Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][C:19]3[N:28]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[C:27](=[O:37])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:38]#[C:39][CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])[N:20]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.CCN=C=NCCCN(C)C.Cl.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][C:19]3[N:28]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[C:27](=[O:37])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:38]#[C:39][CH2:40][CH2:41][CH2:42][C:43]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[O:44])[N:20]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12
Reactant: C1COCCN1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2Cc1nc2cccc(C#CCCCC(=O)O)c2c(=O)n1Cc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2Cc1nc2cccc(C#CCCCC(=O)N3CCOCC3)c2c(=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 4 (16.0 mg, 26 μmol), 4-dimethylaminopyridine (0.6 mg, 5.2 μmol), and EDC hydrochloride (5.3 mg, 28 μmol) in DMF (0.5 mL) was added morpholine (2.3 μL, 26 μmol). The reaction mixture was stirred at RT overnight and then diluted with water (5.0 mL). The resulting solid was collected by filtration and purified by flash column chromatography, eluting with 0-7% methanol in DCM to afford the title compound, Example 5, (7.0 mg, 57%) as a yellow solid: m/z 689/691 (M+H)+ (ES+); Rt 3.54 min; 1H NMR (500 MHz, DMSO-d6) δ: 1.71 (2H, quin), 2.43-2.49 (2H, m), 2.52-2.55 (2H, m), 3.20-3.26 (2H, m), 3.28-3.33 (4H, m), 3.44 (2H, t), 5.28 (2H, s), 5.72 (2H, s), 6.17 (1H, d), 6.78 (1H, t), 6.87 (2H, d), 7.02 (1H, t), 7.10 (1H, d), 7.32 (2H, d), 7.60 (1H, d), 7.67 (1H, d), 7.79 (1H, t), 8.16 (1H, s), 9.75 (1H, s).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[N:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([CH2:40][CH2:41][S:42]([NH2:45])(=[O:44])=[O:43])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>CS(C)=O>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[N:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH:45][S:42]([CH2:41][CH2:40][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)(=[O:43])=[O:44])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2cccnn2)nc1Cl
Reactant: NS(=O)(=O)CCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2cccnn2)nc1NS(=O)(=O)CCc1cccc2ccccc12
Temperature: 90 °C
Reaction time: 72 h
Yield: 89.2 %

Procedure:
To a solution of 3-[4,6-dichloro-5-(2-methoxyphenoxy)-2-pyrimidinyl] pyridazine, (0.06 g, 0.7 mmol) in dimethylsulfoxide (4 ml) was added potassium carbonate (0.13 g, 0.94 mmol) immediately followed by 2-(1-naphthyl) ethanesulfonamide (0.044 g, 0.18 mmol). The mixture was stirred vigorously for 72 hours at 90° C. and then quenched with hydrochloric acid solution (2 M, 4 ml). Ice-cold water (5 ml) was added and a white precipitate was observed. The resultant mixture was partitioned between water (10 ml) and dichloromethane (3×10 ml). The combined organic extracts were washed with water (3×10 ml), dried (magnesium sulfate) and concentrated under vacuum, yielding a yellow oil. Trituration with 1 ml of ice cold water, followed by filtration gave the title compound as a white solid (0.088 g), m.p. 191.5° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][C:5](=[NH:19])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.[C:22](OCC)(=[O:29])[CH2:23][C:24](OCC)=[O:25].C[O-].[Na+]>COCCO>[OH:29][C:22]1[N:19]=[C:5]([CH2:4][CH2:3][C:2]([F:20])([F:21])[F:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]([F:17])([F:18])[F:16])=[CH:11][CH:12]=2)[C:24](=[O:25])[CH:23]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(CCC(F)(F)F)Nc1ccc(OCC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: O=c1cc(O)nc(CCC(F)(F)F)n1-c1ccc(OCC(F)(F)F)cc1

Procedure:
A mixture of 4,4,4-trifluoro-N-[4-(2,2,2-trifluoroethoxy)phenyl]butanimidamide (20.9 g), diethyl malonate (20.2 mL), sodium methoxide (10.8 g) and 2-methoxyethanol (400 mL) was heated under reflux overnight, and the reaction mixture was concentrated under reduced pressure. Similarly, a mixture of 4,4,4-trifluoro-N-[4-(2,2,2-trifluoroethoxy)phenyl]butanimidamide (22.6 g), diethyl malonate (21.8 mL), sodium methoxide (11.7 g) and 2-methoxyethanol (400 mL) was heated under reflux overnight, and the reaction mixture was concentrated under reduced pressure. The obtained residues were combined, and partitioned between diethyl ether and water. The aqueous layer was separated, to the organic layer was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained solid was suspended in diisopropyl ether. The precipitate was collected by filtration, washed with diisopropyl ether, and dried to give the title compound (41.6 g) as a solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2([NH:14][C:15]([C:17]3([NH:20][C:21]([C:23]4[N:27]5[C@@:28]([CH2:41][C:42]6[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=6)([CH3:40])[C:29](=[O:39])[N:30]([C:31]6[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=6)[C:26]5=[N:25][CH:24]=4)=[O:22])[CH2:19][CH2:18]3)=[O:16])[CH2:13][CH2:12]2)[CH:6]=1.CCN(C(C)C)[CH:53]([CH3:55])[CH3:54].BrCCCBr>CC(N(C)C)=O.CCOC(C)=O>[N:3]1([CH2:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([C:11]3([NH:14][C:15]([C:17]4([NH:20][C:21]([C:23]5[N:27]6[C@@:28]([CH2:41][C:42]7[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=7)([CH3:40])[C:29](=[O:39])[N:30]([C:31]7[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=7)[C:26]6=[N:25][CH:24]=5)=[O:22])[CH2:18][CH2:19]4)=[O:16])[CH2:12][CH2:13]3)[CH:6]=2)[CH2:55][CH2:53][CH2:54]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(CN)ccn5)CC4)CC3)n21
Agent: BrCCCBr
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(CN6CCC6)ccn5)CC4)CC3)n21
Temperature: 100 °C
Yield: 13 %

Procedure:
To the solution of (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid {1-[1-(4-aminomethyl-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-amide dihydrochloric acid salt (60 mg, 0.081 mmol) in dry DMA (5 mL) was added DIPEA (0.071 mL, 0.405 mmol) followed by 1,3-dibromopropane (0.0415 mL, 0.405 mmol). The reaction mixture was heated in the microwave at 100° C. for 2×10 min. Diluted with EtOAc (50 mL). Washed with saturated NaHCO3 (2×25 mL). Layers were separated. The organic layer was dried, filtered, and concentrated. The resultant crude product was purified by prep-TLC using 5% MeOH/DCM as the eluent. The prep TLC plate looked messy, presumably due to the significant existence of DMA. The product fraction was collected and redissolved in EtOAc (50 mL), washed with water (3×15 mL), dried, filtered, and concentrated. The crude product was purified by prep-TLC using 5% MeOH/DCM as the eluent to afford 7.5 mg of the title compound as a light yellow solid, m/z 709.8 [M+1]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([I:29])=[C:25]([OH:30])[CH:24]=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:44][C:45]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[CH2:52][CH2:53]O>C1COCC1>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([I:29])=[C:25]([O:30][CH2:53][CH2:52][C:46]2[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:45]=2[Cl:44])[CH:24]=1
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(I)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
6.6 g of triphenylphosphine and 5 g of 4-Iodo-3-hydroxy-benzoic acid methyl ester were dissolved in 65 ml of anhydrous THF. The solution was cooled to 0 ° C. to 10° C. and a solution of 3.7 ml DEAD in 7.5 ml anhydrous THF was added dropwise over 20 min. The reaction was warmed to RT and stirred for 45 min. A solution of 2.8 ml 2-(2,4-Dichlorophenyl)-ethanol in 3 ml anhydrous THF was added with cooling. The reaction was stirred at RT for 3 h, then the solvents were removed under reduced pressure. The residue was treated with n-heptane:ethyl acetate 1:1. The filtrate was dried under reduced pressure. The product was purified by silica gel chromatography, eluting with n-heptane:ethyl acetate/4:1 to n-heptane:ethyl acetate/1:1.
Reaction SMILES: Br/[CH:2]=[CH:3]/[C@H:4]([OH:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(NCC)C.[CH:20](/[C@H:26]1[O:30][C:29]([CH3:32])([CH3:31])[O:28][C@H:27]1[CH2:33][O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:21]\[CH:22]=[CH:23]\[C:24]#[CH:25]>C1COCC1.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.[Cu]I>[OH:14][C@H:4]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)/[CH:3]=[CH:2]/[C:25]#[C:24]/[CH:23]=[CH:22]/[CH:21]=[CH:20]/[C@H:26]1[O:30][C:29]([CH3:32])([CH3:31])[O:28][C@H:27]1[CH2:33][O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]
Reactant: O[C@@H](/C=C/Br)COc1ccc(F)cc1
Reactant: C#C/C=C/C=C/[C@H]1OC(C)(C)O[C@H]1COCC(=O)OC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: C1CCOC1
Product: COC(=O)COC[C@@H]1OC(C)(C)O[C@@H]1/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Reaction time: 4 h
Yield: 79.6 %

Procedure:
In a flame dried flask, a solution of (1E,3S)-1-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butene (0.84 g, 3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.2 mmol) and copper(I) iodide (60 mg, 0.3 mmol) in THF (50 mL) and diethylamine (5 mL, 48 mmol) was carefully deoxygenated by bubbling in argon gas for 45 minutes. The reaction was stirred as a solution of 2-[[(4S,5R)-5-[(1E,3E)-1,3-hexadien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, (0.9 g, 3.2 mmol) in THF (50 mL), which had been deoxygenated by bubbling in argon for 45 minutes, was added. After about 4 hours, the reaction was complete. The reaction mixture was diluted with hexane and filtered through a pad of silica gel and the silica gel was eluted with ether. The combined filtrates were concentrated to give an oil. Purification by chromatography using a 20-75% gradient of ether in hexane gave 1.1 g of 2-[[(4S,5R)-5-[(1E,3E,7E,9S)-9-hydroxy-10-(4-fluorophenoxy)-1,3,7-decatrien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (EE), as an oil; 1H NMR (CDCl3) δ 1.37 (s, 3H), 1.5 (s, 3H), 3.52 (m, 2H), 3.75 (s, 3H), 3.83 (m, 2H), 4.13 (m, 2H), 4.44 (m, 1H), 5.74 (m, 1H), 5.76 (m, 2H), 6.05 (m, 1H), 6.17 (m, 1H), 6.29 (m, 1H), 6.58 (dd, 1H), 6.88 (m, 4H) ppm.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][OH:68])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][OH:68])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCN(CCO)CC1
Reactant: C=C[C@@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(CCO)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 2-(4-aminopiperidin-1-yl)ethanol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47-2.14 (m, 15 H) 2.38 (t, J=6.32 Hz, 3 H) 2.89 (d, J=11.62 Hz, 2 H) 3.28 (s, 3 H) 3.49 (q, J=6.23 Hz, 2 H) 3.67-3.85 (m, 3 H) 3.94 (s, 3 H) 4.37 (t, J=5.43 Hz, 1 H) 4.89 (d, J=8.34 Hz, 1 H) 5.28-5.48 (m, 2 H) 6.01 (ddd, J=17.56, 12.76, 10.86 Hz, 1 H) 7.40-7.54 (m, 2 H) 7.82 (s, 1 H) 8.10 (d, J=7.58 Hz, 2 H) 8.30 (d, J=8.34 Hz, 1 H). [M+H] calc'd for C30H40FN7O4, 582; found 582.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]3[O:15][CH2:14]3)[C:10](=[O:16])[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.S(=O)(=O)(O)[OH:26].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([OH:26])[CH2:14][OH:15])[C:10](=[O:16])[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC1CO1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(O)CO

Procedure:
1 g of crude 7-chloro-1-(2,3-epoxypropyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one is dissolved in 15 ml of methanol and 15 ml of 2 N sulfuric acid and stirred for 1 hour at 25°C. Then the solution is made alkaline with 3 N sodium hydroxide and the methanol is carefully distilled on a rotary evaporator. The aqueous phase is extracted with ethyl acetate and the ethyl acetate solution is washed with water, dried over magnesium sulfate, filtered and concentrated. By chromatography of the residue on silica gel with ethyl acetate/methanol (9:1) there is isolated 7-chloro-1-(2,3-dihydroxypropyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 116°-117°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.[Br:22]N1C(=O)CCC1=O.C(#N)N(C)C>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[S:11][C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:9])=[CH:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(-c2ccc(C(=O)c3ccc(Br)cc3)s2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(Br)cc1)c1ccc(-c2ccc(CBr)cc2)s1
Yield: 84.7 %

Procedure:
0.5 g of (4-bromophenyl)-(5-p-tolyl-thiophen-2-yl)-methanone and 262 mg of N-bromosuccinimide in 20 ml of carbon tetrachloride are held at reflux for 19 hrs. after the addition of a spatula tip of azaisobutyronitrile, concentrated and the residue is chromatographed on silica gel (methylene chloride/hexane). 517 mg of [5-(4-bromomethyl-phenyl)-thiophen-2-yl]-4-bromophenyl-methanone, m.p. 184° C. (decomposition), are isolated.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][S:7][CH2:6][CH2:5]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:28][C:29]1[CH:48]=[CH:47][C:32]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][C:40](O)=[C:41]([O:44][CH3:45])[CH:42]=3)[N:37]=[CH:36][N:35]=2)=[C:31]([F:49])[CH:30]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:28][C:29]1[CH:48]=[CH:47][C:32]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][C:40]([O:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][S:7][CH2:6][CH2:5]4)=[C:41]([O:44][CH3:45])[CH:42]=3)[N:37]=[CH:36][N:35]=2)=[C:31]([F:49])[CH:30]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: OCCN1CCSCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCSCC1
Reaction time: 3.5 h
Yield: 22.3 %

Procedure:
4-(2-Hydroxyethyl)thiomorpholine (114 mg, 0.78 mmol), (J. Am. Chem. Soc. 1934. 56, 1720), in methylene chloride (1 ml) followed by 1,1′-(azodicarbonyl)dipiperidine (525 mg. 2.08 mmol) were added to a stirred solution of 4-(4-chloro-2-fluoroanilino)7-hydroxy-6 methoxyquinazoline (225 mg, 0.70 mmol), (prepared as described for the starting material in Example 2), and tributylphosphine (0.51 ml, 2.08 mmol) in methylene chloride (10 ml) under nitrogen. The mixture was stirred for 3.5 hours and allowed to stand for a further 18 hours. Ether (8 ml) was added, the precipitate removed by filtration and the solvent removed from the filtrate by evaporation. The residue was dissolved in acetone and ethereal hydrogen chloride (2.5 m! of a 1M solution) added. The precipitated product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (150/8/1). The purified product was triturated with ether to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline (70 mg, 22%) as a pale yellow solid.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][S:17][C:18]#[N:19])=[CH:11][CH:10]=1.Cl.[NH2:22][C:23]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24]1>C(O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([NH:22][C:23]3([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24]3)[S:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1(N)CCC1
Reactant: N#CSCC(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(Nc2nc(-c3ccc(Br)cc3)cs2)CCC1
Temperature: 68 °C
Reaction time: 8 h
Yield: 12.1 %

Procedure:
Triethylamine (3.30 mL, 23.7 mmol) was added under nitrogen to a mixture of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.50 g, 21.6 mmol), prepared in step 1 of Example 1, and ethyl 1-aminocyclobutanecarboxylate hydrochloride (4.24 g, 23.6 mmol) in 130 mL of absolute ethanol. The mixture was then stirred at 68° C. overnight. The reaction was concentrated under reduced pressure to remove the ethanol. The residue was partitioned between ethyl acetate and water. The aqueous layer was made basic by the addition of 2 N NaOH. The organic layer was separated, washed two times with water, dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification of the residue on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge) using a linear gradient of 45% methylene chloride in hexane to 100% methylene chloride as the eluent gave ethyl 1-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclobutane carboxylate (1.0 g, 12%) as a brown oil, MS (ESI) m/z 381 [M+H]+.
Reaction SMILES: [S:1]([O-:4])([OH:3])=[O:2].[Na+:5].[CH2:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCCCC)(=O)C=C.C(O)(=O)C(C)=C>O>[CH2:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([S:1]([O-:4])(=[O:3])=[O:2])=[CH:10][CH:9]=1.[Na+:5]
Reactant: C=Cc1ccccc1
Reactant: O=S([O-])O
Agent: C=C(C)C(=O)O
Agent: C=CC(=O)OCCCC
Agent: [Na+]
Solvent: O
Product: C=Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 824.3 %

Procedure:
A 500-ml flask, the inner atmosphere of which was substituted with nitrogen, was charged with 0.07 g of a surface active agent (Emulgen 935 supplied by Kao-Atlas), 0.07 g of another surface active agent (Emulgen 920 supplied by Kao-Atlas), 0.3 g of sodium hydrogensulfite and 46.2 g of water, and the temperature was elevated to 40° C. with stirring in a nitrogen current. A liquid monomer mixture comprising 50 g of styrene, 50 g of n-butyl acrylate and 1 g of methacrylic acid, an aqueous solution of 4.9 g of sodium p-styrene-sulfonate having a purity of 82.0% (Spinomar NaSS supplied by Toyo Soda) in 45.1 g of water and an aqueous solution of a polymerization initiator formed by dissolving 0.5 g of ammonium persulfate in 49.5 g of water were added into the flask over a period of 3 hours and polymerization was carried out at 40° C. After completion of the addition, the polymerization temperature was maintained for 3 hours and the polymerization mixture was then cooled to room temperature.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH2:15][CH2:14][CH2:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1>[Pd].CN(C=O)C.CO>[NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1
Reactant: NC(=O)c1cnc(N)c2cc(C3=CCCC3)sc12
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(N)c2cc(C3CCCC3)sc12
Reaction time: 20 h
Yield: 30.9 %

Procedure:
A suspension of 4-amino-2-cyclopent-1-enyl-thieno[3,2-c]pyridine-7-carboxylic acid amide 34 (prepared in example 6 above) (0.056 g, 0.155 mmol) and 10% palladium on carbon (5 mol %) in DMF (1 mL) was stirred under H2 (1 atm) for 20 h. The suspension was diluted with MeOH (10 mL) and filtered. Solvent was removed in vacuo. To the crude solid of 35 was added concentrated H2SO4 (0.25 mL). The purple solution was stirred for 1 h followed by the addition of ice (2 g). The precipitate was filtered then purified by silica gel column chromatography (eluent: 10% MeOH, 1% NH4OH in CH2Cl2) and converted to the HCl salt to afford 12.5 mg of 36. 1H NMR (400 MHz, d6-DMSO) δ 8.76 (s, 2H), 8.45 (s, 1H), 8.29 (s, 1H), 7.75 (m, 3H), 3.37 (m, 1H), 2.14 (m,2H), 1.72 (m, 6H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1)C.[OH-].[Na+]>C1COCC1>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12](=[O:11])[CH2:2][C:1]#[N:3])=[CH:14][CH:15]=1)[CH3:21]
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(OCC)cc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1ccc(C(=O)CC#N)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.5 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 11 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of 4-ethoxy-benzoic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids and then extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered The organic layer is concentrated in vacuo and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-(4-ethoxy-phenyl)-3-oxo-propionitrile in the amount of 2.5463 gms.