Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C@@H:7]([CH2:11][CH2:12][C@@H:13]([C:17](=[O:35])[NH:18][C@H:19]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[C:20]2=[O:34])[CH2:14][CH2:15][CH3:16])[C:8](O)=[O:9])=[CH:4][CH:3]=1.[NH2:38][C@H:39]1[CH2:45][CH2:44][S:43][C@H:42]2[CH2:46][CH2:47][CH2:48][C@@H:49]([C:50]([F:53])([F:52])[F:51])[N:41]2[C:40]1=[O:54]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([CH2:11][CH2:12][C@H:13]([CH2:14][CH2:15][CH3:16])[C:17]([NH:18][C@H:19]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[C:20]2=[O:34])=[O:35])[C:8]([NH:38][C@H:39]2[CH2:45][CH2:44][S:43][C@H:42]3[CH2:46][CH2:47][CH2:48][C@@H:49]([C:50]([F:51])([F:53])[F:52])[N:41]3[C:40]2=[O:54])=[O:9])=[CH:36][CH:37]=1
Reactant: CCC[C@@H](CC[C@H](Cc1ccc(F)cc1)C(=O)O)C(=O)N[C@H]1CCCCN(c2ccccc2OC)C1=O
Reactant: N[C@H]1CCS[C@H]2CCC[C@@H](C(F)(F)F)N2C1=O
Product: CCC[C@@H](CC[C@H](Cc1ccc(F)cc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(F)(F)F)N2C1=O)C(=O)N[C@H]1CCCCN(c2ccccc2OC)C1=O

Procedure:
(2R,5S)-2-(4-Fluorobenzyl)-N6-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N1-((4S,7S,10aS)-5-oxo-7-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-5-propylhexanediamide was synthesized as described in General Procedure H using Intermediate 76 (22 mg, 0.043 mmol) and Intermediate 77 (12 mg, 0.045 mmol) to give a white solid (14 mg, 43% yield). Anal. Calcd. for C39H50F4N4O5S m/z 762.7. found: 763.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.42-7.22 (3H, m), 7.15-7.02 (3H, m), 7.01-6.94 (2H, m), 6.86 (2H, t, J=8.5 Hz), 5.28-5.15 (2H, m), 4.99-4.83 (2H, m), 4.05-3.88 (1H, m), 3.81 (3H, s), 3.54-3.34 (1H, m), 3.28-3.09 (1H, m), 2.85-2.60 (3H, m), 2.42-2.30 (1H, m), 2.22-1.72 (12H, m), 1.71-1.20 (11H, m), 0.87 (3H, t, J=7.1 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]4[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]4)[C:21]([CH2:31][O:32][CH2:33][CH3:34])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.CO>C(#N)C.[OH-].[Pd+2].[OH-]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]([CH2:31][O:32][CH2:33][CH3:34])[N:22]([CH2:23][CH:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=2[N:16]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1COC(C)(C)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC1COC(C)(C)O1
Reaction time: 24 h

Procedure:
Palladium hydroxide (Pearlman's catalyst) (20% palladium w/w on carbon, 900 mg) was added to a solution of 7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-ylamine (9.00 g, 19.46 mmol, 1 eq), prepared as described in Example 152, in acetonitrile (300 mL) and methanol (300 mL) in a sealed vessel and the reaction mixture was placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 24 hours. The crude reaction mixture was filtered through a layer of CELITE filter aid and the filtrate was concentrated under reduced pressure and triturated with acetonitrile. The resulting crystalline material was collected by filtration and washed with acetonitrile to afford 3.66 of 4-amino-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-ol as an off-white solid. Additional product (0.36 g) was isolated from the filtrate of the initial trituration by concentration under reduced pressure, trituration with acetonitrile, and filtration for a total yield of 4.02 g of 4-amino-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-ol, isolated as an off-white solid, mp 240-242° C. 1H-NMR (300 MHz, DMSO) δ 9.51 (br s, 1H), 7.96 (d, J=8.9 Hz, 1H), 6.95 (d, J=2.5 Hz, 1H), 6.76 (dd, J=8.9, 2.6 Hz, 1H), 6.46 (br s, 2H), 4.92-4.60 (m, 4H), 4.57-4.45 (m, 1H), 4.18 (dd, J=8.6, 6.4 Hz, 1H), 3.83 (dd, J=8.6, 6.5 Hz, 1H), 3.54 (q, J=7.0 Hz, 2H), 1.34 (s, 3H), 1.19 (s, 3H), 1.15 (t, J=7.0 Hz, 3H); 13C-NMR (75 MHz, DMSO) δ 156.41, 152.0, 148.1, 147.2, 133.9, 124.4, 121.7, 111.7, 109.7, 109.0, 107.9, 74.4, 66.0, 65.2, 64.3, 47.6, 26.2, 24.9, 14.8; MS (APCI) m/z 373.0 (M+H)+; Anal. calcd for C19H24N4O4: C, 61.28; H, 6.50; N, 15.04. Found: C, 61.12; H, 6.53; N, 14.98.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:32]=1[CH2:33]Br>C(O)C.O.O1CCOCC1>[F:39][C:36]1[CH:37]=[CH:38][C:31]([C:30]([F:29])([F:40])[F:41])=[C:32]([CH2:33][S:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:28])([F:27])[F:15])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: O=S(=O)(Cc1cc(F)ccc1C(F)(F)F)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
Sodium sulfite (102 g, 809 mmol) was added to sodium phosphate, dibasic (58 g, 409 mmol) and water (550 ml). 4-(trifluoromethyl)benzenesulfonyl chloride (100 g, 409 mmol) and dioxane (65 ml) were then added to the reaction mixture. The reaction was heated to reflux. After 75 min, the reaction was cooled slightly and a solution of 2-trifluoromethyl-5-fluoro-benzyl bromide (75 g, 292 mmol) in ethanol (95 ml) were added and the mixture was refluxed for 1 hr. The reaction was diluted with water (400 ml) and cooled to 0° C. for 1 hr. The reaction mixture was filtered and the solid was washed with water (2×400 ml) and then with heptane (200 ml). The residue was dried under vacuum to a constant weight and carried to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][CH2:20][NH:21]4)=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37](N1C=CN=C1)=[O:38].CN(C=O)C.CCOC(C)=O>O>[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37]([N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([C:12]3[S:13][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[C:10]([C:24]([OH:26])=[O:25])[N:11]=3)[CH:23]=2)[CH2:18][CH2:19][CH2:20]1)=[O:38]
Reactant: COc1ccc(-c2sc(-c3ccc4c(c3)NCCC4)nc2C(=O)O)cc1
Reactant: O=C(Nc1nc2ccccc2s1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc(-c3ccc4c(c3)N(C(=O)Nc3nc5ccccc5s3)CCC4)nc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
The title compound 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(4-methoxyphenyl)thiazole-4-carboxylic acid (1) was prepared by the following procedure: To 5-(4-methoxyphenyl)-2-(1,2,3,4-tetrahydroquinolin-7-yl)thiazole-4-carboxylic acid (1L) (0.070 g, 0.19 mmol) and N-(benzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide (1M) (0.051 g, 0.21 mmol) was added DMF (2 mL). The reaction mixture was allowed to stir at rt overnight. To the reaction mixture was added EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC to provide 0.028 g (27%) of the desired product 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(4-methoxyphenyl)thiazole-4-carboxylic acid (1): LC/MS (APCI): m/z 543.1 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.Br[CH2:8][CH2:9][CH2:10][Cl:11]>CC(C)=O.[OH-].[Na+]>[Cl:11][CH2:10][CH2:9][CH2:8][N:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[CH3:1]
Reactant: C[C@@H]1CCCN1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C[C@@H]1CCCN1CCCCl
Temperature: 80 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
To a solution of (R)-2-methylpyrrolidine (18.0 g) and 1-bromo-3-chloropropane (100.0 g) in acetone (360 mL), aqueous sodium hydroxide (5 M, 50 mL) was added dropwise in an ice bath and the mixture was heated to 80° C., at which it was stirred for 4 hours. The reaction mixture was extracted with diethyl ether, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=4:1 to 1:1) and silica gel column chromatography (eluting solvent: chloroform:methanol=9:1) to give the titled compound (17.8 g, 52%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[CH:23]=O)=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([O:19][C:18]3[CH:28]=[CH:29][C:15]([Cl:14])=[CH:16][CH:17]=3)[CH:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Oc3ccc(Cl)cc3)c2)CC1
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (19.6 g, 105 mmol) and 3-(4-chloro-phenoxy)-benzaldehyde (24.4 g, 105 mmol) in THF (90 mL) was treated with NaB(OAc)3H (33.4 g, 158 mmol). After 3 h, the resulting mixture was treated with 10% aq. KOH (500 mL). The aqueous phase was extracted with EtOAc (2×500 mL) then saturated aqueous NaCl (200 mL). The organic extracts were combined, dried (MgSO4) and purified (FCC) to give 4-[3-(4-chloro-phenoxy)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (29.6 g, 75%). MS (ESI+): calcd for C22H27ClN2O3 m/z 402.17, found 403.2 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[S:16][C:15]([CH3:17])=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[S:16][C:15]([CH3:17])=[N:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: Cc1nnc(S)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2nnc(C)s2)s1
Temperature: 120 °C
Yield: 61.6 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (1.76 g), 5-mercapto-2-methyl-1,3,4-thiadiazole (1.3 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (40 ml) was heated at 120° C. for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure and water was added to this residue. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-5-(2-methyl-1,3,4-thiadiazol-5-ylthio)thiazole (1.65 g, yield: 60.7%). mp: 242°-244° C. IR (Nujol): 3250, 1695, 1550, 1300 cm-1
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([CH2:8][CH3:9])[C:4](OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:15][N:2]([CH3:1])[C:3]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([CH2:8][CH3:9])[CH2:4][OH:5]
Reactant: CCC(C(=O)OC)(c1cccs1)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CO)(c1cccs1)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A solution of methyl 2-dimethylamino-2-(2-thienyl)butyrate (11.4 g) in tetrahydrofuran (50 ml) is added dropwise to a suspension of lithium aluminum hydride (1.6 g) in tetrahydrofuran (50 ml) under ice-cooling. The mixture is stirred at room temperature for 2 hours, and water (1.6 ml), an aqueous 15% sodium hydroxide solution (1.6 ml) and water (4.8 ml) are added to the mixture, successively. After the mixture is stirred, insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. The residue is distilled under reduced pressure, whereby 2-dimethylamino-2-(2-thienyl)-1-butanol (9.1 g) is obtained as colorless crystals. Yield: 91%
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.CC(=O)OCC>ClCCl>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: c1ccc2[nH]ccc2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)CCN2
Reaction time: 0.17 h
Yield: 67 %

Procedure:
A round bottom flask containing trifluoroacetic acid (60 mL) was cooled to 0 C under nitrogen and triethylsilane (1.16 g, 1.6 mL, 9.96 mmol) was added followed by the dropwise addition of indole 1 (1.17 g, 3.32 mmol; prepared using a modification of the procedure reported by Macor, et al. J. Med. Chem. 1992, 35, 4503-4505) in 9 mL dry dichloromethane, added over 1 hour. Following complete addition, the solution was stirred for 10 min. Thin layer chromatography (2/1 Hex/EA) indicated no remaining 1. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with saturated NaHCO3 (2×), and brine. The EtOAc layer was dried over Na2SO4, filtered, and concentrated. Purification by column chromatography on silica gel (2/1 hexane/ethyl acetate) afforded 2 as a yellow oil (0.79 g, 67%). 1H NMR (CDCl3, 300 MHz) δ7.34-7.31 (m, 5H) 6.99-6.85 (m, 1H)/6.34-6.27 (m, 2H), 5.12 (s, 2H), 4.13-3.71 (m, 2H), 3.58-3.16 (m, 5H), 2.05-1.87 (m, 4H), 1.73-1.57 (m, 2H) ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=[C:28]([NH:36][C:37]([O:39][CH3:40])=[O:38])[C:27]=3[O:41][CH3:42])=[O:24])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].O.[Li+].[OH-].Cl>CO>[C:32]([C:30]1[CH:29]=[C:28]([NH:36][C:37]([O:39][CH3:40])=[O:38])[C:27]([O:41][CH3:42])=[C:26]([NH:25][C:23](=[O:24])[NH:22][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=3)=[CH:13][CH:14]=2)[CH:31]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)Nc2ccc(Oc3ccnc(C(=O)OC)c3)c3ccccc23)c1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)Nc2ccc(Oc3ccnc(C(=O)O)c3)c3ccccc23)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To a solution of 4-{4-[3-(5-tert-butyl-2-methoxy-3-methoxycarbonylamino-phenyl)-ureido]-naphthalen-1-yloxy}-pyridine-2-carboxylic acid methyl ester (1.114 g, 2 mmol) in MeOH (12 mL) was added water (2 mL) and LiOH (58 mg, 2.4 mmol). The resulting mixture was stirred at room temperature for 16 h then neutralized with 2N HCl. The resulting suspension was concentrated to dryness and the residual solid triturated with a mixture of methylene chloride and acetonitrile (300 mL, 2:1). The inorganic salt was filtered and the mother liquor concentrated to give the title compound as a dark tan solid (900 mg, 80%).
Reaction SMILES: C([NH:5][C:6]1[N:10]2[CH:11]=[C:12]([C:15]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:16]=3[O:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([S:25]([NH:28][C:29]4[S:33][N:32]=[CH:31][N:30]=4)(=[O:27])=[O:26])=[C:20]([F:34])[CH:19]=3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)(C)(C)C.[OH-].[K+]>ClCCl.FC(F)(F)C(O)=O.CO.O>[NH2:5][C:6]1[N:10]2[CH:11]=[C:12]([C:15]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:16]=3[O:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([S:25]([NH:28][C:29]4[S:33][N:32]=[CH:31][N:30]=4)(=[O:26])=[O:27])=[C:20]([F:34])[CH:19]=3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1
Reactant: CC(C)(C)Nc1cnc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4ncns4)cc3F)cn12
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4ncns4)cc3F)cn12
Temperature: 25 °C
Yield: 15 %

Procedure:
A solution of 4-(2-(3-(tert-butylamino)imidazo[1,2-a]pyridin-6-yl)-4-chlorophenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.35 g, 0.47 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was heated at 80° C. for 16 h in a sealed tube. The mixture was allowed to cool to ambient temperature and was concentrated in vacuo. Methanol (30 mL) was added to the residue. The mixture was filtered and the filtrate concentrated in vacuo. The residue obtained was dissolved in methanol (8 mL) and water (8 mL), and potassium hydroxide (0.079 g, 1.4 mmol) was added. The mixture was heated at 60° C. for 4 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was partitioned between dichloromethane (100 mL) and water (10 mL). The aqueous phase was adjusted to pH 7 with 1 N hydrochloric acid and extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative reverse-phase HPLC to afford 4-(2-(3-aminoimidazo[1,2-a]pyridin-6-yl)-4-chlorophenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as an off-white solid in 15% yield (0.037 g): 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.13-7.95 (m, 2H), 7.87-7.72 (m, 3H), 7.67-7.52 (m, 3H), 7.29-7.15 (m, 3H), 5.85 (br s, 1H); MS (ES+) m/z 534.8 (M+1), 536.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:19]([C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])(=[O:21])=[O:20])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1nc(Cl)cnc1N
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1ccc(Cl)cc1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g) and 2,4-dichlorobenzenesulphonyl chloride (0.13 g). Yield 0.045 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6](C#N)([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:7][CH2:8][C:9]([OH:11])=[O:10]>Cl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH:6]([C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: COC(=O)CCC(C#N)(CCC(=O)O)c1ccncc1
Agent: Cl
Product: COC(=O)CCC(CCC(=O)O)c1ccncc1
Yield: 219.9 %

Procedure:
Into 250 ml of concentrated hydrochloric acid, 13 g of 4-cyano-4-(4-pyridyl)pimelic acid methyl ester was dissolved, and the solution was refluxed for 14 hours. Hydrochloric acid was distilled off under reduced pressure and the residue was dissolved in 200 ml of methanol. To this solution, there was added 1 ml of concentrated sulfuric acid and the mixture was refluxed for 4 hours. After 3 g of sodium bicarbonate was added, methanol was distilled off and 150 ml of water and 150 ml of ethyl acetate were added. Further, 25 g of sodium bicarbonate was gradually added. The organic layer was removed, washed with 50 ml of saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was distilled off, there was obtained 26 g of 4-(4-pyridyl)pimelic acid methyl ester as an oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])=[CH:12][C:13]=2[C:14]2[CH:15]=[C:16]([C:20]#[N:21])[CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2SC(C(O)=O)=CC=2C2C=CC(F)=C(C#N)C=2)C=C([F:37])C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:37])=[C:16]([C:20]#[N:21])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1cccc(-c2cc(C(=O)N3CNC(=O)C3)sc2-c2cc(F)cc(Cl)c2)c1
Reactant: N#Cc1cc(-c2cc(C(=O)O)sc2-c2cc(F)cc(Cl)c2)ccc1F
Product: N#Cc1cc(-c2cc(C(=O)N3CNC(=O)C3)sc2-c2cc(F)cc(Cl)c2)ccc1F

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 1 starting with 82.3 mg (0.22 mmol) of the compound from Example 22A. 35.0 mg (35% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:26]4[C:25]5[N:24]=[CH:23][CH:22]=[CH:21][C:20]=5[N:19]=[CH:18][C:17]=4[N:16]=[C:15]3[CH2:27][CH2:28][CH3:29])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:26]4[C:25]5[N:24]=[CH:23][CH:22]=[CH:21][C:20]=5[N+:19]([O-:38])=[CH:18][C:17]=4[N:16]=[C:15]3[CH2:27][CH2:28][CH3:29])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCc1nc2cnc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Product: CCCc1nc2c[n+]([O-])c3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1

Procedure:
The method described in Part E of Example 12 was used to treat 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridine (1.08 g, 2.79 mmol) with mCPBA (1.1 g of 75% pure material followed by 0.35 g) with the modification that the trituration of the crude product was carried out with diethyl ether. 1-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-5-oxido-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridine was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH2:62])[CH2:58][CH2:59][S:60][CH3:61])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.CO>[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH:62][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][CH2:59][S:60][CH3:61])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: CSCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 64 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropylamine in tetrahydrofuran. Yield: 64%; Rf value: 0.5 (silica gel; dichloromethane/methanol=9:1); C24H27ClN4O2S (471.02); mass spectrum: (M+H)+=471/473 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6]C=1.CC1C=C(C=C(C)C=1)[NH2:23].N1C=CC=CC=1C=O>>[N:23]1[CH:6]=[CH:5][C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:3][CH:2]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: c1ccc(-c2nnn(-c3ccncc3)n2)nc1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3,5-dimethylaniline (72.7 mg, 0.6 mmol) and 2-pyridinecarboxaldehyde (64.2 mg, 0.6 mmol) were employed to obtain 2-[2-(4-pyridyl)-2H-tetrazol-5-yl]pyridine as an orange solid.