Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=O)[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2CC(=O)NC3C=CC=CC=3S2)C=CC=CC=1.[ClH:37].[CH3:38][N:39]([CH3:63])[CH2:40][CH2:41][N:42]([CH3:62])[C:43](N1C2C=CC=CC=2SC(C2C=CC=CC=2)CC1)=[O:44]>>[ClH:37].[CH3:38][N:39]([CH3:63])[CH2:40][CH2:41][N:42]([CH3:62])[C:43]([N:11]1[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12]1)=[O:44]
Reactant: CN(C)CCN(C)C(=O)N1CCC(c2ccccc2)Sc2ccccc21
Reactant: O=C1CC(c2ccccc2)Oc2ccccc2N1
Agent: Cl
Agent: O=C1CC(c2ccccc2)Sc2ccccc2N1
Product: CN(C)CCN(C)C(=O)N1CCC(c2ccccc2)Oc2ccccc21

Procedure:
By substituting an equivalent amount of 2,3-dihydro-2-phenyl-1,5-benzoxazepin-4-(5H)-one, m.p. 123°-125°, (prepared as described in Example 1 of U.S. patent application, Ser. No. 328,048, filed Dec. 4, 1963 now U.S. Pat. No. 3,309,361), for the 2,3-dihydro-2-phenyl-1,5-benzothiazepin-4-one in part (A) of Example 1, and carrying out the procedure of the Example, there is obtained N-(2-dimethylaminoethyl)-2,3,4,5-tetrahydro-N-methyl-2-phenyl-1,5-benzoxazepine-5-carboxamide hydrochloride
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[O:18][CH3:19].[NH:20]1[CH:24]=[CH:23][N:22]=[N:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:19][O:18][C:4]1[CH:5]=[C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][N:20]1[CH:24]=[CH:23][N:22]=[N:21]1.[CH3:19][O:18][C:4]1[CH:5]=[C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][N:21]1[N:22]=[CH:23][CH:24]=[N:20]1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ccnn1
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cn1nccn1

Procedure:
A slurry of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 1.0 mmol) and 1H-1,2,3-triazole (70 mg, 1.0 mmol), and Cs2CO3 (325 mg, 1.0 mmol) and MeCN (10 mL) was stirred vigorously at rt for 8 h. Silica gel (600 mg) was added, and the reaction mixture was concentrated to dryness. The residue was purified by flash chromatography on silica gel (linear gradient of EtOAc in hexanes from 0 to 100% over 25 min) to afford 2-[3-methoxy-4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole and 2-[3-methoxy-4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-1,3-benzoxazole as colorless solids. 2-[3-methoxy-4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole: 1H NMR (CDCl3, 300 MHz) δ 7.72–7.78 (m, 3H), 7.69 (s, 1H), 7.59 (s, 1H), 7.53–7.56 (m, 1H), 7.31–7.34 (m, 2H), 7.20 (d, 1H), 5.59 (s, 2H), 3.96 (s, 3H). MS (ESI) 307 (M+H). 2-[3-methoxy-4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-1,3-benzoxazole: 1H NMR (CDCl3, 300 MHz) δ 7.76–7.80 (m, 3H), 7.68 (s, 1H), 7.56–7.59 (m, 2H), 7.34–7.38 (m, 2H), 7.04 (d, 1H), 5.74 (s, 2H), 3.99 (s, 3H). MS (ESI) 307 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1.[H-].[Na+].CS(O[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]([N:33]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([CH:51]5[CH2:53][CH2:52]5)=[CH:47][CH:46]=4)=[C:39]([O:54][CH3:55])[CH:38]=3)[CH2:34]2)=[O:32])[CH:26]=1)(=O)=O.O>CN(C=O)C>[CH:51]1([C:48]2[CH:49]=[CH:50][C:45]([CH2:44][O:43][C:40]3[CH:41]=[CH:42][C:37]([CH:35]4[CH2:34][N:33]([C:31]([C:27]5[CH:26]=[C:25]([CH2:24][O:16][CH2:15][C:3]6([CH2:2][OH:1])[CH2:4][O:5][CH:6]([C:9]7[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=7)[O:7][CH2:8]6)[CH:30]=[CH:29][N:28]=5)=[O:32])[CH2:36]4)=[CH:38][C:39]=3[O:54][CH3:55])=[CH:46][CH:47]=2)[CH2:53][CH2:52]1
Reactant: OCC1(CO)COC(c2ccccc2)OC1
Reactant: COc1cc(C2CN(C(=O)c3cc(COS(C)(=O)=O)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2CN(C(=O)c3cc(COCC4(CO)COC(c5ccccc5)OC4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5-hydroxymethyl-2-phenyl-[1,3]dioxan-5-yl)methanol (0.66 g) in DMF (10 mL) was added NaH (0.12 g). The mixture was stirred at RT for 1 hr. To the mixture was added 2-{3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidine-1-carbonyl}pyridin-4-ylmethyl methanesulfonate (0.7 g) prepared in Example 1 (7). The reaction mixture was stirred at RT for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over MgSO4. The solvent was removed under reduced pressure to give the crude title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C>[CH3:31][O:30][C:28](=[O:29])[CH2:27][N:7]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1OCc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Cl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of (2-benzyloxy-4-chlorophenyl)-carbamic acid tert-butyl ester (14.75 g, 44.2 mmol) in DMF (150 mL) at 0° C. is added NaH (1.94 g, 60% in mineral oil, 48.6 mmol) and the mixture is stirred at 0° C. for 10 min. To this is added methyl bromoacetate (5.04 mL, 53 mmol) and the mixture is stirred at RT for 8 h. The mixture is poured into ice/water (150 mL) and is extracted with EtOAc (700 mL). The organic phase is washed with 1N HCl (3×150 mL) and brine (150 mL) then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 5-10% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH2:10].C(N(CC)CC)C.C1C=[CH:20][C:21](=[O:34])[C:22]2C=1C(C(Cl)=O)=C1C=2C=CC=C1>ClCCl>[CH:2]([O:34][CH:21]([CH3:20])[CH3:22])([CH3:7])[CH3:3].[NH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[NH-:1]
Reactant: COc1ccc(N)c(N)c1
Reactant: O=C(Cl)C1=c2ccccc2=C2C(=O)C=CC=C12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: COc1ccc([NH-])c(N)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 124.9 %

Procedure:
The procedure used in stage 1 of Example 1 is followed, but starting from 10 g of 1,2-diamino-4-methoxybenzene, 20 ml of triethylamine and 17 g of fluoren-4-one-9-carboxylic acid chloride in 600 ml of dichloromethane. After stirring for 20 hours at room temperature, the precipitate that formed is filtered off, and washed with dichloromethane, with water, then with a 10% saturated aqueous solution of sodium hydrogen carbonate and, finally, with water. After formation of a paste with diisopropyl ether, in this way we obtain 6.2 g of (2-amino-4-methoxyphenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid, in the form of a brown powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[NH:11][C:12](=[O:21])[CH:13]=[CH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([NH:11][C:12](=[O:21])[CH:13]=[CH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)=[CH:25][CH:24]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1NC(=O)C=Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1NC(=O)C=Cc1cccnc1
Reaction time: 0.5 h

Procedure:
To a suspension of the product of step 3 (0.3 g) in anhydrous dichloromethane (30 ml), a solution of 4-fluoroaniline (0.1 g) and triethylamine (0.2 ml) in dichloromethane (15 ml) was added dropwise slowly in an ice-bath with the temperature no more than 5° C. After addition, the reaction was carried out for 30 min in an ice-bath, and then at room temperature overnight. The completion of reaction was indicated by TLC. Potassium carbonate solution (10%) was added. The reaction mixture was extracted with EtOAc (20 ml*3). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to recover solvent. The residue was purified on a silica gel column using EtOAc/petroleum ether/ethanol (1:2:0.5) as an eluent. The concentration of the eluent and crystallization provided a solid powder.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[CH:28][CH:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC(C)(C)c1ccc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-t-butylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>C(#N)C.C1(C)C(C)=CC=CC=1.N12CCN(CC1)CC2>[C:11]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1)=[O:22])(=[O:19])=[O:18]
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1C
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 880.2 %

Procedure:
14.0 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine were suspended in 100 ml of dry acetonitrile, and then 0.1 g of 1,4-diazabicyclo[2,2,2]octane was added thereto. To this mixture was added dropwise a solution of 2.5 g of 2-biphenylylsulfonyl isocyanate in 30 ml of xylene over an hour. During this addition, the reaction was accompanied by slight heat generation, and therefore cooling was applied as necessary. After the addition, the reaction was continued at room temperature for 5 hours and then at 40° C. for 5 hours. After allowing the mixture to cool to room temperature, the precipitated colorless crystals were filtered, washed with ether and dried to obtain 33.9 g of N-2-biphenylylsulfonyl-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl) urea; m.pt. 190°-193° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH3:12]O>OS(O)(=O)=O>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([OH:11])[CH:4]=1
Reactant: O=C(O)c1ccc(Br)c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)c(O)c1

Procedure:
To a solution of 4-bromo-3-hydroxy-benzoic acid (prepared according to J. Amer. Chem Soc. 1946, 68, 574) (5 g, 32.8 mmol) in MeOH (100 mL), conc. H2SO4 (1 mL) is added. The solution is refluxed for 14 h, then concentrated to about 30 mL and poured into a water. The aqueous layer is extracted with ether (50 mL×4) and the combined organic extracts are neutralized with a saturated aqueous solution of NaHCO3 (50 mL×2), washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give the title compound as a white powder. TLC, Rf (AcOEt)=0.9. 1H-NMR (CDCl3, 300 MHz): δ=5.8 (bs, 1H), 7.45 (d, 1H), 7.55 (d, 1H), 7.7 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:44]1([CH2:50][C:51]([NH2:53])=[O:52])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:47]3[CH2:48][CH2:49][N:44]([CH2:50][C:51]([NH2:53])=[O:52])[CH2:45][CH2:46]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:31])=[O:32])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% of 1:1 ethanol/acetonitrile in carbon dioxide).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:48][O:49][C:50]1[CH:51]=[C:52]([N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=1>CN(C=O)C>[CH3:48][O:49][C:50]1[CH:51]=[C:52]([N:58]2[CH2:59][CH2:60][N:61]([C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[O:13])[CH2:62][CH2:63]2)[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(OC)cc(N2CCN(C(=O)c3ccnc4ccccc34)CC2)c1

Procedure:
2 g (11.5 mmol) of quinoline-4-carboxylic acid were suspended in 80 ml of DMF. With stirring, 1.74 g (17.2 mmol) of N-methylmorpholine and then a solution of 8.95 g (17.2 mmol) of Py-BOP (1-benzotriazolyltripyrrolidinophosphonium hexafluorophosphate) and 2.56 g (11.5 mmol) of 1-(3,5-dimethoxyphenyl)piperazine in 25 ml of DMF were added to this mixture. The mixture was stirred at RT for 12 h, the DMF was distilled off under reduced pressure and the residue was purified on a silica gel column (Kieselgel 60, from Merck AG, Darmstadt) using the mobile phase dichloromethane/methanol/25 percent ammonia (90:10:1 v/v/v).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[H-].[Na+].[CH2:24](I)[CH3:25].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:24][CH3:25])[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[N:9]([CH2:24][CH3:25])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(-c2cccc3ccccc23)nc1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc(-c2cccc3ccccc23)n1CC
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)n(CC)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-methyl-2-naphthalen-1-yl-3H-imidazole-4-carboxylic acid ethyl ester (1.5 g) in DMF (30 ml) is added NaH (320 mg, 60%) at rt. The solution is stirred for 30 min, and EtI (0.6 ml) is added. After 30 min, the mixture is cooled to 0° C. and H2O is added. The mixture is then extracted with EtOAc. The extracts are combined, dried, evaporated and purified by column (EtOAc:Hexanes 1:1) to give 3-ethyl-5-methyl-2-naphthalen-1-yl-3H-imidazole-4-carboxylic acid ethyl ester [LCMS 309.4 (M+1); δ 4.10 ppm (CH2CH3)] and its regioisomer 1-ethyl-5-methyl-2-naphthalen-1-yl-1H-imidazole-4-carboxylic acid ethyl ester [LCMS 309.4 (M+1); δ 3.72 ppm (CH2CH3)].
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
A mixture of 7.0 g (E)-3-[1-(4-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester with 200 ml dichloromethane and 21.0 ml TFA is stirred at ambient temperature for 24 h. The dichloromethane and TFA is evaporated and the residue is coevaporated with toluene for 3 times. By this method 6.0 g of the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19]([CH2:21][C:22]5[CH:23]=[N:24][CH:25]=C[CH:27]=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=3.[N:29]1C=C(C=O)C=NC=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19]([CH2:21][C:22]5[CH:23]=[N:24][CH:25]=[N:29][CH:27]=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=3
Reactant: COc1cc2c3c(c1)c(=O)c(Cc1cccnc1)cn3-c1cc(Br)ccc1S2
Reactant: O=Cc1cncnc1
Product: COc1cc2c3c(c1)c(=O)c(Cc1cncnc1)cn3-c1cc(Br)ccc1S2
Yield: 89.8 %

Procedure:
According to Example 1 <step 4>, the compound (2 g) produced in Example 36 <step 2> was reacted with pyrimidine-5-aldehyde (3.11 g) to obtain the title compound (1.8 g; 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([OH:9])=O.[CH3:14][CH:15]1[NH:20][CH2:19][CH2:18][NH:17][C:16]1=[O:21].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:20]2[CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH:15]2[CH3:14])=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: CC1NCCNC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1C(=O)NCCN1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Yield: 69.7 %

Procedure:
A solution of 3,4-dichlorocinnamic acid (190 mg, 0.88 mmol), 3-methylpiperazin-2-one (100 mg, 0.88 mmol), 4-methylmorpholine (443 mg, 4.38 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (500 mg, 1.31 mmol) in N,N-dimethylformamide (1 ml) was stirred at room temperature for 3 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; CH2Cl2/MeOH 95:5) produced the title compound (192 mg, 70%). White solid, MS (ISP)=313.1 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[N:16][CH:15]=[CH:14]2.[C:21]([OH:24])(=[O:23])[CH3:22]>>[Cl:1][C:12]1[C:11]([O:10][CH3:9])=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][N:16]=[CH:17]2.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[N:16][CH:15]=[C:14]2[CH2:22][C:21]([OH:24])=[O:23]
Reactant: CC(=O)O
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2cnccc2c1
Product: COc1ccc2cncc(CC(=O)O)c2c1
Product: COc1ccc2cnccc2c1Cl
Temperature: 50 °C

Procedure:
N-Chlorosuccinimide (0.347 g, 2.60 mmol) is added to a solution of 6-methoxyisoquinoline (Synth. Commun. 1999, 29, 1617) (0.207 g, 1.30 mmol) in acetic acid (9 ml). The reaction is heated at 50° C. for 3 hours, cooled to ambient temperature, evaporated and partitioned between ethyl acetate and 1M aqueous sodium hydroxide. The organic phase is washed with water and brine, dried over magnesium sulfate and evaporated afford 5-chloro-6-methoxyisoquinoline, [MH]+ 194. A solution of this intermediate (0.175 g, 0.90 mmol) in THF (4.5 ml) and acetic anhydride (0.101 ml, 1.08 mmol) is treated with sodium triacetoxyborohydride (0.229 g, 1.08 mmol) and the reaction is stirred at ambient temperature for 22 hours. The solvent is evaporated, the residue is taken into ethyl acetate, washed with 0.5M aqueous hydrochloric acid, then brine and dried over magnesium sulfate. Evaporation affords 1-(5-chloro-6-methoxy-1H-isoquinolin-2-yl)-ethanone, mp 78-80° C. A suspension of this intermediate (0.150 g, 0.60 mmol) and glyoxylic acid (76 mg, 0.80 mmol) in 6M aqueous hydrochloric acid (2.8 ml) is heated at 100° C. for 3 hours. After cooling to ambient temperature, the resultant solid is collected by filtration to afford (5-chloro-6-methoxy-isoquinolin-4-yl)-acetic acid, [MH]+ 252. A suspension of this intermediate (0.970 g, 3.38 mmol) and ammonium formate (1.05 g, 16.9 mmol) in 1:1 acetic acid-water (25 ml) is treated with 10% Pd/C (0.730 g) and stirred at ambient temperature for 16 hours. After filtration through Celite®, the combined filtrate and washings are evaporated and purified by Soxhlet extraction with acetone to afford (6-methoxy-isoquinolin-4-yl)-acetic acid [MH]+ 218. Alternatively reduction of (5-chloro-6-methoxy-isoquinolin-4-yl)-acetic acid to afford (6-methoxy-isoquinolin-4-yl)-acetic acid is accomplished by stirring a suspension of (5-chloro-6-methoxy-isoquinolin-4-yl)-acetic acid (20 g, 69.4 mmol) in 1 Molar sodium hydroxide solution (400 mL) for 20 min, filtering off the resultant salt and then treating with hydgrogen gas in the presence of 10% Pd/C (1.4 g) at atmospheric pressure for 2.25 h. The resulting suspension is filtered through glass wool and celite, washing with water (50 mL). The solution is then cooled in an ice water bath and slowly (30 min) neutralised and then acidified with 5 Molar hydrochloric acid (80 ml). A suspension forms and further crystalisation is encouraged by standing at 5° C. for 20 h. The resulting crystals are removed by filtration and washed with ice cold ethanol (25 ml) drying under reduced pressure gives (6-methoxy-isoquinolin-4-yl)-acetic acid.