Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]([F:12])([F:11])[F:10].[Br:13]Br>C(Cl)Cl.O>[Br:13][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([S:8][C:9]([F:12])([F:10])[F:11])[CH:4]=1
Reactant: BrBr
Reactant: Oc1ccccc1SC(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Br)cc1SC(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a stirred solution of 1-hydroxy-2-trifluoromethylthiobenzene (16 mmol, 1.0 eq.) in CH2Cl2 (40 mL) at −78° C. was added a solution of Br2 (0.83 mL, 16 mmol, 1.0 eq.) in CH2Cl2 (18 mL) slowly. The resulting mixture was stirred at −78° C. for 2 h and then warmed to room temperature overnight. The reaction mixture was diluted with water (300 mL) and extracted with CH2Cl2 (3×150 mL). The combined organic layer was washed with brine (400 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography using 0-10% EtOAc in hexanes as an eluent to afford 4-bromo-1-hydroxy-2-trifluoromethylthiobenzene in 93% yield as a crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.COC1C=CC(C2O[CH:22]=[N:21][C:20]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=CC=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:22]=[N:21][C:20]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)c1ncoc1-c1ccc(OC)cc1
Product: CCOC(=O)c1ncoc1-c1ccc(Br)cc1

Procedure:
Prepared from 4-bromobenzoyl chloride according to the procedure outlined for ethyl 5-(4-methoxyphenyl)oxazole-4-carboxylate in example M-1. 1H NMR (DMSO) δ 1.42 (3H, t), 4.42 (2H, q), 7.61 (2H, d), 7.92 (1H, s), 7.99 (2H, d). LCMS (1) Rt: 2.10 min; m/z (ES+) 268/270 MH+-Et.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])(=O)=O)=CC=1.[CH3:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=1[NH2:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:21]([CH3:20])=[C:22]([NH:23][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])[CH:24]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: Cc1ccc(S(=O)(=O)OCCN2CCOC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C)c(NCCN2CCOC2=O)c1
Temperature: 100 °C

Procedure:
To a flask was added 2.95 g (10.3 mmol) of Toluene-4-sulfonic acid, 2-(2-oxo-oxazolidin-3-yl)-ethyl ester, 1.56 g (11.4 mmol) of 2-methyl-5-methoxyaniline, 2.58 g (18.7 mmol) of potassium carbonate, and 22 mL of anhydrous dimethylformamide, and the mixture was heated at 100° C. for seven hours. The reaction was allowed to cool to room temperature, and was partitioned between ethyl acetate and water. The phases were separated, and the ethyl acetate phase was washed with brine, dried over Na2SO4, filtered, and concentrated to an oil. The oil was purified by chromatography (120 mL silica, 60 ethyl acetate/40 hexanes) to give the corresponding product as a clear oil that solidified upon drying: 1H NMR (DMSO-d6, 400 MHz) 6.81 (d, 1H), 6.11 (s, 1H), 6.04 (d, 1H), 4.92 (t, 1H), 4.21 (t, 2H), 3.65 (s, 3H), 3.59 (m, 2H), 3.31 (m, 2H), 3.23 (m, 2H), 1.95 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.ClC1C=CC(C(O)=O)=NC=1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCc1ccc(Cl)cn1
Agent: O=C(O)c1ccc(Cl)cn1
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cn2)cc1

Procedure:
Following the procedure of Example 1, 5-chloro-2-pyridinemethanol, prepared from 5-chloropicolinic acid, is reacted with 1-fluoro-4-nitrobenzene to give 5-chloro-2-(4-nitrophenoxy)methylpyridine, which is converted to 5-chloro-2-(4-aminophenoxy)methylpyridine by reduction with iron and ammonium chloride. The 5-chloro-2-(4-aminophenoxy)methylpyridine and 3,4,5,6-tetrahydrophthalic anhydride are reacted to yield the final product N-4-[2-(5-chloropyridyl)methoxy]phenyl-3,4,5,6-tetrahydrophthalimide.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1csc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c12
Product: Cc1csc2nc(-n3cncn3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:45]=[C:46]([NH2:59])[C:47]4[C:51]([CH:52]=3)=[N:50][N:49](C3CCCCO3)[CH:48]=4)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:52]=[C:51]4[C:47]([CH:48]=[N:49][NH:50]4)=[C:46]([NH:59][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)=[O:10])[CH:45]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: Cc1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Reaction time: 0.08 h
Yield: 29.9 %

Procedure:
6-Methyl-2-pyridinecarboxylic acid (8 mg, 0.06 mmol) in DMF (0.20 ml) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) in DMF (0.20 ml) and DIPEA (0.030 ml). The reaction mixture was shaken for five minutes then treated with 6-(1H-Indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg, 0.06 mmol) in DMF (0.20 ml). The reaction mixture was shaken for 5 mins then left to stand at room temperature overnight. Solvent was removed, and the product re-dissolved in methanol (1 ml) then applied to an SCX cartridge (1 g) which had been pre-rinsed with methanol. After 1 h, the cartridge was eluted with ammonia in methanol (2M, 2×3 ml). Fractions containing product were combined, dried and then further purified by Mass Directed Automated Preparative HPLC (Method D). Fractions containing product were combined and dried to give the title compound (6.6 mg) as a pale brown gum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>ClCCl>[CH3:19][S:20]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:6])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Reaction time: 1 h
Yield: 80.1 %

Procedure:
N-(2-Aminoethyl)(tert-butoxy)carboxamide (17.5 mL, 0.11 mol) [Alfa #L19947] was stirred in dichloromethane (320 mL) and triethylamine (33 mL, 0.24 mol) was added. A solution of methanesulfonyl chloride (8.5 mL, 0.11 mol) in dichloromethane (10 mL) was added. The resulting mixture was stirred for 1 hour and water (30 mL) was added. The product was extracted with dichloromethane (3×30 mL), dried over sodium sulfate and concentrated in vacuo to give the desired product (21 g, 81%). LCMS calculated for C3H11N2O2S (M-Boc+H)+: m/z=139.1.
Reaction SMILES: Cl[CH:2]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])=[CH:47][CH:46]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:5][CH:4]=1.CN(C=O)C.[N-:92]=[N+:93]=[N-:94].[Na+]>C(Cl)(Cl)Cl>[N:92]([CH:2]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])=[CH:47][CH:46]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:5][CH:4]=1)=[N+:93]=[N-:94]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOc1ccc(C(Cl)c2ccc(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOc1ccc(C(N=[N+]=[N-])c2ccc(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 88.5 %

Procedure:
To chloro-bis[4-(12-docosoxydodecyloxy)phenyl]methane (80.9 mg, 66.3 μmol) were added DMF (3 ml), chloroform (1 ml) and sodium azide (40 mg, 621 μmol) and the mixture was stirred at 80° C. for 6 hr. Sodium azide (40.4 mg, 621 μmol) was added, and the mixture was stirred at 90° C. for 1.5 hr. The mixture was cooled to room temperature. Chloroform (2 ml) was added, and the mixture was washed with purified water (3 ml)×3 for partitioning, and the organic layer was evaporated under reduced pressure. The residue was crystallized from acetonitrile to give azido-bis[4-(12-docosoxydodecyloxy)phenyl]methane (72.0 mg, 58.7 μmol, 89%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([S:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])[S:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]1([C:41]2[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:35]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:40]=[CH:39][C:38]([O:1][CH2:2][CH2:3][C:4]2[N:5]=[C:6]([S:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])[S:7][CH:8]=2)=[CH:37][CH:36]=1
Reactant: CC(C)(Sc1nc(CCO)cs1)C(=O)O
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccccc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 3 %

Procedure:
To a suspension of 2-{[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin (0.3 g) synthesized in Example 713-1 in tetrahydrofuran (3.0 mL) were added triphenylphosphine (0.12 g) and 4-phenylphenol (0.17 g), and the mixture was left standing for 15 min. Thereto was added diisopropyl azodicarboxylate (40% toluene solution, 0.26 ml), and the mixture was stirred at room temperature for 30 min. The resin was collected by filtration from the reaction mixture, and washed three times with tetrahydrofuran. This operation was repeated three times, and the obtained resin was washed three times each with dimethylformamide, tetrahydrofuran and methanol, and vacuum dried. To the resin was added trifluoroacetic acid, and the mixture was left standing at room temperature for 4 hr. The resin was filtered off and the filtrate was concentrated by blowing nitrogen gas thereto, and purified by HPLC to give the title compound (0.012 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:23]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:26]2[CH:27]=[CH:22][N:23]=[C:24]([CH2:28][N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:25]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Clc1ccnc(CN2CCOCC2)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(CN4CCOCC4)n3)s2)c(F)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
2-Amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.34 mmol), 4-[(4-chloropyrimidin-2-yl)methyl]morpholine (72.6 mg, 0.34 mmol), Pd2 dba3 (31.1 mg, 0.03 mmol), K2CO3 (51.6 mg, 0.37 mmol) and X-Phos (81 mg, 0.17 mmol) were combined in a 2 mL microwave vial. Degassed tert-amyl alcohol (0.7 mL) was added and the vial evacuated and back-filled with N2 (3×). The resulting mixture was stirred at 100° C. for 24 hours. The reaction mixture was cooled to room temperature, MeOH was added and the reaction mixture was filtered through Celite. The filtrate was combined with silica gel and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-20% MeOH-EtOAc) gave the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([OH:19])([CH3:18])[CH2:3][N:4]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[N:5]1.Cl[C:21]1[C:29]2[C:24](=[CH:25][N:26]=[C:27]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)[CH:28]=2)[N:23](C2CCCCO2)[N:22]=1>>[CH3:18][C:2]([OH:19])([CH3:1])[CH2:3][N:4]1[CH:8]=[C:7]([C:21]2[C:29]3[C:24](=[CH:25][N:26]=[C:27]([C:30]4[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=4)[CH:28]=3)[NH:23][N:22]=2)[CH:6]=[N:5]1
Reactant: Cn1cc(-c2cc3c(Cl)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2cc3c(-c4cnn(CC(C)(C)O)c4)n[nH]c3cn2)cn1
Yield: 40.7 %

Procedure:
Following the procedures in Example 172, 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol and 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and deprotected to give 250 as a white solid (40.7% over two steps). 1H NMR (500 MHz, DMSO) δ 13.39 (s, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.16 (d, J=10.2 Hz, 2H), 8.10 (s, 1H), 4.78 (s, 1H), 4.13 (s, 2H), 3.90 (s, 3H), 1.13 (s, 6H). LC/MS: m/z 338.1 [M+1]
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:17]=3)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]O)[N:6]2[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>ClCCl>[CH2:23]([O:22][C:18]1[CH:17]=[C:16]([C:8]2[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[N:6]3[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)[CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C1CCNCC1
Reactant: Nc1ncnn2c(CCCCO)cc(-c3cccc(OCc4ccccc4)c3)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ncnn2c(CCCCN3CCCCC3)cc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 0 °C
Reaction time: 4 h
Yield: 4.2 %

Procedure:
To a cooled (0° C.) solution of 4-{4-amino-5-[3-(benzyloxy)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}butan-1-ol (80 mg, 0.21 mmol) in dichloromethane (1 mL) was added triethylamine (32 μL, 0.23 mmol) and methanesulfonyl chloride (17 μL, 0.22 mmol). The reaction was stirred (0° C.) for 4 h and then warmed to rt. The mixture was quenched with the addition of ice water (1 mL). The layers were separated and the organic layer was dried (Na2SO4) and evaporated. The residue was dissolved in DMF (1 mL) and potassium carbonate (85 mg, 0.62 mmol) and piperidine (18 μL, 0.22 mol) were added to the mixture. The reaction was stirred (60° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (15 mL) and water (15 mL). The layers were separated and the aqueous was further extracted with ethyl acetate (2×10 mL). The combined organics were dried (Na2SO4) and evaporated. The residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water to obtain 4 mg (5%) of the desired product. 1H NMR (300 MHz, CD3CN) δ 7.86 (s, 1 H), 7.51-7.46 (m, 2 H), 7.45-7.32 (m, 4 H), 7.12-7.09 (m, 1 H), 7.09-7.06 (m, 1 H), 7.04-7.00 (s, 1 H), 6.56 (s, 1 H), 5.17 (s, 2 H), 2.96 (t, 2 H), 2.47-2.27 (m, 6 H), 1.83-1.73 (m, 2 H), 1.63-1.1.51 (m, 6 H), 1.48-1.40 (m, 2 H); ES-MS m/z 456.3 [M+H]+, HPLC RT (min) 2.29.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][C@H:11]([C:13]([O:15][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of trans-3-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (0.5 g, 2.323 mmol) and potassium carbonate (0.321 g, 2.323 mmol) in dimethylformamide (2.323 ml) was treated with (bromomethyl)benzene (0.401 g, 2.346 mmol) added from a syringe over 3 minutes. The reaction mixture was stirred at room temperature for 17 hours and water was added. The suspension was filtered and the solid collected was washed with water and dried under vacuum to give the title compound.
Reaction SMILES: NN.[CH:3]1[C:8](N=C=S)=[CH:7][C:6]2[C:12]([O:14][C:15]3([C:25]4[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=4[O:23][C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]3=4)[C:5]=2[CH:4]=1)=[O:13].C(N(C(C)C)CC)(C)C.C1C=CC([C:62]([OH:64])=[O:63])=C(C2C3C=CC(O)=CC=3OC3C=2C=CC(C=3)=O)C=1>CN(C=O)C>[CH:3]1[C:8]([C:62]([OH:64])=[O:63])=[CH:7][C:6]2[C:12]([O:14][C:15]3([C:25]4[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=4[O:23][C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]3=4)[C:5]=2[CH:4]=1)=[O:13]
Reactant: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Reaction time: 12 h

Procedure:
Peptide-resin obtained via Method 5 containing an ivDde protecting group on the epsilon nitrogen of lysine, was mixed with a solution of hydrazine in DMF (10% hydrazine/DMF, 2×10 mL, 10 min) to remove the ivDde group. The epsilon nitrogen of the lysine was labeled with fluorescein-5-isothiocyanate (0.12 mmol) and diisopropylethylamine (0.12 mmol) in DMF . The mixture was agitated for 12 h (fluorescein-containing compounds were protected from light). The resin was then washed with DMF (3×10 ml) and twice with CH2Cl2 (10 mL) and dried under nitrogen for 1 h. The peptide was cleaved from the resin using reagent B for 4 h and the solution collected by filtration. The volatiles were removed under reduced pressure, and the residue was dried under vacuum. The peptide was precipitated with ether, collected and the precipitate was dried under a stream of nitrogen. The precipitate was added to water (1 mg/mL) and the pH of the mixture was adjusted to 8 with 10% aqueous meglumine. Cyclization of the peptide was carried out for 48 h and the solution was freeze-dried. The crude cyclic peptide was dissolved in water and purified by RP-HPLC on a C18 column with a linear gradient of acetonitrile into water (both phases contained 0.1% TFA). Fractions containing the pure product were collected and freeze-dried. The peptides were characterized by ES-MS and the purity was determined by RP-HPLC (linear gradient of acetonitrile into water/0.1% TEA).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.CC1CCCC(N)C1>C(O)(=O)C>[CH3:24][CH:3]1[CH2:4][CH2:5][CH2:6][CH:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2]1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: CC1CCCC(N)C1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: CC1CCCC(n2cnc3c(-c4ccccc4)csc3c2=O)C1
Yield: 70.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 3-methylcyclohexanamine (0.120 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 98.4 mg (0.30 mmol, 70.5% yield) of the title compound.
Reaction SMILES: [ClH:1].[CH3:2][S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N.Cl.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.Cl>C(O)C>[ClH:1].[CH3:2][S:3][C:4]1[C:5]2[NH:10][C:17]3[CH2:18][CH2:19][NH:14][CH2:15][C:16]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CSc1ccccc1NN
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CSc1cccc2c3c([nH]c12)CCNC3
Temperature: 25 °C
Yield: 91.3 %

Procedure:
1-[2-(methylsulfanyl)phenyl]hydrazine hydrochloride (27 g, 141.9 mmol) and 4-piperidone monohydrate hydrochloride (21.8 g, 141.9 mmol) were dissolved in ethanol (350 mL) and heated at reflux for 45 minutes. Concentrated HCl (30 mL) was added and heated at reflux for 12 h. The reaction was cooled to room temperature, filtered, washed with cold isopropyl alcohol (50 mL), and dried to give an off white solid, 6-(methylsulfanyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (33 g, 92%). 1H NMR (CD3OD, 300 MHz) δ 7.24 (d, 1H, J=8.7 Hz), 7.08 (dd, 1H, J=0.7, 7.3 Hz), 6.93 (t, 1H, J=7.7 Hz), 3.29-3.27 (m, 2H), 3.17 (t, 2H, J=5.85 Hz), 2.85 (t, 2H, J=5.65 Hz), 2.44 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]([CH3:24])([S:15]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH3:14])[O:8][N:7]=1)([CH3:5])[CH:3]=O.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][CH2:5][C:2]([C:6]2[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]([CH3:24])([S:15]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)(=[O:16])=[O:17])[CH3:14])[O:8][N:7]=2)([CH3:1])[CH3:3])=[CH:30][CH:29]=1
Reactant: CC(C)(C=O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CNCC(C)(C)c2cc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)on2)cc1
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of N-[3-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (130 mg, 0.35 mmol) in THF (2 mL) is added 4-methoxybenzylamine (0.055 mL, 0.42 mmol) and 2.7 mmol/g of MP-triacetoxyborohydride (323 mg, 0.87 mmol). The reaction mixture is placed on a shaker for 18 h. After this time, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/DCM provides the title compound. Yield: 83%; LC-MS retention time: 1.23 mins. ESI+ion mode. Zorbax SB-C18 column (3.5 μm, 4.6×30 mm). Gradient: 5% B to 80% B (0 min to 1.7 mins), 80% B to 95% B (1.7 mins to 2 mins), 95% B to 95% B (2 mins to 2.1 mins). Flow rate: 2.5 mL/min. A=(Water+0.1% Formic Acid) B=(Acetonitrile+0.1% Formic Acid). Diode Array Detector; m/z 494 [M+H].