Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]CC)=[O:27])=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:23][CH:24]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)O)cc2)c1-c1ccc(F)cc1
Yield: 92.1 %

Procedure:
A mixture of ethyl [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetate (1.33 g), a 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (5 mL) and water were added to the reaction mixture and the precipitated crystals were collected by filtration to give [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl]amino}phenyl]acetic acid as colorless crystals (1.14 g, yield 91%). Recrystallization thereof from acetone-hexane gave colorless prism crystals. melting point: 245-246° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[S:7])[CH2:2][CH2:3][CH3:4].[C:13](O)(=[O:18])[CH2:14][C:15](O)=[O:16].C(O[C:24](=[O:26])[CH3:25])(=O)C.O>C(O)(=O)C>[CH2:9]([N:8]1[C:13](=[O:18])[CH:14]([C:24](=[O:26])[CH3:25])[C:15](=[O:16])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1=[S:7])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCNC(=S)NCCCC
Reactant: O=C(O)CC(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCCCN1C(=O)C(C(C)=O)C(=O)N(CCCC)C1=S
Temperature: 70 °C

Procedure:
358 g of N,N'-dibutylthiourea and 225 g of malonic acid are dissolved in 850 ml of glacial acetic acid, with warming, 190 ml of acetic anhydride are added dropwise at 60° C., with stirring, the mixture is warmed at 70° C. for 2 hours, 100 ml of acetic anhydride are added dropwise, the resulting mixture is warmed at 70° C. for 1 hour, a further 100 ml of acetic anhydride are added dropwise, the resulting mixture is warmed at 90° C. for 3 hours and 70 ml of water are added dropwise at 60°-90° C. The solvent is distilled off in vacuo at 50°-90° C. and the residue is stirred with 1 l of methanol. The crystalline precipitate is filtered off, washed with methanol and dried in vacuo at 40° C. 212 g of N,N'-dibutyl-5-acetyl-thiobarbituric acid are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH2:29][C@@H:30]2[O:35][CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]2)=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:43])[C:10]=1[O:44][C:45]1[CH:50]=[C:49]([C:51]#[N:52])[CH:48]=[C:47]([Cl:53])[CH:46]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH2:29][C@@H:30]2[O:35][CH2:34][CH2:33][NH:32][CH2:31]2)=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:43])[C:10]=1[O:44][C:45]1[CH:50]=[C:49]([C:51]#[N:52])[CH:48]=[C:47]([Cl:53])[CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](COc2ccc3[nH]c(C(=O)NCc4ccc(Cl)c(Oc5cc(Cl)cc(C#N)c5)c4F)cc3c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(OC[C@H]5CNCCO5)ccc4[nH]3)c2F)c1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
Trifluoroacetic acid (2 mL) and CH2Cl2 (2 mL) were added to 1,1-dimethylethyl (2R)-2-{[(2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)oxy]methyl}-4-morpholinecarboxylate (0.02 g, 0.03 mmol) and the mixture was stirred for 1 h. The solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized with saturated NaHCO3 and extracted with EtOAc. The organic extracts were combined dried over Na2SO4, filtered and evaporated to afford the title compound (0.015 g, 88%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.51 (br. s., 1H), 9.00 (t, 1H), 7.74-7.89 (m, 1H), 7.44-7.56 (m, 3H), 7.33-7.44 (m, 1H), 7.26-7.33 (m, 1H), 7.01-7.13 (m, 2H), 6.72-6.92 (m, 1H), 4.49-4.60 (m, 2H), 3.85-4.02 (m, 4 H), 3.59-3.71 (m, 1H), 3.15-3.24 (m, 1H), 2.98-3.08 (m, 1H), 2.77-2.97 (m, 2 H). MS: m/z 569.1 (M+1).
Reaction SMILES: [Cl-].[F:2][C:3]1[C:28]([F:29])=[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:26]=[CH:25][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:43][C:44]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:45]=1[CH:46]=O.O>C1COCC1.C1(C)C=CC=CC=1>[F:43][C:44]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:45]=1[CH2:46][CH2:5][C:4]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[C:28]([F:29])[C:3]=1[F:2]
Reactant: O=Cc1cccc(F)c1F
Reactant: CCCCCCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOc1ccc(CCc2cccc(F)c2F)c(F)c1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Well-dried (2,3-difluoro-4-hexyloxybenzyl)triphenylphosphonium chloride (s-16) (7.5 g) and THF (100 ml) were mixed under an atmosphere of nitrogen, which was cooled to −10° C. Potassium t-butoxide (t-BuOK; 1.6 g) was added in the temperature range of −10° C. to −5° C. After 60 minutes of stirring at −10° C., 2,3-difluorobenzaldehyde (s-23) (1.9 g) dissolved in THF (30 ml) was added dropwise in the temperature range of −10 to −5° C. After 30 minutes of stirring at 0° C., the reaction mixture was poured into a mixture of water (100 ml) and toluene (100 ml) and mixed with them. The mixture was then allowed to stand until it had separated into two layers of organic and aqueous layers, and the extraction into an organic layer was carried out. The resulting organic layers were separated, and washed with water, and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent, and the eluent was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of toluene (100 ml) and Solmix A-11 (100 ml), and Pd/C (0.1 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the completion of the reaction, Pd/C was removed, and the solvent was distilled off. The resulting residue was purified by recrystallization from a mixed solvent of ethyl acetate and Solmix A-11 (ethyl acetate:Solmix=1:4 by volume) to give 1-(2,3-difluorophenethyl)-2,3-difluoro-4-(hexyloxy)benzene (s-24) (3.6 g). The yield based on the compound (s-23) was 76.0%.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[C:23]1([C:34](O)=[O:35])[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=23)=[O:35])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (167 mg, 0.53 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (209 mg, 81%).
Reaction SMILES: [Br:1][C:2]1[C:3](C(=O)N)=[C:4]2[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6][N:5]2[C:17]=1[CH:18]1[CH2:20][CH2:19]1.C[Si]([Cl:28])(C)C>CO>[ClH:28].[Br:1][C:2]1[CH:3]=[C:4]2[CH:9]=[N:8][CH2:7][CH2:6][N:5]2[C:17]=1[CH:18]1[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(c(C(N)=O)c(Br)c2C2CC2)C1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: Brc1cc2n(c1C1CC1)CCN=C2
Product: Cl

Procedure:
To a solution under nitrogen of 6.34 g (16.5 mmol) of tert-butyl 7-bromo-8-carbamoyl-6-cyclopropyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylate in 120 ml of methanol are added 10.5 ml of trimethylsilyl chloride. After reaction for 18 hours, the medium is concentrated under reduced pressure, the residue is taken up in toluene and the solvent is evaporated off under reduced pressure. 5.4 g of 7-bromo-6-cyclopropyl-3,4-dihydropyrrolo[1,2-a]pyrazine hydrochloride are thus obtained in the form of a yellow powder.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[C:12]([NH2:18])=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)=O.[H-].[Na+]>CS(C)=O.O>[Br:17][C:15]1[CH:14]=[N:13][C:12]2[NH:18][C:3](=[O:2])[C@@H:5]3[N:6]([CH2:7][CH2:8][CH2:9]3)[CH2:10][C:11]=2[CH:16]=1
Reactant: COC(=O)[C@H]1CCCN1Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1Nc2ncc(Br)cc2CN2CCC[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
A solution of (R)-1-(2-amino-5-bromo-pyridin-3-ylmethyl)pyrrolidine-2-carboxylic acid methyl ester (6.52 g, 20.8 mmol) in DMSO (200 mL) was treated with NaH (60% dispersion in mineral oil, 0.83 g, 20.7 mmol). After stirring at room temperature for 3 h, the mixture was stored in the freezer for 3 d. The mixture was allowed to warm to room temperature, diluted with H2O (400 mL), and extracted with EtOAc (4×200 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2,/MeOH, 99:1) gave the title compound (3.94 g, 67%) as an off-white solid: MS (ESI) m/e 282 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH2:26])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36]([NH:39][C:40]1[CH:49]=[CH:48][C:43]([S:44](Cl)(=[O:46])=[O:45])=[CH:42][CH:41]=1)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH:26][S:44]([C:43]4[CH:42]=[CH:41][C:40]([NH:39][C:36](=[O:38])[CH3:37])=[CH:49][CH:48]=4)(=[O:46])=[O:45])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](Cn1ncc2ccc3oc(CN)cc3c21)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)NCc2cc3c(ccc4cnn(C[C@H](C)NC(=O)OCc5ccccc5)c43)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A solution of the product from Example 17, Step B (0.32 g, 0.85 mmol) in THF (10 mL) containing triethylamine (3.39 mmol, 0.47 mL) was cooled (ice bath) and N-acetylsulfanilyl chloride (0.20 g, 0.85 mmol) was added followed by stirring for one hour. The reaction mixture was warmed to room temperature, water (1 mL) was added, and stirring continued until all the solids dissolved. Saturated aqueous sodium bicarbonate (150 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give an amorphous solid (0.32 g, 66%): LC/MS m/z 576 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9](O)[C@H:8]([N:15](C3C=CN=CC=3)[C:16]([NH2:18])=[O:17])[C:7]=2[CH:25]=1)#[N:2].[CH2:26](N=C=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9][CH:8]([NH:15][C:16]([NH:18][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[C:7]=2[CH:25]=1)#[N:2]
Reactant: O=C=NCc1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N(C(N)=O)c2ccncc2)[C@@H]1O
Solvent: CCO
Product: CC1(C)CC(NC(=O)NCc2ccccc2)c2cc(C#N)ccc2O1
Yield: 89.7 %

Procedure:
A solution of (-)-4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (2.0 g, 9.9 mmole, from Example 19, part B) and benzyl isocyanate (1.32 g, 9.9 mmole) in ethanol (15 ml) under argon was heated at reflux for two hours. The solvent ws recovered under vacuum and the crude product was triturated with isopropyl ether to obtain 2.98 g (89.7%) of the title compound as a pure white solid. m.p.=140-141° C., [α]D25DMF=-41.2°. 1H NMR (DMSO-d6) δ 7.59 (s, 1H), 7.56 (d. J=1.76 Hz, 1H), 7.38-7.22 (m, 5H), 6.89 (d, J=8.21 Hz, 1H), 6.56 (t, J=5.87 Hz, 1H), 6.49 (d, J=8.79 Hz, 1H), 4.94 (m, 1H), 4.30 (d, J=5.87 Hz, 1H), 2.11(dd, J=6.16 and 13.19 Hz, 1H), 1.74 (d, J=12.32 Hz, 1H), 1.41 (s. 3H), 1.28 (s, 3H). 13C NMR (DMSO-d) δ 158.19, 157.27, 140.80, 132.25, 132.15, 128.31, 126.98, 126.69, 126.18, 119.28, 118.13, 102.06., 77.37, 43.08, 42.01, 37.80, 29.15, 24.47. MS: (M+H)+ @336.
Reaction SMILES: [N:1]1([C:65](OC(C)(C)C)=O)[CH2:64][CH2:63][CH2:62][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([N:30]([CH3:61])[C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])CCSC)=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].F[C:73](F)(F)C(O)=O.[CH:79]([SH:82])(S)[CH3:80]>CSC>[NH:1]1[CH2:65][CH2:64][CH2:63][CH2:62][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([N:30]([CH3:61])[C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:80][CH2:79][S:82][CH3:73])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CC(S)S
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Reactant: O=C(O)C(F)(F)F
Solvent: CSC
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-DTrp-Phe-MeDTrpNHNH2 (0.840 g.) and HLeu-MetNH2 (0.328 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-DTrp-Phe-MeDTrp-Leu-MetNH2 in 57% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-MeDTrp-Leu-MetNH2 (0.450 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-MeDTrp-Leu-MetNH2, which was isolated as the crystalline white solid (m.r. 150°-175° C.) hydrochloride hydrate (3:2) in 59% yield.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[OH:6][OH:7].[S:8]([CH2:15][C:16]([OH:18])=[O:17])([CH2:11][C:12](O)=[O:13])(=[O:10])=[O:9].B(O)(O)O>O.C(Cl)Cl>[S:8]([CH2:15][C:16]([O:18][OH:2])=[O:17])([CH2:11][C:12](=[O:13])[O:6][OH:7])(=[O:10])=[O:9]
Reactant: O=S(=O)(O)O
Reactant: OO
Reactant: O=C(O)CS(=O)(=O)CC(=O)O
Agent: OB(O)O
Solvent: O
Solvent: ClCCl
Product: O=C(CS(=O)(=O)CC(=O)OO)OO
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A mixture of 16.32 mL of 90% aqueous hydrogen peroxide (0.6 mole), 2.3 mL of deionized water and 18.17 mL of 95.5% sulfuric acid was formed in a 150 mL beaker equipped with an ice bath, alcohol thermometer and mechanical stirrer. The water and sulfuric acid were added sequentially to the H2O2 with cooling and stirring to hold the temperature of the mixture to about 25° C. This mixture was added to 18.215 g (0.1 mole) of sulfonyldiacetic acid in admixture with 100 mL of methylene chloride without cooling over a period of about 8 minutes with agitation. The resulting combination formed two liquid phases and one solid phase. Agitation of this mixture was continued for three hours with the temperature in the range of 20°-22° C. under cover to reduce loss of methylene chloride. The mixture was then cooled to about 5° C. and diluted with 18 mL of deionized water added gradually with stirring and cooling. The solids were collected, reslurried with methylene chloride and treated with 80 mL of 6% aqueous sodium bicarbonate. The solids were collected and similarly treated with another 40 mL of 6% NaHCOs resulting in a final pH of about 4. The recovered solids appeared reduced by the reslurry operations and were combined with 2.91 g of dry powdered boric acid. The mixed solids were dried to constant weight (5.24 g) and found to have an active oxygen content of 5.03%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:5])[CH3:2].[OH-].[Na+].[CH2:23](O)C>>[CH:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:5])([CH3:23])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)OC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74 %

Procedure:
To the solution (60 ml) in ethanol of 2.04 g of 2-(2-(ethoxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline obtained in Example 2 was added 3.75 ml of 2N aqueous solution of sodium hydroxide, and the solution was stirred at room temperature for 14 hours. The solution was concentrated under reduced pressure, and to the residue were added 300 ml of isopropylalcohol and 0.60 ml of sulfuric acid. The solution was heated under reflux for 20 hours, and concentrated under reduced pressure. After adding saturated aqueous solution of sodium bicarbonate to the residue, the solution was extracted with ethyl acetate, washed with water, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.58 g of 2-(2-(isopropyloxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (yield: 74%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([Cl:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1>>[ClH:22].[Cl:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]5[CH:31]=[CH:30][C:27]6[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=6[N:33]=5)[CH2:3][CH2:4]4)[C:13]=1[C:12]=23
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)CC1
Product: Cl
Product: O=C1COc2ccc(CNC3CCN(CC4Cn5c(=O)ccc6ncc(Cl)c4c65)CC3)nc2N1
Yield: 76 %

Procedure:
The free base of the title compound was prepared from 4-[(4-amino-1-piperidinyl)methyl]-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (75 mg) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e)) (42 mg) according to the general method of Example 2(h) in 76% yield.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[Al+3].[Cl-].[Cl-].[Cl-].S(=O)(=O)(O)O.[C:19]1([CH3:26])[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1>ClC1C=CC=CC=1>[Cl:3][C:2]1[N:4]=[C:5]([C:24]2[CH:23]=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:7]=[C:8]([C:24]2[CH:23]=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:1]=1.[CH3:26][C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][C:24]=1[C:2]1[N:4]=[C:5]([C:24]2[CH:23]=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:7]=[C:8]([C:24]2[CH:23]=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:1]=1
Reactant: Cc1cccc(C)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(C)c1
Product: Cc1ccc(-c2nc(Cl)nc(-c3ccc(C)cc3C)n2)c(C)c1
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
To a stirring mixture of 1 eq of cyanuric chloride, 3.5 eq of AlCl3 in chlorobenzene, was added 0.036 eq of sulfuric acid as a 10% aq. solution at ice-bath temperature. After 10 min of stirring 1.9 eq of m-xylene was added. After 5 min at ice bath temperature the reaction mixture was allowed to warm to 10° C. After 1 h 20 min HPLC analysis showed 89% of the cyanuric chloride had reacted to give 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine and 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine, which were present in a ratio of 89:11 HPLC analysis, after 3 h at 9-11° C., showed 94% of the cyanuric chloride had reacted to give 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine and 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine, which were present in a ratio of 95:5. HPLC analysis, after 5 h at 9-11° C. and 17 h at room temperature, showed 98.5% of the cyanuric chloride had reacted to give 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine and 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine, which were present in a ratio of 97:3.
Reaction SMILES: CN(/C=[N:5]/[C:6]1[C:11]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[N:25]([CH3:33])[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])=[C:17]([O:34][CH3:35])[CH:16]=3)=[CH:13][S:14][C:10]=2[C:9]([NH:36][S:37]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)(=[O:39])=[O:38])=[CH:8][N:7]=1)C.Cl>O1CCOCC1>[NH2:5][C:6]1[C:11]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[N:25]([CH3:33])[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])=[C:17]([O:34][CH3:35])[CH:16]=3)=[CH:13][S:14][C:10]=2[C:9]([NH:36][S:37]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)(=[O:38])=[O:39])=[CH:8][N:7]=1
Reactant: COc1cc(-c2csc3c(NS(=O)(=O)c4cccs4)cnc(/N=C/N(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(-c2csc3c(NS(=O)(=O)c4cccs4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 50 °C
Reaction time: 13 h
Yield: 43.7 %

Procedure:
N-(4-{4-{[(1E)-(dimethylamino)methylene]amino}-7-[(thien-2-ylsulfonyl)amino]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (prepared by reaction of N-[4-(7-amino-4-{[(1E)-(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide with 2-thiophenesulfonyl chloride according to General Procedure G) (0.021 g, 0.033 mmol) was dissolved in dioxane (1 mL), and aqueous hydrochloric acid (6 M, 1 mL) was added. The mixture was stirred at 50° C. for 13 h, cooled to ambient temperature, and quenched with aqueous sodium carbonate (1 M, 10 mL). The mixture was extracted with methanol/dichloromethane (1:9, 3×20 mL), and the combined organic fractions were dried over magnesiuin sulfate, filtered, and concentrated. Purification of the residue by flash column chromatography on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used) afforded the title compound as a white foam (0.0085 g, 45%): 1H NMR (DMSO-d6, 400 MHz) δ 9.70 (br, 1H), 9.49 (s, 1H), 7.97 (d, 1H), 7.80 (m, 1H), 7.70 (d, 1H), 7.58 (d, 1H), 7.47 (s, 1H), 7.40 (m, 1H), 7.37 (s, 1H), 7.34 (m, 2H), 7.17 (s 1H), 7.14 (d, 1H), 7.07 (m, 2H), 5.35 (br, 2H), 4.03 (s, 3H), 3.09 (s, 3H); MS: (M−H)− 588.