Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH:24]=[CH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:27]=3)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=2)[C:11]([CH3:37])([CH3:36])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:35][O:34][C:32](=[O:33])[C:29]1[CH:28]=[CH:27][C:26]([CH:25]=[CH:24][CH:18]([C:15]2[CH:16]=[C:17]3[C:12]([C:11]([CH3:37])([CH3:36])[CH2:10][CH2:9][NH:8]3)=[CH:13][CH:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:31][CH:30]=1
Reactant: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)NCCC2(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
A solution of 7-{1-[2-(4-methoxycarbonyl-phenyl)-vinyl]-hexyl}-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.98 g) in 10 mL of dichloromethane was treated with 1.5 mL of trifluoroacetic acid. The mixture was stirred at room temperature for four hours and then was concentrated in vacuo to yield 0.72 g of 4-[3-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoic acid methyl ester as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:20](=[CH:21][CH:22]=1)[C@@H:19]1[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]1)([CH3:16])[C:14]([F:24])([F:23])[CH2:13][C@H:12]3[CH2:25][CH2:26][C:27]([NH:29][C:30]1[S:31][C:32]([CH3:35])=[CH:33][N:34]=1)=[O:28])[CH2:9][CH2:8]2)=[O:4].[Li+].[OH-].CO.C1COCC1>O>[F:24][C:14]1([F:23])[CH2:13][C@@H:12]([CH2:25][CH2:26][C:27]([NH:29][C:30]2[S:31][C:32]([CH3:35])=[CH:33][N:34]=2)=[O:28])[C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C:20]1[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:22][CH:21]=1)[CH2:8][CH2:9]3
Reactant: COC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]3[C@H](CCC(=O)Nc4ncc(C)s4)CC(F)(F)[C@@]3(C)CC[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cnc(NC(=O)CC[C@@H]2CC(F)(F)[C@@]3(C)CC[C@@H]4c5ccc(C(=O)O)cc5CC[C@H]4[C@H]23)s1
Yield: 8.8 %

Procedure:
0.9 g 17,17-difluoro-15beta-{3-[(5-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl}estra-1(10),2,4-triene-3-carboxylic acid methyl ester and 0.5 g LiOH are mixed with 30 ml MeOH, 50 ml THF and 30 ml H2O and stirred at 80° C. (water bath) for about 30 min. H2O is added, the reaction mixture is extracted with EtOAc three times. The combined aquatic layers are acidified with KHSO4aq to pH 2-3, and extracted the times with EtOAc. The latter organic layers are combined, washed with brine, dried (Na2SO4) and the solvent removed. 620 mg crude compound was obtained which was used in the following step without further purification. Purifying by column chromatography (CH2Cl2: MeOH:AcOH 37:3:0.1) give 77 mg of pure 17,17-difluoro-15beta-{3-[(5-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl}estra-1(10),2,4-triene-3-carboxylic acid (=EXAMPLE 9, NMR spectra see below).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=O)[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C:53]1[CH:54]=[C:55]([NH:60][C:61](=[O:72])[C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:71])([F:70])[F:69])[CH:63]=2)[CH:56]=[CH:57][C:58]=1[CH3:59]>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:52][C:53]3[CH:54]=[C:55]([NH:60][C:61](=[O:72])[C:62]4[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:69])([F:70])[F:71])[CH:63]=4)[CH:56]=[CH:57][C:58]=3[CH3:59])=[O:18])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)Nc1nccc2c(C(=O)O)cccc12
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Reaction time: 0.17 h
Yield: 18.5 %

Procedure:
1-(t-Butylamino)isoquinoline-5-carboxylic acid (0.33 g, 1.35 mmol) obtained in Step (6) of Preparation Example 1 was dissolved in dimethyl formamide (3 mL), added with HATU (0.62 g, 1.62 mmol) and DIPEA (0.47 mL, 2.70 mmol), and stirred for 10 minutes. The reaction mixture was added with N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide (0.40 g, 1.35 mmol) obtained in Step (2) above, and stirred for 12 hours or more at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with a saturated sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography to obtain the title compound (0.13 g, 18%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:51])/[C:19](=[N:45]\[O:46][CH2:47][CH:48]3[CH2:50][CH2:49]3)/[C:20]3[N:21]=[C:22]([NH:25][C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[S:23][CH:24]=3)[C:15](=[O:52])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].[CH2:59]([O:61][C:62]([O:64][CH:65](Br)[CH3:66])=[O:63])[CH3:60]>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:51])/[C:19](=[N:45]\[O:46][CH2:47][CH:48]3[CH2:50][CH2:49]3)/[C:20]3[N:21]=[C:22]([NH:25][C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[S:23][CH:24]=3)[C:15](=[O:52])[N:10]2[C:11]=1[C:12]([O:14][CH:59]([O:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH3:60])=[O:13])(=[O:3])[NH2:2]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC3CC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reactant: CCOC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)C1=C(COC(N)=O)CS[C@@H]2[C@H](NC(=O)/C(=N\OCC3CC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6R,7R)-3-Carbamoyloxymethyl-7-[(Z)-2-cyclopropylmethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]ceph-3-em-4-carboxylic acid (1.1 g) was dissolved in N,N-dimethylformamide (5 ml) and stirred with potassium carbonate (105 mg) under nitrogen with ice-water cooling. After 10 minutes, 1-ethoxycarbonyloxy-1-ethyl bromide was added. After one hour, the mixtured was allowed to attain 21° and was stirred thus for three hours. The mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. The aqueous layer was extracted with more ethyl acetate and the combined organic layers were washed twice with brine, dried with magnesium sulphate and concentrated. The residue was chromatographed on Sorbsil U30 (50 g) in ethyl acetate (10 to 60%) in petroleum ether (bp 40° to 60°) to give the title compound (930 mg); [α]D21 +44.0° (c 1.30, CHCl3); λmax (ethanol) 230 nm (E1 cm1% 312), λ infl 236 nm (ED1% 295) and λnm (E1 cm1% 226).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[CH2:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCc2ccc(OCc3ccccc3)cc2O1
Yield: 99.9 %

Procedure:
A mixture of ethyl 7-hydroxy-chroman-2-carboxylate (6.1 g, 27.5 mmol), potassium carbonate (7.6 g, 55 mmol), potassium iodide (1.8 g, 11 mmol) and benzyl chloride (3.4 mL, 30 mmol) in acetone is heated at reflux for 16 hr under nitrogen, cooled, concentrated, diluted with water and extracted with EtOAc. The combined extracts are dried over MgSO4 and concentrated to afford the title compound as a straw-colored oil 8.58 g (100% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]3[CH:35]=[C:34]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[C:33](B4OC(C)(C)C(C)(C)O4)=[CH:32][C:26]=3[C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[CH:19][CH:18]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1(C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4]([C:33]2[C:34]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][C:25]3[O:24][C:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=4)=[C:27]([C:28](=[O:29])[NH:30][CH3:31])[C:26]=3[CH:32]=2)[N:3]=1
Reactant: CCOC(=O)CCc1ccc(Cl)nc1Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)CCc1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1Cl
Temperature: 70 °C

Procedure:
To a mixture of ethyl 3-(2,6-dichloropyridin-3-yl)propanoate (170 mg, 0.685 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (344 mg, 0.685 mmol), XantPhos Biphenyl precatalyst (60.9 mg, 0.069 mmol), and cesium carbonate (670 mg, 2.056 mmol) was added 1,4-dioxane (5.7 mL) and H2O (1.2 mL). A steady stream of N2 was bubbled through the reaction mixture for 5 minutes then the mixture was heated to 70° C. for 16 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed successively with H2O (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc/Hexanes as eluent. 1H NMR δ (ppm) (CHCl3-d): 8.01˜7.96 (3H, m), 7.75 (1H, t, J=7.74 Hz), 7.69 (1H, s), 7.55 (1H, d, J=7.70 Hz), 7.27˜7.21 (2H, m) 5.91 (1H, br s), 4.19 (2H, q, J=7.12 Hz), 3.27˜3.20 (3H, m), 3.18˜3.12 (2H, m), 3.03 (3H, d, J=4.92 Hz), 2.90˜2.80 (3H, m), 2.77 (2H, t, J=7.51 Hz), 1.30 (3H, t, J=7.15 Hz). MS (M+H)+: 588.
Reaction SMILES: FC(F)(F)C[O:4]C1C=CC(OCC(F)(F)F)=CC=1.C[C:20]([C:22]1[CH:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:25]=[CH:24][C:23]=1[O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[O:21].C(C1C=CC=CC=1)(=O)C.Cl[O-]>>[F:37][C:36]([F:39])([F:38])[CH2:35][O:34][C:23]1[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:27][C:22]=1[C:20]([OH:21])=[O:4]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Agent: [O-]Cl
Solvent: CC(=O)c1ccccc1
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
In yet another aspect of the invention, a method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is provided which comprises the following steps. The compound 1,4-dibromobenzene is contacted with an alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous or cupric ion and in a strongly polar solvent comprising 2,2,2-trifluoroethanol to yield 1,4-bis(2,2,2-trifluoroethoxy)benzene. Then, in the presence of a Lewis acid catalyst, the 1,4-bis(2,2,2-trifluoroethoxy)benzene is treated with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The methyl moiety of the acetophenone function of the 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is thereafter replaced using hypochlorite to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. Subsequently, the 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is treated with an inorganic chloride to provide 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride. Finally, the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride is contacted with 2-aminomethylpiperidine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:27]([O:29][CH2:30][CH2:31][CH2:32][O:33][P:34]([O:41]C(C)(C)C)([O:36]C(C)(C)C)=[O:35])=[O:28])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].C(#N)C.FC(F)(F)C(O)=O.N>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:27]([O:29][CH2:30][CH2:31][CH2:32][O:33][P:34]([OH:36])([OH:41])=[O:35])=[O:28])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OP(=O)(OCCCOC(=O)n1ncc2c(NC(=O)N[C@@H]3CCc4cc(C(C)(C)C)ccc43)cccc21)OC(C)(C)C
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2c1cnn2C(=O)OCCCOP(=O)(O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 81 %

Procedure:
To the product from Example 15D (2.12 g, 3.30 mmol) in a 250 ml round bottom flask was added acetonitrile (40 ml) and 0.1% trifluoroacetic acid in water (40 ml) and the reaction was stirred at room temperature for 4 days. Every 24 hours 0.5 ml of trifluoroacetic acid was added until day four. The reaction was concentrated to give a white powder in 81% yield. 1H NMR (CDCl3, 300 MHz); δ ppm 1.32 (s, 9H), 1.88-1.92 (m, 1H), 2.22-2.26 (m, 2H), 2.57-2.63 (m, 1H), 2.84-2.90 (m, 1H), 2.96-3.32 (m, 1H), 4.21 (m, 2H), 4.65 (t, J=6.11, 12.55Hz, 2H), 5.29 (t, J=7.46, 14.58 Hz, 1H), 7.28-7.31 (m, 3H), 7.52 (t, J=8.14, 16.28 Hz, 1H), 7.73 (d, J=7.45Hz, 1H), 7.83 (d, J=8.48Hz, 1H), 8.36 (s, 1H); MS (DCI/NH3) m/z 531.00; Calc for C25H31N4O7P: C, 54.45; H, 5.59; N, 9.92. Found: C, 54.84; H, 5.88; N, 9.92.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Cl.[C:11]([O:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][NH2:20])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>O1CCOCC1.CCOCC>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:20][CH2:19][CH2:18][CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:21])=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCNc1ccc(C#N)cn1
Reaction time: 48 h

Procedure:
A solution of 6-chloronicotinonitrile (1.0 g, 7.2 mmol), 4-aminobutyric acid tert-butyl ester hydrochloride (2.12 g, 10.8 mmol, Sennchem 09600) and DIEA (4.9 mL, 28.9 mmol) in anhydrous dioxane (20 mL) was heated at 80° C. After 48 hours, an additional amount of 4-aminobutyric acid tert-butyl ester hydrochloride (0.55 g, 2.80 mmol) was added. After 24 additional hours at 80° C., the reaction mixture was diluted with Et2O (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried (MgSO4) and the solvents were removed under reduced pressure. After purification by flash chromatography (silica, EtOAc/cHex), the title compound was obtained as a beige powder. HPLC (Method A), Rt: 3.3 min (purity: 91%). UPLC/MS, M+(ESI): 262.1, M−(ESI): 260.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.37 (d, J=2.2 Hz, 1H), 7.63 (m, 2H), 6.52 (d, J=8.9 Hz, 1H), 3.29 (m, 2H), 2.26 (t, J=7.4 Hz, 2H), 1.73 (tt, J=7.4, 7.0 Hz, 2H), 1.38 (s, 9H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cccc(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 35.4 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate (0.663 g, 1.81 mmol) (from example 99, step 1) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.073 g, 1.81 mmol) dissolved in water (1 mL) was added during 20 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.111 mL, 1.81 mmol) was added during 5 min. The resulting solution was stirred at −40° C. for 4 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (9 mL, 54.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a brown semi-solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (214 mg, 35%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.47-1.77 (m, 2H), 1.82-2.15 (m, 2H), 2.75-3.00 (m, 2H), 3.00-3.15 (m, 2H), 3.40-3.80 (m, 3H), 4.00-4.42 (m, 1H), 4.42-4.80 (m, 1H), 5.64 (s, 1H), 6.83-7.05 (m, 3H), 7.22-7.31 (m, 1H). MS m/z 335 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(O)(=O)C>[Br:13][C:4]1[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:12]
Reactant: CC(=O)c1cc(Cl)c(C)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone (10 g, 54 mmol, from Aldrich) in acetic acid (100 mL) was added N-bromosuccinimide (12 g, 65 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, neutralized with saturated sodium bicarbonate and filtered to remove insoluble succinimide. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated to dryness under reduced pressure. The crude product was recrystallized from a mixture of ethyl acetate and hexane (11.4 g, 80%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>C(#N)C>[N:35]1([CH2:2][C:3]([NH:5][C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[O:19][CH:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]4)=[CH:10][CH:11]=2)=[O:4])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(CN1CCOCC1)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and morpholine (53 mg). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. 2-Morpholin-4-yl-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide was isolated as its hydrochloride salt. 1H-NMR (400 MHz; d6-DMSO) δ: 11.1 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.32 (m, 5H), 7.01 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 1.9, 10.0 Hz), 4.23 (s, 2H), 4.02-3.76 (m, 4H), 3.55-3.20 (m, 4H), 3.00-2.92 (m, 1H), 2.75-2.69 (m, 1H), 2.19-2.15 (m, 1H), 2.03-1.98 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1COCC1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][C:20](=[O:22])[CH3:21])=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tryptamine (192 mg/1.2 mmol) was initially introduced into abs. THF (5 ml), and triethylamine (179 μl/1.3 mmol) was added. Acetic anhydride (132 mg/1.3 mmol) was then added and the mixture was stirred at RT for 4 h. The mixture was concentrated to dryness i. vac. The residue was taken up in ethyl acetate and this solution was washed with saturated NaHCO3 solution (two times 20 ml) and with NaCl solution (two times 20 ml). The organic phase was dried over Na2SO4 and concentrated i. vac.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([CH3:16])[CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:17](Br)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:16][CH:10]1[C:9]([C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[NH:8][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][NH:1]3)=[N:14][NH:13][C:12](=[O:15])[CH2:11]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(N)c1
Reactant: O=C(CBr)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc2c(c1)NCC(c1ccccc1)N2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution containing 0.3 g of 6-(3,4-diaminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)one, 0.3 g of phenacyl bromide and 0.14 g of sodium acetate in 2.6 ml of ethanol was stirred for 3.5 h at room temperature. The product was washed with water and ethanol. Yield 0.1 g (23%), m.p. 209°-215° C.
Reaction SMILES: CC1C=C([N+]([O-])=O)C=CC=1N.C(NC1C=CC([N+]([O-])=O)=CC=1C)=O.C(Cl)C=C.[CH2:29]([N:32](C=O)[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[CH3:42])[CH:30]=[CH2:31]>C(O)=O>[CH2:29]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[CH3:42])[CH:30]=[CH2:31]
Reactant: C=CCN(C=O)c1ccc([N+](=O)[O-])cc1C
Agent: Cc1cc([N+](=O)[O-])ccc1N
Agent: Cc1cc([N+](=O)[O-])ccc1NC=O
Solvent: O=CO
Solvent: C=CCCl
Product: C=CCNc1ccc([N+](=O)[O-])cc1C

Procedure:
The particularly advantageous compound I-8 according to the invention can be prepared, for example, by formylating 2-methyl-4-nitroaniline using 95% strength formic acid, alkylating the resultant N-formyl-2-methyl-4-nitroaniline using allyl chloride under phase-transfer conditions and reducing the resultant N-allyl-N-formyl-2-methyl-4-nitroaniline. On the other hand, it is also possible to hydrolyze the intermediate N-allyl-N-formyl-2-methyl-4-nitroaniline to form N-allyl-2-methyl-4-nitroaniline, and to alkylate the latter using methyliodide to give the compound I-8 according to the invention. To this end, the intermediate N-allyl-2-methyl-4-nitroaniline can also be prepared by alkylating N-formyl-2-methyl-4-nitroaniline using allyl chloride. In addition, it is also possible to reduce the intermediate N-formyl-2-methyl-4-nitroaniline using a boron hydride in tetrahydrofuran to give the corresponding N-methyl derivative, which is subsequently alkylated using allyl chloride to give the compound I-8 according to the invention.