Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1(CCCC1)(=O)=O.C[C:9]([O:11][CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.B(F)(F)F.CCOCC>CO>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][O:11][CH3:9])[CH2:22][S:21][C@H:16]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 50 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 5.8 ml of boron trifluoride ethyl ether and 0.84 ml of methanol. The mixture was heated at 50° C. for 1.25 hours to advance a reaction. After completion of the reaction, substantially the same procedure dure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxy methyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.23 g. The yield of the desired product was 18%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2.[C:16]([CH:18]=[C:19]([O-])[CH3:20])#[N:17].[Na+].[NH2:23]/[C:24](/[CH3:32])=[CH:25]\[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27].C(O)(=O)C>CC(O)C>[C:16]([C:18]1[CH:12]([C:9]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:14])=[CH:5][C:4]3=[O:15])[C:25]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[C:24]([CH3:32])[NH:23][C:19]=1[CH3:20])#[N:17]
Reactant: C/C(N)=C/C(=O)OC(C)C
Reactant: Cc1cc(=O)c2c(F)ccc(C=O)c2o1
Reactant: CC([O-])=CC#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc(F)c3c(=O)cc(C)oc23)C(C(=O)OC(C)C)=C(C)N1

Procedure:
A solution of 100 mg (0.49 mmol) of 5-fluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 50.96 mg (0.49 mmol) of sodium 1-cyanoprop-1-en-2-olate, 69.45 mg (0.49 mmol) of isopropyl 3-aminocrotonate and 0.04 ml (0.73 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated. The resulting residue is crystallized from diethyl ether. The beige-colored crystals are filtered off with suction and dried at 40° C. in a vacuum drying oven. 88.1 mg (45.8% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[CH:7][C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].COS([O-])(=O)=O.[CH3:27][S:28][C:29](=[S+]C)[S:30][CH3:31]>O1CCOCC1>[CH3:27][S:28][C:29]([S:30][CH3:31])=[C:7]1[C:6](=[O:16])[C:5]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:15]
Reactant: CCCCC1(CCCC)C(=O)C=C(O)c2ccccc21
Reactant: CSC(SC)=[S+]C
Agent: COS(=O)(=O)[O-]
Solvent: C1COCCO1
Product: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of the product of Example 5B (25 mg, 0.092 mmol) in dioxane (4 mL) was treated with the product of Example 5A (71 mg, 0.27 mmol) and stirred at 100° C. for 2 hours, cooled to 25° C., diluted with ice water and extracted with ethyl acetate (3×). The combined organic layers were washed with water (3×) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound. 1H NMR (300 MHz, DMSO-d6): δ 8.05 (m, 1 H), 7.66 (m, 1 H), 7.56 (d, J=7.72 Hz, 1 H), 7.43 (t, J=6.80 Hz, 1 H), 2.51 (m, 6 H), 2.10 (m, 2 H), 1.82 (m, 2 H), 1.09 (m, 4 H), 0.69 (m, 10 H).
Reaction SMILES: [F:1][C:2]([CH3:20])([CH3:19])[CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:17][OH:18].C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:28]([O:18][CH2:17][C:5]1[N:4]([CH2:3][C:2]([F:1])([CH3:20])[CH3:19])[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(F)Cn1c(CO)nc2cnc3cccnc3c21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1nc2cnc3cccnc3c2n1CC(C)(C)F
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A solution of [1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol (1.53 g, 5.58 mmol) dissolved in 50 mL of CH2Cl2 was treated with triethylamine (1.55 mL, 11.2 mmol), acetic anhydride (663 μL, 6.70 mmol), and 10 mg of 4-(dimethylamino)pyridine (DMAP). After stirring for 2 hours, the reaction mixture was treated with saturated NaHCO3 solution and the layers were separated. The organic portion was washed successively with 3.5% NaH2PO4 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 40-60% acetone/hexanes) gave 1.59 g of [1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate as an off-white powder.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][NH:13][CH2:14][CH:15]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]1=[O:35].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:59]1([C:65](O)=[O:66])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1>C(Cl)Cl>[CH:59]1([C:65]([N:13]([CH2:12][C:4]2[C:3](=[O:35])[N:2]([CH3:1])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:14][CH:15]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:24][CH2:23]2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:66])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1
Reactant: Cn1c(=O)c(CNCC(c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc2ccccc21
Reactant: O=C(O)C1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1c(=O)c(CN(CC(c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C2CCCCC2)cc2ccccc21
Reaction time: 15 h

Procedure:
tert-butyl 4-(2-{[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-phenylethyl)piperidine-1-carboxylate (1.61 g crude, 3.39 mmol), EDC (1.298 g, 6.77 mmol), HOAT (0.461 g, 3.39 mmol), DIEA (1.182 ml, 6.77 mmol), and cyclohexanecarboxylic acid (0.504 ml, 4.06 mmol) were combined in CH2Cl2 and the reaction stirred for 15 hours. The mixture was partitioned between CH2Cl2 and satd. bicarb, the aqueous portion extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. The resulting material was purified by silica gel chromatography on an Isco Companion. The desired fractions were combined and concentrated in vacuo. 1.63 g, 82% over two steps.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH3:12].[C:21]1([CH3:29])[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1.ClCCl>O1CCCC1.[Cl-].[Na+].O>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([NH:17][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:29])=[CH:22][CH:23]=2)=[NH:28])[CH:18]=[CH:19][CH:20]=1)[CH3:12]
Reactant: CCOc1cccc(N)c1
Reactant: Cc1ccc(C#N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCOc1cccc(NC(=N)c2ccc(C)cc2)c1
Reaction time: 0.33 h

Procedure:
To a solution of 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide in 5.0 mL of tetrahydrofuran at ambient temperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and the resulting solution was stirred for 20 min. To this reaction mixture was slowly added a solution of 0.47 g (4.0 mmol) of p-tolunitrile in 2.0 mL of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 5 hrs and then poured into brine (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as yellow solid which was used without further purification. LC/MS 255.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CN2C(=NCCC2)C1.C([O:52][C:53](=[O:65])[CH2:54]CCCCCCCCCBr)C.COC(C)(C)C>[Cl-].C[N+](C)(C)C.C(OCOCC)C.C1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:54][C:53]([OH:65])=[O:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCOC(=O)CCCCCCCCCCBr
Agent: C1CN=C2CCCN2C1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOCOCC
Solvent: COC(C)(C)C
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-glucopyranose, 0.55 g (5 mmol) of tetramethylammonium chloride and 12.42 g (100 mmol) of DBN in 350 ml of diethoxymethane is cooled to 0° C. At 0° C., 44 g (150 mmol) of 11-bromoundecanoic acid-ethyl ester, dissolved in 50 ml of benzene, is added in drops over 30 minutes while being stirred vigorously. It is stirred for two hours at 20° C. 250 ml of methyl-tert-butyl ether is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol/50 ml of water. 60 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for five hours. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of dichloromethane, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of dichloromethane. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n-hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:21][N:22]([C:39]1[N:44]=[C:43](Cl)[N:42]=[C:41](Cl)[N:40]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:38])[C:30]1[N:35]=[C:34](Cl)[N:33]=[C:32](Cl)[N:31]=1.C([O:50][CH2:51][CH3:52])(=O)C>O1CCOCC1>[CH3:21][N:22]([C:39]1[N:44]=[C:43]([O:16][CH:11]2[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:13]([CH3:14])([CH3:15])[CH2:12]2)[N:42]=[C:41]([O:16][CH:11]2[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:50][CH:51]3[CH2:52][CH2:3][CH2:2][CH2:1][CH2:6]3)[C:13]([CH3:14])([CH3:15])[CH2:12]2)[N:40]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:38])[C:30]1[N:35]=[C:34]([O:16][CH:11]2[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:13]([CH3:14])([CH3:15])[CH2:12]2)[N:33]=[C:32]([O:16][CH:11]2[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:13]([CH3:14])([CH3:15])[CH2:12]2)[N:31]=1
Reactant: CCOC(C)=O
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Reactant: CN(CCCCCCN(C)c1nc(Cl)nc(Cl)n1)c1nc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(CCCCCCN(C)c1nc(OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)nc(OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)n1)c1nc(OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)nc(OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)n1
Temperature: 60 °C
Yield: 85 %

Procedure:
A mixture of 22.6 g (88.6 mmol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, 2.13 g (88.6 mmol) of sodium hydride, and 150 ml of 1,4-dioxane is heated at reflux for 2.5 hours. The reaction mixture is cooled to 60° C. and treated with a solution of 7.8 g (17.7 mmol) of N,N'-dimethyl-N,N'-bis(2,4-dichloro-1,3,5-triazin-6-yl)-1,6-hexanediamine in 50 ml of dioxane. The reaction mixture is quenched with ice. The supernatant liquid is decanted, and the residue is dissolved in ethyl acetate (250 ml). The solution is dried over anhydrous magnesium sulfate and concentrated to a glass. Purification by passage through a short column of silica gel with 4:1 hexane:ethyl acetate as the eluent affords 19.8 g (85% yield) of the title compound, a white glass.
Reaction SMILES: [CH:1]1([CH:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16](C4C=CC=CC=4OC)[C:10]=3[S:9](=[O:26])(=[O:25])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>[Pd]>[CH:1]1([CH:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[CH:34]=4)[C:10]=3[S:9](=[O:26])(=[O:25])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1-c1cccc2c1S(=O)(=O)NC(C1CCCCC1)N2
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd]
Product: COc1cccc(-c2cccc3c2S(=O)(=O)NC(C2CCCCC2)N3)c1

Procedure:
Synthesis as for compound 80 (using 3-methoxyphenylboronic acid for the Pd-cat. cross coupling). M.p. 108–115° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH:3]=1.[Br:25]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[C:3]=1[Br:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Solvent: ClCCl
Product: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)c(Br)c(N)c2F)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.5 %

Procedure:
Propan-2-yl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (500 mg, 1.402 mmol) was dissolved in dichloromethane (3.2 mL). N-Bromo-succinimide (299 mg, 1.682 mmol) was added, and the solution was stirred at ambient temperature for 20 h. The reaction mixture was then concentrated to dryness. The residue was purified by chromatography (40 g silica gel column; 0-70% EtOAc-hexanes) to give a tan solid (504 mg, 83%): 1H NMR (400 MHz, DMSO-d6) δ 7.47 (dd, J=8.5, 1.6 Hz, 1H), 7.29 (dd, J=8.5, 7.1 Hz, 1H), 7.01 (s, 2H), 5.22-5.10 (m, 1H), 3.93 (d, J=0.9 Hz, 3H), 1.32 (d, J=6.3 Hz, 6H); EIMS m/z 350.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:31]=[CH:30][C:9]2[S:10][C:11]([C:17]([NH:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)=[O:18])=[C:12]([S:13][CH:14]([CH3:16])[CH3:15])[C:8]=2[CH:7]=1>CO.O.C(OCC)(=O)C>[CH3:4][O:5][C:6]1[CH:31]=[CH:30][C:9]2[S:10][C:11]([C:17]([NH:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])=[C:12]([S:13][CH:14]([CH3:16])[CH3:15])[C:8]=2[CH:7]=1
Reactant: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2SC(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2sc(C(=O)Nc3ccc(C(=O)O)cc3)c(SC(C)C)c2c1
Temperature: 25 °C
Yield: 78 %

Procedure:
A suspension of lithium hydroxide-monohydrate (20 mg, 0.48 mmol) and methyl 4-[[[5-methoxy-3-[(1-methylethyl)thio]benzo[b]thien-2yl]carbonyl]amino]benzoate (67 mg, 0.16 mmol) in 4 mL of methanol and 2 mL of water is heated at reflux for 1.5 hours. The reaction mixture is cooled to room temperature and then diluted with ethyl acetate and washed sequentially with 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate: hexane gives 4-[[[5-methoxy-3-[(1-methylethyl)thio]benzo[b]thien-2yl]carbonyl]amino]benzoic acid in 78% yield; mp=241°-245° C. dec.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.[CH3:11][N:12]=[C:13]=[O:14]>>[CH3:11][NH:12][C:13]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:14]
Reactant: CN=C=O
Reactant: NCCNCc1cc[nH]n1
Product: CNC(=O)NCCNCc1cc[nH]n1

Procedure:
N-(3-Pyrazolylmethyl)ethylenediamine is reacted with methyl isocyanate by the procedure of Example 24 to give, after concentrating and separating the residue by column chromatography, the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][CH:4]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1[NH2:22].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C>O>[N:31]1([C:29]([C@@H:25]2[CH2:26][CH2:27][CH2:28][N:23]([C:19]3[N:20]=[C:21]4[NH:22][C:9]([C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:12])([F:11])[F:1])[N:8]=5)=[N:15][C:16]4=[CH:17][CH:18]=3)[CH2:24]2)=[O:30])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O=Cc1cccc(C(F)(F)F)n1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cccc(C(F)(F)F)n4)[nH]c3n2)C1)N1CCCC1
Temperature: 110 °C
Reaction time: 16 h
Yield: 23.9 %

Procedure:
Into a tube was added 6-(trifluoromethyl)picolinaldehyde (150 mg, 0.47 mmol), (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (Intermediate 1, Step 3) (82.2 mg, 0.47 mmol), sodium dithionite (310.7 mg, 1.78 mmol), ethanol (10 mL) and water (1.5 mL). The vessel was sealed and the reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure and water was added to the resulting residue. The mixture was extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound (50 mg, 29%) as a yellow solid. MS (ES+APCI) (M+H) 445.2; LCMS retention time 2.657 min (Method G).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:54][C:55]1[CH:62]=[CH:61][C:58]([CH2:59][NH2:60])=[CH:57][CH:56]=1>ClCCl>[F:54][C:55]1[CH:62]=[CH:61][C:58]([CH2:59][NH:60][C:21]([C:19]2[N:20]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:17][CH:18]=2)=[O:22])=[CH:57][CH:56]=1
Reactant: NCc1ccc(F)cc1
Reactant: COc1cc(Nc2nc(C(=O)O)cs2)ccc1-n1cnc(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc(Nc2nc(C(=O)NCc3ccc(F)cc3)cs2)ccc1-n1cnc(C)c1

Procedure:
To a suspension of 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-4-carboxylic acid (61.5 mg, purity 43%, 0.080 mmol) in dichloromethane (2 ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.5 mg, 0.128 mmol), 1-hydroxybenzotriazole hydrate (19.6 mg, 0.128 mmol), triethylamine (30.0 mg, 0.296 mmol) and a solution of 4-fluorobenzyl amine (12 mg, 0.096 mmol) in dichloromethane (1 ml). After 12 h at rt again 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.5 mg, 0.128 mmol), 1-hydroxybenzotriazole hydrate (19.6 mg, 0.128 mmol), triethylamine (30.0 mg, 0.296 mmol) and a solution of 4-fluorobenzyl amine (12 mg, 0.096 mmol) in dichloromethane (1 ml) were added. After 12 h at rt the reaction mixture was directly purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a off-white foam (23.0 mg, 66%). MS ISP (m/e): 438.2 (14) [(M+H)+].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:6][C:4]=1[NH2:5].[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[C:30]=1[N:37]1[C:41](=[O:42])[CH2:40][C:39](OCC)=[N:38]1>C(O)C>[Cl:36][C:31]1[CH:32]=[C:33]([Cl:35])[CH:34]=[C:29]([Cl:28])[C:30]=1[N:37]1[C:41](=[O:42])[CH2:40][C:39]([NH:5][C:4]2[CH:6]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:8]([Cl:10])=[CH:9][C:3]=2[Cl:2])=[N:38]1
Reactant: CCCCCCCCCCCCCCCCOc1cc(N)c(Cl)cc1Cl
Reactant: CCOC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOc1cc(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c(Cl)cc1Cl
Temperature: 150 °C

Procedure:
A mixture of 16 g of the 2,4-dichloro-5-hexadecyloxyaniline hydrochloride obtained in Step (2) described above and 12 g of 1-(2,4,6-trichlorophenyl)-3-ethoxy-2-pyrazolin-5-one was heated to 150° C. and melted. Thereafter, the mixture was reacted at 150 to 160° C. for an hour under a reduced pressure (approximately 20 mm Hg) with stirring while removing the ethanol formed. The reaction mixture was allowed to cool to 100° C. and then 100 ml of ethanol was added thereto. After heating with stirring, the mixture was allowed to cool to room temperature. The precipitate was recovered by filtration. After drying, the precipitate was recrystallized from 100 ml of ethyl acetate to obtain 16 g of the desired coupler. The melting point thereof was 107 to 108° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[N:13]([CH3:15])[CH3:14].[C@@H]1(N)CCCC[C@H]1N.[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29]([C:36]([O:38][CH3:39])=[O:37])=[CH:28]1>CCCCCCCCCCCC.O1CCOCC1.ClCCl>[CH3:14][N:13]([CH3:15])[C:12]1[CH:11]=[C:10]([N:27]2[C:31]3=[N:32][CH:33]=[CH:34][CH:35]=[C:30]3[C:29]([C:36]([O:38][CH3:39])=[O:37])=[CH:28]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c[nH]c2ncccc12
Reactant: CN(C)c1cccc(Br)c1
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCCCCCCCCCCC
Product: COC(=O)c1cn(-c2cccc(N(C)C)c2)c2ncccc12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
0.038 g (0.2 mmol) of cuprous iodide, 0.891 g (4.2 mmol) of potassium phosphate, 0.40 g (2 mmol) of 3-bromo-N,N-dimethylaniline and 0.24 cm3 (2 mmol) of trans-1,2-cyclohexanediamine were added, under an argon atmosphere, to 0.405 g (2.3 mmol) of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate in solution in 0.3 cm3 of dodecane and 6 cm3 of dioxane. After stirring at a temperature in the region of 110° C. for 48 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which was taken up in 20 cm3 of dichloromethane. The resulting organic solution was washed with 20 cm3 of 0.1N hydrochloric acid and filtered, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). Methyl 1-(3-(dimethylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate, characterized by LC/MS (m/z 296 [MH]+), was thus obtained, which was used directly in the following stage.