Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[OH:40].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:33][C:34]1[CH:35]=[C:36]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=3)[N:4]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)[CH:37]=[CH:38][C:39]=1[OH:40]
Reactant: OB(O)c1ccc(O)c(F)c1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1ccc(O)c(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 75 °C

Procedure:
A suspension of 3-bromo-5-nitro-1-trityl-1H-indazole 1AJ (10.0 g, 20.68 mmol), 3-fluoro-4-hydroxyphenylboronic acid 2AW (3.55 g, 22.78 mmol), Pd(dppf)Cl2 (1.6 g, 1.96 mmol) and K3PO4 (10.6 g, 4.99 mmol) in 200 mL of dioxane/H2O (4/1) was heated to 75° C. for overnight. After removal of most of the solvent, the black residue was diluted with EtOAc (250 mL) and H2O (60 mL). The resulting mixture was filtered through a pad of Celite. Additional 150 mL of EtOAc was used to wash the Celite cake. The filtrates were combined. The aqueous layer was separated and the organic layer was washed with brine, dried (MgSO4) and concentrated to give a green solid, which was recrystallized from CH2Cl2/hexane to give 3-(3-fluoro-4-hydroxyphenyl)-5-nitro-1-trityl-1H-indazole 3AW (8.1 g).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:15][CH2:16][C:17](=O)[CH2:18]Cl>C1(C)C=CC=CC=1>[Cl:15][CH2:16][C:17]1[N:6]=[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=2[F:1])[O:5][CH:18]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1cccc(C(F)(F)F)c1F
Solvent: Cc1ccccc1
Product: Fc1c(-c2nc(CCl)co2)cccc1C(F)(F)F
Temperature: 130 °C
Yield: 58.8 %

Procedure:
A mixture of 2-fluoro-3-(trifluoromethyl)benzamide (1.02 g), 1,3-dichloropropanone (1.27 g) and toluene (4 mL) was heated at 130° C. for 40 hr. The reaction mixture was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.81 g) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C=O.Cl.[CH3:24]NC.Cl>C(OCC)(=O)C.CC(C)=O.CC(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[C:17](=[CH2:24])[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9]2)=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=C1CC(c2ccc([N+](=O)[O-])cc2)Oc2ccccc21
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=C1C(=O)c2ccccc2OC1c1ccc([N+](=O)[O-])cc1
Yield: 4.3 %

Procedure:
A mixture of 18.1 g (67 mmol) of 4'-nitro flavanone, prepared as described in J. Chem. Soc. Japan, Pure Chem. Sect. 74, 827 (1953), 4.04 g (134 mmol) of paraformaldehyde, 10.97 g (134 mmol) of dimethylamine hydrochloride, 1 ml of concentrated HCl, and 200 ml of 2-propanol was refluxed for three hours. When cool, the solvent was removed under reduced pressure and the residue partitioned between CHCl3 and 5 percent aqueous HCl. The layers were separated and the organic layer was washed with 3-100 ml portions of 5 percent HCl. The combined aqueous extracts were neutralized with solid Na2CO3 and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and concentrated. The oily residue was dissolved in ethyl acetate and treated with 1 ml of ethanol and 1.5 ml of acetyl chloride. The solvent was then evaporated to give a glassy residue. This was taken up in 500 ml of hot ethyl acetate containing 20 ml of acetone and cooled. A precipitate formed that was recrystallized from methanol to give 810 mg of 4'-nitro-3-methylene flavanone as a solid, m.p. 135°-136° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=3)[C:8](=[O:9])[C:7]2=[CH:22][CH:23]=1)([O-])=O.CC(O)=O>O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=3)[C:8](=[O:9])[C:7]2=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)C(=O)N(c1ccc(C(=O)O)cc1)C2=O
Reaction time: 8 h
Yield: 41.9 %

Procedure:
4-nitro-N-(p-carboxyphenyl)phthalimide (145) (0.2 g, 0.6 mmol) partially dissolved in 30 ml of 1,4-dioxane and 2 ml HOAc was added to a three necked round bottom flask equipped with a rubber septum, a gas inlet adapter and an adapter tightly fitted with a balloon. After the reaction vessel was purged three times with N2, 0.02 g of 10% Pd on activated charcoal was added. The reaction vessel was then flushed three times with H2. The heterogenous mixture was vigorously stirred under a hydrogen atmosphere overnight. The catalyst was removed by filtration through a celite pad and the filtrate concentrated under vacuum to give a bright yellow solid. The crude material which contained unreacted nitro compound was resubjected to the above procedure. Resulting crude material was triturated with hot 1,4-dioxane and undissolved material removed by filtration. The filtrate was diluted with water. The ensuing solid was filtered through a Buchner funnel and washed three times with 1 ml water. The product was dried in air for a short time and then in vacuo for 48–72 hours to afford 0.071 g (39%) 165 as a dark yellow solid: mp=270–271° C.; Rf 0.88 (A): Rf 0.80 (C): Rf 0.49 (D): IR (cm−1): 3366 (NH), 3193 (NH), 2750–3200 (OH), 3075 (C═CH), 2669 (C—H), 1767 (C═O), 1752 (C═O), 1701 (bs, C═O), 1637 (C═C), 1607 (C═C), 1514 (C═C), 1482 (C═C), 1370 (C—N), 1220 (C—O), 740 (C═CH); MS m/z (rel intensity) 282 (16), 281 (100), 237 (71) 120 (43).
Reaction SMILES: [N:1]1([CH2:6][C:7]23[CH2:15][CH:11]4[CH2:12][CH:13]([CH2:14]2)[C:9]([NH:16]C(=O)OC(C)(C)C)([CH2:10]4)[CH2:8]3)[CH:5]=[N:4][N:3]=[N:2]1.Cl>CCOC(C)=O>[N:1]1([CH2:6][C:7]23[CH2:15][CH:11]4[CH2:12][CH:13]([CH2:14]2)[C:9]([NH2:16])([CH2:10]4)[CH2:8]3)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)NC12CC3CC1CC(Cn1cnnn1)(C3)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: NC12CC3CC1CC(Cn1cnnn1)(C3)C2
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of the compound obtained in step I above (0.2 g, 0.62 mmol) in EtOAc (2.0 mL) cooled to ice bath temperature was added a solution of dry HCl in EtOAc (3N, 3 mL). The reaction mixture was stirred at the same temperature for 2 h and the volatiles were removed under reduced pressure to obtain the crude product, which was triturated with ether several times to obtain pure hydrochloride salt of 1-(1H-tetrazol-1-ylmethyl)tricyclo[3.3.1.03,7]nonan-3-amine (160 mg) in 100% yield. m/z (M+1) 220; 1H NMR (CD3OD) 300 MHz δ 8.72 (s, 1H), 4.70 (s, 2H), 2.52-2.43 (m, 1H), 2.42-2.37 (m, 1H), 2.0-1.80 (m, 5H), 1.70-1.50 (m, 5H).
Reaction SMILES: C([O:8][C:9](=[O:22])[CH:10]=[CH:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[CH2:12][CH2:11][CH2:10][C:9]([OH:22])=[O:8]
Reactant: O=C(C=CCC1Cc2ccccc2C1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCCC1Cc2ccccc2C1
Yield: 85.1 %

Procedure:
6.45 g (22.1 mmol) of benzyl-4-(indan-2-yl)-2-butenoate was dissolved in 120 ml of methanol, to which 0.6 g of 10% palladium on carbon was added and stirred vigorously for 2.5 hours in the stream of hydrogen. The catalyst was removed by filtration, the filtrate was condensed to obtain 3.84 g of crystalline 4-(indan-2-yl)butanoic acid. Yield: 85%
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2].C(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)(C)C>>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH:7]1[CH2:12][CH2:11][CH2:10]/[C:9](=[CH:21]\[N:22]([CH3:24])[CH3:23])/[C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCCC1=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)/C=C1\CCCC(O[Si](C)(C)C(C)(C)C)C1=O

Procedure:
2-(tert.-Butyldimethylsiloxy)cyclohexanone (118 mg, 0.50 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (85 mg) as a brown oil which was used directly in the next step. MS ISP (m/e): 284.2 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2.C1C(=O)N([Cl:27])C(=O)C1>C1COCC1>[Cl:27][C:15]1[C:16]2[C:11](=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[Cl:1])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[OH:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc(-c2ccc3cc(O)ccc3c2)c(Cl)c1
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)c(Cl)c1

Procedure:
The title compound was prepared by reacting 6-(2-chloro-4-hydroxyphenyl)-2-naphthol (500 mg, 1.85 mmol) and NCS (321 mg, 2.40 mmol) in THF (40 mL) according to method C to yield 435 mg (77%) of yellowish solid: mp 224-226° C.; 1H NMR (DMDO-d6): δ 6.86 (1H, dd, J=8.42 Hz, J=2.41 Hz), 6.96 (1H, d, J=2.44 Hz), 7.30 (1H, d, J=3.19 Hz), 7.33 (1H, d, J=2.65 Hz), 7.62 (1H, dd, J=8.81 Hz, J=1.71 Hz), 7.83 (1H, d, J=8.93 Hz), 7.86 (1H, d, J=1.54 Hz), 8.04 (1H, J=8.76 Hz), 10.04 (1H, s), 10.51 (1H, s); 13C NMR (DMDO-d6): δ 112.24, 114.84, 116.26, 118.79, 121.84, 128.16, 128.24, 128.35, 129.27, 130.03, 130.40, 131.73, 132.38, 133.98, 151.24, 157.70; MS (ESI) m/z 303/305/307 (M−H)−.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.ClC(OCC(C)C)=O.C([N:33](CC)CC)C.[NH4+]>C1COCC1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([NH2:33])=[O:22])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid (0.31 g, 1.00 mmol), isobutyl chloroformate (0.22 ml, 1.50 mmol) and triethylamine (0.22 ml, 1.50 mmol) were dissolved in THF (10 ml), and the mixture was stirred under ice cooling condition for 1 hr. 25% aqueous ammonium solution was added to the mixture, and the mixture was stirred under ice cooling condition for 0.5 hr. The obtained precipitates were recrystallized from ethanol to give the titled compound (0.20 g, 65%) as white crystals.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:21][C:22]([Cl:27])([Cl:26])[C:23](Cl)=[O:24].[Cl-].[Na+]>C1C=CC=CC=1>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:23](=[O:24])[C:22]([Cl:27])([Cl:26])[Cl:21])=[CH:10][CH:9]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(Nc1ccc(Nc2ccccc2)cc1)C(Cl)(Cl)Cl

Procedure:
The following materials are charged to a reactor: 62.5 g (0.34 mole) 4-aminodiphenylamine, 39 g (0.37 mole) sodium carbonate and 500 ml benzene. To this stirred mixture, under nitrogen, is added a solution of 63.8 (0.35 mole) trichloroacetyl chloride in 100 ml benzene over a thirty minute period. Stirring is continued for another 31/2 hours. The crude product containing sodium chloride by-product is dried to remove solvent. The dried material is washed first with dilute HCl, then distilled water, air dried and the product is recrystallized from a methanol/benzene (1/2) solvent mixture. Melting point and elementary analysis are reported in Table I.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[NH:2][N:3]=[C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1)=[O:21])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
Hydrazine hydrate (0.27 mL, 2.76 mmol) was added to a stirred solution of 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (0.69 g, 2.76 mmol) in EtOH (3 mL). The mixture was stirred at 80° C. for 16 hours and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.66 g, 98% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH:19]=[O:20])[C@H:10]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Mg]Cl>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH:19]([OH:20])[CH3:29])[C@H:10]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Cl
Reactant: O=C[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: C1CCOC1
Product: CC(O)[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of the above crude 3 (1.4 g, 3.6 mmol) in THF (10 mL) was added methylmagnesium chloride (7.0 mL, 2.5M in THF, 17.5 mmol) at −78° C. After 1 hour, the reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with DCM (4×50 mL). The combined organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to give a residue, which was purified by a silica gel column, eluted with 10% MeOH in DCM to give 4 as a white solid (1.0 g, 68% in two steps, the ratio of diastereomers is 1:3 by 1H NMR). (ES, m/z): [M+H]+ 397.9; 1H NMR (300 MHz, CDCl3) δ 7.30-7.45 (m, 10H), 4.91-4.96 (m, 2H), 4.70-4.87 (m, 2H), 4.50-4.69 (m, 2H), 3.74-3.79 (m, 2H), 3.47-3.58 (m, 2H), 1.50-1.76 (m, 2H), 1.15 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][C@@:25]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)([CH3:35])[C:26]([NH:28][C:29]([CH3:34])([C:31]([OH:33])=O)[CH3:30])=[O:27])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:56]C=2C=1.N>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:17])([F:16])[F:18])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][C@@:25]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:45])[F:44])[CH:37]=3)([CH3:35])[C:26]([NH:28][C:29]([CH3:30])([C:31]([NH2:56])=[O:33])[CH3:34])=[O:27])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(NC(=O)[C@](C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1)C(=O)O
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(NC(=O)[C@](C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 31 mg (47 μmol) of the compound of Example 21, 13 mg (70 μmol) of EDC and 9.4 mg (70 μmol) of HOBt in 2 ml of DMF was stirred at RT for 20 min and then poured into 2 ml of ammonia (35% strength solution in water). The reaction mixture was stirred at RT for 30 min, then briefly concentrated on a rotary evaporator, acidified with 1N hydrochloric acid and separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 29 mg (92% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13](C(=NO)C)=[CH:12]2)=[O:5].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:4]([NH:6][C:13]1[CH:14]=[N:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:25])(=[O:5])[CH3:3]
Reactant: CC(=NO)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Reaction time: 0.83 h
Yield: 22.6 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-3-(1-hydroxyiminoethyl)quinoline (168 mg) in pyridine was added phosphoryl chloride (516 mg) at 4° C., and the mixture was stirred for 50 minutes at the same temperature. The mixture was poured into ice and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol and water to give 3-acetylamino-8-(2,6-dichlorobenzoylamino)quinoline (19 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([NH2:10])=[S:9])[CH:2]=1.Br[CH2:12][C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=O>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[S:9][CH:12]=[C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[N:10]=2)[CH:2]=1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)Nc1cccnc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2csc(Nc3cccnc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Pyridin-3-yl-thiourea (2.06 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.06 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z=298.0 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13](Cl)[C:12]([C:16](=O)[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:11]([Cl:26])[N:10]=1.Cl.[CH3:28][O:29][C:30]1[C:35]([CH3:36])=[CH:34][N:33]=[C:32]([CH2:37][NH:38][NH2:39])[C:31]=1[CH3:40]>ClCCl>[Cl:26][C:11]1[N:10]=[C:9]([NH2:8])[N:14]=[C:13]2[N:38]([CH2:37][C:32]3[C:31]([CH3:40])=[C:30]([O:29][CH3:28])[C:35]([CH3:36])=[CH:34][N:33]=3)[N:39]=[C:16]([CH2:17][CH:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)[C:12]=12
Reactant: COc1c(C)cnc(CNN)c1C
Reactant: CC1(C)OCC(CC(=O)c2c(Cl)nc(N)nc2Cl)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(Cn2nc(CC3COC(C)(C)O3)c3c(Cl)nc(N)nc32)c1C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of triethylamine (3.44 mL) in dehydrated dichloromethane was added to a mixture composed of 1-(2-amino-4,6-dichloropyrimidin-5-yl)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethan-1-one of 3) above (1.68 g), [(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-hydrazine hydrochloride of 4) above (2.87 g) and dehydrated dichloromethane (60 mL) under cooling in an ice bath over 20 minutes. The ice bath was removed, followed by stirring for two hours. Then, the reaction mixture was separated with chloroform and water. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain the title compound (1.79 g, 75%) as a solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][N:7]=[C:6]([O:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=2)[CH:5]=1)[CH3:2]>C(O)C.[Pd]>[NH2:10][C:9]1[C:4]([NH:3][CH2:1][CH3:2])=[CH:5][C:6]([O:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH:17]=[CH:18][CH:19]=2)=[N:7][CH:8]=1
Reactant: CCNc1cc(Oc2cccc(NC(=O)OC(C)(C)C)c2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCNc1cc(Oc2cccc(NC(=O)OC(C)(C)C)c2)ncc1N
Yield: 71.3 %

Procedure:
The product from Step 2 (1.26 g, 3.3 mmol) in ethanol (20 mL) was hydrogenated for 3 hours in the presence of 10% palladium on carbon under H2 (50 psi). After filtration of the catalyst through Kieselguhr, the filtrate was concentrated in vacuo to afford the title compound (0.81 g, 70%). MS (ES+) m/e 345 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH3:23].O>C(C(C)=O)C>[CH2:22]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:7]1[CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: Clc1ccc(CC2CCCCCN2)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCN1CCCCCC1Cc1ccc(Cl)cc1

Procedure:
Boil together (under agitation) 4 g of 2-(4-chlorobenzyl)perhydroazepine, 2.5 g of anhydrous potassium carbonate and 2.9 g of ethyl bromide under reflux for 26 hours in 30 ml of ethylmethylketone. Cool the thus-produced reaction mixture to ambient temperature. Mix the cooled reaction mixture with water and then extract it with diethyl ether. Dry the resulting organic phase over sodium sulfate, remove the ether and distil the residue to obtain 5.12 g (70% of theory) of the title compound with a BP of 112° at 0.005 mm of Hg.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11]C(=O)C(F)(F)F.Br[CH2:19][CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:19][CH:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:11][C:4]=2[CH:5]=1
Reactant: CCOC(=O)C=CCBr
Reactant: COc1ccc(O)c(NC(=O)C(F)(F)F)c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC1COc2ccc(OC)cc2N1
Temperature: 0 °C

Procedure:
450 ml of ethanol are introduced into a 1 l reactor, with magnetic stirring, cooled to 0° C., and 7 g (0.32 mol) of sodium are added slowly, in small portions, followed by successive dropwise addition of 37.94 g (0.16 mol) of N-(2-hydroxy-5-methoxyphenyl)trifluoroacetamide and 41.2 g (0.16 mol) of pure ethyl 4-bromo-2-butenoate, and the mixture is heated at 80° C. for 2 h.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1ccc(F)cc1
Yield: 96.9 %

Procedure:
The title compound (3.83 g) was prepared from (RS)-2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.54 g) and 2-bromo-4′-fluoroacetophenone (2.26 g) according to the method of description 36.