Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=[O:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.[C@@H:23]1([NH2:33])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)CCC1.[CH:34]([OH:37])(C)C>>[F:13][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[CH:9]=1)[CH2:5][C@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:3](=[O:22])[CH2:2][NH:33][CH2:23][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([O:37][CH3:34])[CH:27]=1
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)CBr
Reactant: N[C@H]1CCCc2ccccc21
Product: COc1cccc(CNCC(=O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1

Procedure:
tert-butyl (1S)-3-bromo-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III, EXAMPLE 1, 1 equivalent) is dissolved in isopropanol and treated with 3-methoxybenzylamine (VI, 5 equivalents). The reaction is heated at reflux for 2 hours and monitored by TLC for disappearance of the ketone (III). Upon completion, the reaction is concentrated to dryness under reduced pressure and partitioned between equal parts water and ethyl acetate. The organic phase is extracted, washed two additional times with water, then saline, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:48][CH:47]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg) was added toluene/ethanol/water (10/1/1, 19.2 ml) were added 4-(2-propoxyethoxy)phenyl borate (207 mg) and potassium carbonate (234 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (36 mg), and the mixture was refluxed for 8 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 97) (218 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:13][CH2:14][CH3:15])[C:6]([CH3:12])=[N:7]2.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.[ClH:30]>>[OH2:13].[OH2:22].[OH2:13].[ClH:1].[ClH:30].[CH2:14]([O:13][C:5]1[C:6]([CH3:12])=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([NH:27][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)=[CH:29][CH:28]=1)[CH:11]=[CH:10][N:9]=2)[CH3:15]
Reactant: CCOc1cc2c(Cl)ccnc2nc1C
Reactant: Nc1ccc(Oc2ccccn2)cc1
Agent: Cl
Product: CCOc1cc2c(Nc3ccc(Oc4ccccn4)cc3)ccnc2nc1C
Product: O
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-3-ethoxy-2-methyl-1,8-naphthyridine (2.0 g) and 4-(2-pyridyloxy)aniline (1.67 g) in IMS (50 ml) was boiled under reflux for 3 hours and then allowed to stand at ambient temperature overnight. The mixture was evaporated under reduced pressure and the residue recrystallised from IMS to give a solid which was dissolved in hot IMS and then cooled in an ice bath while hydrogen chloride gas was bubbled through. The mixture was evaporated to dryness and the residue was recrystallised from IMS to give 3-ethoxy-2-methyl-5-[4-(2-pyridyloxy)anilino]-1,8-naphthyridine dihyrochloride trihydrate, m.p. 244°-247° C. Borderline active (1/1) at 30 mg/kg.
Reaction SMILES: [CH:1]1([N:4]2[CH2:16][C@@H:7]3[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]3[C:5]2=[O:17])[CH2:3][CH2:2]1.[CH:18]1(CN)CC1>>[CH:3]1([CH2:1][N:4]2[CH2:16][C@@H:7]3[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]3[C:5]2=[O:17])[CH2:2][CH2:18]1
Reactant: COC(=O)[C@@H]1NCCN2C(=O)N(C3CC3)C[C@H]12
Reactant: NCC1CC1
Product: COC(=O)[C@@H]1NCCN2C(=O)N(CC3CC3)C[C@H]12

Procedure:
Compound 97-C was prepared in analogy to compound 82-C by using cyclopropylmethanamine instead of cyclopropylamine.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].C(O[C:12]1(O[Si](C)(C)C)[CH2:14][CH2:13]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C1COCC1>[CH:12]1([N:6]2[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]2)[CH2:14][CH2:13]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: N#CC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CC1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyanopiperidine (2.5 g, 23 mmol, J. Org. Chem. 21, 984-986, 1957) in methanol (16 mL) and THF (65 mL) was added with stirring (1-ethoxycyclopropoxy)-trimethylsilane (7.0 g, 40 mmol), glacial acetic acid (2.3 mL) and sodium cyanoborohydride (3.3 g, 53 mmol). When addition was complete the mixture was stirred 1 h at ambient temperature and then heated overnight at 65° C. under an atmosphere of nitrogen. The solvent was evaporated and to the residue was added water (30 mL) and 1N HCl until pH 1. The mixture was washed with diethyl ether (50 mL) and the acidic aqueous phase was saturated with potassium carbonate. The alkaline mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (MgSO4) and the solvent was evaporated. This afforded 3.2 g of 1-cyclopropyl-4-cyanopiperidine. 1H NMR (400 MHz, CDCl3) δ 0.37-0.50 (m, 4H), 1.59-1.66 (m, 1H), 1.77-1.94 (m, 4H), 2.4-2.9 (m, 5H).
Reaction SMILES: CI.[H-].[Na+].[CH2:5]([C@:8]1([CH2:22][OH:23])[CH2:12][N:11]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:10](=[O:21])[CH2:9]1)[CH:6]=[CH2:7].[CH3:24]N(C)C=O>O1CCCC1.CO>[CH2:5]([C@:8]1([CH2:22][O:23][CH3:24])[CH2:12][N:11]([C@@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[C:10](=[O:21])[CH2:9]1)[CH:6]=[CH2:7]
Reactant: CN(C)C=O
Reactant: C=CC[C@@]1(CO)CC(=O)N([C@H](C)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CI
Product: C=CC[C@@]1(COC)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Methyl iodide (1.87 mL, 30.1 mmol) and sodium hydride (55% in liquid paraffin, 1.31 g, 30.1 mol) were sequentially added to a solution of (4R)-4-allyl-4-hydroxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (7.09 g, 27.3 mmol) in tetrahydrofuran (80 mL)-dimethylformamide (20 mL) in a nitrogen atmosphere at 0° C. The mixture was heated to room temperature and stirred for one hour. Methanol (2 mL) was carefully added and stirred until gas was not generated. Then, the reaction was quenched with a saturated ammonium chloride solution (10 mL). The reaction solution was poured into a mixture of ethyl acetate (100 mL) and water (100 mL), followed by extraction with ethyl acetate (800 mL). The organic layer was sequentially washed with water (200 mL) and brine (200 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1→1:1) to give 7.42 g (99%) of the title compound as a colorless oil.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[CH:11]=[N:12][C:13]([O:16][C:17]3[C:22]4[C:23]([CH3:27])([CH3:26])[CH2:24][O:25][C:21]=4[C:20]([CH3:28])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)C=CC=CC=1.O.[NH2:31][NH2:32].O>O1CCOCC1>[CH3:26][C:23]1([CH3:27])[C:22]2[C:17]([O:16][C:13]3[N:12]=[CH:11][C:10]([NH:9][C:8]([NH:31][NH2:32])=[O:29])=[CH:15][CH:14]=3)=[CH:18][CH:19]=[C:20]([CH3:28])[C:21]=2[O:25][CH2:24]1
Reactant: Cc1ccc(Oc2ccc(NC(=O)Oc3ccccc3)cn2)c2c1OCC2(C)C
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Oc2ccc(NC(=O)NN)cn2)c2c1OCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
Phenyl{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}carbamate (Intermediate 1, 640 mg, 1.64 mmol) was dissolved in dioxane (7 mL) and hydrazine monohydrate (8.2 mmol) was added. The reaction mixture was stirred for 30 minutes at room temperature and then at 70° C. for 1 hour. Water was added and the resulting suspension was stirred for 1 hour and then filtered. The solid was collected, washed with water and dried under vacuum at 25° C. affording the title compound (340 mg) as off-white solid.
Reaction SMILES: O=S(Cl)Cl.[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:19][CH2:20]O>>[CH3:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: CCO
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 20 °C

Procedure:
SOCl2 (8.2 mL, 112.0 mmol) was added to a stirred suspension of (4-methanesulfonylphenyl)acetic acid (20.00 g, 93.3 mmol) in EtOH (80 mL) at −10° C. The mixture was allowed to warm up to 20° C. over 16 h, then the solvents were removed under reduced pressure. The remainder was dissolved in EtOAc, then the resulting solution was washed with H2O until the pH of the aqueous phase was neutral. The EtOAc solution was washed further with saturated aqueous Na2CO3, before being dried (MgSO4). Filtration and solvent evaporation furnished the title compound: m/z (ES+)=284.1 [M+MeCN+H]+.
Reaction SMILES: [CH:1]1([CH:4]=[O:5])[CH2:3][CH2:2]1.[N+:6]([CH3:9])([O-:8])=[O:7].[OH-].[Na+].CC(O)=O>CO.O>[CH:1]1([CH:4]([OH:5])[CH2:9][N+:6]([O-:8])=[O:7])[CH2:3][CH2:2]1
Reactant: O=CC1CC1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])CC(O)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclopropanecarbaldehyde (1.4 g, 20 mmol) and nitromethane (1.2 g, 20 mmol) in MeOH at 0° C. was added a solution of NaOH (840 mmol, 21 mmol) in water (8 mL). The mixture was stirred at room temperature for 1 h and then HOAc (1.3 mL) was added. Volatile solvent was removed in vacuo. The residue was diluted with water and extracted twice with EtOAc. The combined EtOAc extracted was washed with brine, dried (Na2SO4) and concentrated to give the title compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][C:18]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:20])[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=2)=[O:7])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CN
Reactant: COc1ccc(N(CC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)CNC(=O)CN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(p-anisidino)acetic acid and ethyl glycinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]glycinate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]glycine (M.P. 138° to 140°).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:27]=1.O1CCCCC1[N:34]1[C:38](B(O)O)=[CH:37][CH:36]=[N:35]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>CN(C=O)C.O.C(OCC)(=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([NH:17][CH2:16][C:7]2([C:12]([F:15])([F:14])[F:13])[C:6]3[CH:27]=[C:2]([C:36]4[NH:35][N:34]=[CH:38][CH:37]=4)[CH:3]=[CH:4][C:5]=3[NH:10][C:9](=[O:11])[O:8]2)=[O:26])=[CH:20][CH:21]=1
Reactant: OB(O)c1ccnn1C1CCCCO1
Reactant: O=C1Nc2ccc(Br)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1Nc2ccc(-c3ccn[nH]3)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-{[6-Bromo-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (4.0 g, 8.94 mmol), [1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]boronic acid (2.63 g, 13.42 mmol), a palladium chloride-1,1-bis(diphenylphosphino)ferrocene complex (654 mg, 0.894 mmol) and potassium phosphate trihydrate (4.76 g, 17.88 mmol) were suspended in DMF (27 mL) and water (2.7 mL), and the mixed solution was stirred at 120° C. for 15 minutes under microwave irradiation. After the reaction solution was left to cool, water (10 mL) and concentrated hydrochloric acid (5 mL) were sequentially added thereto, and the solution was stirred at room temperature for 2 hours. The solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1). The resulting foamy solid was recrystallized from ethyl acetate-heptane, whereby the objective compound (2.70 g, 69.5%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C@H:15]2[CH2:18][C@@H:17]([CH3:19])[CH2:16]2)[C:11]([OH:13])=O)[C:7](=[O:20])[CH:6]=1.[C:25](Cl)(=O)C(Cl)=O.Cl.[OH:32][C@@H:33]([CH2:63]O)[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:36]1.N1C(C)=CC=CC=1C>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C@H:15]2[CH2:16][C@@H:17]([CH3:19])[CH2:18]2)[C:11]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C:33]([OH:32])([CH3:63])[CH3:25])[N:36]=2)=[O:13])[C:7](=[O:20])[CH:6]=1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: C[C@H]1C[C@@H](CC(C(=O)O)N2CC(Oc3ccccc3Cl)=CC2=O)C1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(C[C@H]2C[C@@H](C)C2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(cis-3-methyl-cyclobutyl)-propionic acid (92 mg, 0.26 mmol), dichloromethane (6 mL) and N,N-dimethylformamide (3 drops) at 25° C. To this mixture was added a 2.0M solution of oxalyl chloride in dichloromethane (300 μL, 0.60 mmol) dropwise, which resulted in gas evolution. The mixture was stirred for 15 min at 25° C. and then concentrated in vacuo. The residue was taken up in dichloromethane (5 mL) and added dropwise into another flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in US20080021032, Example 80, 50 mg, 0.31 mmol), dichloromethane (5 mL) and 2,6-lutidine (150 μL, 0.52 mmol) at 25° C. and stirred for 1 h at 25° C. The mixture was quenched with methanol and then diluted with dichloromethane. The organic layer was then washed with a 1N aqueous hydrochloric acid solution, dried over sodium sulfate and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 33% ethyl acetate/hexanes) and then reverse phase HPLC afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(cis-3-methyl-cyclobutyl)-propionamide, as a mixture of enantiomers (17 mg, 13%): HR-ES-MS m/z calculated for C25H31N4O4Cl [M+H]+ 487.2107, observed 487.2105; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (d, J=6.2 Hz, 3H), 1.05 (s, 3H), 1.06 (s, 3H), 1.16-1.29 (m, 2H), 1.29-1.40 (m, 1H), 1.74-2.25 (m, 6H), 3.90 (s, 2H), 4.21 (d, J=18.3 Hz, 1H), 4.57 (d, J=18.3 Hz, 1H), 4.71 (dd, J=9.6, 5.8 Hz, 1H), 4.78 (s, 1H), 6.44 (d, J=2.2 Hz, 1H), 7.37 (td, J=7.9, 1.7 Hz, 1H), 7.47 (td, J=7.9, 1.4 Hz, 1H), 7.50-7.53 (m, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.66 (dd, J=7.9, 1.4 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:19][C:17](=[O:18])[C@H:16]([CH3:20])[C@@H:15]([O:21][C@@H:22]2[O:27][C@@H:26]([CH3:28])[C@H:25]([OH:29])[C@@:24]([O:31][CH3:32])([CH3:30])[CH2:23]2)[C@H:14]([CH3:33])[C@@H:13]([O:34][C@@H:35]2[O:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([N:42]([CH3:44])[CH3:43])[C@H:36]2[OH:45])[C@:11]2([CH3:46])[O:12][C@@:7]3([C@H:9]([CH3:47])[CH2:10]2)[O:8][C@:4]1([CH3:50])[C@H:5]([OH:49])[C@H:6]3[CH3:48].[OH-:51].[Na+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:63])(=O)=O)=CC=1.C(Cl)Cl>C(O)(=O)C.O>[CH3:1][CH2:2][C@H:3]1[O:19][C:17](=[O:18])[C@H:16]([CH3:20])[C@@H:15]([O:21][C@@H:22]2[O:27][C@@H:26]([CH3:28])[C@H:25]([OH:29])[C@@:24]([O:31][CH3:32])([CH3:30])[CH2:23]2)[C@H:14]([CH3:33])[C@@H:13]([O:34][C@@H:35]2[O:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([N:42]([CH3:44])[CH3:43])[C@H:36]2[OH:45])[C@@:11]([OH:12])([CH3:46])[CH2:10][C@@:9]([F:63])([CH3:47])[C:7](=[O:51])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:8])[CH3:50]
Reactant: [OH-]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)C[C@@H](C)[C@@]3(O[C@]1(C)[C@H](O)[C@H]3C)O2
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 18 h

Procedure:
Anhydroerythromycin A (1 g, 1.4 mmole) was dissolved in glacial acetic acid (4-mL) at room temperature and the pH of the mixture was adjusted to 4.3 with 6N sodium hydroxide (approx. 2.5 mL) while the temperature was maintained below 20° C. N-fluorobenzenesulfonimide (0.44 g, 1.4 mmole) was added and stirring continued for an additional 18 hours at 22° C. Methylene chloride (10 mL) was added, the solution placed in an ice bath while the pH of the mixture was adjusted to 9 with 6N sodium hydroxide (approx. 17 mL) and the temperature maintained below 20° C. Next, water (10 mL) was added, the layers separated and the aqueous layer washed an additional two times with methylene chloride (10 mL each). The combined organic phases were washed 2 to 4 times with 5% sodium hydroxide (10 mL each) and dried over magnesium sulfate. After filtration, the organic phase was concentrated under vacuum at room temperature to afford 0.88 g of crude flurithromycin. The crude material was dissolved in ethanol concentrated to 2 mL. This process was repeated two more times. After standing at 0° C. for one night, the product was filtered under vacuum, washed with 0.5 mL cold ethanol and dried under vacuum at 40° C. to afford 0.53 g (51% yield) of flurithromycin.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.CCCCCC.[C:23]1([Se:29]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([Se:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: Cl[Se]c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1cnc2c(c1)CCCC2[Se]c1ccccc1
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A solution of 5,6,7,8-tetrahydro 3 methylquinoline (7.5 g, 51 mmol) in tetrahydrofuran (100 ml) was treated under an atmosphere of nitrogen with 1.5M-butyllithium in hexane (35 ml, 52 mmol) at 0°. The resulting red solution was added to a solution of phenylselenyl chloride (10 g, 52 mmol) in tetrahydrofuran (50 ml) at 0°. After 30 min, water (100 ml) was added and the mixture concentrated in vacuo. The aqueous residue was partitioned between saturated aqueous sodium chloride (100 ml) and ether (100 ml). The organic phase was dried (Na2SO4) and evaporated in vacuo to give the crude product (15.2 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([N:32]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][N:3]=1>O1CCCC1.Cl.CO.ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([NH2:32])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(N=C(c4ccccc4)c4ccccc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(-c2csc3c(N)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 35.4 %

Procedure:
N-(4-{4-Amino-7-[(diphenylmethylene)amino]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.058 g, 0.096 mmol) in tetrahydrofuran (2 mL) and aqueous hydrochloric acid (2 M, 0.225 mL) was stirred at ambient temperature for 15 h. The reaction mixture was diluted with methanol/dichloromethane (1:49, 50 mL), and the resulting solution was extracted with aqueous sodium carbonate (1 M, 10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by flash column chromatography on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used), using a gradient of methanol/dichloromethane (1:19 to 1:9) as the mobile phase afforded the title compound (0.015 g, 0.034 mmol) as light brown flakes: 1H NMR (DMSO-d6, 400 MHz) δ 9.49 (s, 1H), 7.96 (d, 1H), 7.70 (d, 1H), 7.58 (d, 1H), 7.39 (s, 1H), 7.35 (s, 1H), 7.33 (m, 1H), 7.17 (s, 1H), 7.15 (m, 1H), 7.06 (d, 1H), 4.77 (br, 2H), 4.71 (br, 2H), 4.04 (s, 3H), 3.91 (s, 3H); MS: (MH)+ 444.