Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.CC(=O)[CH2:17][C:18](=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)C.CCOCC>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:17][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)CC(C)=O
Reactant: BrCCCCOCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)CCCCCOCCc1ccccn1
Yield: 83.3 %

Procedure:
A mixture of 2-[2-[(4-bromobutyl)oxy]ethyl]pyridine (6.2 g), 2,4-pentanedione (3.61 g), potassium carbonate (4.75 g) and potassium iodide (3.95 g) in ethanol (125 ml) was stirred and heated overnight under reflux. The solids were removed by filtration and the filtrate evaporated to leave a dark brown semi-solid. Addition of ether (200 ml) and filtration of the solid produced a brown solution which was evaporated to give a brown oil (4.71 g). Purification by FCC eluting with ether-hexane (1:1→3:1) gave the title compound as a pale yellow oil (1.93 g).
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:12]([NH2:14])=O)[C:8]=2O)[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:12]#[N:14])[C:8]=2[Cl:17])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)c1cnc2cc(Br)sc2c1O
Product: N#Cc1cnc2cc(Br)sc2c1Cl

Procedure:
A mixture of ethyl 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxylate (1.3 g, 4.3 mmol) [Elliott, R.; O'Hanlon, P. J.; Rodgers, N. B. Tetrahedron, 43(14), 3295 (1987)] in 20 mL of ethanol and 6 mL of 2.5 N sodium hydroxide is heated at reflux for 4 hours. The mixture is poured into ice water and the pH is adjusted to 5-6 by the addition of acetic acid. The mixture is stirred at room temperature and the resulting precipitate is collected by filtration washing with water to provide 840 mg of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxylic acid. A mixture of 2-bromo-7-hydroxythieno[2,3-b]pyridine-6-carboxylic acid (810 mg, 2.95 mmol) and N,N-carbonyldiimidazole (1.0 g, 6.17 mmol) in 15 mL of N,N′-dimethylformamide is heated at 65° C. for 2 hours. The mixture is poured into 50 mL of ice cold aqueous ammonium hydroxide and stirred for 14 hours. The resultant solids are collected by filtration washing with water to provide 800 mg of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxamide. A mixture of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxamide (273 mg, 1.0 mmol) and 3 mL of phosphorous oxychloride is heated at reflux for 1 hour. The solvent is removed in vacuo and the residue is poured into ice water and treated with sodium bicarbonate. The resultant solids are collected by filtration washing with water. The solids are purified by flash column chromatography eluting with chloroform to provide 240 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 198-199° C.; 1H NMR (DMSO-d6) δ 8.12 (s, 1H), 9.11 (s, 1H); MS 273.1, 275.1, 277.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH:11]([CH3:13])[CH3:12])=O)C.CC(C[AlH]CC(C)C)C.O>C1(C)C=CC=CC=1>[OH:3][CH2:4][C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1scnc1C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1ncsc1CO
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 5.9 g (30 mmol) of 4-isopropyl-thiazole-5-carboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans 1, 1982:159-164) in toluene (100 mL) was cooled in an ice bath under nitrogen and treated dropwise with DIBAL (150 mL of 1.0 M; 150 mmol). The mixture was stirred at low temperature for 45 minutes and then allowed to warm to room temperature overnight. H2O was added cautiously, and the mixture was extracted with EtOAc (3×200 mL). The combined extracts were washed with brine, dried (MgSO4), and concentrated. The crude 5-(hydroxymethyl)-4-isopropyl-thiazole thus obtained was used as is in the next step.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12]([OH:14])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][O:23][C:24](=[O:42])[C@H:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:29]=1)[NH2:26].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:22][O:23][C:24](=[O:42])[C@@H:25]([NH:26][C:12]([C:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH:2]=1)=[O:14])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)c1coc2ccccc2c1=O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1coc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.1 %

Procedure:
To a stirring solution of 360 mg (2 mmol) of chromone-3-carboxylic acid in 25 mL of CH2Cl2 at 0° C. were added several drops of DMF followed by 1 mL of 2M solution of oxalyl chloride in CH2Cl2. The resulting solution was stirred 3 h at rt and 643 mg (2 mmol) of O-benzyl-L-tyrosine methyl ester hydrochloride and 0.2 g (2.0 mmol) of triethylamine in 15 mL of CH2Cl2 were added and stirring continued overnight. Solvent was removed under reduced pressure. Product was purified by LCC on SiO2 (Hexane: EtOAc 13:7) providing 83 mg of title compound as a white solid: low resolution MS (ES+ (M+H), 458; RP-HPLC (Dynamax C-8 25 cm×4.1 mm; 50-90% CH3CN in H2O with 0.1% TFA buffer; 15 minutes; 2 mL/min): tr=10.44 min.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(OC(Cl)=O)C.[NH2:20][CH:21]1[CH2:25][N:24]([CH3:26])[N:23]([CH3:27])[CH2:22]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:20][CH:21]2[CH2:25][N:24]([CH3:26])[N:23]([CH3:27])[CH2:22]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN1CC(N)CN1C
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CN(C)N(C)C1

Procedure:
The title compound was prepared as described in Example 8 of U.S. Pat. No. 4,207,327 from 4-amino-5-chloro-2-methoxybenzoic acid, triethylamine, ethylchlorocarbonate and 4-amino-1,2-dimethylpyrazolidine, m.p. 169°-171° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[N:3]=1.[N:11]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([O-])(O)=O.[Na+]>CS(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:14]2[CH2:15][CH2:16][CH2:17][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][CH2:13]2)=[N:3][C:4]=1[OH:10])=[O:7]
Reactant: O=Cc1ccc(Cl)nc1O
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(C=O)c(O)n2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 102.6 %

Procedure:
6-Chloro-2-hydroxynicotinaldehyde (1 g, 6.37 mmol) was dissolved in DMSO (12 mL) at room temperature. The solution was treated with tert-butyl 1,4-diazepane-1-carboxylate (2.55 g, 12.74 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 2 hours and cooled to room temperature. An aqueous saturated NaHCO3 solution (50 mL) was added. The aqueous layer was extracted with CH2Cl2 three times. The combined organic layers were dried over K2CO3, filtered and concentrated under vacuum to give 2.1 g of tert-butyl 4-(5-formyl-6-hydroxypyridin-2-yl)-1,4-diazepane-1-carboxylate. The concentrated residue was used in next step without further purification. MS m/z 322 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH2:23])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:23][O:34]2)=[CH:18][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.7 %

Procedure:
To a solution of 291 (4.1 g, 12.1 mmol) in dry CHCl3 (60 mL) was added m-CPBA 70% (3.6 g, 14.5 mmol). The reaction mixture was stirred at room temperature for 5 h then additional m-CPBA (0.6 g, 2.4 mmol) was added and the stirring continued for 1 h. A further amount of m-CPBA (0.6 g, 2.4 mmol) was added and the reaction mixture was stirred for 16 h. Chloroform and a 10% solution of NaHCO3 were added and the phases were separated. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/Hexane: 1/3) to afford the title compound 292 (2.86 g, 8.07 mmol, 66% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.20 (s, 1H), 7.95 (d,J=8.1 Hz, 2H), 7.86-7.75 (m, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.26-7.10 (m, 3H), 6.84-6.70 (m, 1H), 3.93 (t, J=3.0 Hz, 1H), 3.20 (t, J=5.0 Hz, 1H), 2.80 (dd, J=5.0, 3.0 Hz, 1H), 1.52 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])=[CH:25][C:24]=3[N+:36]([O-:38])=[O:37])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)(C)C.O1CCCC1>[N+:36]([C:24]1[CH:25]=[C:26]([S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:31])[CH:27]=[CH:28][C:23]=1[O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:39])=[O:3])=[CH:12][CH:11]=2)(=[O:15])=[O:14])=[CH:21][CH:20]=1)([O-:38])=[O:37]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)c2ccc(Oc3ccc(S(=O)(=O)C(F)(F)F)cc3[N+](=O)[O-])cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(S(=O)(=O)c2ccc(Oc3ccc(S(=O)(=O)C(F)(F)F)cc3[N+](=O)[O-])cc2)cc1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
A mixture of {4-[4-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-benzenesulfonyl]-phenoxy}-acetic acid ethyl ester [Example 17, 61 mg, 0.1 mmol] in isopropanol (3.1 mL) and tetrahydrofuran (0.6 mL) was heated to reflux to dissolve all the solids. The mixture was cooled to 35° C. followed by addition of 1M NaOH solution (0.21 mL). It was then stirred at 35° C. for 2 hours. The reaction was concentrated, acidified with 1M HCl and extracted with ethyl acetate. The organic extracts were dried and concentrated to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.2 (br s, 1H, COOH), 10.57 (s, 1H), 8.36 (d, J=2.6 Hz, 1H), 7.79 (m, 1H), 7.78 (d, J=9.0 Hz, 2H), 7.72 (d, J=8.8 Hz, 2H), 7.06 (d, J=9.0 Hz, 2H), 7.01 (d, J=9.3 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 4.77 (s, 2H).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](O)=[O:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C@H:24]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)[C@@H:25]([NH2:27])[CH3:26])=[CH:20][CH:21]=3)[CH:16]=[N:15]2)=[CH:10][CH:9]=1>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C@H:24]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)[C@@H:25]([NH:27][C:3](=[O:4])[C@H:2]([OH:1])[CH3:6])[CH3:26])=[CH:20][CH:21]=3)[CH:16]=[N:15]2)=[CH:12][CH:13]=1
Reactant: C[C@@H](O)C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Solvent: C1CCOC1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)[C@@H](C)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,1-carbonyldiimidazole (31 mg, 190 μmol) in THF (1 ml) was added (2R)-2-hydroxypropanoic acid (18 mg, 20 μmol) to give a colorless solution. The reaction mixture was stirred for 1 h at r.t. Then a solution of (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 39 mg, 100 μmol) in THF (0.5 ml) was added, and the stirring was continued at r.t. overnight. The solvent was removed in vacuo, the residue dissolved in acetonitrile/water mixture, and the crude product purified by preparative HPLC. Yield 16 mg (35%).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28]([CH:27]=[CH:26][C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(OCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(COc3ccc(OCCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
14 mg (0.55 mmol) 95% sodium hydride were given to a solution of 110 mg (0.50 mmol) 4-(3-[1,2,3]triazol-1-yl-propoxy)-phenol in 4.0 ml DMF and stirred for 15 min. 173 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 8 ml water the resulting precipitate was collected , washed with water (2×10 ml), methanol/water 1:1 (2×10 ml), ethyl acetate/n-heptane 1:2, a small amount of diethyl ether and dried to yield 233 mg (88%) of a slightly yellow powder.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](OC(F)(F)F)C=2)[N:6]([CH2:18][C:19]([OH:21])=[O:20])[CH:5]=1)(=[O:3])[CH3:2].[NH:22]1C2C(=NC=CC=2)C(C(=O)C)=C1>>[C:1]([C:4]1[C:12]2=[N:22][CH:10]=[CH:9][CH:8]=[C:7]2[N:6]([CH2:18][C:19]([OH:21])=[O:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: CC(=O)c1c[nH]c2cccnc12
Product: CC(=O)c1cn(CC(=O)O)c2cccnc12

Procedure:
was prepared in a similar manner as described in step B and C of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid from 1-(1H-pyrrolo[3,2-b]pyridin-3-yl)-ethanone (prepared according to J. Org. Chem. 2002, 67, 6226). MS (UPLC/MS): 219.2 [M+H]+, 217.3 [M−H]−, 435.3 [2M−H]−; tR (HPLC conditions f): 1.16 min. 1H-NMR (400 MHz, DMSO): δ (ppm): 8.79 (bs, 1H), 8.64 (m, 2H), 7.64 (m, 1H), 5.33 (s, 2H), 2.67 (s, 3H).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18](I)=[CH:17][C:16]=1[O:24][CH3:25])[CH3:13].C(=O)=O.CC(C)=O.[B:33](OC(C)C)([O:38]C(C)C)[O:34]C(C)C>O1CCCC1>[CH2:12]([O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([B:33]([OH:38])[OH:34])=[CH:17][C:16]=1[O:24][CH3:25])[CH3:13]
Reactant: CCOc1c(OC)cc(I)cc1OC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1c(OC)cc(B(O)O)cc1OC
Yield: 38.7 %

Procedure:
Under argon, a 1.60 M solution of n-butyllithium in hexane (2.5 mL, 4.1 mmol) was added to anhydrous tetrahydrofuran (7.0 mL) stirred in a dry ice-acetone bath, followed by dropwise addition of a solution of 4-ethoxy-1-iodo-3,5-dimethoxybenzene (570.0 mg, 1.85 mmol) in anhydrous tetrahydrofuran (1.5 mL). After the mixture was stirred for 20 minutes in the dry ice-acetone bath, triisopropyl borate (0.50 mL, 2.2 mmol) was added, and the mixture was additionally stirred for 20 minutes. The reaction mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. To the residue, a 0.1 M aqueous sodium hydroxide (4.4 mL) solution was added. The aqueous solution was washed with chloroform, acidified by the addition of concentrated hydrochloric acid, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Chloroform-hexane was added to the residue and the resulting precipitate was collected by filtration to afford the title compound as a colorless amorphous powder (162.0 mg, yield: 39%).
Reaction SMILES: COC(=O)CCC(=O)C1C=CC2OC3C=CC=CC=3C=2C=1.C[O:23][C:24](=[O:42])[CH2:25][CH2:26][C:27](=[O:41])[C:28]1[CH:29]=[CH:30][C:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][C:32]=2[CH:40]=1>>[O:41]=[C:27]([C:28]1[CH:29]=[CH:30][C:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][C:32]=2[CH:40]=1)[CH2:26][CH2:25][C:24]([OH:42])=[O:23]
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)oc1ccccc12
Agent: COC(=O)CCC(=O)c1ccc2oc3ccccc3c2c1
Product: O=C(O)CCC(=O)c1ccc2c(c1)oc1ccccc12

Procedure:
In the same manner but replacing γ-oxo-2-dibenzofuranbutyric acid methyl ester with an equivalent amount of γ-oxo-3-dibenzofuranbutyric acid methyl ester, described in Example 4, there is obtained γ-oxo-3-dibenzofuranbutyric acid, m.p. 208° - 210°C., after recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[N+:11]([CH3:14])([O-])=O>>[NH2:11][CH2:14][CH:4]([OH:5])[C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1c(Cl)cccc1Cl
Product: NCC(O)c1c(Cl)cccc1Cl

Procedure:
The method of Schoenenberger, Archiv. der Pharmazie, 1975, 308(9), 717-719 can be employed. 2,6-Dichlorobenzaldehyde can be reacted with nitromethane and base, followed by reduction of the aliphatic nitro group to yield 1-amino-2-hydroxy-2-(2,6-dichlorophenyl) ethane. This substance can be reacted with 4-nitrobenzaldehyde to yield a mixture of cis-(±) and trans-(±)-5-(2,6-dichlorophenyl)-2-(4-nitrophenyl)-1,3-oxazolidines. The nitrophenyl group can be reduced with tin (II) dichloride or iron powder and ammonium chloride to yield the corresponding aniline. This aniline can be reacted with 2,2-dichloroacetyl chloride and triethylamine to yield a mixture of cis-(±) and trans-(±)-2,2-dichloro-N-[4-[5-(2,6-dichlorophenyl)-2-(1,3-oxazolidinyl)]phenyl]acetamides.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]=1.[O:17]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(O)C>[N+:14]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[CH:2][C:11]([C:12]#[N:13])=[C:10]2[NH:28][C:27]1[CH:26]=[CH:25][C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:30][CH:29]=1)([O-:16])=[O:15]
Reactant: N#Cc1cc2cc([N+](=O)[O-])ccc2nc1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CCO
Solvent: O
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 103.9 %

Procedure:
A mixture of -chloro-6-nitroquinoline-3-carbonitrile (4.1 g, 17.6 mmol, 1.0 eq), 4-phenoxyaniline (2.6 g, 14.1 mmol, 0.8 eq) was dissolved in ethanol (40 mL). The reaction was heated to reflux for 2 hours, cooled to room temperature, poured into water (50 mL), and washed with ethyl acetate (50×2 mL). It was filtrated and dried in vacuum to give 6-nitro-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile (Compound 18) as a solid (5.6 g)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[C:18]1([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:23](=[O:24])[NH:22][C:21](=[O:25])[NH:20][C:19]1=[O:26].CCCCC=CCCCC.C1(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)F>C(#N)C>[NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:18]3([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:19](=[O:26])[NH:20][C:21](=[O:25])[NH:22][C:23]3=[O:24])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: NCc1ccc(Oc2ccc(O)cc2)cc1
Agent: CCCCC=CCCCC
Agent: FC(F)(F)C1(C(F)(F)F)OC(F)(F)C(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)O1
Solvent: CC#N
Product: CCOCCC1(Oc2ccc(Oc3ccc(CN)cc3)cc2)C(=O)NC(=O)NC1=O
Yield: 18.1 %

Procedure:
Following the procedure outlined for the preparation of Example 1, 4-(4-aminomethyl-phenoxy)-phenol (0.70 g, 3.32 mmol) was reacted with 5-bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (0.95 g, 2.4 mmol), 1,5,7-trazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (PTBD, Fluka, 2.22 9) and 11 mL of acetonitrile, affording 5-[4-(4-aminomethyl-phenoxy)-phenoxy]-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (0.180 g) as a colorless solid after purification by reverse phase HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=2[O:21][CH3:22])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[ClH:23]>C(O)C>[ClH:23].[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[O:21][CH3:22])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc([N+](=O)[O-])ccc2OC)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2cc(N)ccc2OC)cc1

Procedure:
2′-Methoxy-5′-nitro-biphenyl-4-carboxylic acid ethyl ester (600 mg) in ethanol 90 ml) and 2M HCl (2.5 ml) was hydrogenated at RTP for 3 h. The mixture was then filtered through celite and the solvent evaporated. The dark solid residue was dissolved in 1:1 aqueous acetonitrile, filtered through celite again and evaporated giving the title compound as a red solid (595 mg).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH:10]2[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])=[O:6]>CO.O1CCCC1.O.CC(C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([NH:16][CH:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=2)[CH2:12][CH2:11]1)=[O:25]
Reactant: COC(=O)c1ccc2c(c1)C(NC(=O)c1ccccc1Cl)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)C(NC(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
LiOH (5 equiv.) was added to a suspension of 3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (B-01) (11.75 mmol) in methanol (40 ml), tetrahydrofuran (40 ml) and water (30 ml) and the reaction mixture was stirred at 25° C. overnight. Methanol and THF were distilled off, the aqueous residue was acidified with 1N HCl and the mixture was filtered. The white solid obtained was taken up in a mixture of 350 ml of acetone and 50 ml of methanol and the mixture was stirred for 1 h. After filtration, the white solid was dried in vacuo to obtain 3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid (E-01). Yield: 75%
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[OH:36][CH:37]1[CH2:40][CH:39]([C:41](O)=[O:42])[CH2:38]1>>[OH:36][CH:37]1[CH2:40][CH:39]([C:41]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:42])[CH2:38]1
Reactant: O=C(O)C1CC(O)C1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)C6CC(O)C6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 3-hydroxycyclobutanecarboxylic acid (Parkway, Cat. No. BX-111). LCMS (M+H)+: m/z=583.3.