Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[C:9]([Cl:19])=[C:10]2[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]2=[N:12][CH:13]=1)(C)(C)C.[H-].[Na+].IC>CN(C=O)C>[Cl:19][C:9]1[C:8]([NH:7][CH3:6])=[CH:13][N:12]=[C:11]2[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:10]=12
Reactant: CCn1ncc2c(Cl)c(NC(=O)OC(C)(C)C)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1ncc2c(Cl)c(NC)cnc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a solution of (4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-carbamic acid tert-butyl ester (3.3 g, 11.1 mmol) in DMF (50 mL) at 0° C. was added NaH (0.694 g, 50% purity, 14.5 mmol). After 20 minutes, iodomethane (2.37 g, 16.7 mmol) was added and the temperature raised to RT. The reaction was quenched by addition of H2O and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4, and concentrated under vacuo to give a crude intermediate which was used directly in the next step without further purification. This residue as dissolved in CH2Cl2 (50 mL) and TFA (10 mL) was added. The reaction mixture was heated at 30° C. for 3 hours, diluted with CH2Cl2 (100 mL) and aqueous NaOH (1N) was added until pH reached 8. The organic phase was dried over Na2SO4, concentrated under vacuo to give the title product 2.24 g with high purity (no further purification needed) (96%) as a light yellow solid. ES-MS m/e: 211.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH3:13].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:13][Br:14]
Reactant: Cc1cc(OS(C)(=O)=O)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)Oc1ccc(Br)c(CBr)c1
Temperature: 80 °C

Procedure:
A mixture of methanesulfonic acid 4-bromo-3-methylphenyl ester, as described above in Step B, (14.3 g, 53.9 mmol), N-bromosuccinimide (14.4 g, 80.9 mmol), and 2,2′-azobisisobutyronitrile (1.34 g, 8.16 mmol) in CCl4 was heated at 80° C. for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with a gradient of hexane—5% to 20% EtOAc, to yield the titled product.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[F:18])C1C=CC=CC=1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].CCN(CC)CC>C(Cl)Cl>[C:20]([Si:23]([CH3:25])([CH3:24])[O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:18])[CH:11]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccc(OCc2ccccc2)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 2-(4-benzyloxy-3-fluoro-phenyl)-ethanol (9.2 g, 37.4 mmol) in CH2Cl2 (150 mL) and TBDMS-Cl (5.6 g, 37.4 mmol), was added Et3N (5.2 mmol, 37.4 mmol) portionwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours at the same temperature. The reaction was washed with H2O (150 mL). The CH2Cl2 was dried over MgSO4 and concentrated under vacuum. To a solution of the residue in MeOH (100 mL), was Pd/C (150 mg) added. The reaction was stirred under H2 (1 atm) for 5 hours. The solid material was filtrated off and the filtrate was concentrated under vacuum to afford the desired compound (8.9 g, 88.3%) as a grayish solid. The crude compound was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 6.99˜6.96 (m, 1H), 6.83˜6.81 (m, 2H), 3.70 (t, 2H), 2.63 (t, 2H), 0.83 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([C:16]([OH:18])=[O:17])([OH:15])[P:11]([OH:14])([OH:13])=[O:12]>[Pd].O>[OH:15][C:10]([P:11]([OH:13])([OH:14])=[O:12])([CH2:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][N:3]1[CH3:2])[C:16]([OH:18])=[O:17]
Reactant: C[n+]1ccccc1CC(O)(C(=O)O)P(=O)(O)O
Agent: [Pd]
Agent: [I-]
Solvent: O
Product: CN1CCCCC1CC(O)(C(=O)O)P(=O)(O)O
Reaction time: 48 h

Procedure:
A mixture of 1 g of 1-methyl-2-(2-carboxy-2-hydroxy-2-phosphonoethyl)pyridinium iodide and 0.5 g of palladium on charcoal catalyst in 50 ml of distilled water is hydrogenated on a Parr apparatus at 40 PSI for about 2 days. The catalyst is removed by filtration, and the filtrate is evaporated to dryness. The residue is triturated with ethanol to give a solid which is collected by filtration. It is recrystallized from water/ethanol to afford 2-hydroxy-3-(1-methyl-2-piperidinyl)-2-phosphonopropanoic acid.
Reaction SMILES: C([NH:18][C@H:19]([C:34]([OH:36])=[O:35])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(NCC)C>CN(C=O)C>[C:24]([NH:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:34]([OH:36])=[O:35])[NH2:18])([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]
Reactant: O=C(NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCc1ccccc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 199.4 %

Procedure:
The compound obtained in Example 8-5 (122.8 mg) was dissolved in DMF (2.6 ml). After the addition of diethylamine (0.26 ml), the mixture was stirred for 2 hours at room temperature. After the reaction, the solvent was removed by distillation under reduced pressure and the residue was dried under vacuum to obtain the title compound (133.5 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[O:18]=[C:19]1[NH:23][C:22](=[O:24])[CH:21]([CH2:25][C:26]2[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=2)[S:20]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:32](=[O:33])[CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH:21]2[S:20][C:19](=[O:18])[NH:23][C:22]2=[O:24])=[CH:36][CH:35]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 64.4 %

Procedure:
To a mixture of N-(2-amino-5-chlorophenyl)-N-methylcarbamic acid t-butyl ester (2.50 g) (obtained in Reference Example 2), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (3.01 g) (obtained in Reference Example 6), triethylamine (1.49 ml) and anhydrous tetrahydrofuran (50 ml) was added diethyl cyanophosphonate (1.75 g) and the resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was chromatographed on a silica gel column using n-hexane/ethyl acetate (2/1) as the eluant to give the desired product (3.26 g). Rf=0.41 (thin-layer chromatography on a silica gel plate using n-hexane/ethyl acetate (2/3) as the eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[N:27][N:26]=[N:25]4)=[CH:20][CH:19]=3)=O)[C:9]=2[F:29])[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.[OH-].[NH4+]>C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[N:27][N:26]=[N:25]4)=[CH:20][CH:19]=3)[C:9]=2[F:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)c2ccc(-n3cnnn3)cc2)c(F)c1-c1cccc(Cl)c1
Agent: CC[SiH](CC)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2ccc(-n3cnnn3)cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
To (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-(4-tetrazol-1-yl-phenyl)-methanone synthesized above (0.1 g, 0.24 mmol) in TFA (1.5 mL) was added triethylsilane (0.28 g, 2.4 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was cooled to 0° C., diluted with water (3 mL), basified with ammonium hydroxide solution (28%), filtered, washed with water dried to afford 0.08 g (81%) of 1-[4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-1H-tetrazole (P-404) as off-white solid. 1H NMR (DMSO-d6, 400 MHz): 7.2-7.4 (m, 6H), 7.04-7.12 (s, 3 H), 6.7 (d, J=8.4 Hz, 1H), 3.95 (s, 2H), 3.77 (s, 3H) ppm; MS (APCI+): 365.1 (M−28), LC-MS: 95.9%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][OH:15])[C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:16](Cl)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[C:16]([O:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][O:15][C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5](=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(c1ccccc1)N(CCO)CCO
Reactant: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCCCCCC)C(=O)c1ccccc1

Procedure:
N,N-bis(2-lauroyloxyethyl)-benzamide was prepared by the procedure of example 1 from 19.5 gms. (0.1 mole) of N,N-bis(2-hydroxyethyl)benzamide and 44 gms. (0.2 mole) of lauroyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(C(O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:26](CC)CC.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:26])([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N)(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4-benzyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.65 mmol) in 1,4-dioxane (2 mL) are added Et3N (0.71 mmol) and DPPA (0.71 mmol) at room temperature. After warming to 100° C. and stirring for 2 h, the reaction mixture is diluted with AcOEt. The organic layer is washed with sat. aq. NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is dissolved in THF (4 mL) and 6N aq. NaOH (0.22 mL) is added at room temperature. After stirring for 4 h, the reaction mixture is diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give the title compound; 1H NMR (CDCl3), δ: 1.18 (2H, bs), 1.28-1.37 (2H, m), 1.46 (9H, s), 1.51-1.64 (2H, m), 2.66 (2H, s), 3.20 (2H, dd), 3.74 (2H, bd), 7.13-7.19 (2H, m), 7.21-7.34 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:40])[F:39])=[N:36][CH:37]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:31][C:32]4[CH:37]=[N:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 65 °C
Yield: 76.1 %

Procedure:
A solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (1.1 g, 3.4 mmol), prepared as described in Example 244, K2CO3 (940 mg, 6.8 mmol), and 5-chloromethyl-2-trifluoromethylpyridine (800 mg, 4.1 mmol) in DMF (8.3 mL) was heated at 65° C. for 40 min. After this time, the solution was cooled to RT The reaction mixture was partitioned between water and EtOAc. The organic layer separated, washed with water and saturated aqueous NaCl. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with hexanes/EtOAc to give the title compound, 7-(4-chlorophenyl)-8-(pyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (1.25 g, 76%) as a yellow solid. HPLC: 2.84 min; MS, M+H=483; 1H NMR (CDCl3) δ 8.80 (d, J=1.4 Hz, 1H), 8.65 (Abq, J=1.6, 4.4 Hz, 2H), 8.23 (s, 1H), 7.96 (m, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.34 (m, 2H), 7.23 (m, 2H), 7.10 (m, 2H), 5.31 (2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([NH:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27])[N:7]=1
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3ccc(F)cc3F)c2n1
Reactant: NC(CO)CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(F)cc1F
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To a solution of 4-chloro-8-(2,4-difluorophenyl)-2-(methylsulfinyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (2.0 g, 5.6 mmol) in DCM (100 ml) was added a solution of serinol (650 mg, 7.1 mmol) in DMF (5 ml). The mixture was stirred for 2 h, washed with water (2×50 ml), dried (Na2SO4), and evaporated. Flash chromatography (EtOAc/Hexane, 3:1) provided the title compound as a white solid (1.1 g, 50%): LC-MS m/z 383 (M+H)+ retention 2.45 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[C:13]([O-])(O)=O.[Na+]>CO>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1cccc(N)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
To a solution of 3-aminophenylacetic acid (3 g, 19.85 mmol) in methanol (50 mL) at room temperature was added HCl conc. (37%, 7.5 mL). The mixture was stirred 6 h at room temperature then treated with a saturated aqueous solution of NaHCO3. The solvent was removed under reduced pressure then the aqueous phase was extracted several times with CH2Cl2. The combined organic extracts were dried over (MgSO4) and evaporated. The crude mixture was purified by flash chromatography using hexane/AcOEt (1:1) yielding 1 as a yellow oil (3.06 g, 79%).
Reaction SMILES: [N:1]1C=CC=[CH:3][CH:2]=1.C(N)C.[NH2:10][C:11]1[C:12]([F:37])=[CH:13][C:14]([F:36])=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[C:24](F)[C:25]=3[CH3:27])[C:20](=[O:32])[C:19]([C:33]([OH:35])=[O:34])=[CH:18]2)[CH:16]=1>C(OCC)C>[NH2:10][C:11]1[C:12]([F:37])=[CH:13][C:14]([F:36])=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[C:24]([NH:1][CH2:2][CH3:3])[C:25]=3[CH3:27])[C:20](=[O:32])[C:19]([C:33]([OH:35])=[O:34])=[CH:18]2)[CH:16]=1
Reactant: c1ccncc1
Reactant: Cc1c(F)c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Agent: CCN
Solvent: CCOCC
Product: CCNc1c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
Pyridine (300 mg) and a 70% aqueous solution (150 mg) of ethylamine were added to 1-(5-amino-2,4-difluorophenyl)-7-fluoro-8-methyl-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (110 mg), and the mixture was stirred at 50° C. for 3 hours. Diethyl ether was added to the reaction mixture, followed by stirring. A supernatant liquid was removed, and solids deposited were recrystallized from N,N-dimethylformamide. The solids were collected by filtration and washed with ethanol to obtain the title compound (75 mg) as a reddish brown powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].CCN=C=NCCCN(C)C>>[OH:24][C:13]1([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:14][CH2:15][CH:10]([N:8]2[CH2:9][CH:6]([NH:5][C:3]([CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([CH3:25])[CH:27]=3)=[O:4])[CH2:7]2)[CH2:11][CH2:12]1
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Reactant: Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C)c4)C3)CC2)cn1

Procedure:
The title compound was prepared as yellow solid from 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, and 3-methylbenzoic acid (Aldrich) by EDCI coupling using the procedure described in Step C of Example 16.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](OC(Cl)(Cl)Cl)=[O:15]>O1CCOCC1>[Cl:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]2[NH:1][C:14](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Solvent: C1COCCO1
Product: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Temperature: 42 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. product of Example 6, Step A) (97 g, 520 mmol) stirred in dry dioxane (750 mL) at room temperature, trichloromethyl chloroformate (63 g, 320 mmol) was added dropwise. The reaction mixture exothermically warmed slowly to 42° C., and the solid almost completely dissolved before a thick suspension formed again. After the suspension was stirred at ambient temperature for 2.5 hours, the title compound was isolated by filtration, washed with ethyl ether, and dried to yield the title product compound, obtained as a white solid (98 g).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([NH:23][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2nc(NCc3ccccc3)c(C=O)cc2c1
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (2.00 g, 9.02 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added benzylamine (4.88 mL, 90.20 mmol) and the reaction mixture was stirred for 1.5 h at 160° C. then 45 min at 180° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 1 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with a saturated NaHCO3 aqueous solution before extraction with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 75:25) provided a mixture of the desired product and its benzyl imine derivative. This mixture was taken up in a mixture of THF:1 N aq. HCl=1:1 (20 mL) and stirred for 2 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with a saturated NaHCO3 aqueous solution before extraction with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 75:25) gave, after evaporation and drying, 2-(benzylamino)-6-methoxyquinoline-3-carbaldehyde SLA 41002 as a yellow solid (0.431 g, 16% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]1[CH2:25][C:17]3([CH2:22][O:21]C(C)(C)[O:19][CH2:18]3)[CH2:16][C:7]1=[C:8]2[C:13](=[O:15])[CH3:14].Cl>C1COCC1>[CH3:26][N:2]([CH3:1])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]1[CH2:25][C:17]([CH2:18][OH:19])([CH2:22][OH:21])[CH2:16][C:7]1=[C:8]2[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)c1c2c(cc3c(N(C)C)cccc13)CC1(COC(C)(C)OC1)C2
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1c2c(cc3c(N(C)C)cccc13)CC(CO)(CO)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
An oven-dried 50 mL one-necked round-bottomed flask was charged with compound 6a (0.036 g, 0.10 mmol) and THF (12 mL). HCl (5 mL of a 1 N aqueous solution) was added and the mixture was stirred at rt for 2 h. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:1). The reaction was basified to pH 7 by the dropwise addition of sat'd aq NaHCO3. The layers were separated and the aqueous phase was extracted with ether (3×15 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, gravity filtered, and concentrated under reduced pressure to provide 0.018 g of the title compound as a yellow solid in 57% yield.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[CH3:15].[C:17](=S)=[S:18].O>C1C=CC=CC=1>[SH:18][C:17]1[O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:16])[CH:15]=1
Reactant: S=C=S
Reactant: CC(=O)c1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: O=c1cc(S)oc2ccccc12
Temperature: 15 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
Part A: Potassium t-butoxide (134 g, 1.2 mole) is covered with benzene (1 L) in a flame dried round bottom flask equipped with an overhead stirrer, addition funnel, thermometer, and a nitrogen inlet. This suspension is maintained at 15° C. A solution of o-hydroxyacetophenone (54.4 g, 48.1 ml, 0.4 mole) and carbon disulfide (30.4, 24 ml, 0.4 mole) in benzene (700 ml) is slowly added over 1.3 hours, applying an ice bath periodically in order to maintain the temperature 18° C. The slurry which forms is stirred at ambient temperature for one day. The reaction mixture is transferred to a separatory funnel containing water (4 L) and extracted with ether (4×250 ml) and EtOAc (3×250 ml). The aqueous layer is acidified with 10% H2SO4 (1 L) and stirred at ambient temperature overnight. The resulting solid is filtered off and dried in vacuo at 50° C. overnight to yield 22.07 g of 2-mercapto-4H-1-benzopyran-4-one. Mp 207°-8° C.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:9][C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)[CH2:7][CH3:8]>CO>[CH2:6]([O:9][C:10]1[N:11]=[N:12][C:13]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:14][CH:15]=1)[CH2:7][CH3:8]
Reactant: C=CCS
Reactant: CCCOc1ccc(Cl)nn1
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OCCC)nn1

Procedure:
1.15 g(0.05 mol) of metallic sodium was dissolved in 75 ml of absolute methanol and then mixed with 4.98 ml(0.05 mol) of allylmercaptan. To this mixture was added 8.63 g(0.05 mol) of 3-(n-propoxy)-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale yellow oily residue.