Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[N:18]=3)[N:16]=[C:10]2[CH:9]1[C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:35][CH:36]=1)C1C=CC=CC=1.C(O)(=O)C.[H][H].C(OCC)(=O)C>CO.[OH-].[Pd+2].[OH-]>[C:33]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:35][CH:36]=[C:31]([CH:9]2[NH:8][CH2:13][CH2:12][N:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]5)=[C:19]([O:29][CH3:30])[N:18]=4)[N:16]=[C:10]23)[CH:32]=1
Reactant: [H][H]
Reactant: COc1nc(-c2nc3n(n2)CCN(Cc2ccccc2)C3c2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1nc(-c2nc3n(n2)CCNC3c2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Yield: 9.9 %

Procedure:
To a solution of 7-benzyl-8-biphenyl-3-yl-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine (541 mg) and acetic acid (1.32 ml) in methanol (52 ml) was added 20% palladium hydroxide (743 mg) and the reaction mixture was stirred at room temperature in a hydrogen atmosphere for 4 days. After the reaction atmosphere was replaced with nitrogen, ethyl acetate was added to the reaction mixture. The catalyst was removed by filtration by Celite. The filtrate was concentrated under reduced pressure and the residue was purified by NH silica gel column chromatography to obtain the title compound (45 mg) and the raw material. (291 mg)
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.Cl[C:26]([O:28][CH2:29][CH2:30][Cl:31])=[O:27]>O>[CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH:4][C:26](=[O:27])[O:28][CH2:29][CH2:30][Cl:31]
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1N
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(N)c([N+](=O)[O-])cc1NC(=O)OCCCl
Temperature: 90 °C

Procedure:
0.6 mol (100 g) of 2-methyl-4-amino-5-nitroaniline and 0.36 mol (50 g) of potassium carbonate are introduced into 500 ml of dioxane to which 145 ml of water have been added. The mixture is heated to 90° C., whilst stirring, and 0.6 mol (86 g) of chloroethyl chloroformate is then added gradually in the course of 10 minutes. When the addition has ended, the heating is maintained for 10 minutes at 90° C., the reaction medium is cooled to 15° C. and the expected product is then filtered off. After washing with a small amount of dioxane and then with water and alcohol, the product is recrystallised from dioxane and then dried in vacuo. It melts at 192° C.
Reaction SMILES: [CH2:1]([N:3]([S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:15])[NH2:14])=[CH:9]2)[CH3:2].Br[CH:25]([CH:28]=O)[CH:26]=[O:27].CN(C)C(=O)C>O>[CH2:1]([N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:15][C:25]([CH2:26][OH:27])=[CH:28][N:14]=1)=[CH:9]2)[S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:18])[CH3:2]
Reactant: CCN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=CC(Br)C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
A mixture of 7-[ethyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (4.10 g), bromomalonaldehyde (3.55 g) and N,N-dimethylacetamide (30 ml) was stirred at 95° C. for 1.5 hr. Water was added to the reaction mixture, and the obtained precipitate was collected by filtration and dissolved in tetrahydrofuran (30 ml) and methanol (30 ml). After cooling with an ice bath, sodium borohydride (508 mg) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, and diluted with ethyl acetate-tetrahydrofuran mixture. The organic layer was washed successively with aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (2:1) mixture to give the title compound (800 mg, yield 17%) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:43])[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C@@H:12]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([NH:19][C:20](=[O:41])[C@@H:21]([NH:33]C(=O)OC(C)(C)C)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[CH:32])=[CH:25][CH:24]=2)[C@H:13]1[OH:42]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:33][C@@H:21]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[CH:32])=[CH:25][CH:24]=1)[C:20]([NH:19][C@H:14]1[C@@H:13]([OH:42])[C@H:12]([N:7]2[CH:6]=[N:5][C:4]3[C:8]2=[N:9][CH:10]=[N:11][C:3]=3[N:2]([CH3:43])[CH3:1])[O:16][C@@H:15]1[CH2:17][OH:18])=[O:41]
Reactant: C#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N(C)C)ncnc43)O[C@@H]2CO)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCOc1ccc(C[C@H](N)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N(C)C)ncnc43)O[C@@H]2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
O-Propargyl Boc-Puromycin 4 (480 mg, 0.81 mmol) was dissolved in a 1:1 TFA (4 mL) and CH2Cl2 (4 mL) mixture and then stirred at room temperature for 30 min. Volatiles were evaporated in vacuo and the residue was dissolved in CH2Cl2. The solution was poured into saturated aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated to dryness in vacuo. The residue was purified by flash chromatography (SiO2, step-wise gradient from 5-15% MeOH in CH2Cl2) to afford the O-propargyl-puromycin 5 (111 mg, 28%) as a white solid. 1H NMR (600 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.24 (s, 1H), 8.06 (br, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.13 (d, J=5.4 Hz, 1H), 5.98 (d, J=3.0 Hz, 1H), 5.13 (t, J=5.4 Hz, 1H), 4.74 (d, J=1.8 Hz, 2H), 4.42-4.51 (m, 2H), 3.91-3.96 (m, 1H), 3.66-3.72 (m, 1H), 3.26-3.58 (m, 9H), 2.92 (dd, J=14.4, 4.8 Hz, 1H), 2.52-2.58 (m, 1H), 2.02 (br, 2H); 13C NMR (150 MHz, DMSO-d6): δ 174.6, 155.7, 154.3, 151.8, 149.6, 137.9, 131.3, 130.2, 119.6, 114.5, 89.4, 83.5, 79.4, 78.0, 73.2, 61.0, 56.1, 55.3, 50.0, 40.4, 40.0; HRMS: (ESI, m/z) calcd [M+H]+ for C24H29N7O5: 496.2303. found 496.2308.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(O)c2ccccc2O)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Cc2ccccc2O)cc1
Reaction time: 40 h

Procedure:
To a solution of crude Part A 4-methyl-2′-hydroxybenzhydrol (9.7 g containing no more than 40 mmol) in 175 mL of MeOH was added 0.59 g of 10% Pd/C and 1.75 mL of TFA. The suspension was stirred for 40 hr under 1 atmos. H2, filtered through celite and concentrated to yield 8.6 of crude 2-(4′-methylbenzyl)phenol as an oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][N:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]([NH:24][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[C:16]2=[O:36])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][N:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]([NH:24][CH:25]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[C:16]2=[O:36]
Reactant: CC(C)(C)OC(=O)NCCNc1ccn2c(=O)c(C(=O)NC(CC(=O)O)c3ccccc3)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNc1ccn2c(=O)c(C(=O)NC(CC(=O)O)c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of (+/−)-3-{[8-(2-tert-butoxycarbonylamino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionic acid (20.5 mg, 0.042 mmol) in dichloromethane (1 ml) at room temperature was added trifluoroacetic acid (1 ml). The resulting mixture was stirred at room temperature for 45 min. The solvent was removed under vacuum and the resulting residue was subjected to a silica gel chromatography (EtOH:H2O: NH4OH, 90:5:5) to give desired product which was further lyophilized to afford a yellowish solid (30 mg, 73%) which was characterized by 1HNMR (400 MHz, D2O) δ: 2.58-2.65 (m, 2H), 2.90-3.10 (m, 2H), 3.15-3.25 (m, 2H), 5.21 (m, 1H), 6.0-8.7 (m, 10H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[NH2:12][C:13]1[CH:29]=[CH:28][C:27]2[C:18]3[NH:19][C:20](=[O:26])[C:21]4[N:22]([CH:23]=[CH:24][N:25]=4)[C:17]=3[CH2:16][C:15]=2[CH:14]=1.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:12][C:13]2[CH:29]=[CH:28][C:27]3[C:18]4[NH:19][C:20](=[O:26])[C:21]5[N:22]([CH:23]=[CH:24][N:25]=5)[C:17]=4[CH2:16][C:15]=3[CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 12 h
Yield: 54.9 %

Procedure:
A solution of 1.76 g of 4-fluorophenyl isocyanate in 20 ml of dimethylformamide is added over 30 minutes to a solution of 2 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 20 ml of dimethylformamide and 1.3 g of triethylamine and stirring is carried out for 12 hours at a temperature in the region of 20° C. The reaction mixture is filtered and the insoluble material is washed with dimethylformamide (2×10 ml) and then with water (3×15 ml) and dried in the air. The crude product is then triturated in 30 ml of dimethylformamide, filtered, washed with water and then with isopropyl ether and dried at 60° C. under vacuum (1 mm Hg, 0.13 kPa). There are obtained 1.5 g of 8-[3-(4-fluoro-phenyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazine-4-one in the form of a beige solid melting above 260° C. (Analysis, % calculated C: 64.00, H: 3.76, F: 5.06, N: 18.66, O: 8.52, % found C: 64.0, H: 3.8, N: 19.0).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([S:12](Cl)(=[O:14])=[O:13])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C(O)(=O)C.O>[F:1][C:2]1[CH:11]=[C:10]([S:12]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:14])=[O:13])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NCc1ccccc1
Reactant: O=S(=O)(Cl)c1cc(F)c2cccnc2c1O
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(NCc1ccccc1)c1cc(F)c2cccnc2c1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A suspension of 5-fluoro-8-hydroxy-7-quinolinesulfonyl chloride (0.150 g) in 2 mL of THF is cooled to −78° C. and treated with benzylamine (0.186 mL). The mixture is allowed to warm to 25° C. over several hours, then diluted with 50 μL of glacial acetic acid and 2 mL of distilled water. The oil which forms is crystallized by scratching, and the resulting suspension is stirred for one hour. The solid is filtered, washed with two 2 mL portions of distilled water and dried in a stream of air to give 0.121 g of the title compound as a solid.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=12.CC1(C)C2[C:41](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:40][C:22]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=C[C:21]1=2.C(N(CC)CC)C.C([OH:70])C>[Pd](Cl)Cl>[CH3:18][O:17][C:7]1[C:6]2[N:5]([N:4]=[CH:3][C:2]=2[C:41]([O:40][CH2:22][CH3:21])=[O:70])[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:8]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(I)c12
Reactant: CCO
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (650.0 mg, 1.835 mmol), palladium (II) chloride (16.3 mg, 0.092 mmol), and Xantphos (53.1 mg, 0.092 mmol) were placed in a 40 mL scintillation vial. Absolute ethanol (6 ml) and triethylamine (0.384 ml, 2.75 mmol) were added and the mixture was sparged with argon for 5 minutes. The vial was transferred to a pressure reactor, which was filled with CO (30 psi) and vented (3×). The vessel was pressurized to 100 psi of CO and heated to 100° C. After 4 h, the system was cooled to ambient temperature. The reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to give ethyl 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[CH:21][C:20]([CH:25]=[CH:26][C:27]([OH:29])=O)=[CH:19][C:18]=2[CH2:17][CH2:16]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH3:12])[C:27](=[O:29])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[N:22][C:23]4[NH:24][C:15](=[O:14])[CH2:16][CH2:17][C:18]=4[CH:19]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CNCc1ccc2occc2c1
Reactant: O=C(O)C=Cc1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc2occc2c1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Temperature: 40 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of benzofuran-5-yl-N-methylmethanamine (297 mg, 1.84 mmol), 3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-acrylic acid hydrochloride (474 mg, 1.86 mmol), HOBt (252 mg, 1.86 mmol) and DIPEA (1.32 mL, 7.58 mmol) in anhydrous DMF (30 mL) was added EDC hydrochloride (357 mg, 1.86 mmol). The mixture was stirred overnight at 40° C. Water (70 mL) was added and the solution was stirred for 1 h. The reaction mixture was extracted with ethyl acetate (3×100 mL). Combined organic layers were washed with water (50 mL) and brine (50 mL) and concentrated to give a red solid which was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to afford (E)-N-(benzofuran-5-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (381 mg, 57%) as a red solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.64-10.62 (m, 1H), 8.36-8.33 (m, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.59-7.49 (m, 3H), 7.38-7.17 (m, 2H), 6.94 (m, 1H), 4.89-4.69 (m, 2H), 3.10-2.85 (m, 5H), 2.54-2.52 (m, 2H); ESI MS m/z 362 [C21H19N3O3+H]+.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:14][N:15]=[C:16]([C:20]1[C:21](=[O:41])[CH2:22][CH:23]([C:27]2[C:36]3[CH2:35][CH2:34][CH2:33][CH:32]([OH:37])[C:31]=3[C:30]([CH3:38])=[N:29][C:28]=2[O:39][CH3:40])[CH2:24][C:25]=1[OH:26])[CH2:17][CH2:18][CH3:19])[CH3:13]>ClCCl>[CH2:12]([O:14][N:15]=[C:16]([C:20]1[C:25](=[O:26])[CH2:24][CH:23]([C:27]2[C:36]3[CH2:35][CH2:34][CH2:33][C:32](=[O:37])[C:31]=3[C:30]([CH3:38])=[N:29][C:28]=2[O:39][CH3:40])[CH2:22][C:21]=1[OH:41])[CH2:17][CH2:18][CH3:19])[CH3:13]
Reactant: CCCC(=NOCC)C1=C(O)CC(c2c(OC)nc(C)c3c2CCCC3O)CC1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCC(=NOCC)C1=C(O)CC(c2c(OC)nc(C)c3c2CCCC3=O)CC1=O

Procedure:
Pyridinium chlorochromate (1.1 equiv) was added in small portions to a stirred solution of 2-[1-(ethoxyimino)butyl]-3-hydroxy-5-(8-hydroxy-3-methoxy-1-methyl-5,6,7,8-tetrahydroisoquinolin-4-yl)cyclohex-2-en-1-one (0.1 g) in dichloromethane (40 ml) at room temperature. The mixture was filtered through a small silica chromatography column with dichloromethane/ethyl acetate (5:1 v/v) elution to give 2-[1-(ethoxyimino)butyl]-3-hydroxy-5-(3-methoxy-1-methyl-8-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)cyclohex-2-en-1-one as a white solid, mp 162° C. The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is recorded in Table 4, Example 10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[CH2:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:37]1[C:28]2[CH2:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH2:32][N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=4)=[CH:42][CH:41]=3)=[O:25])[C:27]=2[CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A mixture of 314 mg of 3,4-dichlorobenzoyl chloride and 151 mg of triethylamine in 2 ml of methylene chloride is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. Stirring is continued for 2 hours. The reaction mixture is partitioned with water and the organic layer is washed 1N HCl, water, 0.5N NaOH and brine. The organic layer is dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.35 g of off-white crystalline solid, m.p. 238°-241° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C@H:8]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:6])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H]1CCNC[C@H]1C(=O)OCC
Reaction time: 16 h
Yield: 37.1 %

Procedure:
A solution of 259B (680 mg, 1.9 mmol) in CH2Cl2 (10 mL) was treated with TFA (1 mL) at room temperature. The reaction mixture was stirred for 16 hours, then concentrated. The residues was dissolved in EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (2×20 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 170 mg of Compound 259C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][S:9][C@@H:8]([CH2:11][SH:12])[CH2:7]1)=[O:5])[CH3:2].[O-]CC.[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC=CC=1>C(O)C>[CH2:17]([S:12][CH2:11][C@H:8]1[CH2:7][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][S:9]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)[C@@H]1CS[C@@H](CS)C1
Reactant: BrCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)[C@@H]1CS[C@@H](CSCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of trans-4-ethoxycarbonyl-2-mercaptomethyltetrahydrothiophene (compound No. 15-1, 0.3 g) in ethanol (2 ml), sodium ethoxide (0.11 g) is added under nitrogen atmosphere and ice-cooling and the mixture is stirred for 30 minutes. Benzyl bromide (0.28 g) dissolved in ethanol (1 ml) was added to the mixture and the mixture is stirred for 30 minutes under ice-cooling and 1 hour at room temperature. Benzene is added to the reaction mixture. The organic layer is washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue is purified by a silica gel column chromatography to give titled compound (compound No. 25-1).
Reaction SMILES: O[C:2](C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=4)=[O:43])=[CH:37][CH:36]=3)[N:24]=1)[CH2:16]2.C=O>C(O)=O>[CH3:2][N:32]1[CH2:33][CH2:34][N:29]([C:27]2[N:28]=[C:23]([N:17]3[CH2:16][CH:15]4[O:22][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:24]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[O:43])=[CH:39][CH:40]=3)[N:26]=2)[CH2:30][CH2:31]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Agent: C=O
Solvent: O=CO
Product: CN1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (115 mg) in 1:1 98% formic acid and 37% formalin (4 mL) was heated at 75° C. for 90 minutes, then concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 502.3 (M+H)+
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[N:20]([CH3:33])[C:19](=[O:34])[CH:18]=2)[CH2:12]1>>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[N:20]([CH3:33])[C:19](=[O:34])[CH:18]=2)[CH2:12]1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Agent: O=C(O)c1ccccc1
Product: Cn1c(=O)cc(N2CCCC(N)C2)n(Cc2ccccc2C#N)c1=O

Procedure:
The benzoic acid salt was formed by treating the benzonitrile product (D) with benzoic acid to form 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile benzoate. Preparation and isolation of the benzoate salt was performed by conventional methods for the formation of acid addition salts. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.82 (d, 1H, J=7.6 Hz), 7.65 (t, 1H, J=7.6 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.23 (d, 1H, J=8.0 Hz), 5.42 (s, 1H), 5.50-5.00 (ABq, 2H, J=41.6, 15.2 Hz), 3.30 (m, 2H), 3.16 (s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H). MS (ES) [m+H] calc'd for C18H22N5O2, 340.2; found, 340.2.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35]O)=[CH:30][CH:29]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:35][CH2:34][C:31]1[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=1
Reactant: OCCc1ccncc1
Reactant: Oc1ccccc1I
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1ccccc1OCCc1ccncc1
Reaction time: 4 h
Yield: 71.5 %

Procedure:
A stirred solution of 2-iodophenol (8.8 g, 0.040 mole), triphenylphosphine (10.5 g, 0.040 mole) and 2-(4-pyridyl)ethanol (D65, 5.5 g, 0.045 mole) in THF (200 ml) at 0° C. under argon was treated with a solution of diethyl azodicarboxylate (6.3 ml, 0.040 mole) in THF (30 ml). The solution was allowed to warm to room temp. and stirred for 4 h, then concentrated in vacuo and the residue treated with 10% Na2CO3 solution (80 ml) and extracted with ethyl acetate (2×80 ml). The combined organic was extracted with 1M HCl acid (150 ml), then the acid extract basified by addition of potassium carbonate and extracted with ethyl acetate (2×100 ml). The combined extract was dried (Na2SO4) and concentrated in vacuo to leave a brown oil, which was chromatographed on silica gel eluting with 0 to 15% ethyl acetate/ether to afford the title compound as a colourless oil (9.3 g, 72%).