Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]([CH3:35])[C:28]([O:30]C(C)(C)C)=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]([CH3:35])[C:28]([OH:30])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:14][CH:15]=1)#[N:2]
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a stirred solution of tert-butyl 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)propanoate (25 mg, 0.049 mmol) in DCM (1 ml) was added TFA (250 μl). The reaction was stirred at ambient temperature for 4 hours and then concentrated. The crude product was purified via preparative TLC (5% MeOH/DCM) to give 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)propanoic acid (0.0174 g, 0.0382 mmol, 78%). 1H NMR (400 MHz, CDCl3): 8.04 (bs, N—H), 7.96 (s, 1H), 7.64-7.71 (m, 3H), 7.61 (s, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.44 (dd, J=8.6, 2.2 Hz, 1H), 7.08 (d, J=8.9 Hz, 2H), 6.83 (d, J=8.5 Hz, 1H), 3.74 (q, J=7.4 Hz, 1H), 1.53 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:46]=[S:47]1(=[O:70])[NH:58][C:57]2[C:59]3[C:53]([CH:54]=[C:55]([CH2:60][CH2:61][O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH:56]=2)=[CH:52][CH:51]=[CH:50][C:49]=3[NH:48]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:48]3[C:49]4=[C:59]5[C:53](=[CH:52][CH:51]=[CH:50]4)[CH:54]=[C:55]([CH2:60][CH2:61][O:62][Si:63]([CH2:66][CH3:67])([CH2:64][CH3:65])[CH2:68][CH3:69])[CH:56]=[C:57]5[N:58]([CH3:27])[S:47]3(=[O:46])=[O:70])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC[Si](CC)(CC)OCCc1cc2c3c(cccc3c1)NS(=O)(=O)N2
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4cccc5cc(CCO[Si](CC)(CC)CC)cc(c45)N(C)S3(=O)=O)[C@H](C)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (365 mg, 1.0 mmol), triphenylphosphine (315 mg, 1.2 mmol), and 2,2-dioxo-5-(2-triethylsilanyloxy-ethyl)-2,3-dihydro-2-thia-1,3-diaza-phenalene (432 mg, 1.1 mmol) in anhydrous tetrahydrofuran (7 mL) is cooled in an ice-bath and stirred under a nitrogen atmosphere while diisopropyl azodicarboxylate (0.24 mL, 1.2 mmol) is added dropwise over a few minutes. The resulting solution is stirred in the cold for 30 minutes, then diluted with chloroform, washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel flash chromatography, eluting with hexane-ethyl acetate, to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-1-methyl-2-[3-methyl-2,2-dioxo-5-(2-triethylsilanyloxy-ethyl)-2,3-dihydro-2-thia-1,3-diaza-phenalen-1-ylmethyl]-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:24])([CH3:23])[CH2:11][C:12]([OH:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH:13]=O.[NH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][C:30](=[O:36])[NH:31]2>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:22][C:12]1([C:15]([F:20])([F:21])[C:16]([F:18])([F:19])[F:17])[CH2:11][C:10]([CH3:23])([CH3:24])[C:4]2[C:5](=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[O:2][CH3:1])[CH:13]1[NH:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][C:30](=[O:36])[NH:31]2
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)C(F)(F)F
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)cc2c1C(C)(C)CC(O)(C(F)(F)C(F)(F)F)C2Nc1cccc2[nH]c(=O)ccc12
Yield: 0.7 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal and 93 mg of 5-aminoquinolin-2(1H)-one. 2 mg of the title compound is obtained by reaction of 80 mg of the imine with 1.6 ml of titanium tetrachloride solution (1 M in dichloromethane) in 5 ml of dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:28]=[CH:27][C:20]3[NH:21][C:22](=[O:26])[C@@H:23]([CH3:25])[O:24][C:19]=3[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:29]I>>[F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:28]=[CH:27][C:20]3[N:21]([CH3:29])[C:22](=[O:26])[C@@H:23]([CH3:25])[O:24][C:19]=3[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)O[C@H](C)C(=O)N4)c2)CCOCC1
Reactant: CI
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)O[C@H](C)C(=O)N4C)c2)CCOCC1
Yield: 42 %

Procedure:
Using a similar procedure to that described in Example 16, (R)(-)-4-[5-fluoro-3-(2-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl]-4-methoxytetrahydropyran was reacted with methyl iodide to give (R)-(-)-4-[5-fluoro-3-(2,4-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl]-4-methoxytetrahydropyran in 42% yield, m.p. 107°-109° C. Specific Rotation: [alpha]D =-36.8° (methylene chloride, c=1 g/100 ml, temp.=25° C).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.CCCCCC.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:26]([NH:25][C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)=[O:27])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Fc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc(F)ccc23)CC1

Procedure:
7-Fluoro-4-(piperazin-1-yl)quinoline (0.29 g, 1.25 mmol) and 4-fluorophenyl isocyanate (142 μL, 1.25 mmol) in THF (10 mL) are reacted according to method C yielding the product as colorless crystals after column chromatography with hexane-EtOAc.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C)C=O.[F:12][CH:13]([F:23])[C:14]1[C:18]([C:19](O)=[O:20])=[CH:17][N:16]([CH3:22])[N:15]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[NH2:38])=[CH:27][C:26]=1[F:39]>ClCCl.O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[NH:38][C:19]([C:18]2[C:14]([CH:13]([F:23])[F:12])=[N:15][N:16]([CH3:22])[CH:17]=2)=[O:20])=[CH:27][C:26]=1[F:39]
Reactant: Nc1ccc(F)cc1-c1ccc(Cl)c(F)c1
Reactant: Cn1cc(C(=O)O)c(C(F)F)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cn1cc(C(=O)Nc2ccc(F)cc2-c2ccc(Cl)c(F)c2)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
1.6 ml (18.4 mmol) of oxalyl dichloride and 0.2 ml of dimethylformamide are added to a mixture consisting of 2.96 g (16.8 mmol) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid in 100 ml of dichloromethane. After 2 hours at room temperature, a solution consisting of 3.83 g (16.0 mmol) of 4′-chloro-5,3′-difluorobiphenyl-2-yl-amine and 2.9 ml (20.8 mmol) in 100 ml of dichloromethane is added. The reaction mixture is stirred for 16 hours at room temperature. For work-up, the reaction mixture is poured into water, and the organic phase is separated, dried over magnesium sulphate and concentrated in vacuo. Column chromatography (petroleum ether/acetone 3:1) yields 5.94 g (93% of theory) of N-(4′-chloro-3′,5-difluorobiphenyl-2-yl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide with a logP (pH 2.3) of 3.05.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:39]=[CH:38][C:19]3[N:20]=[CH:21][N:22]([C:23]4[S:24][C:25]([C:35](=[O:37])[NH2:36])=[C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=5)[N:27]=4)[C:18]=3[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>ClCCl>[Cl:34][C:30]1[CH:29]=[C:28]([C:26]2[N:27]=[C:23]([N:22]3[C:18]4[CH:17]=[C:16]([O:15][CH2:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:39]=[CH:38][C:19]=4[N:20]=[CH:21]3)[S:24][C:25]=2[C:35]([NH2:36])=[O:37])[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1sc(-n2cnc3ccc(OCC4CCNCC4)cc32)nc1-c1cccc(Cl)c1
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To 0.13 g (0.23 mmole) of 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-yl]-3H-benzoimidazol-5-yloxymethyl}-piperidine-1-carboxylic acid tert-butyl ester (I.23a) in 5 mL of dichloromethane at 0 degrees, was added 5 mL of dichloromethane-trifluoroacetic acid (1:1). The mixture was stirred at 0 degrees for 1 hour and then concentrated under reduced pressure. The residue was diluted with dichloromethane, washed with saturated aqueous sodium carbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from methanol to give 0.10 g of 4-(3-chloro-phenyl)-2-[6-(piperidin-4-ylmethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.23). MH+/Z=468
Reaction SMILES: N=NC=NN.C(=O)([O-])[O-].[K+].[K+].[CH:12](=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([O:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[CH:12]=[O:20])[CH:22]=[CH2:21]
Reactant: O=Cc1ccccc1O
Reactant: C=CCBr
Agent: N=NC=NN
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccccc1C=O

Procedure:
Synthesis of formazan monomer used copolymers E34, E35, E36, E37 of table 1, infra. ##STR6## Potassium carbonate (24.0 g, 173.9 mmol) was added to an ethanolic solution containing salicylaldehyde (19.0 g, 155.7 mmol) an allyl bromide (22.0 g, 181.8 mmol). The resulting suspension was heated to reflux overnight. The precipitated inorganic salt was filtered off. The filtrate was evaporated under reduced pressure to give the desired product, 2-allyloxy-benzaldehyde.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[OH-:20].C([N+](C)(C)C)C1C=CC=CC=1.O=O>O.CO>[C:1]1(=[O:20])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [OH-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=O
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: O=C1C=CC=C2C1=Cc1ccccc12
Yield: 94 %

Procedure:
Into a 150 ml three-necked flask, 6.5 g of the thus obtained fluorene compound and 100 ml of pyridine were introduced. The mixture was cooled with ice and then 0.5 ml of a 40% methanol solution of benzyltrimethylammonium hydroxide was added thereto. The resulting mixture was stirred for one hour in an oxygen stream. After completion of the reaction, the contents were poured into 100 ml of water, resulting in a yellow precipitate. This precipitate was filtered off, washed with diluted hydrochloric acid and then with water, and dissolved in methylene chloride. This solution was dried with Na2SO4 and then purified with a silica gel short column (methylene chloride/hexane=1/1). Subsequently, the solvent was removed by evaporation under reduced pressure, and then the residue was recrystallized from a mixture of ethyl acetate and ethanol. Thus, 6.5 g (yield 94%) of a fluorenone compound having the following structural formula was obtained as orangish yellow needle crystals. The melting point of this compound was 172°-173.5° C. ##STR6##
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1.[CH2:12]([O:14][C:15](=[O:34])[CH:16]([C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][N:27]=[C:26](Cl)[N:25]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:13].C(OC(C)(C)C)(=O)CC(OCC)=O>CCO.CCOC(C)=O>[CH2:12]([O:14][C:15](=[O:34])[CH:16]([C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][N:27]=[C:26]([NH:11][CH:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9]2)[N:25]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:13]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Reactant: COCCN1CCC(N)CC1
Agent: CCOC(=O)CC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1nc(NC2CCN(CCOC)CC2)ncc1[N+](=O)[O-]
Yield: 29 %

Procedure:
To 1-(2-methoxy-ethyl)-piperidin-4-ylamine (4, 1.7 g, 11 mmol) in EtOH (20 mls) was added a solution of the 1:1 mixture of 2-(2-chloro-5-nitro-pyrimidin-4-yl)-malonic acid tert-butyl ester ethyl ester (3) and tert-butyl ethyl malonate (2) (˜5.3 mmol of 3) in EtOH (20 mls) dropwise with stirring. The resulting mixture was stirred at room temperature overnight and then diluted with EtOAc, washed with H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by flash chromatography (eluting solvents=CH2Cl2, followed by 2% MeOH in CH2Cl2, followed by 4% MeOH in CH2Cl2) to give 2-{2-[1-(2-methoxy-ethyl)-piperidin-4-ylamino]-5-nitro-pyrimidin-4-yl}-malonic acid tert-butyl ester ethyl ester (5, 733 mgs, 29%). LC/MS Calcd for [M+H]+ 468, found 468.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.[C:17]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]12
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Nc1cc[nH]n1
Product: CCOC(=O)C1=C(c2ccccc2)Nc2n[nH]cc2C1c1ccccc1OC

Procedure:
The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl benzoylacetate in the same manner as in Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C1(O[C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)C=CC=CC=1.C1(O)C=CC=CC=1>>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[O:7][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:21][CH:22]=1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: Oc1ccccc1
Product: Oc1ccc(-c2nnc(-c3ccc(O)cc3)o2)cc1
Temperature: 210 °C
Reaction time: 0.29 h
Yield: 45 %

Procedure:
Into a 250 ml three neck round bottem flask equipped with a magnetic stirbar, nitrogen inlet, glass stopper and distillation head is placed 4-hydroxybenzoic hydrazide (60.9 g, 0.4 mol) and phenyl-4-hydroxybenzoate (85.7 g, 0.4 mol). The mixture is heated to approximately 210° C. by use of a Wood's metal bath. The solids melt and phenol begins to evolve and is removed via the distillation head. The melt begins to solidify after about 15-20 minutes. The temperature is then increased to 300° C. and held for approximately one hour while under nitrogen. After cooling, the tan solid is pulverized and stirred with methanol (150-200 ml). The undissolved solid is collected and dried at 150° C. in a forced air oven. The white solid (approximately 56 g) is recrystallized from N,N-dimethylacetamide (DMAc, 225 ml) and water (105 ml) and after drying at 200° C. under vacuum (45.7 g, 45% yield), it exhibited a melting point of 347° C. by differential thermal analysis (DTA). [Y. Iwakura, U. Keikichi, Y. Imai, and Y. Takase, Die Makromoleculare Chemie, 95, 261 (1966) melting point 338° C⟧ Elemental analysis for C14H10O3N2. Calculated: C, 66.13%; H, 3.96%; O, 18.88%; N, 11.02%. Found C, 66.17%; H, 4.05%; N, 11.12%.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>Cl>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH:10][C:8]2[S:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]=2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C(C)(C)C)s2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)c1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Yield: 74.5 %

Procedure:
Compound 114 (1.0 g, 2.82 mmol) was suspended in 3 N HCl (15 mL) and the suspension heated to reflux for 30 min. Following neutralization with saturated aqueous Na2CO3 solution, the precipitated product was collected by filtration, washed with water (70 mL), and dried under vacuum. The residue was crystallized from MeOH to give the product (655 mg, 2.1 mmol, 74%) as a solid, mp 220-221° C.; 1H NMR (500 MHz, DMSO) δ 1.28 (9, s), 5.91 (2, br s), 6.60 (2, d, J=7.0 Hz), 7.45 (2, d, J=7.0 Hz), 13.95 (1, br s); 13C NMR (125 MHZ, DMSO) δ 29.3, 36.0, 112.6, 127.3, 127.7, 152.5, 166.1, 166.6; MS (LCQ, ESI+) Calculated for C12H17N4O2S2 313.1, found 313.0 (M+H)+; HRMS (FAB+, m/z) Calculated for C12H17N4O2S2 313.0793, found 313.0793 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:8][CH:2]([CH3:1])/[CH:3]=[CH:4]/[C:5]([N:27]1[CH2:28][CH2:29][CH2:30][N:24]([C:20]2[CH:19]=[C:18]([CH3:17])[CH:23]=[CH:22][N:21]=2)[CH2:25][CH2:26]1)=[O:7]
Reactant: CC(C)/C=C/C(=O)O
Reactant: Cc1ccnc(N2CCCNCC2)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccnc(N2CCCN(C(=O)/C=C/C(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.3 %

Procedure:
(E)-4-Methylpent-2-enoic acid (26 mg, 0.23 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (20 μl, 0.23 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 1-(4-methyl-2-pyridyl)-1,4-diazepane dihydrochloride (40 mg, 0.15 mmol) in DCM (2 ml). DIPEA (80 μl, 0.5 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 13 mg of a solid (0.047 mmol, 20%).
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[C:22]3[CH3:28])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[C:22]3[CH3:28])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]cc(C)c4c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c[nH]c2ccc(-c3nc4ccc(C(=O)O)cc4nc3N(C)C(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(3-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate (80 mg, 0.21 mmol) in MeOH (10 mL) was added sodium hydroxide (52 mg, 0.29 mmol) and water (1 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The residue was dissolved in water (3 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(3-methyl-1H-indol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (45.8 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.[NH2:47][C:48]1C=NC=[CH:52][CH:53]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:20]([NH:22][C:23]2[CH:24]=[N:47][CH:48]=[CH:53][CH:52]=2)=[O:21])[CH2:31][CH3:32])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: Nc1cccnc1
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1cccnc1

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, 3-aminopyridine was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([OH:16])[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:34]1(I)[CH2:38][CH2:37][CH2:36][CH2:35]1.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:16][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C=Cc2cc(O)c(OC)cc2C1Cc1cccc(OC)c1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1C=Cc2cc(OC3CCCC3)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 85 °C
Reaction time: 18 h
Yield: 33.2 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (890 mg, 2.41 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added potassium carbonate (2.0 g, 14.5 mmol) and cyclopentyl iodide (0.84 mL, 7.24 mmol) dropwise. The reaction mixture was heated with stirring at 85° C. for 18 h. The solvent was evaporated and the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 20% ethyl acetate/hexane) afforded 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (350 mg, 32% yield) as a colorless oil.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][CH3:22])[CH:15]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(Cl)(Cl)Cl>[Br:1][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([O:13][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][C:16]=1[CH2:21][CH3:22]
Reactant: CCCCCCCCCCOc1cc(C)cc(CC)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCOc1cc(C)c(Br)c(CC)c1

Procedure:
A solution of bromine (5.44 g, 0.034 mol) in chloroform (50 ml) was added dropwise to a stirred, refluxing solution of 1-decyloxy-3-ethyl-5-methylbenzene (9.4 g, 0.034 mol) in chloroform (200 ml). The reaction mixture was then allowed to cool, washed with water and dried (MgSO4). The solvent was removed and the residue purified by gravity column chromatography (silica gel/dichloromethane) to yield a pale orange oil.