Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:36].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][C:45]#[N:46]>CN(C=O)C.C(OCC)(=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:5]4[N:4]([CH2:44][C:45]#[N:46])[C:3](=[O:36])[CH:2]([CH3:1])[O:7][C:6]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: N#CCBr
Reactant: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.3 %

Procedure:
A solution of tert-butyl 1-(4-(3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.103 mmol) in DMF (2 ml) was added potassium carbonate (42.7 mg) and 2-bromoacetonitrile (22 μl, 0.309 mmol). The reaction mixture was stirred at room temperature for 48 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give crude product which was purified by column (biotage, 25 g) eluted with ethyl acetate and cyclohexane to afford product (45 mg). 1H NMR (500 MHz, CDCl3): 7.35 (s, 1H), 7.20-7.32 (m, 9H), 4.98 (q, 1H), 4.87 (dd, 2H), 2.44-2.49 (m, 4H), 2.06 (m, 1H), 1.80 (m, 1H), 1.75 (d, 3H), 1.24-1.36 (br, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[C:19]([CH3:20])=[C:18]([Cl:21])[CH:17]=[C:16]([CH3:22])[N+:15]=1[O-:23]>C1COCC1>[Cl:21][C:18]1[C:19]([CH3:20])=[C:14]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[N+:15]([O-:23])=[C:16]([CH3:22])[CH:17]=1
Reactant: Cc1c(Cl)cc(C)[n+]([O-])c1Cl
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(Oc2c(C)c(Cl)cc(C)[n+]2[O-])c(C)c1
Yield: 90.1 %

Procedure:
To a solution of 2,4,6-trimethylphenol (415 mg, 3.05 mmol) in dry THF (20 ml) was treated with 60% sodium hydride in oil (122 mg, 3.05 mmol) at room temperature. After all H2 was evolved, 2,4-dichloro-3,6-dimethyl-pyridine 1-oxide (585.4 mg, 3.05 mmol) was added and the resulting mixture was heated at reflux for 2 hours. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness to give solid. The solid was recrystallized from pet ether to give 802 mg (90%) of the title compound as white crystals, mp 106–107° C. 1H NMR (CDCl3) δ 7.04 (s, 1H), 6.78 (s, 2H), 2.41 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H), 2.06 (s, 6H) ppm.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[NH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[N:20]=2)[CH2:14][CH2:13]1>CO>[C:1]([N:3]=[C:4]([S:5][CH3:6])[NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[N:20]=2)[CH2:14][CH2:13]1)#[N:2]
Reactant: NCCN1CCC(Nc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Reactant: CSC(=NC#N)SC
Solvent: CO
Product: CSC(=NC#N)NCCN1CCC(Nc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A mixture of 1.9 parts of dimethyl cyanocarbonimidodithioate, 4.8 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-3-[(4-fluorophenyl)-methyl]-3H-imidazo[4,5-b]pyridin-2-amine and 80 parts of methanol was stirred for 2 hours at room temperature. The reaction mixture was evaporated and the residue was crystallized from acetonitrile, yielding 4.5 parts (74%) of S-methyl N'-cyano-N-[2-[4-[[3-[(4-fluorophenyl)methyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinyl]ethyl]carbamimidothioate; mp. 172.2° C. (compound 21).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][C:11]([Br:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:27][C@H:26]([CH3:28])OS1(=O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[N:15]([C@H:26]([CH3:28])[CH2:27][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:9]2=[N:10][C:11]([Br:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(Br)nc2[nH]1
Product: CCOC(=O)c1cc2ccc(Br)nc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to example 3, intermediate j) from 6-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo- [1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH:9]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O)(C)(C)C.[NH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1>>[CH2:28]([C@H:9]1[NH:8][CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:35][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC1Cc1ccccc1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CN4CCN[C@H](Cc5ccccc5)C4)c3)n2)cc1

Procedure:
Intermediate 110 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 481. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.59 (s, 1H), 8.33 (d, 2H), 7.90 (d, 1H), 7.67 (t, 1H), 7.61 (d, 1H), 7.28 (m, 5H), 7.11 d, 2H), 6.68 (s, 2H), 4.64 (d, 2H), 4.16 (m, 1H), 3.91 (m, 2H), 3.56 (m, 6H), 3.30 (m, 2H), 2.92 (t, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][CH2:9][C:10]2=[O:12])=[O:5])[CH3:2].CCN(CC)CC.O([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])S(C(F)(F)F)(=O)=O>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][CH:9]=[C:10]2[O:12][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C1C2CCC(=O)C21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1C2CC=C(O[Si](C)(C)C(C)(C)C)C21
Temperature: 22 °C

Procedure:
To a solution of (1RS,5SR,6RS)-2-oxo-bicyclo[3,1,0]hexane-6-carboxylic acid ethyl ester (28.93 g, 172 mmole) in dichloromethane (430 ml) was added at 22° C. NEt3 (36.0 ml, 258 mmole), the mixture was cooled to 0° C. and treated with tert-butyldimethylsilyl triflate (43.5 ml, 189.2 mmole) keeping the temperature below 10° C. The mixture was allowed to warm to 22° C. over 2 h, washed with saturated aqueous NaHCO3, the organic layer was dried, evaporated and the residue purified over aluminiumoxide (100 g) using cyclohexane/AcOEt (9:1) to give the title compound as a yellow oil which was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[C:12]3\[O:13][C:14]4[C:21]([CH2:22][N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=4[C:16]\3=[O:17])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[ClH:37].[NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[C:12]3\[O:13][C:14]4[C:21]([CH2:22][N:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=4[C:16]\3=[O:17])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4cc(N)ccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCNCC4)C3=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(6-amino-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.023 g, 0.047 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-2-[(6-amino-1H-indol-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.010 g, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[C:4]([F:9])[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Nc1ccc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1cc(Br)ccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.9 %

Procedure:
A mixture of 4-bromo-2-fluoro-phenylamine (1 g, 5.26 mmol), tetrahydro-4H-pyran-4-one (0.73 ml, 7.89 mmol), and sodium triacetoxyborohydride (1.66 g, 7.89 mmol) in 1,2-dichloroethane (50 ml) was stirred at room temperature for 72 hours. The mixture was filtered through a diatomaceous earth pad. The diatomaceous earth pad was washed with dichloromethane. The combined filtrates were washed with NaHCO3 (aqueous saturated solution), dried over Na2SO4 and evaporated till dryness. The crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM/MeOH(NH3) up to 5%). The desired fractions were collected and evaporated in vacuo to yield intermediate 11 as a yellow oil (1.44 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][S:9]1.[CH3:20][Si:21]([CH3:42])([CH3:41])[CH2:22][CH2:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[NH:35][CH2:36][C:37](O)=[O:38])[CH:30]=[CH:31][CH:32]=1)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>>[C:16]([O:15][C:13]([C@@H:11]1[CH2:10][S:9][C@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:12]1[C:37](=[O:38])[CH2:36][NH:35][C:34](=[O:40])[NH:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:25]([O:24][CH2:23][CH2:22][Si:21]([CH3:42])([CH3:41])[CH3:20])=[O:26])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(c2ccccc2F)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCC[Si](C)(C)C)c1
Yield: 33.6 %

Procedure:
2-Trimethylsilylethyl (2R,4R)-3-{3-{2-[4-tertbutoxycarbonyl]-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoate may be prepared in a fashion similar to that described in Example 41 §A, but starting from 3.35 g of tert-butyl (2RS,4R)-2-(2-fluorophenyl)-4-thiazolidinecarboxylate, 4.0 g of 2-{3-[3-(2-trimethylsilylethoxycarbonyl)phenyl]ureido}acetic acid and 2.45 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 2.4 g of 2-trimethylsilylethyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoate are thus obtained in the form of an amorphous beige solid, used as it is in subsequent syntheses ([α]D20 =±50.2°+1.6° (C=0.38%; CHCl3))
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][CH2:11][N:12]=1.C(O)(=O)C.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][CH2:10][CH2:11][NH:12]1
Reactant: Brc1ccccc1C1=NCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Brc1ccccc1C1CCCN1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
5-(2-Bromophenyl)-3,4-dihydro-2H-pyrrole (compound 8; 393 mmol, 88 g) was dissolved in methanol (1300 mL), then the acetic acid (330 mL) was added and the solution cooled to −65° C. under a nitrogen atmosphere. Sodium borohydride (589 mmol, 22.28 g) was added portionwise over 1 hour. The reaction was stirred at −65° C. for 30 minutes, then the cooling bath was removed and the reaction mixture temperature was allowed to rise to room temperature. The bulk of the methanol was removed under vacuum then 5N HCl (950 mL) was added and the solution extracted with ether (2×500 mL). The aqueous solution was then basified with sodium hydroxide pellets (310 g) with ice-bath cooling, maintaining the reaction temperature less than 30° C. The basified aqueous was then extracted with ethyl acetate (3×800 mL), the combined organics washed with brine (800 mL), dried with sodium sulfate, evaporated and chromatographed on 1 Kg of silica gel eluting with 19:1 to 9:1 methylene chloride-ethanol to give 2-(2-bromophenyl)pyrrolidine (68.5 g).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:28]OS(C)(=O)=O)[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][NH:39][CH:36]([CH3:38])[CH3:37])[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)OCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Reactant: CC(C)N
Product: CC(C)NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1

Procedure:
A solution of methanesulfonic acid 4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]pyridine-2-ylmethyl ester (150 mg, 0.30 mmol) and isopropyl amine (5 mL) is stirred at rt for 2 h. The reaction is concentrated under reduced pressure and the residue separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give 5-[2-(isopropylamino-methyl)-pyridin-4-yloxy]-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 469.2 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.25-8.37 (m, 2H), 7.97 (s, 1H), 7.88 (d, J=3.8 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.30 (d, J=2.3 Hz, 1H), 7.00 (dd, J=9.0, 2.4 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.81 (dd, J=5.8, 2.3 Hz, 1H), 6.66 (d, J=3.8 Hz, 1H), 4.01 (s, 2H), 3.09-3.18 (m, 1H), 1.18 (d, J=6.6 Hz, 6H).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:95]=[CH:94][CH:93]=[CH:92][C:64]=1[CH2:65][O:66][C:67]([NH:69][CH2:70][C@@H:71]([S:89][S:90][CH3:91])[CH2:72][CH2:73][C@H:74]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C:75](OCC#N)=[O:76])=[O:68])=[N+:61]=[N-:62]>C(#N)C>[N:60]([C:63]1[CH:95]=[CH:94][CH:93]=[CH:92][C:64]=1[CH2:65][O:66][C:67]([NH:69][CH2:70][C@H:71]([S:89][S:90][CH3:91])[CH2:72][CH2:73][C@@H:74]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C:75]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:76])=[O:68])=[N+:61]=[N-:62]
Reactant: CSS[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N)CNC(=O)OCc1ccccc1N=[N+]=[N-]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CSS[C@H](CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O)CNC(=O)OCc1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 5.2 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (30.3 mg, 0.048 mmol) and (2S,5S)-cyanomethyl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk16) (77 mg, 0.143 mmol) in acetonitrile (0.7 mL) was added to buffer A (8 mL), and the mixture was stirred at room temperature for 40 minutes. Acetonitrile (3 mL) was added, followed by stirring for 55 minutes. Acetonitrile (2 mL) was further added, followed by stirring for 5 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S,5S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk17) (2.8 mg, 5%).
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:33])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH:24]=[CH:25][N:26]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.Cl>>[ClH:1].[C:28]([CH2:27][N:23]1[CH:24]=[CH:25][N:26]=[C:22]1/[CH:21]=[C:16]1\[CH2:15][N:14]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:5]([CH:2]2[CH2:3][CH2:4]2)=[O:33])[CH2:19][CH2:18][CH:17]\1[SH:20])([OH:30])=[O:29]
Reactant: CCOC(=O)Cn1ccnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Agent: Cl
Product: O=C(O)Cn1ccnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Yield: 101.5 %

Procedure:
Following a procedure similar to that described in Example 134, (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-2-yl]methylidene}-4-sulfanylpiperidine hydrochloride (155.6 mg) was treated with 3N hydrochloric acid (5 ml) at 50° C. for 2.5 hours. After the reaction solution of was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 15/85, v/v) to afford the title compound (149.0 mg, yield: quantitative) as a colourless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:44][C:45]1[CH:46]=[CH:47][C:48]([F:60])=[C:49]([C:51]23[CH2:58][CH:57]2[CH2:56][O:55][CH2:54][C:53](=[S:59])[NH:52]3)[CH:50]=1>ClCCl>[F:60][C:48]1[CH:47]=[CH:46][C:45]([NH:44][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[CH:50][C:49]=1[C:51]12[CH2:58][CH:57]1[CH2:56][O:55][CH2:54][C:53](=[S:59])[NH:52]2
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: Nc1ccc(F)c(C23CC2COCC(=S)N3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)c(C23CC2COCC(=S)N3)c1)c1ccc(Cl)cn1
Reaction time: 0.25 h
Yield: 198.5 %

Procedure:
To a solution of 5-chloro-2-pyridinecarboxylic acid (60 mg, 0.38 mmol) and diisopropylethylamine (0.17 ml, 0.99 mmol) in dichloromethane (20 ml) at 23° C. was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (174 mg, 0.46 mmol), the mixture was stirred for 15 min, then (1SR,7RS)-1-(5-amino-2-fluoro-phenyl)-5-oxa-2-aza-bicyclo[5.1.0]octane-3-thione (intermediate B13A) (91 mg, 0.36 mmol) was added and the resulting light yellow solution was stirred for 1 h at 23° C. The reaction mixture was poured on ice cold sat. NaHCO3-solution and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give a brown solid (280 mg, 168%), which was purified by silica gel column chromatography with dichloromethane/ethyl acetate to give the title compound as a light yellow solid (147 mg, 88%). MS (ISP): m/z=392.1 [(M+H)+] and 394 [(M+2+H)+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[N:21]([C:24]1[CH:33]=[CH:32][C:27]2[O:28][CH2:29][CH2:30][O:31][C:26]=2[CH:25]=1)=[C:22]=[O:23].C(N(CC)CC)C.Cl>C(#N)C>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([NH:21][C:22]([NH:1][CH2:2][C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[CH2:6]4)=[O:23])=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: O=C=Nc1ccc2c(c1)OCCO2
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc5c(c4)OCCO5)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1.00 mmol) and 6-isocyanato-2,3-dihydro-benzo[1,4]dioxine (0.18 g, 1.00 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.00 mmol) at room temperature under nitrogen. After 2 h, dil. aq. HCl (25 mL) was added. The solids were collected by filtration and washed with water (3×30 mL). The product was slurried in EtOAc for 24 h, then filtered and dried in vacuo to give 1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.41 g, 91% yield): HPLC: Waters Nova-Pak C18 column, 3.9×150 mm, 4 min; 10/90 to 90/10 CH3CN/0.1% aq H3PO4, Gradient over 15 min, 1.0 mL/min, 7.26 min (99.20%); mp: 230-232° C.; 1H NMR (DMSO-d6) δ 1.86-2.10 (m, 1H, CHH), 2.27-2.47 (m, 1H, CHH), 2.59 (d, J=17.6 Hz, 1H, CHH), 2.79-3.04 (m, 1H, CHH), 4.17 (q, J=4.8 Hz, 4H, CH2, CH2), 4.30 (d, J=17.4 Hz, 1H, CHH), 4.36-4.53 (m, 3H, CHH, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 6.62 (t, J=5.9 Hz, 1H, NH), 6.66-6.83 (m, 2H, Ar), 7.05 (d, J=2.1 Hz, 1H, Ar), 7.43 (d, J=7.7 Hz, 1H, Ar), 7.50 (s, 1H, Ar), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.41 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.18, 42.76, 47.10, 51.56, 63.81, 64.19, 107.05, 111.15, 116.66, 121.85, 122.91, 126.86, 130.26, 134.08, 137.90, 142.36, 142.99, 144.94, 155.28, 167.95, 170.99, 172.85; LCMS: MH=451; Anal Calcd for C23H22N4O6: C, 61.33; H, 4.92; N, 12.44. Found: C, 61.14; H, 4.82; N, 12.40.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14].CN1CCOCC1>ClCCl>[CH3:8][C@@H:7]([CH2:9][CH3:10])[C@H:5]([NH:6][C:13]([O:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:14])[C:4]([O:3][CH3:2])=[O:11]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 64 h
Yield: 98.2 %

Procedure:
A solution of L-iso-leucine methyl ester hydrochloride (2.5 g, 13.75 mmol) in dichloromethane (35 mL) at 0° C. was treated with 4-nitrophenyl chloroformate (3.05, 15.13 mmol) and 4-methylmorpholine (3.2 mL, 29.11 mmol), stirred at 25° C. for 64 hours, and partitioned between dichloromethane and saturated NaHCO3. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (4.19 g, 98% yield).