Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][N:27]1[C:31]([CH3:32])=[N:30][N:29]=[C:28]1[SH:33].O.OC1N=CN=C2C=1NC(S)=N2>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:33][C:28]3[N:27]([CH3:26])[C:31]([CH3:32])=[N:30][N:29]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Cc1nnc(S)n1C
Agent: Oc1ncnc2nc(S)[nH]c12
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nnc(C)n3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 4,5-dimethyl-4H-1,2,4-triazole-3-thiol, as shown in Example C(88), Step 1, was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.49-1.64 (m, 8H) 1.92 (m, 2H) 2.33 (m, 1H) 2.37 (s, 3H) 2.50 (m, 2H, overlap with dmso) 2.62 (d, J=15 Hz, 1H) 2.80 (d, J=17.6 Hz, 1H) 3.55 (s, attenuation due to proximity to H2O peak) 3.80 (s, 3H) 7.02 (d, J=8.5 Hz, 1H) 7.12 (dd, J=8.5, 1.9 Hz, 1H) 7.24 (d, J=1.9 Hz, 1H). MS (APCI) calcd for C23H28ClN3O4S: 478.01; found M=478.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:10]1[C:9](=[O:26])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Li+].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.CI.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:10]1[C:9](=[O:26])[CH:8]([CH3:28])[CH2:7][CH2:6][C:5]2=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCCC3=O)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCC(C)C3=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 394.6 %

Procedure:
6,7-Dichloro-9-tosyl-2,3,4,9-tetrahydro-1H-carbazol-1-one 0.1 g, 0.024 mmol) was dissolved in dry THF, cooled to −78° C. and LiHMDS (0.6 mL, 0.61 mmol) was added dropwise. The reaction mixture was slowly warmed to 0° C. and stirred for an additional 30 min. The reaction mixture was cooled to −78° C. and MeI (0.040 mL, 0.61 mmol) was added slowly, warmed to room temperature and stirred for 4 h. Saturated NH4Cl (10 mL) was added to the reaction mixture and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to obtain the title compound (0.04 g, 40%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.49 (s, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.67 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 2.98-2.85 (m, 2H), 2.71-2.66 (m, 1H), 2.43 (s, 3H), 2.27-2.23 (m, 1H), 1.96-1.89 (m, 1H), 1.25-1.17 (m, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].O>N1C=CC=CC=1>[CH3:19][C:18]1[CH:20]=[CH:21][C:15]([S:12]([O:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCC2(CC1)OCCO2
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M) (99.8 g, 0.63 mol) in pyridine (450 mLs) at 0° C. under nitrogen was added tosylchloride (132.4 g, 0.69 mol) portionwise such that T<2° C. On complete addition, the mixture was allowed to warm slowly to room temperature and stirred at room temperature overnight. Treated with water (750 mL) and extracted with EtOAc (500 mL then 2×250 mL). Combined extracts were washed with 3N HCl (3×300 mL), brine (300 mL) and dried over Na2SO4. Filtered and evaporated to yield a pale yellow oil (200 g crude). This oil was treated with petroleum ether (40-60°) (200 mL) and scratched to induce solid formation. 1,4-dioxaspiro[4.5]dec-8-yl 4-methyl-1-benzenesulfonate was filtered, washed with petroleum ether (40-60°) (200 mL) and dried in vacuo. Yield=181.0 g, 92%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[C:10]=1[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[C:10]=1[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=C(O)CCCc1c(OCc2ccccc2)cccc1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCCc1c(O)cccc1C(=O)O
Yield: 110.8 %

Procedure:
A solution of 4-[2-benzyloxy-6-carboxy-phenyl]butanoic acid (5 g, 15.9 mmol) in ethanol was hydrogenated at 60 psi for 4 hr over 10% Pd/C (1 g). The mixture was filtered, and the filtrate was concentrated in vacuo to give a white solid (3.95 g, 99%)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[C:15]1([CH:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:15]1([CH:21]([N:23]2[CH2:24][CH2:25][N:26]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:27][CH2:28]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(c1ccccc1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 80 °C
Yield: 76.2 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (400 mg, 1.80 mmol), 1-(1-phenylethyl)piperazine (342 mg, 1.80 mmol) and DIPEA (0.34 mL, 1.98 mmol) in DMF (4 mL) were stirred and heated at 80° C. for 30 minutes. The mixture was cooled to ambient temperature then applied to an SCX column and eluted with methanol followed by 2M ammonia in methanol. Fractions containing pure product were evaporated to give a solid which was recrystallised from MTBE/isohexane to give 6-[4-(1-phenylethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (516 mg, 76%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][N:7]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH2:8][CH:4]2[CH2:3][NH:2]1.Cl[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=2)[N:20]=1>>[F:26][C:24]([F:25])([F:27])[C:21]1[N:19]2[N:20]=[C:15]([N:2]3[CH2:3][CH:4]4[CH:5]([CH2:6][N:7]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH2:8]4)[CH2:1]3)[CH:16]=[CH:17][C:18]2=[N:23][N:22]=1
Reactant: CCCC(=O)N1CC2CNCC2C1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: CCCC(=O)N1CC2CN(c3ccc4nnc(C(F)(F)F)n4n3)CC2C1

Procedure:
A mixture of 1-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl)butan-1-one and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.2% aqueous ammonia) and acetonitrile as eluents to give 1-[2-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]butan-1-one.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([C:39]([F:42])([F:41])[F:40])[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.CCOC(C)=O.O>[CH:1]1([C:4]2[C:5]([N:24]([C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([C:39]([F:40])([F:42])[F:41])[CH:31]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(F)(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 93 %

Procedure:
A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.00 g, 2.49 mmol), 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (1.04 g, 4.97 mmol), K2CO3 (1.03 g, 7.45 mmol) in HMPA (6.2 mL) was stirred at 60° C. for 15 h. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (1.37 g, 93%) as an orange solid. LCMS (m/z, ES+)=592.2 (M+H+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[CH:2]1.CN(C)C=O.Br[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[C:13]([CH2:12][N:3]1[CH2:4][CH2:5][N:1]=[CH:2]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: C1=NCCN1
Reactant: O=C(CBr)OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C=NCC1)OCc1ccccc1

Procedure:
To a solution of 14.0 g. (0.2 mole) of imidazoline in 150 ml. of dry dimethylformamide is added dropwise with cooling 22.9 g. (0.1 mole) of benzyl bromoacetate. When the addition is complete, the reaction is warmed to 50°-60° C. for several hours, and is then cooled and diluted with water (250 ml.). The product is extracted with diethyl ether, and the extracts are combined and washed several times with a saturated brine solution. The ether phase is dried over sodium sulfate and concentrated to an oil, which is used in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]([I:15])=[C:12](I)[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].S([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C(O)C.O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][CH:12]=[C:11]([I:15])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-c2nc(I)c(I)[nH]2)cc1Cl
Agent: O=S([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Clc1ccc(-c2nc(I)c[nH]2)cc1Cl
Yield: 84.1 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-4,5-diiodo-lH-imidazole (0.93 g, 2.0 mmol) and sodium sulfite (1.01 g, 8.0 mmol) in ethanol (33 ml) and water (8 ml) was refluxed for 24 h. After addition of EtOAc (200 ml) and brine (20 ml) the organic layer was separated, then dried with Na2SO4, evaporated and chromatographed over SiO2 with EtOAc-hexane (6:1) to obtain 2-(3,4-dichloro-phenyl)-4-iodo-1H-imidazole (0.57 g, 84%) as a solid mass. Mp. 206-207° C. (EtOAc/hexane), MS: m/e=338 (M+).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[N:4]=1)=[CH2:2].[Br:13][C:14]1[C:15]2[N:16]([C:20](=[O:23])[NH:21][N:22]=2)[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1.C(Cl)Cl>[N:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:1][CH2:2][N:21]1[C:20](=[O:23])[N:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Br:13])[C:15]2=[N:22]1
Reactant: C=Cc1ccc2ncccc2n1
Reactant: O=c1[nH]nc2c(Br)cccn12
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O=c1n(CCc2ccc3ncccc3n2)nc2c(Br)cccn12
Temperature: 160 °C
Yield: 61.7 %

Procedure:
2-Vinyl-1,5-naphthyridine (10-2) (109 mg, 0.70 mmol) and triazolopyridinone 1-5 (150 mg, 0.70 mmol) were placed in a microwave vial and dissolved in NMP (1 mL). To the mixture was added catalytic powdered KOH (7.9 mg, 0.14 mmol), and the vial was capped and heated at 160° C. under microwave irradiation for 20 min. After cooling, the mixture was diluted with CH2Cl2 (100 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography (40 g cartridge), eluting with 20-100% EtOAc/hexanes, then 1-10% EtOH/EtOAc. The fractions containing the desired product (10-3) were pooled, and after solvent removal in vacuo, 160 mg (62%) of a fluffy yellow solid were obtained. LC/MS: m/z (M+H)=370.0.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[CH3:17][NH:18][C:19](=[O:32])[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.CS(C)=O>[CH3:17][NH:18][C:19](=[O:32])[C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 90 °C

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1.500 g, 6.84 mmol), N-methyl-4-(piperazin-1-yl)benzamide (1.500 g, 6.84 mmol), (cyanomethyl)trimethylphosphonium iodide (2.494 g, 10.26 mmol) and N,N-diisopropylethylamine (5.97 ml, 34.2 mmol) were suspended in propiononitrile (Volume: 27.4 ml) and heated in a closed vial at 90° C. The crude reaction was cooled to RT, DMSO (1 ml) was added, and the mixture was purified via HPLC (55-90, basic) to give the product as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[OH-].[Na+:38]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([O-:35])=[O:34])(=[O:10])=[O:11])[CH:8]=1)#[N:2].[Na+:38]
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)[O-])c1

Procedure:
To a stirred solution of 146 g of [4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetic acid in 580 mL of ethanol was added 137 mL of 2 mol/L sodium hydroxide solution under ice-cooling, and the solvent was removed under reduced pressure. The residue was suspended with 1.16 L of ethanol, and the mixture was stirred under reflux for an hour, then at room temperature overnight. The obtained white solid was collected by filtration to give 129 g of sodium [4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[CH:35][C:34]=1[N:48]1[CH2:60][CH2:59][N:51]2[C:52]3[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=3[CH:58]=[C:50]2[C:49]1=[O:61])(=[O:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[CH:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:30])[CH3:29]
Reactant: Cn1cc(Br)cc(Nc2ccc3c(n2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc4c(n3)CCN(C(=O)OC(C)(C)C)C4)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, tert-butyl 2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate 158c (300 mg, mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (352 mg, 0.758 mmol), Pd(PPh3)4 (39.8 mg, 0.035 mmol), Na2CO3 aqueous solution (1.0 N, 2.27 mL, 2.27 mmol), and 1,2-dimethoxyethane (3.5 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 166a.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH2:13].[C:17](Cl)(Cl)=[O:18].[S:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23]([OH:30])=[N:22]1>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:13][C:23]([N:22]1[C:17](=[O:18])[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[S:21]1)=[O:30]
Reactant: O=C(Cl)Cl
Reactant: NCc1cccc(COCc2ccco2)c1
Reactant: Oc1nsc2ncccc12
Solvent: Cc1ccccc1
Product: O=C(NCc1cccc(COCc2ccco2)c1)n1sc2ncccc2c1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 3-(furan-2-ylmethoxymethyl)benzylamine (218 mg, 1 mmol) in toluene (10 ml) is admixed at 25° C. with phosgene (5 ml, 10 mmol; 20% solution in toluene) and heated to reflux. After 3 h, the mixture is filtered and the filtrate is concentrated. The residue is taken up in THF (25 ml) and admixed with compound 1 (122 mg, 0.8 mmol). The mixture is stirred at 60° C. for 3 h. The reaction is monitored by HPLC-MS. The solvent is reduced, and the product crystallizes. C20H17N3O4S, Mw 395.44. Yield: 239 mg (75.7%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:21])=[C:4]([Br:20])[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[CH:19]=1.[C:22](OC)(OC)(OC)[CH3:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[Br:20][C:4]1[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[CH:19]=[C:2]2[N:1]=[C:22]([CH3:23])[O:21][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)c(Br)c2CC1
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: Cc1nc2cc3c(c(Br)c2o1)CCN(C(=O)OC(C)(C)C)CC3
Yield: 90 %

Procedure:
1,1-Dimethylethyl 8-amino-6-bromo-7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (1.604 g) was treated with trimethyl orthoacetate (0.856 ml) and pyridinium p-toluenesulfonate (112 mg) in dry DMF (23 ml) at 60° C. for 1.5 hours. Volatiles were evaporated under reduced pressure and the residue was purified on silica gel (ethyl acetate/petroleum ether: 1/6) providing the title compound as white solid (1.553 g, 90% yield).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([O:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])(=[O:23])=[O:22])[CH:11]=2)[CH2:4][CH2:3]1.Cl.[C:32](=[NH:37])([O:34]CC)[CH3:33].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:12]([OH:20])(=[O:34])[CH3:13].[C:32]([N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([O:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])(=[O:22])=[O:23])[CH:11]=2)[CH2:4][CH2:3]1)(=[NH:37])[CH3:33]
Reactant: O=S(=O)(Oc1cc(OCC2CCNCC2)c2ccccc2c1)c1ccccc1Cl
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=N)N1CCC(COc2cc(OS(=O)(=O)c3ccccc3Cl)cc3ccccc23)CC1
Product: CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 100 mg (0.214 mmol) of 2-chlorobenzenesulfonic acid 1-[(piperidin-4-yl)methoxy]naphthalen-3-yl ester hydrochloride, as prepared in the preceding step, in N,N-dimethylformamide (2 mL) containing 55 mg (0.45 mmol) of ethyl acetimidate hydrochloride and 125 μL of N,N-diisopropylethylamine was stirred at ambient temperature overnight. To the reaction mixture was added another 125 μL of N,N-diisopropylethylamine and 55 mg (0.45 mmol) of ethyl acetimidate hydrochloride. The reaction mixture was stirred for another 4 h. The reaction mixture was concentrated to dryness, quenched with 1 N sodium hydroxide (2 mL), extracted into methylene chloride, dried (K2CO3), and concentrated in vacuo. The residue was diluted with methylene chloride (1 mL), treated with 1 mL of glacial acetic acid and directly purified by preparative thin layer chromatography using methylene chloride/methanol/glacial acetic acid (93.6:6.5:0.5) as developing solvent to give the title compound. 1H-NMR (300 MHz, DMSO-d6) δ 8.14 (d, 1 H, J=8 Hz), 7.8-7.97 (m, 4 H), 7.50-7.59 (m, 3 H), 7.19 (s, 1 H), 6.68 (d, 1 H, J=2 Hz), 4.11 (d, 2 H, J=6 Hz), 3.92 (d, 2 H, J=6 Hz), 3.11 (t, 2 H, J=2.6 Hz), 2.2 (m, 1 H), 1.92 (d, 2 H), 1.75 (br s, 3 H), and 1.41 (q, 2 H). Mass spectrum (MALDI-TOF; α-cyano-4-hydroxycinnamic acid matrix) calcd. for C23H24ClN3O4S: 474.1 (M+H). Found: 473.8.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].NO[C:8]([NH:10][C:11]([NH2:13])=[NH:12])=O.[N+:14]([O-])(O)=O>>[C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[NH2:13][C:11]1[N:10]=[C:8]([CH2:1][OH:5])[NH:14][N:12]=1
Reactant: N=C(N)NC(=O)ON
Reactant: O=[N+]([O-])O
Agent: O=C(O)CO
Product: Nc1n[nH]c(CO)n1

Procedure:
While stirring 1738 g (16 moles) of a 70% glycolic acid, 1088 g (8 moles) of aminoguanidino-carboxylic acid was added thereto with little by little. To the mixture was added 8 ml of conc. nitric acid and the mixture was stirred under reflux for 24 hours. The reaction mixture was ice-cooled, and then precipitates were collected by filtration, washed with water and then dried.
Reaction SMILES: O1CCOCC1.[OH-].[Na+:8].[C:9]1([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:24][C:25]([C:27]3[CH:28]=[N:29][C:30]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[CH:31][CH:32]=3)=[O:26])[CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[C:9]1([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O-:21])=[O:20])=[C:17]([NH:24][C:25]([C:27]3[CH:28]=[N:29][C:30]([C:33]4[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=4)=[CH:31][CH:32]=3)=[O:26])[CH:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1.[Na+:8]
Reactant: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(-c2ccncc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)[O-])c1ccc(-c2ccncc2)nc1

Procedure:
Dioxane (2 mL), methanol (2 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.025 mL) were added to the obtained 4-phenyl-2-(6-(pyridin-4-yl)pyridine-3-carboxamido)benzoic acid (20 mg), and the solvent was evaporated under reduced pressure. Acetone was added to the obtained residue. The solid substance was collected by filtration to obtain 17 mg of sodium 4-phenyl-2-(6-(pyridin-4-yl)pyridine-3-carboxamido)benzoate as a yellow solid.