Azzindani/Open_Reaction_Data huggingface dataset:
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][CH2:13][CH:14]([C:18]1([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:30])[C:15](O)=[O:16].[OH:35][N:36]1C2C=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1.Cl.NO>ClCl.CN(C=O)C.O>[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][CH2:13][CH:14]([C:18]1([CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:30])[C:15]([NH:36][OH:35])=[O:16]
Reactant: On1nnc2ccccc21
Reactant: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)O)CCN(Cc2ccccc2)C1=O
Agent: Cl
Agent: ClCl
Agent: NO
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)NO)CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A cold (0° C.) solution of α-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetic acid (559 mg) in CH2 Cl2 /DMF (8 mL/2 mL) is treated with 1-hydroxybenzotriazole (158 mg, 1.17 mmol), 4-methyknorpholine (129 μL, 1.17 mmol), and EDC (224 mg, 1.17 mmol). After 1 hour, additional 4-methylmorpholine (159 μL, 1.45 mmol) and hydroxylamine HCl (101 mg, 1.45 mmol) are added. The solution is allowed to slowly warm to room temperature, stirring under N2 overnight. The reaction mixture is diluted with H2O (25 mL) and extracted into CH2Cl2 (3×50 mL). The organic extracts are dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and reconstituted in EtOAc (50 mL). The EtOAc layer is washed with more H2O (3×25 mL) and brine (25 mL). The organic layer is dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 416 mg of white foam. The foam is purified by silica gel chromatography (50 g SG, 2% MeOH/CHCl3) to yield 220 mg of white foam which is triturated with Et2O to give 181 mg (39%) of the title compound as a white solid (mp 162°-164° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH3:20])[C:11]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([O:15][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH3:20])[C:11]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=3[S:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.3 %

Procedure:
A mixture of 1.6 g of (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.69 g of benzoyl chloride, 5 ml of pyridine and 2 ml of benzene is stirred at room temperature for 2 hours. The mixture is poured into ice-water, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated under reduced pressure to remove solvent. 2.14 g of (±)-cis-2-(4-methylphenyl)-3-benzoyloxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[C@H:21]1[CH2:22][CH2:23][C@H:24]([O:27][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)[CH2:25][CH2:26]1
Reactant: C1=COCCC1
Reactant: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](OC2CCCCO2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9-(trans-4-hydroxycyclohexyl)-7H-purin-8(9H)-one (0.8 mmol) and dihydropyran (15 equiv.) in anhydrous chloroform/THF (30 mL/15 mL) containing p-TsOH (0.1 equiv.) was stirred at 50° C. for 1 day (LCMS indicative of complete reaction). The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on neutral alumina to give the desired product. MS (EI) m/z 487.3 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[CH:4]([Se]C1C=CC=CC=1)[CH2:5][CH2:6][CH2:7][C:8](=[O:38])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:12][C@@H:11]1[OH:37].C(=O)(O)[O-].[Na+].OO>C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3](=[O:46])/[CH:4]=[CH:5]/[CH2:6][CH2:7][C:8](=[O:38])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:12][C@@H:11]1[OH:37]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](CC(=O)CCCC([Se]c2ccccc2)C(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](CC(=O)CC/C=C/C(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 2.333 g of (13E)-(9α,11α,15S)-2-phenylseleno-6-oxo-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester [prepared as described in Reference Example 8(h)] in a mixture of 22 ml of ethyl acetate and 11 ml of tetrahydrofuran were added 733 mg of sodium bicarbonate and 1 ml of 30% (v/v) hydrogen peroxide at 34° C. and the mixture was stirred at that temperature for 30 minutes. The reaction mixture was then diluted with ethyl acetate, washed with water, an aqueous solution of sodium sulphate, water, an aqueous solution of ammonium chloride and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 1.524 g of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([C:5]1[C:18]([CH2:19][CH2:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:17]([OH:29])[C:8]2[N:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].[BH4-].[Na+].[Cl-].[NH4+].O>C(O)C>[CH3:30][N:2]([CH3:1])[C:3]([C:5]1[C:18]([CH2:19][CH2:20][CH:21]([OH:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:17]([OH:29])[C:8]2[N:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2c(nc(C(F)(F)F)n2C)c(O)c1CCC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)c1cc2c(nc(C(F)(F)F)n2C)c(O)c1CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
A solution of 3.0 g (7.2 mmol) 7-hydroxy-3-methyl-6-(3-oxo-3-phenyl-propyl)-2-trifluoromethyl-3H-benzimidazole-5-carboxylic acid dimethylamide in ethanol (100 ml) was treated with 324 mg (8.6 mmol) sodium borohydride and the reaction was stirred at room temperature for 3 h. A saturated ammonium chloride solution was added, the reaction was poured into water (100 ml) and extracted with dichloromethane. The organic layers were dried over magnesium sulphate and concentrated in vacuo to afford 3.0 g (98%) of the title compound as a brown foam.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:14]([CH2:13][Br:12])=[O:9])=[CH:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(SCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=S(CBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
90% m-Chloroperbenzoic acid (17 mmol) in chloroform (35 ml) solution was added dropwise with stirring over 1 h at 0° C. to a solution of 1-bromomethylsulfenyl-4-chlorobenzene (15 mmol) in chloroform (35 ml). The mixture was stirred at room temperature overnight, shaken with 1M K2CO3 aq., the dried (MgSO4) chloroform solution evaporated and the solid residue recrystallized from CHCl3 : pet. ether; yield 3.20 g (84%), m.p. 100° C. 1H NMR (CDCl3): δ 4.28 (CH2), 7.53 (Ph). IR (KBr): 1040-1030 cm-1 (SO).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C@@H:17]([NH:23][C:24]([C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]3)[CH2:27]2)=[O:25])[CH2:18][C:19]([O:21]C)=[O:20])[CH:14]=[N:15][CH:16]=1.CO.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C(O)(C)(C)C>[F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C@H:17]([NH:23][C:24]([C@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[CH2:27]2)=[O:25])[CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[N:15][CH:16]=1
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCCOCCOCCF)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)C[C@@H](NC(=O)[C@H]1CCCN(C(=O)CCC2CCNCC2)C1)c1cncc(OCCOCCOCCF)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 12.8 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(5-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}pyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (16.5 mg, 22 μmol) as solved in tert.-butanol (0.62 mL) and methanol (0.6 mL) and barium hydroxide octahydrate (34 mg, 315 μmol) was added. After stirring for 45 minutes room temperature the solvent was distilled off at 0° C. by high vacuum. The residue was solved in water (0.3 mL) and acidified by formic acid (0.9 mL). After 18 hours at 5° C. the solvent was distilled off at 0° C. by high vacuum and the residue was purified by preparative HPLC to yield 1.6 mg of (3R)-3-(5-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}pyridin-3-yl)-3-[({(3S)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]1(C)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1([Li])C=CC=CC=1.O>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]([OH:11])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccccc1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(O)c2ccccc2)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (10.00 g, 45.40 mM) in dry tetrahydrofuran (50 ml) was cooled to −78° C., a toluene solution of phenyllithium (49.94 mM) was dropped into this solution, and the resultant mixture was stirred at that temperature for 5 hours. Water was added to the solution obtained, the solution was warmed to room temperature and extracted with diethyl ether, the extract was dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo to obtain a crude product of α-(3-cyclopentyloxy-4-methoxyphenyl)benzyl alcohol 13.56 g as a yellow oil. The crude product thus obtained of α-(3-cyclopentyloxy-4-methoxyphenyl)benzyl alcohol in an amount of 10.00 g was dissolved in dry methylene chloride (110 ml), manganese dioxide (16.00 g) was added to the solution, and the solution was vigorously stirred at room temperature for 2 days. The undissolved material in the solution obtained were removed by filtration through Celite, and the filtrate was concentrated in vacuo to obtain a residue as a yellow solid. The residue was purified by flash chromatography (SiO2: eluted with 20% ethyl acetate/hexane). The solvent was removed in vacuo and the product was dried to obtain 3-cyclopentyloxy-4-methoxybenzophenone 9.20 g (yield 92.6%) as a light yellow solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12.N1C(C)=CC=CC=1C.[C:38]([NH:57][C:58]1[S:62][C:61]([CH2:63][C:64](O)=[O:65])=[N:60][N:59]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.O.O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[C:38]([NH:57][C:58]1[S:62][C:61]([CH2:63][C:64]([NH:2][CH:3]2[C:28](=[O:29])[N:5]3[C:6]([C:12]([O:14][CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]23)=[O:65])=[N:60][N:59]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(O)Cc1nnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3nnc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)s3)[C@H]2SC1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
To a suspension of benzhydryl 7-amino-3-vinyl-3-cephem-4- carboxylate monohydrochloride (2.15 g) in methylene chloride (100 ml) was added 2,6- lutidine (0.54 g) under ice-cooling. To the resultant solution were added 2-(5-tritylamino-1,3,4- thiadiazol-2- yl)-acetic acid (2,4 g), N,N'-dicyclohexylcarbodiimide (1.03 g), tetrahydrofuran (200 ml) and N,N-dimethylformamide (60 ml), and the mixture was stirred at ambient temperature for a day. Removal of the solvent gave a residue, to which a mixed solvent of ethyl acetate, tetrahydrofuran and water was added. The insoluble substances were removed by filtration, and the filtrate was washed with dilute hydrochloric acid, a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave a residue, which was washed with diisopropyl ether to obtain benzhydryl 7-[2-(5-tritylamino-1,3,4- thiadiazol-2-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (2.6 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br>C1COCC1>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: BrCc1cccc(Br)c1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(Cc2cccc(Br)c2)CC1
Reaction time: 2 h

Procedure:
0.30 g 1-Methylpiperazine in 2 ml THF were treated dropwise at RT with a solution of 0.5 g 3-bromobenzyl bromide in 3 ml THF. After stirring for 2 hrs, the mixture was heated to 60 C for 30 min. The solvent was evaporated and the residue chromatographed on silica using a gradient from heptane to heptane/dichloromethane/conc. ammonia (4/6/0.5).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:29])[C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[CH:39][CH:38]=1>CCOC(C)=O.CCCCCC>[Cl:28][C:27]1[N:26]([CH3:29])[N:25]=[CH:24][C:23]=1[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:36][C:37]3[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[CH:41][CH:42]=3)[C:4](=[O:30])[NH:5]2)=[CH:10][CH:9]=1)=[O:13])=[O:22]
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCC(=O)O)cc3)c2)c1Cl
Temperature: 65 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A small screw cap test tube was charged with 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 328, 100 mg, 0.2365 mmol) and THF (2.5 mL). To the resulting solution was added 3-(4-Amino-phenyl)-propionic acid (39.1 mg, 0.237 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜50 mL). The precipitate that formed was collected by filtration and washed with acetone (˜15 mL) to afford the title compound in 57% yield (0.077 g, 0.1351 mmol).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N>O1CCOCC1.ClCCl.[Cu]I>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=2)[C:3]1=[O:14]
Reactant: Cn1cncc1Br
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1C(=O)N(c2cncn2C)CC1C(=O)OC(C)(C)C
Yield: 35 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (801 mg, 4.00 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 5-bromo-1-methylimidazole (644 mg, 4.00 mmol) in 1,4-dioxane (30 ml) was added potassium phosphate (4246 mg, 20.00 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (0.631 ml, 4.00 mmol) and copper(I) iodide (762 mg, 4.00 mmol) and the mixture stirred at reflux overnight. The reaction mixture was diluted with dichloromethane and filtered through celite. The filter pad was washed with dichloromethane and the filtrate was reduced under vacuum. The residue was re-dissolved in dichloromethane, washed with 0.880 ammonia (×2), water then brine and passed through a hydrophobic frit and the solution was concentrated under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-10% methanol in dichloromethane to give 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-5-yl)-2-oxo-4-imidazolidinecarboxylate (393 mg, 32.6% yield). LC/MS [M+H]+=281. (ii) Trifluoroacetic acid (2 ml) was added to a solution of 1,1-dimethylethyl (4S)-3-methyl-1-(1-methyl-1H-imidazol-5-yl)-2-oxo-4-imidazolidinecarboxylate (390 mg, 1.391 mmol) in dichloromethane (4 ml) and stirred at room temperature for 2 hours, then allowed to stand overnight. The solvent was evaporated and the residue was co-evaporated with toluene and dried under heated vacuum (40° C.) overnight to give 3-methyl-1-(1-methyl-1H-imidazol-5-yl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜1.4 mmol) which was used which was used in the next step. LC/MS [M+H]+=225.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.Br[CH2:26][CH2:27][Cl:28]>>[CH3:1][C:2]1([CH3:24])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH:9]2[CH2:26][CH2:27][Cl:28])[CH:4]=[N:3]1
Reactant: ClCCBr
Reactant: CC1(C)N=CC2=C3N=C(c4ccc(Cl)cc4)N=C3C(=O)CC2C1=O
Product: CC1(C)N=CC2=C3N=C(c4ccc(Cl)cc4)N=C3C(=O)C(CCCl)C2C1=O

Procedure:
Prepared analogous to Example 23 from 7.5 gm of 7,7-dimethyl-2-(4-chloro phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione and 6.9 gm of 1-bromo-2-chloro-ethane.
Reaction SMILES: [H-].[Na+].[C:3]([C:6](=[C:11]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH3:4].[CH3:25]I.O>O1CCCC1.C(OCC)(=O)C>[C:3]([C:6](=[C:11]([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:12]([CH3:25])[C:13]([O:15][CH3:16])=[O:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH3:4]
Reactant: CI
Reactant: COC(=O)CC(NCc1ccccc1)=C(C(C)=O)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(C(C)=O)=C(NCc1ccccc1)C(C)C(=O)OC
Reaction time: 0.25 h

Procedure:
Under nitrogen stream, 60 % sodium hydride (1.68 g; 42 mmole) was added to dry tetrahydrofuran (10 ml), and a solution of dimethyl 2-acetyl-3-benzylamino-2-pentenedioate (6.2 g; 20 mmole) in dry tetrahydrofuran (40 ml) was portionwise added thereto with ice-cooling, followed by stirring at the same temperature for 15 minutes. Methyl iodide (5.68 g; 40 mmole) was added thereto at room temperature, and the resultant mixture was stirred at room temperature for 1 hour and at 40° C. for 1 hour. Water was added to quench the reaction, and the reaction mixture was diluted with ethyl acetate. The organic layer was washed successively with water, dilute hydrochloric acid and an aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give dimethyl 2-acetyl-3-benzylamino-4-methyl-2-pentenedioate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:16])[C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([NH:31][CH2:15][CH:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[OH:16])[C:11]([O:13][CH3:14])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: C=C(C(=O)OC)C(O)c1ccc(F)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(CNCc1ccccc1)C(O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-[(3-chloro-4-fluorophenyl)(hydroxy)methyl]prop-2-enoate (11.5 g) and triethylamine (6.85 mL) in methanol (100 mL) was added benzylamine (5.38 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (12.0 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:19][CH2:18][CH2:17][C:9]2[CH:10]=[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:30][CH2:29]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccccc1N1CCN(CCCc2cc(-c3cccs3)n(-c3ccccc3)n2)CC1

Procedure:
62 mg (91%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-(2-fluorophenyl)piperazine (26 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).