Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][NH2:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.C(O)C.I.CS[C:26]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)=[NH:27]>C(OCC)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][NH:19][C:26]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[NH:27])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: CN1CCCC1CCn1ccc2cc(CN)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: CN1CCCC1CCn1ccc2cc(CNC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 56.6 %

Procedure:
Compound 36 (124 mg, 0.482 mmol) and anhydrous ethanol (10 mL) were charged to a dry argon purged flask fitted with magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (178.5 mg, 0.626 mmol) is added to the flask and the reaction was stirred under argon at ambient temperature for 96 hours. The solution was diluted with diethyl ether (50 mL) resulting in the formation of an off-white precipitate which was collected on a sintered glass funnel and washed with ether. The solid was partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 1:9) to afford a pale yellow residue 37 (100 mg, 56.6%); 1H NMR (DMSO-d6) δ 7.60 (d, 1H, J=3.8 Hz), 7.51 (m, 2H), 7.39-7.34 (2×m, 2H), 7.16-7.13 (m, 1H), 7.06 (dd, 1H, J=3.8, 5.1 Hz), 6.86-6.54 (brs, 2H), 6.37 (d, 1H, J=3.0 Hz), 4.38 (s, 2H), 4.16 (t, 2H, J=7.3 Hz), 2.94-2.87 (m, 1H), 2.16 (s, 3H), 2.11-1.92 (2×m, 3H), 1.89-1.80 (m, 1H), 1.69-1.55 (m, 3H), 1.48-1.36 (m, 1H); ESI-MS (m/z, %): 367 (M+1, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (52.8 mg, 45%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[OH2:13]>C(#N)C>[OH:13][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4]
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: O
Solvent: CC#N
Product: N#Cc1cccc(C(=O)CO)c1

Procedure:
A solution of 776 mg of 3-(2-bromoacetyl)benzonitrile in acetonitrile (5 mL) and water (10 mL) is treated under microwave irradiation (125° C., 50 min). The same experiment is realized a second time with 976 mg. All the vials are collected, extracted with ethyl ether, dried over magnesium sulfate and concentrated under vacuum to give the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14]O)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:22][CH2:14][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([CH:7]=1)[O:5][CH2:4][C:3]1[C:2]([CH3:1])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:20]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(CO)cc1OCc1c(C)cccc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CBr)cc1OCc1c(C)cccc1C
Reaction time: 1.5 h

Procedure:
To a solution of (3-(2,6-dimethylbenzyloxy)-4-methoxyphenyl)methanol (Step C, 5.23 g, 20.4 mmol) and CBr4 (10.16 g, 30.6 mmol) in dry CH2Cl2 (20 ml) was added portion wise triphenylphosphine (8.03 g, 30.64 mmol) at 0° C. The reaction mixture was stirred for 1.5 hours, filtered, concentrated and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4](Cl)=[N:5][CH:6]=[CH:7][N:8]=1)#[N:2].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CO>[N:10]1([C:4]2[C:3]([C:1]#[N:2])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: N#Cc1nccnc1Cl
Solvent: CO
Product: N#Cc1nccnc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 3-cyano-2-chloropyrazine (0.7 g, 5.0 mmol) in methanol (20 mL) was added morpholine (1.0 mL, 11.0 mmol) and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo, then the residue was dissolved in diethyl ether. The precipitate was filtered off and the filtrate was concentrated under reduce pressure to give the title compound as an orange solid (0.95 g).
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:59])[CH2:21][C:22]1([CH2:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=2[CH:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:50])[CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:36][CH2:35]2)[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.CN1C(=O)CCC1>C(#N)C>[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:33][C:31]2[CH:30]=[CH:29][C:28]([CH:34]3[CH2:35][CH2:36][N:37]([C:40](=[O:50])[CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:38][CH2:39]3)=[C:27]([C:24]3[CH2:23][C:22]([CH2:51][C:52]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:58])([CH2:21][C:20](=[O:59])[O:19][C:15]([CH3:17])([CH3:18])[CH3:16])[O:26][N:25]=3)[CH:32]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: CC(C)(C)OC(=O)CCC(=O)N1CCC(c2ccc(O)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCC(=O)N1CCC(c2ccc(OC(=O)c3ccc(NC(=N)N)cc3)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (12.99 mg) was added to a mixture of tert-butyl 4-(4-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)piperidin-1-yl)-4-oxobutanoate (35.0 mg), pyridine (0.1 mL), and NMP (0.1 mL) at 50 C, and the obtained mixture was stirred at 50 C for 10 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (12.99 mg) was added thereto, and the obtained mixture was stirred at 50 C for 10 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (12.99 mg) was added thereto, and the obtained mixture was stirred at 50 C for 10 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (12.99 mg) was added thereto, and the obtained mixture was stirred at 50 C for 10 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (12.99 mg) was added thereto, and the obtained mixture was stirred overnight at 50 C. To the reaction mixture, acetonitrile was added, and the obtained mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane, subsequently methanol/ethyl acetate) to obtain the title compound (29.2 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@H:7]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:46][CH:47]([CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:48][S:49][CH2:50][CH2:51][C:52](O)=[O:53])(=[O:45])[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]>N1C=CC=CC=1.P(Cl)(Cl)Cl.O>[C:1]([O:5][C:6](=[O:28])[C@H:7]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:52](=[O:53])[CH2:51][CH2:50][S:49][CH2:48][CH:47]([O:46][C:29](=[O:45])[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])[CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[CH:12][C:11]=1[F:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N)cc1F)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(F)c1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 4-amino-2-fiuorobenzoylglutamic acid di-t-butyl ester (181 mg) in pyridine (2.3 ml), phosphorus trichloride (0.020 ml) was added, followed by stirring at room temperature for 2 hours. To this mixture, 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 24 (150 mg) was added, followed by stirring at room temperature for 24 hours. The reaction mixture was diluted with water, extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield the title compound (205 mg, yield 87%) as a wax-like substance.
Reaction SMILES: N1C=CC=CC=1.[C:7]([NH:14][CH2:15][CH2:16]O)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>CCOCC>[C:7]([NH:14][CH2:15][CH2:16][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)CCNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Pyridine (1.5 mL, 18.5 mmol) was added to 2-(N-Boc-amino)-ethanol (280 mg, 1.7 mmol) at 0° C. Tosyl chloride (1.65 g, 8.7 mmol) was then added and the reaction was allowed to stir at 0° C. overnight. The resulting cloudy reaction was diluted with Et2O and washed with water, saturated NaHCO3 and brine, dried over MgSO4 and concentrated. The resulting white solid was purified using SiO2 with AcOEt/petroleum ether 20:80 to 30:70. A white solid was obtained (250 mg, 46%). NMR 1H (ppm, CDCl3): 7.77 (d, J3=8.3 Hz, 2H), 7.33 (d, J3=8.0 Hz, 2H), 4.82 (br. s., 1H), 4.05 (t, J3=5.08 Hz, 2H), 3.38-3.33 (m, 2H), 2.43 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][NH:27]3)[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2].C1(C)C([S:36]([OH:39])(=[O:38])=[O:37])=CC=CC=1.C(O)C>O>[S:36]([C:6]1[CH:5]=[CH:4][C:3]([CH3:1])=[CH:12][CH:7]=1)([OH:39])(=[O:38])=[O:37].[C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][NH:27]3)[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:14][CH2:15]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2]
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: N#Cc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
250 mg (0.63 mmol) of 8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in 2 ml of water, and one equivalent of toluenesulfonic acid is added. The solution is stirred at room temperature for 30 minutes and then poured onto 20 ml of ethanol. The resulting precipitate is filtered off with suction and then dried.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].C[Mg]Br.[CH2:8](OCC)C.[CH:13]([C@H:16]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])([CH3:15])[CH3:14]>>[OH:21][C@@:20]1([CH3:8])[CH2:19][CH2:18][N:17]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C@H:16]1[CH:13]([CH3:15])[CH3:14]
Reactant: CCOCC
Reactant: CC(C)[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Agent: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Product: CC(C)[C@@H]1N(C(=O)OCc2ccccc2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (6.35 g), 3 mol/L methylmagnesium bromide-diethyl ether solution (7.55 mL) and benzyl (2S)-2-isopropyl-3-oxopyrrolidine-1-carboxylate (2.7 g), the title compound was obtained as pale-yellow oil (yield: 1.78 g, yield: 62%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([NH:12][NH2:13])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH2:14](O)C>C([O-])([O-])OCC>[Cl:1][CH2:2][C:3]1[N:4]2[CH:14]=[N:13][N:12]=[C:5]2[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: NNc1nc(CCl)nc2ccsc12
Reactant: CCO
Agent: CCOC([O-])[O-]
Product: ClCc1nc2ccsc2c2nncn12
Temperature: 125 °C
Reaction time: 3 h

Procedure:
4. 15.7 g of 2-(chloromethyl)-4-hydrazinothieno[3,2-d]pyrimidine are suspended in 280ml of ethyl orthoformate. The suspension is heated (bath temp. 125° C.) while stirring and the ethanol which results is distilled off. After 3 h., the mixture is cooled to 0° C., the precipitate is filtered off and washed with ethanol. The product is dried in a vacuum. There are obtained 15.2 g of 5-(chloromethyl)thieno[2,3-e][1,2,4]triazolo[4,3-c]-pyrimidine. m.p. above 400° C. (dec.).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([C:9]([OH:11])=O)=[CH:5][CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:14])=O>C1C=CC=CC=1.CN(C=O)C>[Br:1][CH2:2][C:3]1[C:4]([C:9]([Cl:14])=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1CBr
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1CBr

Procedure:
--A solution of α-bromotoluic acid (1.08 g) in dry benzene (10 ml) was stirred for 2 hours with thionyl chloride (0.73 ml) and dry DMF (five drops). The reaction mixture was evaporated to dryness, taken up in toluene and evaporated again. The crude product was crystallized from n-hexane (10 ml, charcoal) thereby obtaining pure α-bromotoluic acid chloride (0.95 g) as white flakes.
Reaction SMILES: [Cl-].[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH3+:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:4])[CH3:3].C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])[CH3:13])=[CH:10][CH:11]=1)([CH3:4])[CH3:3]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(C)Oc1ccc([C@H](C)[NH3+])cc1
Agent: [Cl-]
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(OC(C)C)cc3)cc12

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with (S)-1-(4-isopropoxyphenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 560 [M+1]+.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[C:10]([NH:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:26][CH:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:14][C:12]1[CH:11]=[C:10]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[N:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]([NH:26][CH:27]3[CH2:31][CH2:30][NH:29][C:28]3=[O:32])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: NC1CCNC1=O
Reactant: Nc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(F)nc2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Nc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCNC3=O)nc2)c1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
6′-Fluoro-N6-[4-(trifluoromethyl)pyridin-2-yl]-2,3′-bipyridine-4,6-diamine (50 mg, 0.143 mmol), 3-aminopyrrolidin-2-one (39.1 mg, 0.286 mmol), tribasic potassium phosphate (60.8 mg, 0.286 mmol), and N,N-diisopropylethylamine (0.050 ml, 0.286 mmol) were dissolved in dimethylsulfoxide (0.5 mL). The mixture was heated to 130° C. with stirring for three days. After allowing to cool to room temperature, the reaction mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated, and the organic layer was washed with water (3×5 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified using reverse phase HPLC (15 to 85% acetonitrile/water with 0.1% TFA gradient). The fractions containing the product were partitioned between 10% isopropanol/chloroform and 1:1 saturated aqueous sodium bicarbonate solution:brine. The layers were separated, and the aqueous layer was extracted with additional 10% isopropanol/chloroform. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-[(4-amino-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)amino]pyrrolidin-2-one. MS ESI calcd. for C20H19F3N7O [M+H]+ 430. found 430. 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.62 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.40 (d, J=5.1 Hz, 1H), 7.88 (dd, J=2.4, 8.8 Hz, 1H), 7.83 (s, 1H), 7.08 (d, J=5.3 Hz, 1H), 6.94 (d, J=7.3 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 6.53 (d, J=1.6 Hz, 1H), 6.46 (s, 1H), 5.97 (s, 2H), 4.60-4.52 (m, 1H), 3.25-3.20 (m, 2H), 2.52-2.46 (m, 1H), 1.87-1.79 (m, 1H). rhSyk IC50=4 nM.
Reaction SMILES: C[O-:2].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6](OC)=O.BrC[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>CO>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:6][C:5](=[O:2])[C:4]([O:11][CH3:12])=[O:10]
Reactant: C[O-]
Reactant: ClCCCCCBr
Reactant: COC(=O)CC(=O)OC
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CCCCCCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 28 % solution of sodium methylate in methanol (19.3 g) and methanol (50 g) are charged in a flask, and the mixture is cooled to 0° C. To the mixture is added dimethyl malonate (13.2 g) and the mixture is stirred at 50° C. for 1 hour. To the mixture is added 1-bromo-5-chloropentane (18.6 g) and stirred under refluxing for 14 hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added toluene (200 g) and water (100 ml) and the mixture is further stirred. The organic layer is separated and magnesium sulfate (10 g) is added to the organic layer. The mixture is filtered and the filtrate is concentrated. Separately, a 43.5 % nitrosylsulfuric acid solution (35.3 g) is charged in another flask and cooled to 0° C. To the mixture is added dropwise the above concentrated organic layer over a period of 1 hour. The mixture is stirred at 0° C. for 1 hour, and the temperature thereof is raised to 20° C. The mixture is stirred at the same temperature for 1 hour. Separately, toluene (100 g) and 10 % aqueous formalin solution (100 g) are charged in another flask and cooled to 5° C. Thereto is added dropwise the above reaction mixture over a period of 1 hour. The reaction mixture is kept at 5° C. for 1 hour, and stirred at 20° C. for 12 hours. The organic layer is separated and washed with water, and to the mixture is added magnesium sulfate (5 g) and filtered. The filtrate is concentrated under reduced pressure to give crude methyl 7-chloro-2-oxoheptanoate (24 g), which is purified by distillation under reduced pressure to give methyl 7-chloro-2-oxoheptanoate (14.3 g).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([NH:40][S:41]([N:44]([CH2:46][CH:47](OC)[O:48]C)[CH3:45])(=[O:43])=[O:42])=[O:39])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@H:16]([N:26]([CH3:37])[CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[NH2:29][CH2:28][CH2:27][N:26]([CH3:37])[C@@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:38]([NH:40][S:41]([N:44]([CH3:45])[CH2:46][CH:47]=[O:48])(=[O:42])=[O:43])=[O:39])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1
Reactant: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1ccccc1-3)OC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN(CCN)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC=O)cc3n2C1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl {2-[{(7R)-14-cyclohexyl-11-[({[(2,2-dimethoxyethyl)-(methyl)amino]sulfonyl}amino)carbonyl]-7,8-dihydro-6H-indolo[1,2-e][1,5]-benzoxazocin-7-yl}(methyl)amino]ethyl}carbamate (0.03 M) in DCM was treated with TFA (100 eq) and water (180 eq) at RT and the resulting mixture stirred vigorously for 3 h at 40° C. The volatiles were removed in vacuo and the residue diluted with Et2O and re-evaporated to drive off excess TFA. The product was used in the subsequent step without further purification. MS (ES+) m/z 582 (M+H)+; 600 (M+H2O+H)+.
Reaction SMILES: CC(OC([NH:8][C@@H:9]([C:23]([OH:25])=[O:24])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)C.[NH:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:14]1[CH:13]=[CH:12][C:11]([CH:10]([C@@H:9]([NH2:8])[C:23]([OH:25])=[O:24])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][CH:15]=1.[NH:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](C(=O)O)C(c1ccccc1)c1ccccc1

Procedure:
A solution of Boc-D-3,3-diphenylalanine-L-proline-N-(trans-4-imidazoleallyl) amide (55 mg, 0.1 mmol) in 2:1 methylene chloride/TFA (30 ml) was stirred at room temperature for 4 h. The solvents were removed in vacuo and the residue was purified by preparative HPLC. 1H NMR (CH3OD) d 1.10-1.37 (m, 2 H), 1.70-1.90 (br s, 2 H), 2.70-2.90 (br m, 1 H), 3.50-3.65 (br m, 1 H) 3.95 (br s, 2 H), 4.00-4.10 (br m, 1 H), 4.45 (d, J=11.5 Hz, 1 H), 4.95 (d, J=11.5 Hz, 1 H) 6.30-6.40 (m, 1 H), 6.58 (d, J=16 Hz, 1 H), 7.25-7.70 (m, 11 H), 7.85 (s, 1 H); MS (FAB) 444 (M+1)+.