Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:23](=[O:24])[C:11]3([CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=4)[CH2:12]3)[NH:10][C:9]2=[O:25])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[CH2:30]([N:10]1[C:11]2([CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=3)[CH2:12]2)[C:23](=[O:24])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=2)[C:9]1=[O:25])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CN2C(=O)NC3(Cc4ccc([N+](=O)[O-])cc4C3)C2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N(Cc3ccccc3)C3(Cc4ccc([N+](=O)[O-])cc4C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (±)-1-(4-methoxybenzyl)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione from Step A (165 mg, 0.45 mmol) in DMF (1 mL) was added sodium hydride (18 mg of a 60% dispersion in mineral oil, 0.45 mmol). The mixture was stirred for 5 min at ambient temperature and benzyl bromide (230 mg, 1.35 mmol) was added. After 30 min, the mixture was partitioned between saturated aqueous NaHCO3 (3 mL) and CHCl3 (5 mL). The aqueous phase was extracted further with CHCl3 (5 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—75:25, to give the title compound. MS: m/z=458 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][CH:10]1[CH2:26][CH2:25][C:13]2([CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14]2)[CH2:12][CH2:11]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][CH:10]2[CH2:11][CH2:12][C:13]3([CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:15][CH2:14]3)[CH2:25][CH2:26]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3ccnc(Cl)n3)CC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (0.5 g, 3.4 mmol) and tert-butyl 8-amino-2-azaspiro[4.5]decane-2-carboxylate (0.89 g, 3.5 mmol) in EtOH (20 mL) was added Et3N (0.5 g, 5 mmol). The mixture was stirred at rt for 24 h, then the reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the product as a white solid (0.4 g, 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:20][CH2:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][C:23]=1[N:37]1[CH2:49][CH2:48][C:47]2[N:46]3[C:41]([CH2:42][CH2:43][CH2:44][CH2:45]3)=[CH:40][C:39]=2[C:38]1=[O:50])(=O)C>>[OH:20][CH2:21][C:22]1[C:27]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:26][CH:25]=[CH:24][C:23]=1[N:37]1[CH2:49][CH2:48][C:47]2[N:46]3[C:41]([CH2:42][CH2:43][CH2:44][CH2:45]3)=[CH:40][C:39]=2[C:38]1=[O:50]
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(cc3n2CCCC3)C1=O
Product: Cc1cc(Nc2cc(-c3cccc(N4CCc5c(cc6n5CCCC6)C4=O)c3CO)cn(C)c2=O)n[nH]1
Yield: 17 %

Procedure:
Using the same general procedure as described for 118, reaction of 112a (200 mg, 0.706 mmol) and 118f (330 mg, 0.710 mmol) afforded a 17% yield (60 mg) of 225 as a green-yellow solid: mp 199-200° C.; 1H NMR (500 MHz, DMSO-d6) d 11.69 (s, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.41 (t, 1H, J=8.0 Hz), 7.25 (d, 3H, J=8.5 Hz), 6.00 (s, 1H), 5.86 (s, 1H), 4.69 (br s, 1H), 4.31 (m, 2H), 3.97 (m, 1H), 3.91 (m, 1H), 3.79 (m, 2H), 3.56 (s, 3H), 3.01 (m, 1H), 2.90 (m, 1H), 2.70 (m, 2H), 2.15 (s, 3H), 1.90 (m, 2H), 1.74 (m, 2H); MS (ESI+) m/z 499.2 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:16]2[C:15]([NH:14][CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: Nc1ccccc1NCC1CCN(c2ccncc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(Nc1ccccc1NCC1CCN(c2ccncc2)CC1)c1ccc(Cl)cc1
Yield: 55.2 %

Procedure:
Using a similar procedure to that described in Example 2, Part D, N1-[1-(4-pyridyl)piperidin-4-ylmethyl)-1,2-benzenediamine (167 mg, 0.59 mmol) and 4-chlorobenzoyl chloride (0.075 mL, 0.59 mmol) yielded 137 mg (55%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][C@@H:17]([C:21]([OH:23])=[O:22])[C@@H:18]([CH3:20])[OH:19]>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([NH:16][C@@H:17]([C:21]([OH:23])=[O:22])[C@@H:18]([CH3:20])[OH:19])=[O:15])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(CC(=O)O)cc1
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Product: CCCCOc1ccc(CC(=O)N[C@@H](C(=O)O)[C@@H](C)O)cc1

Procedure:
4-Butoxyphenylacetic acid (288 mg, 1.38 mmol) is converted to the acid chloride and added to D-allo-Thr (150 mg, 1.26 mmol) to get 2c-9, following the procedure described in Example 6. The crude product is purified by chromatography (2.5×18 cm column, gradient 4% CH3OH and 0.3% HOAc in CH2Cl2): NMR δ0.96 (t, J=7.4, 3H), 1.14 (d, J=5.8, 3H), 1.47 (m, 2H), 1.74 (m, 2H), 3.53 (br s, 2H), 3.91 (t, J≈6.5, 2H), 4.10 (br s, 1H), 4.53 (br s, 1H), 4.90 (br s, >2H), 6.76 (br d, J=6.0, 1H), 6.84 (d, J=8.4, 2H), 7.13 (d, J=8.4, 2H); MS (HR-E ) m/z 309.1567 (M calcd. for C16H23NO5, 309.1576); [α]D26±2 (CHCl3); m.p. 90°-94° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][C:10](=O)[NH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]2=[N:8][CH:9]=1
Reactant: O=c1cnc2c(Cl)nccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cnc2c(Cl)nccc2n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A suspension of 5-chloropyrido[3,4-b]pyrazin-2(1H)-one (0.57 g, 3.14 mmol) in phosphorus oxychloride (10.24 mL, 110 mmol) was stirred at 110° C. for two hours, and then concentrated. The residue was dissolved in DCM, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (580 mg, 2.90 mmol). MS m/z=200 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-])=O)[CH:14]=1)[C:9]=2[NH2:22])(=[O:3])[CH3:2].C(OCC)(=O)C.CO.C([O-])=O.[NH4+]>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]([NH2:19])[CH:14]=1)[C:9]=2[NH2:22])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(N)c3ccc([N+](=O)[O-])cc3nc2c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc2c(N)c3ccc(N)cc3nc2c1
Yield: 29.4 %

Procedure:
To a 50 mL rbf equipped with a nitrogen bubbler were charged 3-acetamidyl-6-nitro-9-aminoacridine (110 mg, 0.37 mmol) and ethyl acetate (1.9 mL). Methanol (950 μL) and Pd/Alumina 10% (12 mg) were added and the reaction mixture was stirred to a fine suspension. Ammonium formate (47 mg, 0.74 mmol) was added and the mixture was stirred for 20 min at room temperature. A further portion of ammonium formate (70 mg, 1.11 mmol) was then added. Stirring was maintained overnight. The suspension was filtered and washed with ethyl acetate to afford the crude product (106 mg). The solid was dissolved in water and washed with ethyl acetate. The aqueous layer was concentrated in vacuo to afford 3-acetamidyl-6,9-diaminoacridine as a brown solid (29 mg, 29%). 1H NMR and LCMS analyses conformed to structure.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[S:6])[CH2:2][CH3:3].[CH2:7]([OH:10])[CH2:8][CH3:9]>>[CH2:1]([NH:4][C:5](=[S:6])[O:10][CH2:7][CH2:8][CH3:9])[CH2:2][CH3:3]
Reactant: CCCO
Reactant: CCCN=C=S
Product: CCCNC(=S)OCCC
Temperature: 25 °C

Procedure:
To 10 g (0.099 g) of propyl isothiocyanate was added 50 mL of n-propanol. The reaction mixture was heated to reflux for 3 h and cooled to room temperature. An aliquot was removed and concentrated under reduced pressure to give the title compound, 1H NMR (300 MHz, CDCl3): δ0.94-1.02 (m,6H); 1.49-1.83 (m,4H); 3.22 (q), 3.51 (q,2H total); 4.37 (t), 4.45 (t,2H total), 6.25 (br s), 6.78 (br s,1H total). The remaining reaction mixture was concentrated under reduced pressure as above to provide 13.5 g of oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)=[CH:16][CH:15]=1.Cl>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:41])[CH3:42])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)=[CH:18][CH:19]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.23 (s, br, 1H), 7.74-6.88 (m, 11H), 5.20-5.12 (m, 1H), 3.68-3.52 (m, br, 2H), 3.02-2.82 (m, br, 2H), 2.82-2.60 (m, 4H), 2.58-2.38 (m, br, 2H), 2.12-2.02 (m, br, 1H), 2.02-1.80 (m, br, 5H), 1.68-1.52 (m, br, 1H), 1.52-1.36 (br, 3H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 603.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:23]4[CH:31]=[C:30](F)[N:29]=[CH:28][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:17][C:16]=2[CH3:33])[CH2:10][CH2:9]1)=O)(C)(C)C.CCN(CC)CC.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CS(C)=O.CCOC(C)=O>[CH3:33][C:16]1[CH:17]=[C:18]([NH:21][C:22]2[C:23]3[CH:31]=[C:30]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:29]=[CH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCNCC1

Procedure:
A solution of 4-[4-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.21 mmol), NEt3 (0.67 g, 6.63 mmol), and morpholine (0.57 g, 6.63 mmol) in DMSO (10 mL) was heated to 120° C. in a sealed tube. After 24 h the reaction was diluted with EtOAc, the organic layer was washed 2× 1N NaOH and 2× water. The organic layer was treated with HCl (g) and the title compound was collected by filtration as a yellow solid (0.63 g, 67%). LRMS: 421.3 (MH+). 1H NMR (DMSO-d6, 400 MHz): δ 9.15 (br. s, 1H), δ 9.05 (br. s, 1H), δ 8.92 (s, 1H), δ 8.65 (s, 1H), δ 8.18 (s, 1H), δ 7.49-7.51 (m, 2H), δ 7.096 (d, J=9.55, 1H), δ 4.66-4.69 (m, 1H), δ 3.65-3.73 (m, 8H), δ 3.16 (br. s, 2H), δ 3.06 (br. s, 2H), δ 2.17 (s, 3H), δ 2.07-2.13 (m, 2H), δ 1.85-1.94 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[O:9][C:10]1[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:19].[Cl:20][C:21]1[N:22]=[N:23][C:24]([O:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:38])=[CH:25][C:26]=1Cl>>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:9][C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:19])=[C:2]([O:28][CH3:24])[CH:7]=1.[Cl:20][C:21]1[N:22]=[N:23][C:24]([O:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:38])=[CH:25][C:26]=1[O:9][CH3:3]
Reactant: CC(C)c1cccc(Cl)c1Oc1nnc(Cl)cc1Cl
Reactant: CC(C)c1cccc(Cl)c1Oc1cc(Cl)c(Cl)nn1
Product: COc1cc(Cl)nnc1Oc1c(Cl)cccc1C(C)C
Product: COc1cc(Oc2c(Cl)cccc2C(C)C)nnc1Cl
Yield: 71.3 %
Yield: 17.1 %

Procedure:
To methanol (10 mL) was added 0.080 g (3.5 mmol) of sodium, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 0.830 g (2.61 mmol) of 4,6-dichloro-3-(2-chloro-6-isopropylphenoxy)pyridazine obtained in (6), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), washed with hexane and crystallized to obtain 0.720 g (2.30 mmol, Yield: 88.1%) of 6-chloro-3-(2-chloro-6-isopropylphenoxy)-4-methoxypyridazine. On the other hand, 1.78 g (5.60 mmol) of the mixture of 4,6-dichloro-3-(2-chloro-6-isopropylphenoxy)pyridazine and 3,4-dichloro-6-(2-chloro-6-isopropylphenoxy)pyridazine was reacted in the same manner as mentioned above to obtain 1.25 g (3.99 mmol, Yield: 71.3%) of 6-chloro-3-(2-chloro-6-isopropylphenoxy)-4-methoxypyridazine and 0.300 g (0.958 mmol, Yield: 17.1%) of 3-chloro-6-(2-chloro-6-isopropylphenoxy)-4-methoxypyridazine.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[N:14]([C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of 0.20 g of 5'-O-acetyl-3'-O-benzyl-2'-deoxy-5-fluorouridine in 10 ml of dioxane were added 0.29 g of benzoyl chloride and 0.73 ml of triethylamine, and the mixture was left to stand at 80° C. for 2 hours. The solvent was distilled off and the residue was dissolved in 50 ml of ethyl acetate. The solution was washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was placed on a silica gel column and eluted with chloroform, giving 0.2 g of the title compound as an oil in a yield of 78%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5]CCNC)=[O:4].CCN(C(C)C)C(C)C.[CH2:21]([O:28][C:29]([N:31]1[C:35](=O)[CH2:34]C[C:32]1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:28][C:29](=[O:30])[N:31]([CH3:32])[CH2:35][CH2:34][NH:5][C:3](=[O:4])[C:2]([F:11])([F:10])[F:1])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CNCCNC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(CCNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of compound A (88.2 g, 311 mmol) and DIEA (54.1 mL, 311 mmol) in THF (350 mL) was cooled in an ice bath, followed by the addition of a solution of N-(benzyloxycarbonyl)succinimide (76.6 g, 307 mmol) in THF (150 mL) drop wise over the period of 20 min. The temperature of the reaction mixture was raised to ambient temperature and stirring was continued for an additional 30 min. Solvents were then evaporated and the resulting residue was dissolved in EtOAc (600 mL). The organic layer was extracted with 5% aq. NaHCO3 (2×150 mL) and brine (150 mL). The organic layer was evaporated to provide compound B as yellowish oil. LC-MS [M+H] 305.1 (C13H15F3N2O3+H, calc: 305.3). Compound B was used directly in the next reaction without purification as a MeOH solution.
Reaction SMILES: [CH3:1][N:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[CH2:30])[C:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])([OH:21])[CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:9][CH:8]=1)=[O:6])[O:3][CH3:4].C([O-])=O.[NH4+]>[Pd].O1CCCC1.C(O)C>[CH3:1][N:2]([C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]([CH3:30])[C:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])([OH:21])[CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:11][CH:12]=1)=[O:6])[O:3][CH3:4]
Reactant: C=C(c1ccc(C(=O)N(C)OC)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C(C)C(O)(Cn2cncn2)c2ccc(F)cc2F)cc1
Yield: 54.6 %

Procedure:
A mixture of N,O-dimethyl-4-(2-[2,4-difluorophenyl]-2-hydroxy-1-[1,2,4-triazol-1-yl]-3-buten-3-yl) benzene hydroxamic acid (0.9 g, 2.2 mmol-see Preparation 50), 10% palladium on charcoal (0.2 g) and ammonium formate (0.68 g, 11 mmol) was suspended in a tetrahydrofuran/ethanol (1:1, 40 ml) solution and heated under reflux for 3 hours. The cooled suspension was filtered through "Arbocel" and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 ml) and the solution was washed with saturated sodium carbonate solution (20 ml) and brine (20 ml), then dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica by gradient elution with dichloromethane followed by dichloromethane/methanol (39:1). Fractions containing the desired product were combined and evaporated under reduced pressure to yield the title compound (0.5 g, 55%) as a colourless foam.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[CH2:12][C:13]([CH:15]1[CH2:20][C:19](=[CH2:21])[CH2:18][CH2:17][CH:16]1[C:22]([OH:24])=[O:23])=[O:14])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O.C(OCC)(=O)C>[CH2:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH2:12][C:13]([CH:15]1[CH2:20][C:19](=[CH2:21])[CH2:18][CH2:17][CH:16]1[C:22]([O:24][CH3:25])=[O:23])=[O:14])[CH3:11]
Reactant: C=C1CCC(C(=O)O)C(C(=O)Cc2c(CC)cc(C)cc2CC)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=C1CCC(C(=O)OC)C(C(=O)Cc2c(CC)cc(C)cc2CC)C1
Yield: 66.6 %

Procedure:
5.45 g (17.33 mmol) of 2-[(2,6-diethyl-4-methylphenyl)acetyl]-4-methylidenecyclohexane-carboxylic acid (XIII-1), together with 2.38 g of potassium carbonate and 2.62 g (20.8 mmol) of dimethylsulphate, are boiled at reflux in 50 ml of acetone for 5 h, and after cooling, the reaction mixture is taken up in ethyl acetate, extracted with water and dried (magnesium sulphate), and the solvent is distilled off. Chromatography on silica gel using ethyl acetate/hexane (v/v=30:70) gives 3.93 g (69%) of methyl 2-[(2,6-diethyl-4-methylphenyl)acetyl]-4-methylidenecyclohexane-carboxylate of the formula (II-1).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(OC(O[CH2:27][CH3:28])OCC)C.C(OC(=O)C)(=O)C.[NH2:36][C:37]1[S:38]C=[CH:40][N:41]=1>C(O)(C)C>[F:10][C:5]1[CH:4]=[C:3]2[C:2](=[C:7]([F:8])[C:6]=1[F:9])[N:41]([C:37]1[S:38][CH:27]=[CH:28][N:36]=1)[CH:40]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]2=[O:18]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: Nc1nccs1
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn(-c2nccs2)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 18 h
Yield: 68 %

Procedure:
To 3.0 g (11.33 mmol) of 2,3,4,5-tetrafluoro-β-oxo-benzeneproprionic acid, ethyl ester was added 2.49 g of triethylorthoformate and 2.76 g of acetic anhydride. The mixture was refluxed for two hours and concentrated to dryness under high vacuum at 80° C. The residual oil was treated with 1.32 g (1.2 equivalents) of 2-aminothiazole suspended in 70 ml of isopropanol. At 70° C., 1.6 g (1.0 equivalent) of 1,8-diazobicyclo[5.4.0]undec-7-ene was added. After 18 hours, the mixture was cooled and filtered to give 2.73 g of the 6,8,7-trifluoro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-3-quinolinecarboxylic acid, ethyl ester, mp 172°-174° C. This material was dissolved in 100 ml of hot acetic acid and 50 ml of 2N hydrochloric acid and was heated at 100° C. for 2.5 hours. The mixture was cooled, partially concentrated, and filtered to give 1.81 g of 6,7,8-trifluoro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-3-quinolinecarboxylic acid, mp 198.5°-200° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([CH2:31][CH3:32])([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([CH2:28][CH3:29])([OH:27])[CH2:25][CH3:26])=[C:18]([CH3:30])[CH:17]=3)[CH2:14][CH3:15])[S:10][C:9]=2[CH:33]=1)=[O:4].[OH-].[Na+].Cl>CO.O>[CH2:14]([C:13]([C:11]1[S:10][C:9]2[CH:33]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[CH:12]=1)([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([CH2:25][CH3:26])([OH:27])[CH2:28][CH3:29])=[C:18]([CH3:30])[CH:17]=1)[CH2:31][CH3:32])[CH3:15]
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc3ccc(C(=O)OC)cc3s2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc3ccc(C(=O)O)cc3s2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
2-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}benzo[b]thiophene-6-carboxylic acid methyl ester (0.48 g, 1.02 mmol) is dissolved in MeOH (2 mL) and treated with H2O (0.5 mL) and NaOH (0.20 g, 5.12 mmol). The resulting mixture is heated at a reflux for 2 h, cooled to RT, and stirred overnight. The solution is diluted with H2O (10 mL), adjusted to pH 3-4 using 1 M HCl, and extracted with EtOAc (40 mL). The EtOAc layer is washed with brine (20 mL), dried with MgSO4, filtered, and concentrated to yield the title compound (0.42 g, 0.92 mmol, 89%). 1H NMR (CDCl3), δ 0.76 (t, J=7.5 Hz, 6H), 0.95 (t, J=7.5 Hz, 6H), 1.68 (q, J=14.8, 7.5 Hz, 4H), 2.25-2.27 (m, 7H), 3.82 (s, 2H), 6.74 (d, J=8.8 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 7.09 (dd, J=8.5, 2.1 Hz, 1H), 7.24 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.96 (dd, J=8.3, 1.7 Hz, 1H), 8.48 (d, J=1.7 Hz, 1H). Exact mass (m/z): calcd. for C27H35O4S (M+H)+: 454.2; found: 472.3.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=4)=[O:32])=[C:26]([F:44])[CH:25]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.C(OCC)(=O)C>ClCCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:37]=[CH:36][N:35]=4)=[O:32])=[C:26]([F:44])[CH:25]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c3c(N)ncnn23)CC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
A suspension of Example 270 (930 mg, 1.5 mmol) in 60 mL 1,2-dichloroethane was treated with 15 mL TFA at rt. The reaction quickly became homogeneous and at 10 min no starting material remained by RP-HPLC. The reaction mixture was concentrated in vacuo, and the residue taken up again in fresh 1,2-dichloroethane and concentrated again; this was repeated 2 times. The residue was taken up in THF (15 mL) and EtOAc (85 mL) and washed with aq. sodium carbonate. The organic layer was dried with sodium sulfate and concentrated in vacuo to provide a tan solid. Trituration with ethyl acetate provided the title compound (705 mg, 91%) as a tan solid. 1H-NMR (DMSO-d6) δ 10.14 (bs, 1H), 10.06 (bs, 1H), 8.54 (d, 1H), 8.26 (t, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.31-7.40 (m, 2H), 7.24 (dd, 1H), 6.65 (s, 1H), 3.18 (tt, 1H), 3.01 (broad d, 2H), 2.61 (td, 2H), 1.92 (broad d, 2H), 1.54 (ddd, 2H); MS [M+H]+=515.2; LCMS RT=2.34.