Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC=CC=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:61]=[CH:60][CH:59]=[CH:58][C:50]=1[C:51](NCCOC)=O>>[C:19]([CH2:18][CH2:51][C:50]1[CH:49]=[CH:61][CH:60]=[CH:59][C:58]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH3:9])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19]1)#[N:20]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COCCNC(=O)c1ccccc1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCC#N)cc1

Procedure:
Analogously to Method G. 0.456 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 027 g of 2-hydroxy-N-(2-methoxyethyl)benzamide are reacted. The title compound is obtained as a yellow oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.60.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[O:24][CH:25]=1>>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1/[CH:27]=[CH:26]/[C:23]1[O:24][CH:25]=[C:21]([CH2:20][O:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[CH:15][CH:14]=2)[N:22]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Product: Fc1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)c(F)c1
Yield: 83.2 %

Procedure:
Using 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (152 mg), 65% oily sodium hydride (28 mg) and 4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (188 mg), the same reaction as Example 2 was carried out to yield the titled compound (254 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].[C:17]([O:21][C:22]([N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]([S:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:25]1[N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH:28]=[CH:27][CH:26]=1)(=[O:13])=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1-c1cccn1C(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 96.2 %

Procedure:
To a mixture of 19B (3.0 g, 9.7 mmol), 3A (2.5 g, 11.7 mmol) and sodium carbonate (19.5 mL, 2M, 38.9 mmol) in 1,2-dimethoxyethane (100 mL, flushed and degassed (3×) with nitrogen) was added Pd(PPh3)4 (2.2 g, 1.9 mmol) under nitrogen. The reaction was heated to 95° C. for 3 h. The catalyst was filtered over celite and washed with ethyl acetate. The organic layer was washed with water, brine and then dried over sodium sulfate. The solvent was removed and the crude residue was purified by flash column chromatography to give 3.68 g of product 19C (96% yield). 1H NMR (400 MHz, Methanol-d4) δ ppm 1.01 (d, J=6.85 Hz, 3H) 1.15 (d, J=6.85 Hz, 3H) 1.20 (d, J=7.83 Hz, 9H) 3.00 (m, 1H) 6.29 (m, 2H) 7.41 (dd, J=3.18, 1.71 Hz, 1H) 8.20 (d, J=2.20 Hz, 1H) 8.25 (d, J=8.56 Hz, 1H), 8.41 (dd, J=8.68 Hz, 2.32 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([Cl:25])=[CH:27][CH:28]=3)[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Nc1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1c(Nc2ccc(Cl)cc2)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 150 °C
Reaction time: 12 h
Yield: 48.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazo-1-yl]butanoate (Reference Example 33; 1.00 g, 2.70 mmol) and 4-chloroaniline (1.04 g, 8.0.9 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was stirred at 150° C. for 12 hr. After cooling, the mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, water and brine. Organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (600 mg, 1.30 mmol, 48%) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.Cl.[NH2:18][C@@H:19]([CH2:23][OH:24])[C:20]([NH2:22])=[O:21].C(N(CC)CC)C>>[OH:24][CH2:23][C@H:19]([N:18]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)[C@@H](N)CO
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(=O)[C@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 52 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (2 g, 0.01 mol), methanol (40 mL, 1 mol), (S)-2-amino-3-hydroxypropanamide hydrochloride (2.2 g, 0.016 mol) and triethylamine (2.55 mL, 0.0183 mol) and stirred at 52° C. overnight. The product precipitated out and was filtered and dried to yield the pure product as a yellow solid. MS m/z=278.3 (M+H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16]([OH:22])[CH2:17][O:18][CH2:19][CH2:20][OH:21]>>[CH2:1]([O:22][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCBr
Reactant: OCCOCCO
Product: CCCCCCCCCCCCCCOCCOCCO

Procedure:
Using 13.9 g of tetradecyl bromide and 15.9 g of diethylene glycol and proceeding as in Example 17, there is obtained the title compound. Yield 6.1 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[CH3:28][S-:29].[Na+]>O1CCOCC1.CN(C=O)C>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([S:29][CH3:28])[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: C[S-]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(SC)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium methanethiolate in dioxane and DMF. ES-MS m/e (%): 417 (M+H+, 100).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[N+:12]1([O-:9])[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: c1cnc2cccnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cccc2ncccc21
Yield: 84.2 %

Procedure:
m-CPBA (1.2 g, 6.91 mmol) was added in 3 portions (after every 3 h) to a solution of 1,5-naphthyridine (1.0 g, 7.68 mmol) in dry DCM (60 ml). After completion of the reaction, the mixture was concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (98:2) as the eluent to get title compound (0.85 g, 76%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH:12]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[NH:14][C:13]2=[O:29])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:37][N:14]1[C:15]2[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=2[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:18][CH:12]([NH:11][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])[C:13]1=[O:29])[CH3:36]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)CCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 1,3-dihydro-3-phenylmethyloxycarbonylamino-5-phenyl-2H-1,4-benzodiazepin-2-one and ethyl bromopropionate. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.: m.p. 57°-59° C.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH:10]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.C(O)(=[O:23])C>>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[CH:10]1[CH2:9][C:8]2[C:13]3=[C:4]([NH:3][C:2](=[O:23])[N:12]3[CH2:11]1)[CH:5]=[CH:6][CH:7]=2)[CH2:16][CH3:17]
Reactant: CC(=O)O
Reactant: CCCN(CCC)C1Cc2cccc3nc(Cl)n(c23)C1
Product: CCCN(CCC)C1Cc2cccc3[nH]c(=O)n(c23)C1

Procedure:
2-Chloro-5,6-dihydro-N,N-dipropyl-4H-imidazo(4,5,1-ij)quinolin-5-amine was refluxed in acetic acid for 1 hour. The solvent was removed and the residue was partitioned between ethyl acetate and sodium hydroxide solution. Evaporation of the ethyl acetate afforded 5(dipropyl amino)-5,6-dihydro-4H-imidazo(4,5,1-ij)quinolin-2(1H)-one.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](=[O:12])([O-])[O-:10].[K+].[K+]>CN(C)C=O.[Cu]I>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[C:9]([OH:10])=[O:12])=[CH:1][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)cc1
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccccc2C(=O)O)cc1
Yield: 90.3 %

Procedure:
To a solution of 5.95 g of p-cresol and 7.83 g of 2-chlorobenzoic in 50 mL of dimethylformamide at 25° was added, in portions, 14.50 g of anhydrous potassium carbonate. The resulting mixture was heated to 80°, and 0.10 g of copper(I) iodide was added. The reaction mixture then was refluxed for 16 hours. While still hot the mixture was poured onto water-ice. The resulting suspension was filtered, and the filtrate was adjusted to pH 3.0 using aqueous hydrochloric acid. The precipitate was recovered by filtration. The crude solid was dissolved in an aqueous sodium hydroxide solution. This solution was acidified to pH 6.0 using hydrochloric acid, filtered, and then acidified to pH 3.0. Filtration provided 5.67 g of 2-(4-methylphenoxy)benzoic acid which was employed in the following reaction without further purification. NMR (200 MHz, CDCl3): δ8.15 (d of d, 1H); 7.42 (d of d of d, 1H); 7.23-7.12 (m, 3H); 6.97 (d, 2H); 6.80 (d, 1H); 2.37 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[N:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: O=C(O)c1cncc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 5 mg of 349. MS (Q1) 459.1 (M)+
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[CH:26]([O:28][CH2:29][CH3:30])=[O:27]>CC#N>[CH2:29]([O:28][C:26]([NH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1)=[O:27])[CH3:30]
Reactant: CCOC=O
Reactant: NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Solvent: CC#N
Product: CCOC(=O)NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21

Procedure:
[7-[(4-Oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acid ethyl ester (482) was synthesized following the general scheme above, from amine (273-I) and ethyl formate. Overall yield (18%). HPLC ret. time 2.84 min, 10-99% CH3CN, 5 min run; ESI-MS 406.5 m/z (MH+).
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:24]=[O:25])=[C:11]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:12](N(CC)CC)=[O:13])C1C=CC=CC=1.C(O)(=[O:28])C>Cl>[OH:28][CH:24]1[C:10]2[C:11](=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[C:9]=2[OH:8])[C:12](=[O:13])[O:25]1
Reactant: CC(=O)O
Reactant: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1C=O
Agent: Cl
Product: COc1ccc2c(c1O)C(O)OC2=O

Procedure:
A solution of 3-benzyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide (11.6 g, 34 mmoles), prepared as described in example 56, in 10% HCl (80 ml) and acetic acid (80 ml) was refluxed for 18 hours. The solvents were evaporated and the crude taken up in toluene. The solid was washed with ethyl ether and brought to dryness to give 6.66 g of the title compound (quantitative yield) which was used as such in the subsequent step.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:1][C:2]1[CH:6]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[O:4][N:3]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: Oc1cc(-c2cccc3ccccc23)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2cccc3ccccc23)on1
Yield: 89.4 %

Procedure:
3-Hydroxy-5-(1-naphthyl)isoxazole (0.20 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.17 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.30 g, 89%) as a colorless powder.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][C:8]1=O.C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)Cl>[C:1]([N:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CN1CCNCC1=O
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acryloyl chloride (90.5 g) in methylene chloride (100 ml) was added into a methylene chloride (500 ml) solution of N-methyl piperazone (100 g) over a period of one hour. The reaction temperature was kept below 25° C. with cooling. After the addition was completed, the reaction mixture was stirred at ambient temperature for two hours. Then, sodium carbonate (53 g) in 250 ml. of water was added into the reaction mixture with stirring. A crude product (76 g) of 1-acryloyl-4-methyl piperazine was recovered from the methylene chloride solution. The product was distilled and the fraction collected at 65°-69° C./1.5 mm Hg was characterized by I.R. and C13 NMR and was found to be 97% pure by G. C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]=[N+]=[N-])=[CH:12][CH:11]=2)[C:5]([C:22]#[N:23])=[C:4]([S:24][CH2:25][C:26]2[N:27]=[C:28]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[S:29][CH:30]=2)[N:3]=1.[H][H].[ClH:41]>O1CCOCC1.[Pd]>[ClH:41].[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][NH2:19])=[CH:14][CH:15]=2)[C:5]([C:22]#[N:23])=[C:4]([S:24][CH2:25][C:26]2[N:27]=[C:28]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[S:29][CH:30]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(Nc3ccc(F)cc3)n2)c(C#N)c1-c1ccc(OCCN=[N+]=[N-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(N)nc(SCc2csc(Nc3ccc(F)cc3)n2)c(C#N)c1-c1ccc(OCCN)cc1
Reaction time: 3 h

Procedure:
1000 mg (1.84 mmol) of the compound from Example 39A are dissolved in 100 ml of dioxane, 150 mg (1.41 mmol) of palladium-on-activated carbon are added and the mixture is hydrogenated with hydrogen at 3 bar. After 3 h, 4 ml of 2M hydrochloric acid are added and the mixture is hydrogenated with hydrogen at 3 bar for a further 20 h. The mixture is then filtered off with suction through a Seitz clarifying sheet filter, the product is then washed with 50 ml of dioxane, and 50 ml of toluene are added to the filtrate. After removal of the solvent on a rotary evaporator, the residue is taken up in a mixture of 50 ml of water and 50 ml of ethyl acetate. By cautious addition of aqueous dilute sodium bicarbonate solution, the pH is adjusted to about pH 9. The phases formed are separated. The organic phase is dried over magnesium sulphate, the solvent is then removed using a rotary evaporator and the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5, with addition of 0.5% concentrated hydrochloric acid). The product-containing fractions are combined and concentrated using a rotary evaporator.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.CCN(C(C)C)C(C)C.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[S:30]([O:1][C:2]1[CH2:3][N:4]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:5][CH2:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:31])=[O:29]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (2.0 g, 7.37 mmol) in DCM (45 mL) was added DIPEA (1.54 ml, 8.84 mmol) and Tf2O (1.36 mL, 8.11 mmol) at −78° C., then the temperature was warmed up to room temperature and the solution was stirred at RT for 1.5 h, the mixture was diluted with DCM (100 mL), organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give 1-(tert-butyl) 4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate, which was used for next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)C(O)C1C2C(=CC=CC=2)C=CC=1.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH:31]=[O:32]>>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([CH:18]=[CH:5][CH:4]=1)[CH:31]([OH:32])[C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: COc1cccc(C(O)c2cccc3ccccc23)c1
Product: COc1cccc(C(O)c2ccc3ccccc3c2)c1

Procedure:
The compound 6 was prepared by following the synthesis procedure as described for compound 1, but substituting 1-naphtaldehyde for 2-naphtaldehyde.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=NCCCN(C)C)C.[C:12]([C:16]1[N:17]=[C:18]([C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH2:30][N:31]4[C:39]5[C:34](=[CH:35][C:36]([O:40][CH2:41][C:42]([OH:44])=O)=[CH:37][CH:38]=5)[C:33]([CH2:45][C:46]([O:48][CH3:49])=[O:47])=[CH:32]4)=[CH:26][C:24]=3[CH:25]=2)[S:19][CH:20]=1)([CH3:15])([CH3:14])[CH3:13].Cl.CNC>ClCCl>[C:12]([C:16]1[N:17]=[C:18]([C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH2:30][N:31]4[C:39]5[C:34](=[CH:35][C:36]([O:40][CH2:41][C:42](=[O:44])[N:3]([CH3:4])[CH3:1])=[CH:37][CH:38]=5)[C:33]([CH2:45][C:46]([O:48][CH3:49])=[O:47])=[CH:32]4)=[CH:26][C:24]=3[CH:25]=2)[S:19][CH:20]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(OCC(=O)O)cc12
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(OCC(=O)N(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide (46.5 mg) was added to a mixture of methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(carboxymethoxy)indole-3-acetate (145 mg), dimethylamine hydrochloride (24.4 mg) and 1H-hydroxybenzotriazole hydrate (40.4 mg) in dichloromethane (2 ml) and then the mixture was stirred at room temperature for 2 hours. After removal of solvent, the residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(N,N-dimethylcarbamoylmethoxy)-indole-3-acetate (0.16 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[CH:23]=[N:22][N:21]=[C:20]2[CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10])([O-:3])=[O:2].[Br:36]N1C(=O)C2=CC=CC=C2C1=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[C:20]([CH2:24][N:25]3[C:29](=[O:30])[C:28]4=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]4[C:26]3=[O:35])=[N:21][N:22]=[C:23]2[Br:36])=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10])([O-:3])=[O:2]
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Reactant: O=C1c2ccccc2C(=O)N1Br
Product: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1c(Br)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 1, 5-nitro-2-(3-phthalimidomethyl-4H-1,2,4-triazol-4-yl)-2'-chlorobenzophenone is reacted with N-bromophthalimide to form 5-nitro-2-(3-bromo-5-phthalimidomethyl-4H-1,2,4-triazol-4yl)-2'-chlorobenzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[H][H]>C(O)C.[Rh]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH3:15])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=CCc1cc(C(=O)OC)cc(Cl)c1O
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: CCCc1cc(C(=O)OC)cc(Cl)c1O
Reaction time: 0.5 h

Procedure:
A Parr flask was charged with a solution of 14.784 g (65.2 mmol) of the product of step A dissolved in 80 mL ethanol and 0.485 g of 5% rhodium on alumina catalyst was added. The reaction mixture was mounted in a Parr hydrogenation apparatus, pressurized to 40 psig hydrogen and shaken for 30 minutes. The reaction vessel was then removed from the apparatus, the contents were filtered and the flitrate was evaporated and dried in vacuo to afford 14.878 (99%) of the title compound.