Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:25]#[N:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[Cl-].CC1(C)CCCC(C)(C)[N-]1.[Mg+2].[Li+].[CH:41]1([CH:46]=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]4)[C:15]([CH:46]([CH:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[OH:47])=[N:16][C:12]=3[CH:11]=[C:10]([C:25]#[N:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=CC1CCCC1
Agent: CC1(C)CCCC(C)(C)[N-]1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(C(O)C3CCCC3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (product of Step 2, Preparative Example 3.1) (500 mg, 1.367 mmol) was dissolved in THF (13.7 mL) and cooled to −78° C. in a flask under nitrogen before adding lithium magnesium 2,2,6,6-tetramethylpiperidin-1-ide dichloride, 1.0 M in THF (3.01 mL, 3.01 mmol). After stirring at −78° C. for 45 minutes, cyclopentanecarbaldehyde (321 μL, 3.01 mmol) was added, and the reaction was allowed to stir at −78° C. for 30 minutes before removing the cooling bath. After warming to room temperature over 1 hr, the reaction mixture was quenched with sat. aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/0-65% EtOAc) to afford 4-(5-chloropyridin-3-yl)-2-(cyclopentyl(hydroxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C26H30ClN5O [M+H]+ 464. found 464. 1H NMR (600 MHz, CD3OD) δ 8.78 (d, J=2.1, 1H), 8.74 (d, J=1.3, 1H), 8.27-8.24 (m, 1H), 8.23 (s, 1H), 4.68 (d, J=9.1, 1H), 4.15-3.88 (m, 2H), 2.73 (dd, J=8.0, 16.0, 1H), 1.99-1.91 (m, 1H), 1.76-1.54 (m, 6H), 1.50 (d, J=13.3, 2H), 1.31-1.22 (m, 1H), 1.19-1.09 (m, 1H), 1.02-0.96 (m, 1H), 0.92-0.77 (m, 4H), 0.75 (d, J=6.5, 3H), 0.60-0.47 (m, 2H).
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43]1[S:47][C:46]([CH2:48][N:49]2[N:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)=[N:45][CH:44]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][CH2:42][C:43]1[S:47][C:46]([CH2:48][N:49]2[N:53]=[C:52]([NH:54][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:51]=[N:50]2)=[N:45][CH:44]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: COCc1cnc(Cn2ncc(N)n2)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COCc1cnc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (30 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with DMAP (4.8 mg, 0.04 mmol), HOBt (26 mg, 0.19 mmol), EDC (76 mg, 0.40 mmol) and DIPEA (0.11 mL, 0.63 mmol) and the resulting mixture was stirred for 30 min at rt. A solution of 2-((5-(methoxymethyl)thiazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (36 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the reaction mixture was stirred overnight at rt. The solvents were removed under reduced pressure. Purification of the residue by preparative HPLC gave the title compound as a yellow oil. TLC: rf (4:6 hept-EA)=0.31. LC-MS-conditions 07: tR=0.85 min, [M+H]+=397.40.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:27][CH:28]1[CH2:30][CH2:29]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:27][CH:28]3[CH2:30][CH2:29]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reactant: OCC1CC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 24 h

Procedure:
A mixture of 9.4 g (26.1 mmol) of tert.butyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 30 g (416 mmol) of hydroxymethyl-cyclopropane and 1.4 g (6 mmol) of tetraethyl orthotitanate is stirred at 120° for 24 hours, a small amount of solvent being distilled off in vacuo three times. The mixture is subsequently evaporated in vacuo, the residue is taken up in 60 ml of chloroform, the chloroform solution is treated with 40 ml of water and stirred for 15 hours. The mixture is then filtered through siliceous earth while washing with chloroform, the chloroform phase is dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate, there is obtained cyclopropylmethyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 193-194°.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[CH:14][C:7]=2[S:6]1(=[O:20])=[O:19])(C)(C)C>FC(F)(F)C(O)=O>[O:19]=[S:6]1(=[O:20])[C:7]2[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:8]=2[C:9](=[O:10])[NH:5]1
Reactant: CCCOc1ccc2c(c1)S(=O)(=O)N(C(C)(C)C)C2=O
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccc2c(c1)S(=O)(=O)NC2=O
Yield: 46.3 %

Procedure:
A solution of 2-tert-butyl-1,1-dioxo-6-propyloxy-1,2-dihydro-1λ6 -benzo[d]isothiazol-3-one (0.346 g, 1.165 mmol) in trifluoroacetic acid (10 mL) was refluxed for 48 hours. NMR of the reaction mixture revealed quantitative deprotection. The mixture was concentrated in vacuo and crystallized from methylene chloride, methanol and hexane, to afford the required product (0.130 g, 46%);
Reaction SMILES: Cl[C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1>O.Cl>[Cl:9][C:8]1[CH:2]=[CH:3][C:4]([O:10][CH3:11])=[C:5]([CH:7]=1)[NH2:6]
Reactant: COc1cc(Cl)c(Cl)cc1N
Agent: Cl
Solvent: O
Product: COc1ccc(Cl)cc1N
Yield: 40 %

Procedure:
Following the general procedure I, 0.25 mol of 4,5-dichloro-2-methoxyaniline in 200 ml of water and 60 ml of concentrated hydrochloric acid are hydrogenated in the presence of the catalyst from Example 1 at 180° C. over the course of 45 minutes under a hydrogen pressure of 100 atmospheres gauge. 5-Chloro-2-methoxyaniline is obtained in a yield of 40% and a purity of 74%.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:31][C@H:32]1[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1.C(N(CC)CC)C>C1COCC1>[N:34]12[CH2:39][CH2:38][CH:37]([CH2:36][CH2:35]1)[C@H:32]([N:31]1[C:10](=[O:12])[CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][C:14]1=[O:16])[CH2:33]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CN(Cc2ccccc2)CC(=O)N1[C@@H]1CN2CCC1CC2
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a solution of N-benzyliminodiacetic acid (2.23 g, 10.0 mmol) in THF (30 mL) was added 1,1′-carbonylbis-1H-imidazole (3.57 g, 22.0 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at reflux temperature for 30 min (until the evolution of C02 gas ceased, giving a clear solution), then cooled to room temperature. To the resulting mixture was added a solution of (3S)-3-aminoquinuclidine dihydrochloride (2.00 g, 10.0 mmol) and triethylamine (3.06 mL, 22.0 mmol) in THF (10 mL) stirred at room temperature under nitrogen atmosphere for 30 min via a cannula. The combined reaction mixture was stirred under reflux for 24 h, then cooled to room temperature and quenched with H2O (10 mL). The organic layer was extracted with EtOAc (50×2 mL) and the combined organic layers were dried over MgSO4, concentrated in vacuo. The residue was purified by column chromatography (NH gel, 200-350 mesh, 150 g, EtOAc) to give a product (2.17 g, 69%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[O:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[Br:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:16][C:17](=[O:30])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[O:25][CH:26]1[CH2:27][CH2:28][CH2:29]1)([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(Br)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(Br)cc3C2)c1OC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
The mixture 5-bromo-2-(2-cyclobutoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (100) (442 mg, 0.94 mmol) and KOH (700 mg, 12 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (101) as white solid (390 mg, 93%).
Reaction SMILES: [C:1]([N:3]=[S:4]([C:7]1[CH:24]=[CH:23][C:10]([CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:9][CH:8]=1)[CH2:5][CH3:6])#[N:2].[CH:25](SC1C=CC(CN)=CC=1)(C)C>>[C:1]([N:3]=[S:4]([C:7]1[CH:24]=[CH:23][C:10]([CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:9][CH:8]=1)[CH:5]([CH3:25])[CH3:6])#[N:2]
Reactant: CC(C)Sc1ccc(CN)cc1
Reactant: CCS(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Product: CC(C)S(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
The title compound is prepared in analogy to preparation 13a, substituting 4-(ethylthio)-benzylamine with 4-(isopropylthio)benzylamine ESI mass spectrum: [M+H]+=352; r.t. HPLC: 0.50 min (X012_S01).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2N=N[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1)[CH3:2].[CH:26](N1CCCC1)=[CH2:27]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:26]=[CH:27][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=CN1CCCC1
Reactant: CCOC(=O)c1nnc(-c2ccc(CC)cc2)c(-c2ccccc2)n1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccc(CC)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure D, ethyl 6-(4-ethyl-phenyl)-5-phenyl-1,2,4-triazine-3-carboxylate (Compound 13, 105 mg, 0.30 mmol) and crude 1-vinylpyrrolidine (Compound 38, 2 g) in CHCl3 (10 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:51])[CH:10]([C:13]1[CH:50]=[CH:49][CH:48]=[CH:47][C:14]=1[CH2:15][CH2:16][C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[N:18]=1)[CH2:11][CH3:12]>C(Cl)Cl>[NH:37]1[CH2:38][CH2:39][CH:34]([C:31]2[CH:30]=[CH:29][C:28]([NH:27][C:19]3[N:18]=[C:17]([CH2:16][CH2:15][C:14]4[CH:47]=[CH:48][CH:49]=[CH:50][C:13]=4[CH:10]([CH2:11][CH3:12])[C:9]([NH2:8])=[O:51])[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=3)=[CH:33][CH:32]=2)[CH2:35][CH2:36]1
Reactant: CCC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Yield: 71.1 %

Procedure:
A solution of TFA (0.84 mL, 11 mmol) and tert-butyl 4-(4-((4-(2-(1-amino-1-oxobutan-2-yl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A2) (168 mg, 0.275 mmol) in DCM (20 mL) was stirred for 24 hours at room temperature under a nitrogen atmosphere. The volatiles were removed in vacuo and the residue was taken up in MeOH and loaded onto an SCX cartridge (10 g). The column was eluted with 5 column volumes of MeOH and then 5 column volumes of 5% v/v aqueous ammonia in MeOH to elute the amine product. The ammoniacal filtrate was evaporated under reduced pressure and the residue was taken up in DCM (˜2 mL). Cyclohexane (˜10 mL) was added and the resulting suspension sonicated for 10 minutes. The precipitate was isolated by filtration to give the title compound 1 as an off-white solid (100 mg, 71%); 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 8.67 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.51-7.43 (m, 1H), 7.31 (s, 1H), 7.22-7.10 (m, 5H), 6.87 (s, 1H), 3.61 (dd, J=8.8, 6.1 Hz, 1H), 3.22-2.89 (m, 6H), 2.62-2.53 (m, 3H), 2.07-1.91 (m, 1H), 1.67 (d, J=12.0 Hz, 2H), 1.62-1.42 (m, 3H), 0.87-0.80 (m, 3H). LCMS-A: rt 4.973 min; m/z 512 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].C[O:13][P:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]2[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=2[O:15]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([P:14]1(=[O:13])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]2[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=2[O:15]1)=[O:6]
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: Cc1ccc(C(=O)Cl)cc1C
Product: Cc1ccc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)cc1C
Temperature: 100 °C

Procedure:
50.6 g (0.3 mol) of 3,4-dimethylbenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 69 g (0.3 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise while stirring. Crystallization began even during the dropwise addition, and the temperature was therefore increased to 100° C.; at the same time, an additional 100 ml of toluene were added dropwise. When the dropwise addition was complete, the mixture was heated to reflux. When the reaction was complete and after crystallization, 87 g (83% of theory) of the abovementioned compound, which had a melting point of 160° to 162° C., were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([S:32]([F:37])([F:36])([F:35])([F:34])[F:33])[CH:31]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N:15]2[C:22]3[N:18]([N:19]=[C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[CH:17]=[CH:16]2)[CH:9]=1)=[O:6].CS(O[CH:43]1[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+].FC(F)(F)C(O)=O>CN(C=O)C.ClCCl>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([O:1][CH:43]3[CH2:47][CH2:46][NH:45][CH2:44]3)[CH:31]=[C:30]([S:32]([F:36])([F:35])([F:34])([F:37])[F:33])[CH:29]=2)=[CH:9][C:10]=1[N:15]1[C:22]2[N:18]([N:19]=[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=2)[CH:17]=[CH:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Reactant: Cc1ccc(NC(=O)c2cc(O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(OC3CCNC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
150 mg (0.28 mmol) of the compound of Example 20, 89 mg (0.34 mmol) of tert-butyl 3-[(methyl-sulphonyl)oxy]pyrrolidine-1-carboxylate [lit. e.g.: P. Kocalka et al., Tetrahedron 2006, 62 (24), 5763-5774] and 201 mg (0.62 mmol) of caesium carbonate in 3 ml of DMF were heated at 90° C. for 6 h. The reaction was then stirred into 15 ml of 0.1 M aqueous sodium hydroxide solution and the mixture was stirred at RT for another 10 min. The precipitate formed was filtered off, washed with water and dried under reduced pressure. The intermediate obtained in this manner was stirred in 3 ml of dichloromethane and 1 ml of trifluoroacetic acid at RT for 1 h. The mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Method 18). After concentration of the product-containing fractions, the residue was dissolved in ethyl acetate and washed successively with saturated potassium carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Drying of the residue gave 101 mg (90% pure, 60% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[CH:16]=[O:17].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])[C:3]=1[CH2:16][OH:17]
Reactant: CC(C)(C)OC(=O)Nc1nccc(F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1nccc(F)c1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a solution of the product of step A (480 mg, 2 mmol) in MeOH (3 mL) was added NaBH4 (76 mg, 2 mmol) at 0° C. The reaction was stirred at 0° C. for 30 min. The reaction was quenched with saturated NH4Cl (1 mL) and water (5 mL), extracted with ethyl acetate (2×15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (460 mg, 95%) as a white solid which was used directly in the next step. 1H-NMR (600 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.31-8.28 (m, 1H), 7.11-7.09 (m, 1H), 5.26 (t, J=6.0 Hz, 1H), 4.48 (d, J=6.0 Hz, 2H), 1.45 (s, 9H) ppm. MS: M/e 243 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[C:23]([O:24][CH3:25])[CH:22]=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: COc1cccc2c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)[nH]c12
Yield: 83.9 %

Procedure:
2.00 g (9.19 mmol) of 4-chlorobenzenesulfonylisocyanate and 1.40 g (8.38 mmol) of 2-amino-3-methoxybenzoic acid were treated in the same way as in Example 1 to obtain 2.58 g of the above-identified compound (yield 84.0%). Properties: colorless crystal, Melting point: 220°-222° C., PMR (δppm, DMSO-d6): 3.88 (3H,s), 7.16 (1H,t), 7.32 (1H,d), 7.43 (1H,d), 7.76 (2H,d), 8.17 (2H,d), 10.95 (1H,br).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:36])=[C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:36])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Br)nc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(Br)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(5-bromo-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (271 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N lithium hydroxide aqueous solution (1.00 mL), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (271 mg, 90%) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([C:19]([NH:21][C@@H:22]3[C@@H:27]([OH:28])[CH2:26][O:25][CH2:24][CH2:23]3)=[O:20])[CH:10]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)CCC>O1CCOCC1.C(OCC)(=O)C.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>[N:35]1[CH:36]=[CH:37][N:38]=[CH:39][C:34]=1[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([C:19]([NH:21][C@@H:22]3[C@@H:27]([OH:28])[CH2:26][O:25][CH2:24][CH2:23]3)=[O:20])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2c(n1)CCCC2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Cc2ccc(-c3cnccn3)nc2)c2c(n1)CCCC2
Temperature: 25 °C

Procedure:
To a solution of 1,5-anhydro-3-[({4-[(6-chloropyridin-3-yl)methyl]-5,6,7,8-tetrahydroquinolin-2-yl}carbonyl)amino]-2,3-dideoxy-L-threo-pentitol (Example 1, 0.038 g, 0.095 mmol) in 1 mL of dioxane under an atmosphere of nitrogen was added 2-(tributylstannyl)-pyrazine (0.060 mL g, 0.19 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.0095 mmol). The mixture was irradiated in a microwave reactor at 130° C. for 1.5 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-6% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 446.0 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 9.52 (s, 1H), 8.74-8.70 (m, 2H), 8.64 (s, 1H), 8.34-8.30 (m, 2H), 7.77-7.66 (m, 1H), 7.63 (s, 1H), 4.16 (s, 2H), 3.82-3.72 (m, 3H), 3.69-3.53 (m, 1H), 3.04-2.99 (m, 1H), 2.92 (br s, 2H), 2.75 (br s, 2H), 1.96-1.66 (m, 4H), 1.65-1.55 (m, 2H), 1.13-1.09 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH2:43])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:44]([CH2:46]N)[OH:45]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH:43][CH2:46][CH2:44][OH:45])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(N)=O)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(=O)NCCO)cc1
Reaction time: 3 h
Yield: 21 %

Procedure:
A portion of the crude intermediate of example 58 above, (25 mg, 0.03 mmol) was added to a solution of ethanolamine in ethanol (1M, 10 mL). The resulting solution was stirred for 3 h before evaporation of the solvent. The residue was purified by preparative HPLC to yield 15 mg, 21% of the desired material.