Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:57][CH2:58][O:59][CH3:60])[CH2:9][CH2:10][N:11]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([CH2:26][C:27]([O:29][C@H:30]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:50])[F:49])=[C:43]([O:51][CH2:52][CH:53]3[CH2:55][CH2:54]3)[CH:42]=1)[CH2:31][C:32]1[C:37]([Cl:38])=[CH:36][N+:35]([O-:39])=[CH:34][C:33]=1[Cl:40])=[O:28])[C:19]2=[O:56])[S:12]([CH3:15])(=[O:14])=[O:13])=O)(C)(C)C>C(Cl)Cl.Cl.O1CCOCC1>[Cl:40][C:33]1[CH:34]=[N+:35]([O-:39])[CH:36]=[C:37]([Cl:38])[C:32]=1[CH2:31][C@@H:30]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:49])[F:50])=[C:43]([O:51][CH2:52][CH:53]2[CH2:54][CH2:55]2)[CH:42]=1)[O:29][C:27](=[O:28])[CH2:26][N:20]1[C:19](=[O:56])[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([N:11]([CH2:10][CH2:9][NH:8][CH2:57][CH2:58][O:59][CH3:60])[S:12]([CH3:15])(=[O:13])=[O:14])[CH:17]=2)[C:21]1=[O:25]
Reactant: COCCN(CCN(c1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O)S(C)(=O)=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCCNCCN(c1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of (S)-4-(2-(2-(5-(N-(2-(tert-butoxycarbonyl(2-methoxyethyl)amino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.078 g, 0.086 mmol) in dry DCM (3 ml), 4M HCl in dioxane (0.103 ml, 0.412 mmol) was added, and the mixture was stirred for at room temperature overnight. Additional 4M HCl in dioxane (0.086 ml, 0.344 ml) was added, and the reaction was stirred at the same temperature for 72 hours. The mixture was washed with aqueous sat. NaHCO3; the organic phase was dried over sodium sulfate and the solvent was removed affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-(2-methoxyethylamino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide as a yellow solid (54.72 mg, 0.068 mmol, 79% yield, MS/ESI+ 801.13 [MH]+, [αD]=−20.82, c=0.512, MeOH). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.98 (s, 1H), 7.96 (dd, 1H), 7.90 (dd, 1H), 7.19 (d, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.43 (s, 2H), 3.91-4.02 (m, 2H), 3.86 (t, 2H), 3.39 (dd, 1H), 3.30 (t, 2H), 3.23 (dd, 1H), 3.19 (s, 3H), 3.13 (s, 3H), 2.56-2.67 (m, 4H), 1.05-1.38 (m, 1H), 0.48-0.69 (m, 2H), 0.27-0.48 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([O:12]C)=[O:11])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.CO.Cl>O>[C:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc([N+](=O)[O-])c(C(=O)O)s1
Temperature: 75 °C
Yield: 96.6 %

Procedure:
LiOH monohydrate (0.122 g, 2.90 mmol) was dissolved in 1 mL water and added to methyl 5-tert-butyl-3-nitrothiophene-2-carboxylate (0.235 g, 0.966 mmol) in 3 ml of a 3:1 mixture of THF:MeOH. The resulting mixture was heated at 75° C. for 5 hours. The reaction was cooled down to room temperature, acidified with 1N HCl, extracted with ethyl acetate, and the crude product was recrystallized from dichloromethane:hexane to afford 0.214 g of 5-tert-butyl-3-nitrothiophene-2-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:21]([CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(O)[CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12]([OH:32])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:12]([OH:32])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2CNCCC2(O)CCCc2ccccc2)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCC(C)(C)c1ccc(C2=C(CCCc3ccccc3)CCNC2)c(O)c1

Procedure:
A mixture of 2.0 g. (4.57 mmols.) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-(3-phenylpropyl)-4-piperidinol, 0.95 g. (5.0 mmols.) of p-toluenesulfonic acid monohydrate and 100 ml. of toluene is heated under reflux for 2 hours with a Dean Stark trap. The reaction mixture is cooled and added to 100 ml. of 20% potassium carbonate-200 ml. dichloromethane. The dichloromethane extract along with two additional 200 ml. dichloromethane extracts of the basic phase is dried over magnesium sulfate and evaporated. The residue is crystallized from ether-pentane to yield the title compound.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=O)(C)(C)C.[OH:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[C:20]1=[O:37]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11].[OH:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]([N:26]2[C:27](=[O:36])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]2=[O:35])[C:20]1=[O:37]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoate (410 mg) was dissolved in 30% TFA/DCM (5 mL), the mixture was stirred on a magnetic stirrer for 4 hrs at room temperature. White foam was obtained after reduced pressure distillation to distill off the solvent. The foam was dissolved in DCM (30 mL). The resultant solution was washed with aqueous saturated sodium bicarbonate solution and brine (30 mL), dried over anhydrous magnesium sulfate, and filtered. Title compound was obtained as a white solid (260 mg) after rotary evaporation. 1H NMR (CDCl3, ppm) δ 7.87-7.91 (m, 2H), 7.76-7.79 (m, 2H), 4.97-5.08 (m, 1H), 4.38-4.43 (m, 1H), 4.05-4.30 (m, 3H), 3.25 (dd, 1H, J=4.8, 13.2Hz), 2.95-3.05 (m, 1H), 2.80-2.95 (m, 2H), 2.10-2.20 (m, 1H), 1.90-2.10 (m, 2H), 1.00-1.20 (m, 1H), 0.95-0.98 (m, 3H), 0.87-0.91 (m, 3H). MS (m/e): 402 (M+H+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:19]3[C:20]4[N:12]([C:13](=[O:22])[NH:14][C:15](=[O:21])[C:16]=4[CH:17]=[N:18]3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:28]1([CH2:27][N:14]2[C:13](=[O:22])[N:12]3[C:20]4[N:19]([C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=5)=[CH:10][CH2:11]3)[N:18]=[CH:17][C:16]=4[C:15]2=[O:21])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1[nH]c(=O)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cnn3c2n(c(=O)n1Cc1ccccc1)CC=C3c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 4.0 g of 8-(3-(trifluoromethyl)phenyl)-3H,6H-1,4a,8a-tetraazaacenaphthylene3,5(4H)-dione (prepared as described in Example 14) in 40 ml of dry N,N-dimethylformamide, under nitrogen, is added 650 mg of 60 percent sodium hydride (dispersion in mineral oil). The mixture is stirred at room temperature for 2 hours, then 2.5 g of benzyl bromide is added and the mixture is stirred for 40 hours.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1>ClCCl>[C:25]([Si:28]([CH3:30])([CH3:29])[O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][C:14]1[CH:13]=[CH:12][C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([NH:2][CH3:1])=[CH:8][CH:7]=2)=[CH:23][CH:22]=1)([CH3:27])([CH3:26])[CH3:24]
Reactant: CNc1ccc(C=Cc2ccc(OCCOCCO)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CNc1ccc(C=Cc2ccc(OCCOCCO[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
Compound 3a (45 mg, 0.14 mmol) and TBDMSCl (33 mg, 0.22 mmol) were dissolved in dichloromethane (10 ml) followed by imidazole (20 mg, 0.29 mmol). The solution was stirred at room temperature for 2 hours. After standard workup with dichloromethane, the residue was purified by silica gel column chromatography (1.5% methanol in dichloromethane) to afford 7a (56 mg, 91%): 1H NMR δ 7.40 (m, 4H), 6.90 (m, 4H), 6.75 (d, 2H, J=7.9 Hz), 4.15 (t, 2H), 3.88 (t, 2H), 3.82 (t, 2H), 3.66 (t, 2H), 2.85 (s, 3H), 0.92 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:13][CH2:12]2.[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:24][CH2:25][CH3:26])[CH2:27][CH2:28][CH3:29])[CH2:13][CH2:12]2)[CH2:36][C:32]1[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCN1CCc2cc(CNCc3ncc[nH]3)ccc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN1CCc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2C1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 89.4 %

Procedure:
The compound (104 mg) obtained in Example 17-7 was dissolved in anhydrous methanol (4.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (42.9 mg) and sodium cyanoborohydride (49.0 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 16.5 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution, subjected to extraction with chloroform, and dried with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (115 mg) of the subject compound as a white solid.
Reaction SMILES: [F:1][C:2]([C:7]1[N:12]=[CH:11][C:10]2[C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:9]=2[CH:8]=1)([F:6])[CH2:3][CH2:4][CH3:5].C(N(CC)C(C)C)(C)C.Cl[CH2:28][C:29](Cl)=[O:30].[C:32]([O:36][C:37]([N:39]1[CH2:44][C@H:43]([CH:45]([OH:51])[C:46]2[S:47][CH:48]=[CH:49][N:50]=2)[NH:42][CH2:41][C@H:40]1[CH3:52])=[O:38])([CH3:35])([CH3:34])[CH3:33].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:44][C@H:43]([CH:45]([OH:51])[C:46]2[S:47][CH:48]=[CH:49][N:50]=2)[N:42]([CH2:28][C:29]([N:15]2[C:9]3[CH:8]=[C:7]([C:2]([F:6])([F:1])[CH2:3][CH2:4][CH3:5])[N:12]=[CH:11][C:10]=3[C:13]([CH3:16])([CH3:17])[CH2:14]2)=[O:30])[CH2:41][C@H:40]1[CH3:52])=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: C[C@@H]1CN[C@@H](C(O)c2nccs2)CN1C(=O)OC(C)(C)C
Reactant: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1C(O)c1nccs1
Reaction time: 1.5 h
Yield: 21.3 %

Procedure:
To 6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (0.252 g, 1.05 mmol) and N,N-diisopropylethylamine (0.28 g, 2.2 mmol) in DCM (4.2 mL) cooled with an ice bath under nitrogen was added chloroacetyl chloride (0.09 g, 0.8 mmol), dropwise. After stirring at this temperature for 1.5 h, (2R,5R)-5-(hydroxy-thiazol-2-yl-methyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.18 g, 0.6 mmol) in DCM (0.5 mL) was added. The reaction was stirred at room temperature for 18 h, then saturated aqueous sodium bicarbonate was added and the mixture extracted with DCM (3×). The combined organic extracts were filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (0.076 g). MS: [M+H]+=594.
Reaction SMILES: I[C:2]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC.[Cl-].[Li+].O>CN(C)C=O>[CH3:23][C:21]1[C:20]([CH3:24])=[CH:19][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3I)c2cc1OC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3-c3ccccn3)c2cc1OC
Temperature: 100 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
4-(2-Iodo-4,5-dimethyl-phenoxy)-6,7-dimethoxyquinoline (compound 164) (95 mg), tri-n-butyl(2-pyridyl)tin (0.25 ml), and tetrakistriphenylphosphine palladium (64 mg) were dissolved in N,N-dimethylformamide (7 ml), lithium chloride (102 mg) was added to the reaction system, and the mixture was stirred at 100° C. for one hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (3 mg, yield 4%).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:31]=[C:30]([CH3:32])[O:29][N:28]=3)=[CH:23][CH:22]=2)[C:17]([NH2:19])=[S:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:33](OCC)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:33][S:18][C:17](=[NH:19])[CH:16]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=1)[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc1OC
Reactant: CCOC(C)=O
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
After adding 170 mg of Me3O+BF4− to a solution of 385 mg of 2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 30 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 18 hours. Next, 200 ml of ethyl acetate and 100 ml of a 5% aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was washed 100 ml of saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (371 mg, crude product).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[N:12]=[C:13]([S:22][CH3:23])[N:14]=[N:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][CH:29]=[CH:28]2>C(#N)C>[CH3:23][S:22][C:13]1[N:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][CH:29]=[CH:28]3)[N:12]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nnc(SC)nc1Nc1ccc2ncccc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Diisopropylethylamine (0.53 ml) was added to a solution of ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (234 mg) and 6-aminoquinoline (173 mg) in acetonitrile (3 ml), and the reaction solution was stirred in a microwave reactor at 100° C. for 1 hour. The solvent was evaporated under vacuum, and then the residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain ethyl 3-(methylthio)-5-(quinolin-6-ylamino)-1,2,4-triazine-6-carboxylate as a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4ncc(C(F)(F)F)cn4)CC2)C3)CC1
Temperature: 25 °C

Procedure:
A mixture of (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned; 110 mg}, 2-chloro-5-trifluoromethyl-pyrimidine (76 mg), K2CO3 (100 mg), and dimethyl sulfoxide (1.5 mL) is stirred at 110° C. for 3 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 30:70→10:90) to give the title compound. LC (method 5): tR=1.32 min; Mass spectrum (ESI+): m/z=510 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[N:17]=[C:18]([NH:32]C(=O)C)[S:19][C:20]=2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[NH2:32][C:18]1[S:19][C:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[C:16]([CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:6](=[O:36])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13][CH:12]=2)[N:17]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(CCc2nc(N)sc2Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
tert-Butyl[4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]-carbamate (230 mg), 1N—NaOH (1.09 ml) and EtOH (5 ml) were combined, and the mixture was refluxed for 16 hours. After cooled to r.t., the organic solvent was removed in vacuo. The aqueous solution was neutrallized with 1N—HCl, and extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by preparative silica gel chromatography with CHCl3/MeOH (30:1) as an eluent to give tert-butyl [4-(2-{2-amino-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamate (151.2 mg) as an off-white amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[ClH:10].[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:13][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Product: CCOC(=N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 92 %

Procedure:
Into a solution of 4-fluorobenznitrile (50.9 g, 0.420 mol) in ethanol (500 mL) was blown hydrogen chloride to saturation under ice-cooling and the mixture was stirred at room temperature for 21 hours. The solvent was evaporated under reduced pressure and the obtained crystals were washed with ether and dried in vacuo to give ethyl 4-fluorobenzimidate hydrochloride as white crystals (78.8 g, 92%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([N:13]([CH3:38])[C@H:14]([C:18]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][CH:9]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:11]([N:13]([CH3:38])[C@H:14]([C:18]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:24]=1)=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH2:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccccc1F
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
To a solution of Boc-Phe(2-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.33 g, 0.525 mmol) in methylene chloride (3 ml), TFA (1.5 ml) was added, stirred for 15 min. and then evaporated to remove the solvent under reduced pressure. The residue was mixed with methylene chloride, washed with a saturated aqueous NaHCO3 solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=40:1:0.1) to give Phe(2-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (235 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=S)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:16]([N:20]([CH2:25][C:26]1[CH:27]=[C:28]([NH2:46])[C:29]([NH:32][CH2:33][CH2:34][CH2:35][N:36]([CH3:45])[CH2:37][CH2:38]C2C=CN=CC=2)=[CH:30][CH:31]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:17]([CH3:19])[CH3:18].[NH3:47]>O1CCCC1>[CH2:16]([N:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]2[N:32]([CH2:33][CH2:34][CH2:35][N:36]([CH3:45])[CH2:37][CH2:38][C:5]3[CH:4]=[CH:3][CH:8]=[CH:7][N:47]=3)[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[N:46][C:28]=2[CH:27]=1)[CH2:21][CH:22]([CH3:23])[CH3:24])[CH:17]([CH3:18])[CH3:19]
Reactant: N
Reactant: COc1cc(N=C=S)cc(OC)c1OC
Reactant: CC(C)CN(Cc1ccc(NCCCN(C)CCc2ccncc2)c(N)c1)CC(C)C
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3cc(CN(CC(C)C)CC(C)C)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,4,5 trimethoxyphenylisothiocyanate (57 mg, 1.2 eq) and N-methylcyclohexylcarbodiimide-N-methyl polystyrene resin (acquired from Novabiochem; load 1.69 mmol/g, 501 mg, 4 eq) are added successively to a solution of 4-[(diisobutylamino)methyl]-N-(3-{methyl[2-(4-pyridinyl)ethyl]amino}propyl)-1,2-benzenediamine (90 mg, 1 eq) in tetrahydrofuran (2 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and aminomethyl polystyrene resin (acquired from Novabiochem, 2 eq) is added. After stirring for 4 hours at ambient temperature, the mixture is filtered on frit and the filtrate is concentrated under reduced pressure at 40° C. Purification by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of a beige foam (92 mg, 83% yield).