Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:33])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([O:41][C:42]1[CH:47]=[CH:46][C:45]([C@@H:48]([OH:51])[CH2:49][NH2:50])=[CH:44][C:43]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54])C1C=CC=CC=1>>[CH2:1]([NH:7][C:8]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][CH:29]([NH:50][CH2:49][C@H:48]([OH:51])[C:45]4[CH:46]=[CH:47][C:42]([OH:41])=[C:43]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:44]=4)[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)(=[O:17])=[O:18])=[CH:14][CH:15]=1)=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1OCc1ccccc1
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 225) and N-[2-benzyloxy-5-(2-amino-(1R)-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Example 8) according to the procedure of Example 255 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 0.86 (t, J=6.9 Hz, 3H), 1.20-1.80 (m, 10H), 1.95-2.15 (m, 2H), 2.50-3.30 (m, 7H), 2.97 (s, 3H), 3.55-3.70 (m, 2H), 4.70-4.85 (m, 1H), 5.90-6.10 (m, 1H), 6.48 (t, J=5.6 Hz, 1H), 6.83 (d, J=9.2 Hz, 2H), 6.90 (d, J=9.2 Hz, 2H), 6.91 (d, J=8.4 Hz, 1H), 7.07 (dd, J=8.4, 2.0 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.46 (d, J=9.2 Hz, 2H), 7.51 (d, J=9.2 Hz, 1H), 8.50-8.90 (brs, 1H), 9.39 (s, 1H), 9.61 (s, 1H); MS (ES) m/z: 703.4 (MH+); HRMS Calcd. for C33H47N6O7S2 (MH+): 703.2948. Found: 703.2946.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[Br:18][CH2:19][CH2:20]Br.O>O1CCCC1>[Br:18][CH2:19][CH2:20][N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: BrCCBr
Reactant: CCOC(=O)c1c[nH]c(C(=O)OCC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CCBr)c1
Temperature: 25 °C

Procedure:
A solution of diethyl pyrrole-2,4-dicarboxylate (5.50 g, 29.4 mmol) in tetrahydrofuran (200 ml) was cooled in an ice bath and a suspension of NaH (60%) (6.5 g, 68.6 mmol) in tetrahydro-furan (50 ml) was added in a stream. The reaction flask was warmed to room temperature. After stirring 1 h at room temperature 1,2-dibromoethane (25.2 ml, 294 mmol) was added and the mixture was refluxed for 24 h. Water (50 ml) was added to the reaction flask. The mixture was rotary evaporated to remove tetrahydrofuran. Saturated sodium bicarbonate solution (100 ml) was added to the residue and the resulting solution was extracted with methylene chloride (4×50 ml). The combined organic extracts were dried with anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was rotary evaporated to give a yellow solid. This material was recrystalized from hexane ethyl acetate 80:20 to give 8-2 as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=2)[N:10]=1.[F:25][C:26]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:27]=1[NH2:28].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:28][C:27]3[CH:29]=[C:30]([C:33]([F:34])([F:35])[F:36])[CH:31]=[CH:32][C:26]=3[F:25])=[O:21])=[CH:23][CH:24]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Agent: C[Al](C)C
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 36.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.28 mmol), 2-fluoro-5-trifluoromethyl aniline (0.077 g, 0.43 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.050 g of desired product. 1HNMR (DMSO-d6): δ 7.48-7.61 (m, 3H), 7.68-7.73 (m, 2H), 8.08-8.12 (m, 5H), 10.41 (br s, 1H), 12.78 (br s, 1H); MS (m/z): 493.09 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[C:5]2[CH2:6][N:7]([C@H:12]3[CH2:17]C[CH2:15][CH2:14][C@@H:13]3[OH:18])[C:8](=[O:11])[C:9]=2[CH:10]=1.NC1CCCCC1[OH:30]>>[Br:1][C:2]1[C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[C:5]2[CH2:6][N:7]([C@@H:12]3[C@@H:13]([OH:18])[CH2:14][CH2:15][O:30][CH2:17]3)[C:8](=[O:11])[C:9]=2[CH:10]=1
Reactant: NC1CCCCC1O
Reactant: O=C1c2cc(Br)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Product: O=C1c2cc(Br)c3ccccc3c2CN1[C@H]1COCC[C@@H]1O

Procedure:
5-Bromo-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-1,2-dihydro-3H-benzo[e]isoindol-3-one was prepared employing the procedures described for the construction of 5-bromo-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one in Example 1, substituting (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol for 2-amino-cyclohexanol.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:40][CH:26]1[CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:25][CH:26]([CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]1)[CH2:40][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: CCOC(=O)C1CCC(OCC2CO2)CC1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COC2CCC(C(=O)O)CC2)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(ethoxycarbonyl)-cyclohexyloxy]-propane are added in 80 ml of dioxane/60 ml of water and adjusted to pH 13 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted to pH 7 with 5N hydrochloric acid and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed-phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24]CC3C=CC=CC=3)[C:19]=2[O:32]CC2C=CC=CC=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>[Pd].CO>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:19]=2[OH:32])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1cc(OCCCCCCc2cccc(O)c2O)ccc1O
Yield: 69.1 %

Procedure:
A mixture of 0.22 g of 2-hydroxy-5-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid and 30 mg of 10% palladium on carbon in 10 ml of methanol was stirred in a hydrogen atmosphere for 5 hours. Workup as in example 36 and recrystallization from acetone-hexane gave 0.10 g, mp 159°-161° of 2-hydroxy-5-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])=[CH:5][CH:4]=1.[CH:27]1(Br)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH:13]2[CH2:18][CH2:17][N:16]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:15][CH2:14]2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(Cl)cc2)C2CCNCC2)cc1
Reactant: BrC1CCCC1
Product: COc1ccc(CC(=O)N(Cc2ccc(Cl)cc2)C2CCN(C3CCCC3)CC2)cc1

Procedure:
Starting materials: 42ELH89 (0.25 g, 0.67 mmol, 1.0 eq.), cyclopentylbromide (0.3, 3.0 eq.)
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)=[CH:16][CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.C(O)C>[Pd].[H][H]>[CH3:30][N:29]([CH3:31])[C:28](=[O:32])[C:25]1[CH:24]=[CH:23][C:22]([O:21][C:15]2[CH:14]=[C:13]3[C:18]([CH2:19][CH2:20][NH:11][CH2:12]3)=[CH:17][CH:16]=2)=[CH:27][CH:26]=1
Reactant: CN(C)C(=O)c1ccc(Oc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)c1ccc(Oc2ccc3c(c2)CNCC3)cc1

Procedure:
A mixture of 10% palladium on carbon (1.50 g), 7-(4-dimethylcarbamoyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (2 mL), and ethanol (200 mL) is shaken in hydrogen atmosphere (3 bar) at room temperature for 2 h. Then the catalyst is separated by filtration and the filtrate is concentrated. The residue is purified by chromatography on silica gel (methanol/methanol containing 1% ammionia 1:0→0:1) to furnish the title compound that is precipitated from dioxane with 6 M HCl in dioxane.
Reaction SMILES: FC1C=C2C(=CC=1)C=NC([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=O)=[O:14])=C2.[F:20][C:21]1[C:30]2[CH:29]=[N:28][C:27]([OH:31])=[CH:26][C:25]=2[C:24]([C:32]#[N:33])=[CH:23][CH:22]=1>>[C:32]([C:24]1[CH:23]=[CH:22][C:21]([F:20])=[C:30]2[C:25]=1[CH:26]=[C:27]([O:31][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:14])=[O:12])[N:28]=[CH:29]2)#[N:33]
Reactant: O=S(=O)(Oc1cc2cc(F)ccc2cn1)C(F)(F)F
Reactant: N#Cc1ccc(F)c2cnc(O)cc12
Product: N#Cc1ccc(F)c2cnc(OS(=O)(=O)C(F)(F)F)cc12

Procedure:
Following the procedure for trifluoromethanesulfonic acid 6-fluoroisoquinolin-3-yl ester, using 8-fluoro-3-hydroxyisoquinoline-5-carbonitrile in place of 6-fluoroisoquinolin-3-ol, the title compound was obtained as a yellow solid. MS (ES+): m/z=321.06 [MH+]. HPLC: tR=3.58 min (ZQ2, polar—5 min).
Reaction SMILES: [CH2:1]([C:8]1[CH:43]=[CH:42][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]2[CH:41]=[CH:40][C:25]([O:26][C@H:27]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+].Cl>C1COCC1.CO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]2[CH:23]=[CH:24][C:25]([O:26][C@H:27]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]([OH:30])=[O:29])=[CH:40][CH:41]=2)=[CH:42][CH:43]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(OCCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCc1ccc(OCCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a mixed solution of ethyl (2R)-2-(4-{l-[3-(4-heptylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate (480 mg, 0.825 mmol) in THF (15 ml) and methanol (15 ml) was added 1N aqueous potassium hydroxide solution (3 ml, 3 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 353 mg (yield: 77.3%)
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=N1.Cl.[OH-:32].[Na+]>C(O)C>[C:24]1([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C:10]3[C:9]4[C:14](=[CH:15][CH:16]=[C:7]([C:4]([OH:5])=[O:32])[CH:8]=4)[N:13]=[CH:12][CH:11]=3)=[CH:23][CH:22]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC1(C)COC(c2ccc3nccc(Cc4ccc(-c5ccccc5)cc4)c3c2)=N1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc2nccc(Cc3ccc(-c4ccccc4)cc3)c2c1

Procedure:
A mixture of 6-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-4-(4-phenylbenzyl)-quinoline (132 mg), ethanol (1 ml) and 3N hydrochloric acid (3 ml) was refluxed under heating for 2 hr. Then 6N hydrochloric acid (3 ml) was added and the mixtured was refluxed for 4 hr. The mixture was basified with aqueous sodium hydroxide solution, and washed once with chloroform. The aqueous layer was adjusted to pH 4 with 1N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water to give the objective compound (87 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[O:9][C:10]3[C:15]([C:16]([O:18][CH2:19][C:4]=2[CH:3]=1)=[O:17])=[C:14]([O:20][CH3:21])[C:13]([C@@H:22]([OH:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:12][CH:11]=3.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[OH:8][C:6]1[C:5]2[O:9][C:10]3[CH:11]=[CH:12][C:13]([C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[C:14]([O:20][CH3:21])[C:15]=3[C:16](=[O:17])[O:18][CH2:19][C:4]=2[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1c(C(=O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2

Procedure:
800 mg (2.2 mmol) of penicillide (Ib) are stirred at 25° C. under argon for 3 h in 15 ml of methylene chloride and 880 mg (4.1 mmol) of pyridinium chlorochromate. After addition of 200 ml of diethyl ether, the mixture is filtered through silica gel Si60. The evaporation residue of the filtrate is chromatographed on silica gel using petroleum ether/ether =1:1
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:19][C:18]4[C:13](=[N:14][C:15]([F:21])=[N:16][C:17]=4[NH2:20])[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1C(=O)N([Cl:29])C(=O)C1>CN(C=O)C>[F:21][C:15]1[N:14]=[C:13]2[C:18]([NH:19][C:11]([CH2:10][C:8]3[C:7]([Cl:29])=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:12]2)=[C:17]([NH2:20])[N:16]=1
Reactant: Nc1nc(F)nc2nc(Cc3ccc4c(c3)OCO4)[nH]c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Nc1nc(F)nc2nc(Cc3cc4c(cc3Cl)OCO4)[nH]c12

Procedure:
A solution of 8-Benzo[1,3]dioxol-5-ylmethyl-2-fluoroadenine (20 mg, 0.07 mmol), NCS (35.6 mg, 0.27 mmol) in anhydrous DMF (0.4 mL) was stirred at room temperature for 2.5 h. Following solvent removal, the product (11 mg, 48.8%) was collected through silica gel column purification (CHC13:EtOAc at 9:1 to 5:5). 1H NMR (400 MHz, DMSO-d6) 7.40 (bs, 2H), 6.97 (s, 1H), 6.89 (s, 2H), 5.97 (s, 2H), 4.04 (s, 2H); MS m/z 322.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[CH:64]=[CH:63][N:62]=[CH:61][N:60]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:58][C:59]2[CH:64]=[CH:63][N:62]=[CH:61][N:60]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccncn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccncn2)cc1[N+](=O)[O-]
Yield: 30.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 14, 150 mg, 0.439 mmol), triethylamine (0.184 mL, 1.32 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (291 mg, 0.659 mmol), and 4-aminopyrimidine (63 mg, 0.659 mmol) in methylene chloride (4 mL) was stirred at 25° C. overnight. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40M, Silica, 1/2 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-pyrimidin-4-yl-propionamide (56 mg, 30%) as a pale yellow foam: mp 91–95° C. (foam to gel); EI-HRMS m/e calcd for C19H22N4O5S (M+) 418.1311, found 418.1310.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]([C:14]([NH2:16])=[O:15])[C:11]([NH2:13])=[O:12].Br.Br.[O:19]1[CH2:25][CH2:24]NN[CH2:21][CH2:20]1.C(N(CC)CC)C.Cl>C1(C)C(C)=CC=CC=1>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH:10]1[C:11](=[O:12])[N:13]2[CH2:21][CH2:20][O:19][CH2:25][CH2:24][N:16]2[C:14]1=[O:15]
Reactant: Cc1cc(C)c(C(C(N)=O)C(N)=O)c(C)c1
Reactant: C1COCCNN1
Agent: Br
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C2C(=O)N3CCOCCN3C2=O)c(C)c1
Temperature: 22 °C

Procedure:
A solution of 1.5 g (0.0068 mol) of 2,4,6-trimethylphenylmalonic acid diamide, 2.16 g (0.0082 mol) of [1,4,5]oxadiazepane dihydrobromide and 2.93 g (0.029 mol) of triethylamine. in 50 ml of xylene is heated for two hours at reflux temperature in a nitrogen atmosphere. The suspension formed is cooled to 22° C., stirred with 1N hydrochloric acid and filtered. The crystalline residue is washed with water and then with diethyl ether and dried in vacuo at 60° C. The desired title compound has a melting point of 248-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:35]=[CH:34][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:18][C:17]=3[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:34][CH:35]=2)=[O:10])=[CH:36][CH:37]=1
Reactant: CN(C)Cc1cc(CC(=O)OC(C)(C)C)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
To tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-((dimethylamino)methyl)phenyl)acetate (0.005 g, 0.010 mmol) in dichloromethane (1.0 ml) was added TFA (1.0 ml) and the reaction stirred for 1 hour at ambient temperature. The reaction was concentrated to give 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-((dimethylamino)methyl)phenyl)acetic acid (0.005 g). MS −465.1 [M−1].
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:22]([O-])=O.[Na+].O>CC(O)=O.OS(O)(=O)=O>[CH2:14]([C:13]1[N:22]=[N:1][C:2]2[C:3]([C:12]=1[OH:21])=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:9])([F:10])[F:11])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1c(C(=O)CCc2ccccc2)cccc1C(F)(F)F
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1c(Cc2ccccc2)nnc2c(C(F)(F)F)cccc12
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(2-amino-3-trifluoromethyl-phenyl)-3-phenyl-propan-1-one (4.2 g, 13.8 mmol) in AcOH (70 ml) and H2SO4 (10 ml) was added a solution of NaNO2 (1.8 g in 10 ml H2O). The reaction was then heated to 70° C. After 1.5 hr, the reaction was cooled, poured into water and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to give 3-benzyl-8-trifluoromethyl-cinnolin-4-ol
Reaction SMILES: [NH:1]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31](OC)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.O.[NH2:43][NH2:44]>CO>[NH:1]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:43][NH2:44])=[O:32])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: NN
Solvent: CO
Solvent: O
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reaction time: 24 h

Procedure:
43 g of Boc-Tyr-(D)-Ala-Gly-Phe-OCH3 are dissolved in 300 ml of methanol and 35 ml of hydrazine hydrate are added. After one day at room temperature, the mixture is evaporated and the residue is triturated with water which has been acidified to pH 3 with HCl. The precipitated product is filtered and dried to yield the title compound. M.P. 195° (decomp.). [α]D20 =-20.9 (C=1 in DMF).
Reaction SMILES: C([O:5][C:6](=[O:60])[C@@H:7]([NH:11][C:12]([C@@H:14]1[CH2:18][C@@H:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:21]=2)[CH2:16][C@H:15]1[C:38](=[O:59])[NH:39][C@H:40]([C:45](=[O:58])[NH:46][C@@H:47]([CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)[C:48](=[O:51])[NH:49][CH3:50])[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:13])[CH2:8][CH2:9][CH3:10])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:52]1([C@H:47]([NH:46][C:45]([C@@H:40]([NH:39][C:38]([C@@H:15]2[CH2:16][C@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:18][C@H:14]2[C:12]([NH:11][C@@H:7]([CH2:8][CH2:9][CH3:10])[C:6]([OH:60])=[O:5])=[O:13])=[O:59])[C:41]([CH3:42])([CH3:43])[CH3:44])=[O:58])[C:48](=[O:51])[NH:49][CH3:50])[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
Compound 44 (21 mg, 0.025 mmol) was dissolved in CH2Cl2 (1.5 mL) and triethylsilane (10 uL, 0.063 mmol) and TFA (1.5 mL) were added. The solution was stirred for 2 hours at room temperature after which the solvents were evaporated and co-evaporated with toluene to provide compound 45 (20 mg, 100%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: Cc1ccc2nc(C)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2cc(CBr)ccc2n1
Yield: 27.4 %

Procedure:
In carbon tetrachloride (26 ml), 2,6-dimethylquinoline (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.0398 g), N-bromosuccinimide (1.2353 g), and azobisisobutyronitrile (98.5 mg) were dissolved and then the whole was subjected to thermal reflux for 2 hours under an argon atmosphere. After the reaction, a precipitate was removed through filtration and then washed with water, followed by drying with magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (427.3 mg) as a white solid.