Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@@H:9]3[CH2:20][C@@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[N:12]1[C:11]2[C@H:10]3[CH2:20][C@H:9]3[CH2:8][C:7]=2[C:6]([C:4]([OH:5])=[O:3])=[N:13]1
Reactant: CCOC(=O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 23 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
To a suspension of (1aS,5aS)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (106 g, 392 mmol) in MeOH (300 mL) and THF (300 mL) was added a 2.0 M aqueous solution of NaOH (235 mL, 471 mmol). The reaction was stirred at 23° C. for 20 h. The organic solvents were removed on rotovap. The remaining aqueous solution was diluted to −1.5 L with H2O then acidified to pH ˜2 with 6 M HCl (ca. 95 mL). The resulting fine precipitate was collected by filtration, rinsed with water, and dried to give the title compound (95 g) as a white solid. LCMS m/z=243.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.43 (td, J=4.6, 3.2 Hz, 1H), 1.26 (td, J=8.0, 4.4 Hz, 1H), 2.27-2.33 (m, 1H), 2.71-2.75 (m, 1H), 2.76 (d, J=16.8 Hz, 1H), 2.89 (dd, J=16.4, 6.4 Hz, 1H), 8.61 (dd, J=2.7, 1.5 Hz, 1H), 8.67 (d, J=2.5 Hz, 1H), 9.17 (d, J=1.5 Hz, 1H), 13.02 (s, 1H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[NH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[NH2:9][CH2:10][CH2:11][CH2:12][C:13]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: Nc1ccccc1N
Reactant: O=C1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: NCCCc1nc2ccccc2[nH]1

Procedure:
162 g (1.5 mols) of o-phenylene diamine, 85 g (1 mol) of pyrrolidone and 8 g of p-toluene sulphonic acid are melted, while stirring, in a nitrogen atmosphere and the water which is gradually eliminated is distilled off over a period of 5 hours at a sump temperature of 150° to 250°C. The reaction mixture is then subjected to fractional distillation under reduced pressure. 150 g (85.5 % of the theoretical) of 2-(3'-aminopropyl)-benzimidazole are obtained at a pressure of 0.1 Torr and a boiling temperature of 190° to 196°C in the form of a brownish-yellow crystalline mass melting at 118°C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([CH:25]=[O:26])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([CH:25]=[O:26])=[C:11]([C:31]3[CH2:32][CH2:33][O:28][CH2:29][CH:30]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:21][C@H:11]1[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][Mg]Br)[CH:23]=1>>[CH2:14]([O:13][CH2:12][C@@H:11]([CH2:31][C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1)[C@@H:10]([OH:21])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H]1COCc1ccccc1
Reactant: Cc1cccc(C[Mg]Br)c1
Product: Cc1cccc(C[C@H](COCc2ccccc2)[C@@H](O)CO[Si](C)(C)C(C)(C)C)c1

Procedure:
325 mg of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol tert-butyldimethylsilyl ether obtained in Example 53, was subjected to Grignard reaction in the same manner as in Example 53 by using 3-tolylmethyl magnesium bromide (0.8M diethyl ether solution). The product was purificated by silica gel column chromatography to obtain 210 mg of (2R,3R)-4-benzyloxy-1-tert-butyldimethylsilyloxy-3-(3-tolylmethyl)-2-butanol as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]([Cl:12])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(OC=C(Cl)Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClC(Cl)=COc1cccc(CBr)c1
Yield: 65 %

Procedure:
3-Tolyl 2,2-dichlorovinyl ether (12.2 g) was dissolved in carbon tetrachloride (75 ml), and N-bromosuccinimide (12.0 g) and a trace of wet benzoyl peroxide added, and the mixture refluxed for 3 hours. After filtration the solvent was evaporated from the filtrate, and the residue dissolved in ether and extracted with 1% w/v sodium hydroxide solution. The ethereal solution was dried over anhydrous magnesium sulphate, the solvent removed by evaporation under reduced pressure, and the residual oil distilled to yield a fraction boiling at 150° C/0.5 mm Hg. This fraction was shown by NMR to contain about 65% of the required product together with about 30% of unchanged starting material, the remainder being a small proportion of the dibromomethyl compound.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:24]([C:32]1[S:41][CH2:40][C@H:39]2[C@:34]([C:44]3[CH:49]=[C:48](Br)[CH:47]=[CH:46][C:45]=3[F:51])([CH2:35][O:36][C@@H:37]([CH2:42][F:43])[CH2:38]2)[N:33]=1)C(OC(C)(C)C)=O)=O)(C)(C)C>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:51][C:45]1[CH:46]=[CH:47][C:48]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:49][C:44]=1[C@@:34]12[N:33]=[C:32]([NH2:24])[S:41][CH2:40][C@@H:39]1[CH2:38][C@H:37]([CH2:42][F:43])[O:36][CH2:35]2
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](CF)C[C@H]2CS1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)ccc3F)CO[C@@H](CF)C[C@H]2CS1
Temperature: 85 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
2-Fluoropyridine-3-boronic acid (51.1 mg), tetrakis(triphenylphosphine)palladium (19.1 mg) and a 1 N sodium carbonate solution (363 μl ) were added to a solution of N,N-di(tert-butyloxycarbonyl)-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-fluoromethyl-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (95 mg) in DMF (6.79 ml). After replacement with nitrogen, the mixture was stirred at 85° C. for two hours. After cooling to room temperature, the mixture was diluted with water. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in dichloromethane (4.0 ml). TFA (1.0 ml) was added and the mixture was stirred at room temperature for three hours. Ice was added to the reaction mixture, followed by neutralization with a sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (59.0 mg).
Reaction SMILES: C(=O)(O)O.[C:5]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[C:7]=1[OH:8])[OH:6].[CH2:14]([C@H:16]1[O:18][CH2:17]1)Cl.N1C=CC=CC=1>C(OCC)(=O)C>[OH:6][C:5]1[C:7]2[O:8][C@@H:16]([CH2:17][OH:18])[CH2:14][O:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: ClC[C@@H]1CO1
Reactant: Oc1cccc(O)c1O
Agent: O=C(O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: OC[C@H]1COc2cccc(O)c2O1
Yield: 10.1 %

Procedure:
A mixture of pyrogallol carbonate (8.2 g), (S)-epichlorohydrin (5.0 g) and dry pyridine (0.2 ml) in dry ethyl acetate (50 ml) was heated under reflux for 2 hours. The solvent was removed in vacuo, water (30 ml) was added, and the mixture heated under reflux for 30 minutes. A solution of potassium hydroxide (10 g) in water (20 ml) was added dropwise and the mixture heated under reflux under nitrogen for a further 30 minutes. The cooled mixture was diluted with water (100 ml), acidified with hydrochloric acid (5 M) then extracted with ethyl acetate (3×200 ml). The combined extracts were washed with water (2×100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo and the residue purified by chromatography over silica eluting with a 1:1 mixture of ethyl acetate and petroleum ether (b.p. 60-80° C.) followed by neat ethyl acetate. Appropriate fractions were combined and the solvent removed in vacuo to give (S)-8-hydroxy-1,4-benzodioxan-2-ylmethanol (0.8 g).
Reaction SMILES: CO[C:3]([C:5]1([CH3:26])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:18])[CH:14]=3)[NH:9][C:8]=2[CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[NH:6]1)=[O:4].[Br:27][CH2:28][CH2:29][N:30]=[C:31]=[O:32]>CC(=O)CC>[Br:27][CH2:28][CH2:29][N:30]1[C:31](=[O:32])[N:6]2[CH:7]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[CH2:17][C:5]2([CH3:26])[C:3]1=[O:4])=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=4
Reactant: O=C=NCCBr
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(Cl)cc23)C(c2cccc(O)c2)N1
Solvent: CCC(C)=O
Product: CC12Cc3c([nH]c4ccc(Cl)cc34)C(c3cccc(O)c3)N1C(=O)N(CCBr)C2=O
Temperature: 80 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a suspension of 1.66 g (5.39 mmol) (1RS,3SR)-6-Chloro-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester in 20 ml 2-butanon are added 490 μl 2-bromoethyl isocyanate. After heating the mixture to reflux for 4 h, additional 490 μl 2-bromoethyl isocyanate are added and the mixture is heated to reflux over night. The solvent is removed at reduced pressure and the residue is dissolved in 20 ml dimethyl formamide. The mixture is stirred at 80° C. for 15 h. The solvent is removed at reduced pressure and the residue is dissolved in ethyl acetate. Water is added and the organic layer is dried with magnesium sulfate. The solvent is removed at reduced pressure and the residue is suspended in a mixture of toluene and ethyl acetate (4:1). The suspension is filtered. 1.35 g (62%) of the title compound are obtained as the precipitate. m.p.: 262-264° C., MS: m/z (MH+)=488.0/490.0
Reaction SMILES: O.[NH2:2][NH2:3].Cl.CO[C:7]([C:9]1[CH:14]=[CH:13][N:12]2[CH:15]=[CH:16][N:17]=[C:11]2[CH:10]=1)=[NH:8]>CO>[N:17]1[CH:16]=[CH:15][N:12]2[CH:13]=[CH:14][C:9]([C:7]([NH:2][NH2:3])=[NH:8])=[CH:10][C:11]=12
Reactant: NN
Reactant: COC(=N)c1ccn2ccnc2c1
Agent: Cl
Solvent: CO
Solvent: O
Product: N=C(NN)c1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrazine hydrate (80% in water, 0.25 ml, 2 equiv) was added to a mixture of imidazo[1,2-a]pyridine-7-carboximidic acid methyl ester hydrochloride (1.0 g, 4.7 mmol, 1 equiv) in methanol (30 ml). The mixture was heated to 70 deg C. for 1 hour then allowed to cool to room temperature. After leaving to stand overnight, any solid was removed by vacuum filtration and the solution was concentrated in vacuo and re-concentrated from methanol and was used crude without further purification in the cyclisation step
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][C:17](=[O:19])[CH3:18])[C:9]=3[S:8][C:7]=2[C:6]([CH:20]=[O:21])=[CH:5][CH:4]=1.S(=O)(=O)([OH:24])N.Cl([O-])=O.[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][C:17](=[O:19])[CH3:18])[C:9]=3[S:8][C:7]=2[C:6]([C:20]([OH:24])=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)c2sc3c(NC(C)=O)cccc3c12
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)O)c2sc3c(NC(C)=O)cccc3c12
Temperature: 10 °C

Procedure:
To a solution of 1-methoxy-6-acetamido dibenzo[b,d]thiophene-4-carbaldehyde (800 mg, 0.00266 mol) in THF(15 ml) and water(2 ml) was added sulfamic acid (387 mg, 0.004 mmol) while stirring at 10° C. A solution of 80% sodium chlorite (360 mg, 0.004 mmol) in water (2.0 mL) was added drop wise to the above reaction mixture over a period of 5 min and was allowed to stir at 110° C. for additional 30 min. Water (150 ml) was added to obtain a precipitate which filtered and dried under vacuum (350 mg).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[CH3:16].[OH-].[Na+].CN([CH:22]=[O:23])C>O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:22]=[O:23])=[C:8]1[CH3:16]
Reactant: CN(C)C=O
Reactant: Cc1cc2ccccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A solution of POCl3 (7.0 mL, 75 mmole) in DMF (100 mL) was stirred for 5 minutes at 0° C., then 1,2-dimethylindole (10.0 g, 69 mmole) was added in one portion. The reaction was allowed to warm to RT and stirred for 4 h. The thick slurry was poured into ice water (300 mL) and the flask was rinsed with additional water (50 mL). The aqueous mixture was basified with a solution of NaOH (13.2 g, 330 mmole) in H2O (50 mL), and the thick suspension was filtered to collect the solid. This was washed with water and dried under vacuum to give the title compound (11.59 g, 97%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.09 (d, J=7.9 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.21 (dt, 2H), 3.73 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: C(=O)=[N:2][S:3](Cl)(=[O:5])=[O:4].[CH:8]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([CH:20]([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH:14]=[O:15])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[S:3](=[O:4])(=[O:5])([O:19][C:18]1[C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[CH:8]([CH3:10])[CH3:9])[NH2:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C=O)cc(C(C)C)c1OS(N)(=O)=O
Temperature: 25 °C
Yield: 33.1 %

Procedure:
N-Chlorosulfonyl isocyanate (21.6 mL, 248 mmol) was added slowly to a warm solution of 3,5-diisopropyl-4-hydroxy-benzaldehyde (24.4 g, 118 mmol) in 500 mL toluene. The resulting solution was heated to reflux for 4 hours and then cooled to room temperature and concentrated to give a brown oil. Quenched with 200 g ice and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate, filtered, and concentrated to give a tan solid. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 11.15 g of the title compound as an off-white solid.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]2[C:5]([CH:6]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:38]=[O:39])C>C1COCC1>[Si:13]([O:12][CH:6]1[CH2:7][CH2:8][NH:9][C:10]2[N:11]=[C:2]([CH:38]=[O:39])[CH:3]=[CH:4][C:5]1=2)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](OC1CCNc2nc(Br)ccc21)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CCNc2nc(C=O)ccc21)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 7-bromo-4-((tert-butyldiphenylsilyl)oxy)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 72, 400 mg, 0.856 mmol) in THF (6 ml) at −78° C. was treated with n-BuLi (1.6 M in hexane, 1.34 ml, 2.14 mmol). The reaction mixture was stirred 15 min at −78° C. and then, the solution was warmed up to −20° C. and stirred at this temperature for 30 min. The mixture was then cooled to −78° C., treated with DMF (0.66 mL, 8.6 mmol), stirred at −78° C. for 15 min and then warmed up to −20° C. and stirred at −20° C. for 30 min. The reaction was quenched with water and extracted with DCM (3×). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (heptanes/EtOAc) to give the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.66-9.71 (m, 1H), 7.63-7.69 (m, 2H), 7.43-7.56 (m, 6H), 7.35-7.42 (m, 2H), 7.21 (br. s., 1H), 7.01 (d, 1H), 6.88 (d, 1H), 4.80-4.85 (m, 1H), 3.43-3.52 (m, 1H), 3.23-3.31 (m, 1H), 1.77-1.87 (m, 1H), 1.56-1.67 (m, 1H), 1.00 (s, 9H).
Reaction SMILES: [NH:1]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:2]([C:14]([N:16]([CH3:42])[C@H:17]([C:35]([NH:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:34])[NH:23][S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].O[N:51]1[C:56](=[O:57])[CH2:55][CH2:54][C:52]1=[O:53].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:2]([C:14]([N:16]([CH3:42])[C@H:17]([C:35]([NH:37][CH2:38][C:39]([O:41][N:51]1[C:56](=[O:57])[CH2:55][CH2:54][C:52]1=[O:53])=[O:40])=[O:36])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:34])[NH:23][S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:25])=[O:26])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]([F:11])([F:13])[F:12])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)O)N(C)C(=O)[C@@H](CCCCNC(=O)C(F)(F)F)NC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)ON2C(=O)CCC2=O)N(C)C(=O)[C@@H](CCCCNC(=O)C(F)(F)F)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.3 %

Procedure:
Boc-D-Lys(Tfa)-NMeArg(Tos)-Gly (8.00 g, 11.0 mmol), HOSu (1.25 g, 10.8 mmol) and DCC (2.22 g, 10.8 mmol) were dissolved in DMF (75 ml) and stirred at room temperature for 2 days. The solids were removed by filtration and washed with DMF (2×15 ml). The filtrate was concentrated under reduced pressure and the resulting syrup dried under reduced pressure at 40° C. to give a tan solid (6.50 g, 72%). MP=66°-69° C.; FAB-MS: [M+H]=821.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:10]3[CH2:11][CH2:12][NH:13][C:14]=3[CH:15]=2)=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:44]([O:48][C:49]([C@@H:51]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:52](O)=[O:53])=[O:50])([CH3:47])([CH3:46])[CH3:45].CCN(C(C)C)C(C)C>CN(C=O)C>[C:44]([O:48][C:49]([C@@H:51]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:52]([N:13]1[C:14]2[CH:15]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:10]=2[CH2:11][CH2:12]1)=[O:53])=[O:50])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)c1cc(-c2ccncc2)cc2c1CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[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: COC(=O)c1cc(-c2ccncc2)cc2c1CCN2C(=O)[C@H](Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 22 h
Yield: 75.4 %

Procedure:
To a 500 ml flask was added methyl 6-(pyridin-4-yl)indoline-4-carboxylate 54.1.C (2.0 g, 7.9 mmole), of HBTU (4.5 g, 12.0 mmole), (S)-2-(tert-butoxycarbonyl)-3-phenylpropanoic acid (2.5 g, 9.4 mmole) 50 ml of DMF and DIEA (2.7 ml, 16.0 mmole). The reaction was stirred at 60° C. for 22 hours, at which time the crude reaction was partitioned between 700 ml of EtAc and 200 ml of water. The solvent was removed and the crude purified using a silica gel column (Elutent; 50/50 EtAc/Hex) to give (S)-methyl 1-(2-(tert-butoxycarbonyl)-3-phenylpropanoyl)-6-(pyridin-4-yl)indoline-4-carboxylate 54.8.A as a yellow solid (2.9 g, 74% yield).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:22][CH3:23])=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.FC1C([I:31])=C(F)C(F)=C(F)C=1F.O.C1COCC1>O1CCCC1>[CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:22][CH3:23])=[N:15][N:16]3[C:21]([I:31])=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CCc1nn2ccccc2c1N(CC1CCOCC1)CC1CC1
Reactant: Fc1c(F)c(F)c(I)c(F)c1F
Solvent: O
Solvent: C1CCOC1
Product: CCc1nn2c(I)cccc2c1N(CC1CCOCC1)CC1CC1
Reaction time: 0.33 h
Yield: 87.2 %

Procedure:
A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled with dry ice-ethanol bath. A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C. After stirring the reaction mixture for 1 hour at the same temperature, pentafluoroiodobenzene (115 mL, 861 mmol) was added dropwise. The reaction-mixture was additionally stirred for 1 hour and 20 minutes, and then water/THF (1/1, v/v, 360 mL) was added thereto. Cooling was terminated, and then water (3600 mL) and heptane (3600 mL) were added to the reaction mixture, the aqueous layer was removed and the organic extract was washed with water (3600 mL). A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer and the aqueous layer was separated off. After cooling the aqueous layer in an ice bath and adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture and the organic layer was separated off. The aqueous layer was extracted with toluene (3600 mL), and both organic extracts were combined and concentrated to afford 220 g of the title compound as a dark green oil (87.3% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])OC2C=CC=CC=2)=[CH:11][N:10]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[C:34]2[C:30]([CH2:31][CH2:32][NH:33]2)=[CH:29][CH:28]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:33]2[C:34]3[C:30](=[CH:29][CH:28]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:35]=3)[CH2:31][CH2:32]2)=[O:24])=[CH:11][N:10]=1
Reactant: O=C(Nc1ccc(OCc2ccccn2)nc1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc2c(c1)NCC2
Product: O=C(Nc1ccc(OCc2ccccn2)nc1)N1CCc2ccc(C(F)(F)F)cc21

Procedure:
Phenyl N-[2-(pyridin-2-ylmethyloxy)pyridin-5-yl]carbamate (D3) and 6-trifluoromethylindoline (WO 96/23783) were converted into the title compound using a method similar to that of Example 1, m.p. 178-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:20](OC)=[O:21])[C:13](=[CH:18][CH:19]=2)[C:14](OC)=[O:15])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([CH2:14][OH:15])=[C:12]([CH2:20][OH:21])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CSc2cccc(Br)c2)cc1C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(CSc2cccc(Br)c2)cc1CO

Procedure:
Dimethyl 4-(3-bromophenylsulphanylmethyl)phthalate (10 g, 26 mmol) is dissolved in 120 mL of anhydrous THF. 2.2 g of lithium borohydride (100 mmol) are then added slowly, after which the reaction medium is refluxed for 12 h. After cooling and treatment with saturated ammonium chloride solution, the reaction medium is extracted with ethyl acetate. The organic phases are combined, dried and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, to give a colourless oil (7.8 g, Y=89%).