using ethyl 2-(2-methoxyphenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (3.6 g, 14 mmol) and methyl trifluoromethanesulfonate (3 mL) as starting materials, the title compound (2.5 g, 66%) was obtained as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18](N)=[O:19])[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:29])[N:13]2[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28].[OH-].[Na+].O.Cl[O-].[Na+].[O:36]1CCOC[CH2:37]1>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]([O:36][CH3:37])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:29])[N:13]2[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28]
Reactant: C1COCCO1
Reactant: NC(=O)c1cc(-c2ccccc2Cl)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2c1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2Cl)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2c1
Temperature: 60 °C

Procedure:
To 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2-dihydroquinoline-7-carboxamide (920 mg) in dioxane (330 mL) was added 5N NaOH (10 mL) and water (41 mL) followed by sodium hypochlorite (19.3 mL of a 10-13% aqueous solution) and the reaction mixture heated to 60° C. for 2 h. The cooled reaction mixture was then poured into brine and extracted into ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.61-7.32 (m, 8H); 6.48 (d, J=2.1 Hz, 1H); 6.45 (d, J=9.7 Hz, 1H); 5.73 (d, J=2.1 Hz, 1H; 4.00 (br.s, 2H). Mass spectrum: m/z 415 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:34])[CH:40]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Br)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccc(Cl)c2)NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The procedure described in Example 125 was repeated, except that ((RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (315 mg) was reacted with 3-chlorophenol (113.2 μl) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (214.48 mg).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH3:29])[CH:10]=[C:11]([C:27]#[N:28])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]=[O:26])=[CH:15][CH:14]=1)=[O:7])[CH3:4].O>CO>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH3:29])[CH:10]=[C:11]([C:27]#[N:28])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][OH:26])=[CH:17][CH:18]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ccccc3C=O)cc2)c(C#N)cn1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3CO)cc2)c(C#N)cn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add sodium borohydride (0.79 g, 2.1 mmol) to 4-cyano-3-(2′-formyl-biphenyl-4-yl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.50 g, 1.40 mmol, prepared in example E-23) in methanol at 0° C. with stirring. After 1 hour, allow the reaction mixture to warm to ambient temperature. After 2 hours, pour the reaction mixture into water and extract with ethyl acetate. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexane to provide the title compound. Mass spectrum: EI+=360.2
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[N:27]([CH2:28][C:29](=[O:37])[NH:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:26]4[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:25]=4[N:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22][C:23]3[N:27]([CH2:28][C:29](=[O:37])[NH:30][CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)[C:26]4[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:25]=4[N:24]=3)[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3nc4cc(C#N)ccc4n3CC(=O)NC3CCCCC3)cc2)CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1nc2cc(C#N)ccc2n1CC(=O)NC1CCCCC1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[4-(1-tert-butoxycarbonylpiperidin-4-yloxy)-phenylaminomethyl]-1-(cyclohexylcarbamoylmethyl)-5-cyanobenzimidazole (247 mg) in dimethylformamide (2.5 ml) were added potassium carbonate (175 mg) and ethyl bromoacetate (0.07 ml), and the mire was stirred at room temperature for 24 hours. Thereto were added potassium carbonate (175 mg) and ethyl bromoacetate (0.07 ml), and the mixture was stirred at room temperature for 24 hours. Further, ethyl bromoacetate (0.07 ml) was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (124 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14](O)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[NH2:25][CH2:26][CH2:27][NH:28]C(OC(C)(C)C)=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl>C(Cl)Cl.O.O1CCOCC1>[NH2:25][CH2:26][CH2:27][NH:28][C:14]([C:5]1[S:6][C:7]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[C:3]([C:1]#[N:2])[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(N2CCOCC2)sc(C(=O)NCCN)c1-c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (3.10 g, 8.2 mmol) and N-(2-aminoethyl)(tert-butoxy)carboxamide (1.98 gr, 12.3 mmol) in methylene chloride (60 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.15 gr, 16.4 mmol) and 1-hydroxybenzotriazole (2.22 gr, 16.4 mmol) at room temperature. The solution was allowed to stir overnight. The reaction was diluted with methylene chloride and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the intermediate boc-protected product as a yellow solid. The material was dissolved in dioxane (4 mL) and a solution 4N HCl in dioxane (9 mL) was added. The solution was stirred at room temperature for 30 minutes. The solvents were evaporated and the residue was dried under vacuum overnight. The product was converted to the free base by suspension in methylene chloride followed by addition of sodium carbonate solution. The layers were separated and the aqueous layer was extracted twice with methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the product as a free base (2.55 gr, 67%). LCMS: (FA) ES+ 463. 1H NMR (400 MHz, d1-chloroform) δ: 7.59-7.55 (m, 1H), 7.43-7.30 (m, 2H), 3.90-3.82 (m, 4H), 3.64-3.57 (m, 4H), 3.53-2.85 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:16][C:12]=2[C:11](=[O:23])[N:10]([CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[C:9]1=[O:37].[ClH:38]>O1CCOCC1>[ClH:38].[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:16][C:12]=2[C:11](=[O:23])[N:10]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:9]1=[O:37]
Reactant: Cc1ncoc1Cn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2sc(-c3ccccc3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ncoc1Cn1c(=O)n(C2CCNCC2)c(=O)c2sc(-c3ccccc3)cc21

Procedure:
According to the procedure described for compound B92 tert-butyl 4-{1-[(4-methyl-1,3-oxazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (701 mg, compound B72) and a solution of hydrogen chloride in 1,4-dioxane (5.0 ml, 6.8 M) are reacted in 1,4-dioxane (25 ml) to afford the title compound as a solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1cccc(CN=C=O)c1
Product: COc1cccc2c1ncc1c(=O)n(Cc3cccc(C)c3)c(=O)n(C3CCCC3)c12
Yield: 43.3 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(3-methyl-benzyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (18 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanatomethyl-3-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]=[C:3](N1CCOCC1)[CH2:4][CH3:5].[CH:12]([CH:14]=[CH2:15])=[O:13]>O1CCOCC1.Cl>[CH3:15][C:14]1[C:12](=[O:13])[CH:2]([CH3:1])[CH2:3][CH2:4][CH:5]=1
Reactant: CC=C(CC)N1CCOCC1
Reactant: C=CC=O
Agent: Cl
Solvent: C1COCCO1
Product: CC1=CCCC(C)C1=O
Reaction time: 8 h

Procedure:
26.1 g (0.168 mole) of N-(3-pent-2-enyl)-morpholine is slowly added dropwise to a solution, cooled to 0°, of 16.8 g (0.3 mole) of freshly distilled acrolein in 150 ml of dioxane, with the temperature rising to 5° C. After completion of the addition, stirring is maintained for half an hour with ice-cooling, and the mixture is then allowed to stand overnight. The solvent is afterwards evaporated off and the oil obtained as residue is dissolved in 120 ml of 20% aqueous hydrochloric acid. On stirring of the acidified solution at room temperature, there precipitates an oil which, after one to two days' stirring, is taken up in ether. The aqueous phase is extracted a further five times with ether. The combined ether phases are dried over magnesium sulphate and the ether is distilled off. There is obtained 18.5 g of crude 2,6-dimethyl-cyclohex-2-en-1-one in the form of oil, which yields, after distillation in a water-jet vacuum, 15.0 g of 2,6-dimethyl-cyclohex-2-en-1-one (72% of theory); b.p. 62°-63° C./ 10 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][C:29]1([C:33](O)=[O:34])[CH2:32][O:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:33]([C:29]5([CH3:28])[CH2:32][O:31][CH2:30]5)=[O:34])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C(=O)O)COC1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: CC1(C(=O)N2CC[C@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)C2)COC1
Yield: 42 %

Procedure:
According to the procedure for compound 398 using 3-methyloxetane-3-carboxylic acid (15 mg, 0.13 mmol) afforded 17.7 mg (42% yield) of 482, as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]=[C:4]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[NH:3]1.[CH2:17]([NH:19][C:20](=[O:34])[NH:21][C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[C:23]=1[C:31](O)=[O:32])[CH3:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH2:17]([NH:19][C:20](=[O:34])[NH:21][C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[C:23]=1[C:31]([N:9]1[CH2:8][CH2:7][C:6]2([N:5]=[C:4]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[NH:3][C:2]2=[O:1])[CH2:11][CH2:10]1)=[O:32])[CH3:18]
Reactant: CC(=O)NCC1=NC2(CCNCC2)C(=O)N1
Reactant: CCNC(=O)Nc1sc2ccccc2c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1sc2ccccc2c1C(=O)N1CCC2(CC1)N=C(CNC(C)=O)NC2=O
Reaction time: 12 h

Procedure:
Solutions each of 2B (1.0 equivalent), 2-(3-ethylureido)benzo[b]thiophene-3-carboxylic acid (2C, 1.25 equivalents), DMF (0.14 M), EDC (1.25 equivalents), and HOBT (1.25 equivalents) is added triethylamine (1.0 equivalent) at room temperature. After stirring for 12 hr, the reaction is complete as determined by LCMS analysis. The reaction mixture is then partitioned between ethyl acetate and water and the separated organics is dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory LCMS provides N-((8-(2-(3-ethylureido)benzo[b]thiophene-3-carbonyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-2-yl)methyl)acetamide (2), respectively.
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:9]([O:11]CC)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[ClH:1].[C:2]1([CH:8]([N:14]2[CH2:15][CH2:16][S:17][CH2:18][CH2:19]2)[C:9]([OH:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(c1ccccc1)N1CCSCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C(c1ccccc1)N1CCSCC1
Yield: 35.2 %

Procedure:
37% aq HCl (1.1 ml, 13.5 mmol) was added dropwise to a solution of ethyl 2-phenyl-2-thiomorpholinoacetate (0.36 g, 1.35 mmol) in dioxane (11 ml). The mixture was stirred at reflux overnight. Then 37% aq HCl (1.1 ml, 13.5 mmol) was added again and the reaction was refluxed for additional 24 hours. Solvents were evaporated, the residue was triturated with acetonitrile and collected by suction filtration to obtain 2-phenyl-2-thiomorpholinoacetic acid hydrochloride (0.13 g, 34.4% yield) as a off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:54])[C:34]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41](B4OC(C)(C)C(C)(C)O4)[CH:40]=3)=[CH:35][NH:36]2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>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>[C:25]([C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:54])[C:34]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:2]4[CH:3]=[C:4]([NH:10][C:11]5[CH:16]=[CH:15][C:14]([C:17]([N:19]6[CH2:24][CH2:23][O:22][CH2:21][CH2:20]6)=[O:18])=[CH:13][N:12]=5)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=4)[CH:40]=3)=[CH:35][NH:36]2)=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(C)(C)c1ccc2c(=O)c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)c[nH]c2c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2cccc(-c3c[nH]c4cc(C(C)(C)C)ccc4c3=O)c2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 17 %

Procedure:
A solution of 5-Bromo-1-methyl-3-[5-(morpholine-4-carbonyl) -pyridin-2-ylamino]-1H-pyridin-2-one (19 mg, 0.050 mmol), 7-tert-Butyl-3-[3-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-quinolin-4-one (20 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0.0052 mmol), and sodium carbonate (16 mg, 0.15 mmol) in 2 mL 1,2-dimethoxyethane and 1 mL water was microwaved at 170° C. for 12.5 minutes. The resulting mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by preparative TLC (5% methanol/dichloromethane) to yield 7-tert-Butyl-3-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1H-quinolin-4-one (5.7 mg, 0.0085 mmol). MS (ESI) 590.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:19][CH3:20]>CN(C=O)C>[CH2:19]([O:10][C:9]([C:3]1[C:2]([Br:1])=[CH:6][S:5][C:4]=1[CH:7]=[O:8])=[O:11])[CH3:20]
Reactant: CCI
Reactant: O=Cc1scc(Br)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)csc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.5 %

Procedure:
4-Bromo-2-formyl-thiophene-3-carboxylic acid (0.16 g, 0.68 mmol), K2CO3 (0.188 g, 1.36 mmol), and 4 mL of anhydrous DMF were stirred at room temperature for 10 min, then iodoethane was added (0.128 g, 0.8 mmol) dropwise. The reaction solution was stirred at 50° C. for 3 h. The reaction mixture was cooled, extracted with EA (3×50 mL), concentrated and the residue was purified by TLC (PE/EA=8/1) to give 0.4 g of the title compound (yield: 63.5%).