Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH:15]1([CH2:18][O:19][C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[C:22]([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)=[CH:23][NH:24]3)[CH2:17][CH2:16]1.[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37]>C(OCC)(=O)C>[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:32]3[CH2:33][CH:34]=[C:29]([C:22]4[C:21]5[C:25](=[CH:26][CH:27]=[CH:28][C:20]=5[O:19][CH2:18][CH:15]5[CH2:16][CH2:17]5)[NH:24][CH:23]=4)[CH2:30][CH2:31]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: C1=C(c2c[nH]c3cccc(OCC4CC4)c23)CCNC1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: C1=C(c2c[nH]c3cccc(OCC4CC4)c23)CCN(CCCOc2cccc3[nH]ccc23)C1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 4-(4-cyclopropylmethoxy-1H-indol-3-yl)-1,2,3,6-tetrahydropyridine (which was prepared by condensing 4-cyclopropylmethoxyindole with 4-piperidone monohydrate hydrochloride in refluxing methanol with potassium hydroxide). The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 20% overall yield as a white foam. FDMS m/e=441 (M+ of free base).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O.C(O)(=O)C>[CH2:7]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(N)CO
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
Acetic acid (5.4 ml) was added to a solution of 2-amino-2-methyl-1-propanol (8.4 g) and benzaldehyde (10 g) in 1,2-dichloroethane (140 ml) under ice-cooling. After 30 minutes of stirring at the same temperature, sodium triacetoxyborohydride (26 g) was added by small portions to the solution over 10 minutes. After 2 hours of stirring at room temperature, the mixture was poured into a solution of sodium hydrogen carbonate (48 g) in water (300 ml). The aqueous layer was separated and adjusted to pH 12 with 24% sodium hydroxide aqueous solution. The alkaline solution was extracted with ethyl acetate (2 times). The extract was dried over sodium sulfate and evaporated under reduced pressure to give colorless crystals of 2-benzylamino-2-methyl-1-propanol (13.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]#[N:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>FC(F)(F)C(O)C(F)(F)F>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH2:14][N:15]([C:18]([NH:25][C:24]4[CH:26]=[CH:27][C:21]([F:20])=[CH:22][CH:23]=4)=[NH:19])[CH2:16][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: N#CN1CCN(c2ccnc3cc(Cl)ccc23)CC1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: N=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(4-cyanopiperazin-1-yl)quinoline (150 mg, 0.55 mmol) and 4-fluoroaniline (66 μL, 0.7 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (5 mL) are heated at 150° C. in a sealed tube for 66 h. The reaction mixture is concentrated, and the residue is purified by column chromatography with CH2Cl2—NH3-MeOH to give the title product as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:12][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: COc1cc(CBr)ccc1C#N
Yield: 35.3 %

Procedure:
4.6 g (31.3 mmol) of 4-methyl-2-methoxybenzonitrile were brominated with 34.7 mmol of N-bromosuccinimide in the presence of catalytic amounts of azobisisobutyronitrile in 60 ml of 1,2-dichloroethane under reflux. 2.5 g of the product were obtained. 1H-NMR (DMSO-d6, δ in ppm): 7.75 (d, 1H), 7.35 (s, broad, 1H), 7.15 (d, broad, 1H), 4.73 (s, 2H), 3.95 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:14][CH:15]1C(=O)O[C:18](C)([CH3:22])[O:17][C:16]1=[O:24])=[CH:5][NH:6]2.C(O)C.CCOCC>N1C=CC=CC=1.C(OCC)(=O)C.[Cu]>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:14][CH2:15][C:16]([O:17][CH2:18][CH3:22])=[O:24])=[CH:5][NH:6]2
Reactant: Cc1c([N+](=O)[O-])ccc2[nH]cc(CC3C(=O)OC(C)(C)OC3=O)c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCc1c[nH]c2ccc([N+](=O)[O-])c(C)c12
Yield: 50.4 %

Procedure:
To a solution of 5-[(4-methy-5-nitroindol-3-yl)methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (1.009 g, 3.04 mmol) in a mixture of pyridine (18 mL) and absolute ethanol (2 mL) was added 0.05 g of copper powder and the mixture was heated to reflux under Ar for 2 h. The cooled mixture was filtered and the filtrate was evaporated in vacuo to give a viscous brown oil. This material was taken up in ethyl acetate and the solution was washed (1N HCl, saturated aqueous NH4Cl, brine), dried (Na2SO4) and evaporated to give a yellow solid. Trituration with ether gave 423 mg of the title compound as a tan solid. An additional 166 mg of the product could be recovered by evaporation of the supernatant and retrituration with ether. Total yield=671 mg (80%). An analytical sample was crystallized from ethyl acetate-hexane to give tan crystals, mp 105°-106° C.: IR (KBr) 3340, 1717, 1517, 1335 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ11.47 (br s, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 7.28 (s, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.18 (t, J=7.1 Hz, 2H), 2.77 (s, 3H), 2.68 (m, 2H), 1.16 (t, J=7.1 Hz, 3H). Anal. Calcd for C14H16N2O4 : C, 60.86; H, 5.84: N, 10.14. Found: C, 60.76; H, 5.74; N, 10.00.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl>CO.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1cccc(N)c1
Temperature: 25 °C
Yield: 127.4 %

Procedure:
To a stirred solution of methyl 2-(3-nitrophenyl)acetate (7.3 g, 0.038 mol) and Fe (6.3 g, 0.113 mol) in MeOH (200 mL) was added concentrated HCl (20 mL). Then the mixture was stirred at room temperature over night. The mixture was filtered, the solvent was concentrated and the residue was dissolved in ethyl acetate and washed with brine, dried and concentrated to give the crude product of methyl 2-(3-aminophenyl)acetate (8.0 g, yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[N:15]4[N:16]=[C:17]([CH3:25])[CH:18]=[C:19]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:14]4=[N:13][C:12]=3[CH3:26])[NH:8]2)=[CH:4][CH:3]=1.[CH3:27]N(C=O)C.[H-].[Na+].CI>CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[N:15]4[N:16]=[C:17]([CH3:25])[CH:18]=[C:19]([CH:20]([CH2:21][CH3:22])[CH2:23][CH3:24])[C:14]4=[N:13][C:12]=3[CH3:26])[N:8]2[CH3:27])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1cc(C)nn2c(-c3cc4ccc(Cl)cc4[nH]3)c(C)nc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3cc4ccc(Cl)cc4n3C)c(C)nc12
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 3-(6-chloro-1H-indol-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.050 g, 0.14 mmol) and DMF (2 mL) is added 60% NaH (0.013 g, 0.33 mmol). The solution is stirred for 30 minutes and MeI (0.010 mL, 0.16 mmol) is added. The solution is stirred for 1 hour, diluted with EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated. The residue is purified by silica gel chromatography (30%-50% EtOAc gradient) to furnish the title compound (0.021 g, 0.055 mmol, 40%). 1H NMR (CDCl3), δ 0.90 (t, J=7.4 Hz, 6H), 1.75-1.95 (m, 4H), 2.49 (s, 3H), 2.51 (s, 3H), 3.31-3.40 (m, 1H), 3.57 (s, 3H), 6.65 (d, J=0.9 Hz, 1H), 6.72 (s, 1H), 7.12 (dd, J=8.4, 1.8 Hz, 1H), 7.40-7.42 (m, 1H), 7.58 (8.4 Hz, 1H) ppm. LC/MS (m/z): calcd. for C22H25ClN4 (M+H)+: 380.2. found: 381.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:24])[CH2:23][O:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[O:32]1[C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=[N:33]1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:24][C:37]([C:36]4[O:32][N:33]=[CH:34][CH:35]=4)=[O:38])[CH2:21][O:22][CH2:23]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: O=C(O)c1ccno1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)COC2)no1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)c3ccno3)COC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 3-amino-oxetane-3-carboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 49) was coupled with isoxazole-5-carboxylic acid to yield the title compound as yellow oil. MS: 538.1 (MH+, 1Cl).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C2(C3C=CC=CC=3)CC2(P(C(C)(C)C)C(C)(C)C)C)C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Under a nitrogen atmosphere, 4-chloroanisole (0.30 g, 2.1 mmol), phenylboronic acid (0.37 g, 3.0 mmol), potassium phosphate n-hydrate (0.85 g), (π-allyl)palladium chloride (3.7 mg, 0.01 mmol), 2,2-diphenyl-1-(di-tert-butylphosphino)-1-methylcyclopropane (14.1 mg, 0.04 mmol) obtained in Example 4 and toluene (4 ml) were placed in a reaction flask and stirred for 3 hours at 80° C. The reaction mixture was cooled, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure, and the concentrate was purified by column chromatography to give the title compound (0.35 g, 90%) as white crystal.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)=[CH2:2].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23](=[O:24])[CH:22]=[CH:21][C:20]2=[O:25])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[C:23](=[O:24])[CH:22]3[CH:21]([CH2:2][CH:1]=[C:3]4[O:4][C:5]5[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=5[CH:7]43)[C:20]2=[O:25])=[CH:17][CH:18]=1
Reactant: C=Cc1cc2ccccc2o1
Reactant: Cc1ccc(N2C(=O)C=CC2=O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N2C(=O)C3CC=C4Oc5ccccc5C4C3C2=O)cc1
Yield: 48.9 %

Procedure:
10 ml of toluene was added to a mixture of 0.40 g of 2-vinylbenzofuran and 0.52 g of N-(4-methylphenyl)maleimide. The mixture was refluxed for 3 hours. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=50/1 to 20/1) to obtain 0.45 g (yield: 49%) of 2-(4-methylphenyl)-3a,4,10b,10c-tetrahydro-1H-benzofuro-[3,2-e]isoindole-1,3(2H)-dione as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][NH:13]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCc3ccccc3C2)c(Cl)c1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
A mixture of 3,4-dichloronitrobenzene (1.0 g, 5.2 mmol), 1,2,3,4-tetrahydroisoquinoline (0.97 g, 7.3 mmol), K2CO3 (3.6 g, 26 mmol), and DMSO (20 mL) was heated to 80° C. for 16 h with stirring. The mixture was allowed to cool to rt, and was then poured over ice. The resulting precipitate was collected by filtration and dried to provide the titled compound (1.5 g, 98%). MS (ESI): mass calcd. for C15H13ClN2O2, 288.7; m/z found, 289.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH2:10][CH3:11])[C:7](O)=[O:8])=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.Cl.[CH3:25][O:26][C:27](=[O:75])[NH:28][CH:29]([C:33]([N:35]1[CH:41]([C:42]2[NH:43][C:44]([C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:62]=[CH:61][C:60]5[C:55](=[CH:56][CH:57]=[C:58]([C:63]6[NH:64][C:65]([CH:68]7[CH2:72][CH:71]([C:73]#[N:74])[CH2:70][NH:69]7)=[N:66][CH:67]=6)[CH:59]=5)[CH:54]=4)=[CH:49][CH:48]=3)=[CH:45][N:46]=2)[CH2:40][C:37]2([CH2:39][CH2:38]2)[CH2:36]1)=[O:34])[CH:30]([CH3:32])[CH3:31].CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH3:25][O:26][C:27](=[O:75])[NH:28][CH:29]([C:33]([N:35]1[CH:41]([C:42]2[NH:43][C:44]([C:47]3[CH:48]=[CH:49][C:50]([C:53]4[CH:62]=[CH:61][C:60]5[C:55](=[CH:56][CH:57]=[C:58]([C:63]6[NH:64][C:65]([CH:68]7[CH2:72][CH:71]([C:73]#[N:74])[CH2:70][N:69]7[C:7](=[O:8])[CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH3:11])=[N:66][CH:67]=6)[CH:59]=5)[CH:54]=4)=[CH:51][CH:52]=3)=[CH:45][N:46]=2)[CH2:40][C:37]2([CH2:38][CH2:39]2)[CH2:36]1)=[O:34])[CH:30]([CH3:32])[CH3:31]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: CCC(NC(=O)OC)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(NC(=O)OC)C(=O)N1CC(C#N)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC7(CC7)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.4 %

Procedure:
2-Methoxycarbonylamino-butyric acid (37 mg, 0.227 mmol) EDC-HCl (44 mg, 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (1-{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0° C. and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 1.5 h, the reaction mixture was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHCO3, then 1:1 brine/5M NaOH. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (85 mg, 54%). MS (ESI) m/z 826 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH:9]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]([CH3:12])[CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1)=O.Cl.[NH2:25][OH:26].C([O-])(=O)C.[K+].O>CO>[OH:26][N:25]=[CH:1][C:3]1[C:8]([CH:9]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]([CH3:12])[CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: NO
Reactant: CC(C)C(c1cncnc1C=O)N(C)C(=O)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)C(c1cncnc1C=NO)N(C)C(=O)Cc1ccccc1
Yield: 43.1 %

Procedure:
1.0 g (3.2 mmol) of N-(1-(4-formylpyrimidin-5-yl)-2-methylpropyl]-N-methylphenylacetamide was dissolved in 30 ml of methanol, and 0.45 g (6.5 mmol) of hydroxylamine hydrochloride and 0.63 g (6.4 mmol) of potassium acetate were added and reacted at room temperature for 1 hour. After completion of the reaction, the product was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution, an aqueous citric acid solution, water and an aqueous sodium chloride solution, in this order, dried and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 to ethyl acetate) to obtain 0.45 g (yield: 43%) of N-[1-(4-hydroxyiminomethylpyrimidin-5-yl)-2-methylpropyl]-N-methylphenylacetamide as colorless crystals (melting point: 171-172° C.).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](=[O:10])[CH2:8]Cl.[CH2:11]1[C:19]2[C:14](=[CH:15]C=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22].Cl>ClCCCl>[Cl:5][CH2:6][C:7]([C:8]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[CH2:11][N:12]([C:20](=[O:25])[C:21]([F:23])([F:24])[F:22])[CH2:13]2)=[O:10]
Reactant: O=C(CCl)CCl
Reactant: O=C(N1Cc2ccccc2C1)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 5.00 g (37.5 mmol) aluminium(III)-chloride in 20 mL 1,2-dichloroethane is added at 0° C. dropwise 2.24 mL (28.1 mmol) 1,3-dichloro-propan-2-one keeping the temperature below 15° C. Then 4.48 g (18.7 mmol) 1-(1,3-dihydro-isoindol-2-yl)-2,2,2-trifluoro-ethanone in 5 mL 1,2-dichloroethane is added dropwise at RT keeping the temperature between 40-45° C. The reaction is stirred for 18 h at RT and is poured onto aqueous HCl-solution. The aqueous phase is extracted twice with DCM, the organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is elutriated with PE and the precipitate is collected.
Reaction SMILES: C(=N)(C1C=CC=CC=1)C1C=CC=CC=1.[C:15]([O:19][C:20](=[O:36])[CH2:21][N:22]=[C:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:18])([CH3:17])[CH3:16].[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O.CCCCCC.CCOC(C)=O>[C:30]1([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:22][C@H:21]([C:20]([O:19][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:36])[CH2:42][C:41]2[CH:44]=[CH:45][C:38]([Cl:37])=[CH:39][CH:40]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N=C(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(Cl)cc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 90 %

Procedure:
The benzophenone imine of glycine t-butyl ester 3 (1.8 mmol), tetra-n-butyl-ammonium bromide (0.2 mmol), dichloromethane (6 mL), and 4-chlorobenzyl bromide 136 (2 mmol) were added to a three-necked round-bottom flask equipped with a stirring bar. 50% aqueous NaOH (36.5 mmol) was added at once and the resulting mixture was stirred vigorously at room temperature until starting Schiff base had disappeared by TLC (4:1 hexane/EtOAc) (approximately 8 h). Water (3 mL) and dichloromethane (3 mL) were added and the mixture was transferred to a separatory funnel. The organic layer was separated and evaporated in vacuo. The residue was taken up in ether (10 mL) and water (6 mL), and the ether layer was separated and washed with water (3×3.0 mL). The organic layer was dried (Na2SO4), filtered, and evaporated in vacuo. The resulting crude product (95%) was purified by flash chromatography (dichloromethane) to afford white crystals 141 (90%): m.p. 102–103° C., which was analyzed by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:23])=[C:12]3[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][OH:22])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:34][CH2:35][N:36]([CH2:39][CH3:40])[CH2:37][CH3:38]>CN(C=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][OH:22])[S:16][C:13]=3[N:14]([CH2:34][CH2:35][N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CCCO)cc2c1O
Reactant: CCN(CC)CCBr
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCN(CC)CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCO)sc21
Temperature: 90 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
To a solution of N-(4-chlorobenzyl)4-hydroxy-2-(3-hydroxypropyl)thieno[2,3-b]pyridine-5-carboxamide (Example No. 8) (0.300 g) in DMF (4 mL) are added K2CO3 (0.550 g) and 2-bromo-N,N-diethylethylamine hydrobromide (0.623 g). The reaction is heated to 90° C. and stirred for 3 d. An additional 0.220 g of K2CO3 and 0.415 g of 2-bromo-N,N-diethylethylamine hydrobromide are added. The reaction is stirred at 90° C. for 6 h. The reaction mixture is concentrated in vacuo, and the resulting residue is partitioned between CH2Cl2 (25 mL) and H2O (25 mL). The aqueous layer is extracted with CH2Cl2 (3×25 mL). The combined organic layers are dried with MgSO4, filtered and concentrated in vacuo. The resulting yellow oil is purified via column chromatography (CH2Cl2:CH3OH; 98:2, 95:5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a yellow oil. This material is dissolved in methanolic HCl and then concentrated in vacuo. The residue is recrystallized twice from ethyl acetate/methanol to yield 0.078 g (19%) of the title compound as an off-white, crystalline solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]([F:26])([F:25])[C:5]([F:24])([F:23])[O:6][C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[O:9][C:10]([F:18])([F:17])[CH2:11][O:12][CH2:13][CH2:14][CH2:15]Cl.BrCCCCl.FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)CO.[CH2:58]([C:66]1[CH:67]=[N:68][C:69]([C:72]2[CH:77]=[CH:76][C:75]([OH:78])=[CH:74][CH:73]=2)=[N:70][CH:71]=1)[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]>>[CH2:58]([C:66]1[CH:71]=[N:70][C:69]([C:72]2[CH:77]=[CH:76][C:75]([O:78][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:10]([O:9][C:8]([F:19])([F:20])[C:7]([F:21])([F:22])[O:6][C:5]([F:23])([F:24])[C:4]([F:25])([F:26])[O:3][C:2]([F:28])([F:27])[F:1])([F:18])[F:17])=[CH:74][CH:73]=2)=[N:68][CH:67]=1)[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCl
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: ClCCCBr
Agent: OCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F
Product: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy) 1-chloropropane (18.3 g, 38.5 mmol; prepared from 1-bromo-3-chloropropane (107 g, 0.7 mol) and 2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol (125 g, 0.31 mol) essentially as in Example 2) with 5-octyl-2-(4-hydroxyphenyl) pyrimidine (10 g, 35 mmol). The crude product was further purified by Kugelrohr distillation (b.p. 200°-210° C. at 0.4 torr; yield of 10.0 g).