Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[N:12]=[CH:13][C:14]([C:30]2[CH:31]=[N:32][CH:33]=[C:28]([F:27])[CH:29]=2)=[CH:15][CH:16]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cncc(F)c1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Br)cn1)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(-c2cncc(F)c2)cn1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[2-(5-bromo-pyridin-2-yl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 5-fluoropyridine-3-boronic acid in analogy to Example 1b): MS (ISP): 476.1 and 478.1 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(-c2cccc(OC)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccc(-c2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.9 %

Procedure:
A solution of boron tribromide in dichloromethane (1N, 24.8 ml) was added to a solution of methyl 3′-methoxybiphenyl-4-carboxylate (2.00 g) in anhydrous dichloromethane (10 ml) at −70° C. The mixture was stirred at ambient temperature for 4 hours and a mixture of ice and water was added to the reaction mixture in an ice bath and then the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from a mixture of hexane and diisopropyl ether to afford the title compound (1.82 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.CO.Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.O>C(OCC)(=O)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)=[N:13][CH:14]=1)([O-:20])=[O:19]
Reactant: NCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(NCCN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2-aminoethyl)pyrrolidine (237 μl) was added to a methanol (1 ml) suspension containing 2-chloro-5-nitropyridine (100 mg), followed by stirring at room temperature for 3 hours and 30 minutes. 1-(2-aminoethyl)pyrrolidine (158 μl) was added, followed by stirring for 2 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with 10% saline and then with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Diisopropylether was added to the obtained residue, solid matter was collected by filtration and washed with diisopropylether and hexane, and a yellow solid of 5-nitro-N-(2-(pyrrolidin-1-yl)ethyl)pyridin-2-amine (27 mg) was thus obtained.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.C(OC(Cl)=O)C.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(C)=O.O>[N:24]([C:4]([C:3]1[C:2]([CH3:1])=[N:10][CH:9]=[CH:8][CH:7]=1)=[O:5])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ncccc1C(=O)O
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ncccc1C(=O)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.9 %

Procedure:
To a solution of 2-methylnicotinic acid (500 mg, 3.65 mmol) in a mixture of acetone (6.6 mL) and water (3.3 mL) was added triethylamine (1.02 mL, 7.3 mmol). The mixture was cooled to 0° C. in a ice-bath. Ethylchloroformate (0.79 g, 7.3 mmol) was then added and the resulting mixture was stirred for 1.5 hours at 0° C. To the mixture was added sodium azide (0.47 g, 7.3 mmol), and the mixture was stirred for another 1.5 hours. The mixture was concentrated, the residue was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated to give desired product (390 mg, 62%). 1HNMR (CDCl3) (δ) 8.67 (d, 1H), 8.21 (d, 1H), 7.24 (t, 1H), 2.88 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:7]2=[N:6][C:5]1=[O:17])([CH3:3])[CH3:2].CC(C)=[O:21]>O>[OH:21][C:7]12[NH:6][C:5](=[O:17])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:18])[N:8]1[C:9](=[O:16])[C:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)=O
Reactant: CC(C)C1(C)C(=O)N=C2c3ncccc3C(=O)N21
Solvent: O
Product: CC(C)C1(C)C(=O)NC2(O)c3ncccc3C(=O)N21

Procedure:
A solution of 2 g of 3-isopropyl-3-methyl-2H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-2,5(3H)-dione in 90 ml of acetone and 10 ml of water is stirred at room temperature for about 16 hours. The solution is subsequently evaporated to dryness and the residue is crystallized from ethyl acetate/n-hexane. There is obtained 1,9b-dihydro-9b-hydroxy-3-isopropyl-3-methyl-2H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-2,5(3H)-dione as colorless crystals, m.p. 151°-153° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.Cl.[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][CH2:41][NH2:42])[CH2:35][CH2:34]1.C(N(CC)CC)C>C(O)C>[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[CH2:34][CH2:35][N:36]([CH2:39][CH2:40][CH2:41][NH:42][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:6]3[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:37][CH2:38]1
Reactant: Cc1cccc(N2CCN(CCCN)CC2)c1C
Reactant: Clc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCN(CCCNc3ncnc4c3nc(-c3ccccc3)n4-c3ccccc3)CC2)c1C
Temperature: 80 °C
Reaction time: 15 h
Yield: 46.1 %

Procedure:
To a mixture of 6-chloro-8,9-diphenyl-9H-purine (150 mg, 0.49 mmol) and 3-(4-(2,3-dimethylphenyl)piperazin-1-yl)propan-1-amine dihydrochloride (313 mg, 0.98 mmol) in ethanol (4.9 mL) was added triethyl amine (0.27 mL, 1.96 mmol) and stirred at 80° C. for 15 hrs. The resulting reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The organic layer thus separated was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was purified by preparative HPLC (purification system, Gilson) to provide the title compound (117 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[CH2:35]Br>CN(C=O)C.C(OCC)(=O)C>[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[C:40]([F:41])([F:42])[F:43])[CH2:35][N:15]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][N:6]2[C:2]=1[CH3:1])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: Cc1c(NS(=O)(=O)c2ccccc2)nc2ccc(C(F)(F)F)cn12
Reactant: Fc1cc(CBr)ccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(N(Cc2ccc(C(F)(F)F)c(F)c2)S(=O)(=O)c2ccccc2)nc2ccc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a solution of compound 10-G (0.023 g, 0.048 mmol) in DMF (1 mL) was added Na2CO3 (0.015 g, 0.14 mmol) and 3-fluoro-4-trifluoromethylbenzyl bromide (0.014 g, 0.053 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give Compound 100 as a yellow solid (0.017 g, 66%); MS m/z (M+H+) 532.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.I[CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(C)(C)CI
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(CC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 19.7 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol), 1-iodo-2,2-dimethylpropane (0.100 mL; 0.75 mmol) in DMF (2 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.043 g (20%) of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[O:8]=[C:2]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: COC(=O)CC(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-chloro-3-oxopropanoate (2.0 g, 14.7 mmol) in dry DCM (100 ml) was added aniline (2.68 g, 3.6 mmol) and the reaction mixture was stirred at 0° C. for 1 hr, evaporated then dissolved in EtOAc, washed with dilute HCl, NaHCO3, and brine. The organic phase was collected, dried over sodium sulfate, filtered and the solvent was evaporated to afford methyl 3-oxo-3-(phenylamino)propanoate as a brown oil which was used without further purification (2.8 g, 100%, crude). To a solution of this material (2.8 g, 14.5 mmol) in THF (40 ml) and water (20 ml) was added NaOH (1.16 g, 29 mmol) and the reaction mixture was stirred overnight, evaporated (to remove the THF) and then extracted with Et2O. The aqueous phase was acidified to pH 1 and extracted with EtOAc. The extract was dried over Na2SO4, filtered and evaporated to afford the title compound 1 as a brown solid, which was used without further purification (2.0 g, 77% yield). MS (m/z): 18.0 (100%) (M+H), 202.0 (44%) (M+Na).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].FC1C=CC(C(C2C=CC(F)=CC=2)=O)=CC=1.[C:23]([O:31]C)(=[O:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].O>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]([C:25](=[CH2:1])[CH2:24][C:23]([OH:31])=[O:30])=[O:27]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CCC(=O)OC
Agent: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(CC(=O)O)C(=O)OC
Temperature: 70 °C

Procedure:
Potassium t-butoxide (68.8 g) was weighed into a reaction flask equipped with a mechanical stirrer, placed under a nitrogen atmosphere and 700 mL of toluene was added followed by 4,4′-difluorobenzophenone (100 g). The reaction mixture was stirred mechanically and heated to 70° C. A solution of dimethyl succinate (80 g) in 100 mL of toluene was added to the reaction mixture over a 60 minute period. The reaction mixture was heated at 70° C. for 4 hours. After cooling to room temperature, the reaction mixture was poured into 500 mL of water and the toluene layer discarded. The aqueous layer was extracted with diethyl ether (1×400 mL) to remove the neutral products, and then acidified the aqueous layer with concentrated HCl. A brownish-yellow oily solid was obtained from the aqueous layer, and was extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with saturated NaCl solution (1×500 mL) and dried over anhydrous sodium sulfate. Removal of the solvent by rotary evaporation yielded 122 g of 4,4-di(4-fluorophenyl))-3-methoxycarbonyl-3-butenoic acid as a brownish oily solid. This material was not purified further but was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH:5]([CH3:7])[CH3:6]
Reactant: ClCCN1CCOCC1
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)N(CCN2CCOCC2)C(C(=O)OC)C(C)C)cc1
Yield: 90.5 %

Procedure:
According to the procedure of Example 21, 0.419 g (1.236 mmol) of 2-(4but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester and 0.408 g (2.20 mmol) of 4-(2-chloroethyl)morpholine hydrochloride provided 0.506 g of 2-[(4-but-2-ynyloxy-benzenesulfonyl)-(2-morpholin-4-yl-ethyl)-amino]-3-methyl-butyric acid methyl ester as a colorless oil. Electrospray Mass Spec 453.0 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9](Cl)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22](B(O)O)[CH:21]=[N:20]2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH:23]=[C:22]([C:9]3[N:10]=[C:3]4[CH:2]=[CH:7][CH:6]=[CH:5][N:4]4[N:8]=3)[CH:21]=[N:20]2)=[CH:17][CH:18]=1
Reactant: OB(O)c1cnn(-c2ccc(F)cc2)c1
Reactant: Clc1nc2c(Br)cccn2n1
Product: Fc1ccc(-n2cc(-c3nc4ccccn4n3)cn2)cc1

Procedure:
2-Chloro-8-([1-(4-fluoro-phenyl)1H-pyrazol-4-yl]-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 1-(4-fluorophenyl)pyrazole-4-boronic acid in a manner analogous to Example 2c (0.45 g, 67%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[CH2:11](Br)[CH:12]=[CH2:13]>>[CH2:11]([NH:1][C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1)[CH2:12][CH3:13]
Reactant: C=CCBr
Reactant: COC(=O)c1cnc(N)s1
Product: CCCNc1ncc(C(=O)OC)s1

Procedure:
Methyl 2-aminothiazole-5-carboxylate, prepared by the procedure described in U.S. Pat. No. 4,001,421, is reacted with allyl bromide using the conditions described in Example 15A. This product is then hydrogenated using the procedure described in Example 15B to give methyl 2-propylaminothiazole-5-carboxylate.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]=[O:25])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:26][Mg]I.CO>ClCCl.CCOCC>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]([OH:25])[CH3:26])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C=O)cccc2c1Nc1ccccc1C
Reactant: C[Mg]I
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CCCC(=O)c1cnc2c(C(C)O)cccc2c1Nc1ccccc1C

Procedure:
A solution of 3-butyryl-4-(2-methylphenylamino)-quinoline-8-carbaldehyde (2.0 g, 6 mmol) in dichloromethane (100 ml) was stirred at 0° C. -5° C. and treated with a solution of methylmagnesium iodide in ether until T.L.C. (2% methanol in dichloromethane) showed that mostly new product had formed. The mixture was washed with ammonium chloride solution, dried and evaporated. Chromatography (silica gel, 0.5% methanol in dichloromethane) afforded the required 3-butyryl-4-(2-methylphenylamino)-8-(1-hydroxyethyl)quinoline (0.28 g) as yellow crystals, m.p. 140° C.-2° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[CH:15]1([CH2:21][CH2:22][C:23]([N:6]2[CH:7]([C:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[NH:26][CH:27]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)CCC1CCCCC1
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: O=C(CCC1CCCCC1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
3-Cyclohexyl-1-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-propan-1-one was prepared from phenanthridine, 3-cyclohexylpropionyl chloride, and indole according to GP 2. Yield, 5.5%. 1H-NMR (CD3OD): δ=0.56-0.79 (m, 2H), 0.86-1.09 (m, 4H), 1.26-1.62 (m, 7H), 2.47-2.70 (m, 2H), 6.08 (s, 1H), 6.96-7.05 (m, 2H), 7.07 (td, J=7.2 Hz, J=1.3 Hz, 1H), 7.13 (td, J=7.9 Hz, J=1.4 Hz, 1H), 7.21 (“d”, J≈7.4 Hz, 1H), 7.27 (“t”, J≈7.6 Hz, 1H), 7.36-7.42 (m, 3H), 7.46-7.53 (m, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.98 (d, J=7.7 Hz, 1H); (+)-ESI-MS: m/z=435 [M+H]+, 318 [M-indole+H]+, 180.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(N(CC)C(C)C)(C)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>>[CH2:34]([S:36]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:38])=[O:37])[CH3:35]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CCS(=O)(=O)Cl
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: -78 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
To a stirring suspension of D-phenylalanine (50 g, 300 mmol) in THE (400 mL) was added N,O-bis(trimethylsilyl) acetamide (92 g, 450 mmol). After stirring for 12 h, the solution was cooled to −78° C. and N,N-diisopropylethylamine (58 mL, 330 mmol) was added. To this solution was slowly added ethanesulfonyl chloride (31 mL, 330 mmol) and the cold bath was removed. After stirring for 20 h, the solvents were removed in vacuo and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate. The aqueous phase was washed with diethyl ether, acidified with solid citric acid and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 61 g (79%) of a thick colorless oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[S:34][C:35]=1[CH3:36].O>CN(C)C=O>[CH3:36][C:35]1[S:34][C:33]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[N:32][C:31]=1[CH2:30][O:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)sc3C)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-5-methyl-2-phenylthiazole (336 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (690 mg, yield: 86%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [C:1]([CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:10]=1[O:23][CH3:24])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[CH2:27](Cl)[CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[C:1]([C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:10]=1[O:23][CH3:24])([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Reactant: CCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Yield: 97.1 %

Procedure:
A solution of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (5 g) in dimethylformamide (10 ml) was added dropwise to a suspension of sodium hydride (65%, 600 mg) in dimethylformamide (30 ml) in 10 minutes at temperature below 10° C. with stirring, and the mixture was stirred at the same temperature for 10 minutes. n-Pentyl chloride (3.3 g) was added to the mixture and stirred at 110° C. for 2 hours. The reaction mixture was treated in a similar manner to that of Example 25-(1) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]-n-heptanoate (5.9 g).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])=[O:9]
Reactant: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a suspension of 5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-vinyloxyethoxy)-amide (1.33 g, 3.05 mmol) in methanol (40 mL) was added aqueous hydrochloric acid (6.7 mL, 1M, 6.7 mmol). The reaction mixture was stirred at room temperature for 30 minutes then concentrated in vacuo to remove the methanol. The resultant residue was dissolved in 1:1 diethylether:ethyl acetate (30 mL) and aqueous saturated sodium hydrogen carbonate solution (30 mL) added. The resultant mixture was sonicated until a precipitate formed, the precipitate collected by filtration and washed with water then diethyl ether to yield the title compound as a yellow solid (1.12 g, 90%). LCMS (method A): RT=5.22 min, [M+H]+=409/411. 1H NMR (DMSO-d6, 400 MHz) 9.20 (1H, s), 8.07 (1H, s), 7.51 (1H, dd, J=10.86, 2.22 Hz), 7.44 (1H, s), 7.40 (1H, d, J=9.33 Hz), 7.16 (1H, ddd, J=8.61, 2.20, 1.07 Hz), 6.89 (1H, d, J=9.31 Hz), 6.50 (1H, t, J=8.84 Hz), 4.63 (1H, s), 3.65 (2H, t, J=4.79 Hz), 3.46 (3H, s).