Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:5][C@H:6]([C:19]([O:21]C)=[O:20])[N:7]2[NH:13][C:14]([CH2:16][O:17][CH3:18])=[O:15].[OH-].[Li+]>O1CCCC1.O>[C:19]([C@H:6]1[CH2:5][C@H:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]1[NH:13][C:14]([CH2:16][O:17][CH3:18])=[O:15])([OH:21])=[O:20]
Reactant: COCC(=O)NN1c2cc(Cl)cc(Cl)c2[C@@H](c2ccccc2)C[C@@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCC(=O)NN1c2cc(Cl)cc(Cl)c2[C@@H](c2ccccc2)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
To a solution of trans-5,7-dichloro-2-methoxycarbonyl-4-phenyl(methoxy)methylcarbonylamino-1,2,3,4-tetrahydroquinoline (Isomer B) (0.140 g, 0.331 mmol) (Example 44a) in a mixture of tetrahydrofuran (10 ml) and water (5 ml) was added aqueous lithium hydroxide (0.73 ml of a 0.5M solution, 0.364 mmol) and the resulting mixture was stirred at room temperature for 2 h. The organic solvent was removed under vacuum and the residue was diluted with sodium bicarbonate solution (50 ml) then washed with diethyl ether (1×30 ml). The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2×40 ml). The combined extracts were washed with saturated bring (1×40 ml), dried (MgSO4) and evaporated to give the crude product which was recrystallised from hot ethyl acetate/petroleum ether (bp 60°-80° ) to give the title compound as colourless crystals (0.070 g), m.p. 238°-239° C. δ (360 MHz, DMSO) 1.63 (1H, ddd, J=13.2, 12.6 and 4.0 Hz, CHACHBHCCHD), 2.07 (1H, dm, J=13.2 Hz, CHACHBHCCHD), 3.28 (3H, s, NHCOCH(OCH3)Ph), 3.83 (1H, dd, J=12.6 and 2.6 Hz, CHACHBHCCHD), 4.67 (1H, s, NHCOCH(OCH3)Ph), 5.04 (1H, m, CHACHBHCCHDNHCO), 6.66 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.77 (1H, s, ArNH), 6.88 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.26-7.40 (5H, m, ArH), 8.49 (1H, d, J=7.4 Hz, CHDNHCO); m/e(CI+) 409 (M+H), 166 (100%); Found C, 55.77; H, 4.57; N, 6.64; C19H18Cl2N2O4 requires C, 55.76; H, 4.43; N, 6.85%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[CH3:8].[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1>>[CH3:7][C:5]1[S:6][C:2]([NH:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([CH3:18])=[CH:10][CH:11]=2)=[C:3]([CH3:8])[N:4]=1
Reactant: Cc1ccc(CCN)cc1
Reactant: Cc1nc(C)c(Br)s1
Product: Cc1ccc(CCNc2sc(C)nc2C)cc1

Procedure:
In analogy to the procedure described for the synthesis example 32 (step 1), the title compound (2,4-dimethyl-thiazol-5-yl)-(2-p-tolyl-ethyl)-amine (MS m/e: 247.0 [M+H]+) was prepared from 5-bromo-2,4-dimethyl-1,3thiazole and 2-(p-tolyl)ethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[C:40]3[C:32](=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][CH:35]([C:41]([N:43]3[C:54]5[C:46](=[C:47]6[C:51](=[CH:52][CH:53]=5)[NH:50][CH:49]([C:55]([N:57]5[C:68]7[C:60](=[C:61]8[C:65](=[CH:66][CH:67]=7)[NH:64][CH:63]([C:69]([O:71]C)=[O:70])[CH2:62]8)[CH:59]=[CH:58]5)=[O:56])[CH2:48]6)[CH:45]=[CH:44]3)=[O:42])[CH2:34]4)[CH:31]=[CH:30]2)=[O:28])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)/[C:10](/[CH3:14])=[CH:11]/[CH:12]=[CH2:13])=[CH:5][CH:4]=1.CO.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[C:40]3[C:32](=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][CH:35]([C:41]([N:43]3[C:54]5[C:46](=[C:47]6[C:51](=[CH:52][CH:53]=5)[NH:50][CH:49]([C:55]([N:57]5[C:68]7[C:60](=[C:61]8[C:65](=[CH:66][CH:67]=7)[NH:64][CH:63]([C:69]([OH:71])=[O:70])[CH2:62]8)[CH:59]=[CH:58]5)=[O:56])[CH2:48]6)[CH:45]=[CH:44]3)=[O:42])[CH2:34]4)[CH:31]=[CH:30]2)=[O:28])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)/[C:10](/[CH3:14])=[CH:11]/[CH:12]=[CH2:13])=[CH:5][CH:4]=1
Reactant: C=C/C=C(\C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)n1ccc2c4c(ccc21)NC(C(=O)n1ccc2c5c(ccc21)NC(C(=O)OC)C5)C4)C3)(c1ccccc1)c1ccc(OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C/C=C(\C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)n1ccc2c4c(ccc21)NC(C(=O)n1ccc2c5c(ccc21)NC(C(=O)O)C5)C4)C3)(c1ccccc1)c1ccc(OC)cc1
Temperature: 55 °C
Reaction time: 30 h
Yield: 60.4 %

Procedure:
A suspension of 10 (270 mg, 0.28 mmol) in a mixture of THF (6 ml), MeOH (4 ml) and 4M LiOH (2 ml) was stirred at 55° C. for 30 h. The reaction was cooled and neutralized to pH 6 with cold 10% citric acid. Insoluble material was collected by filtration and washed with water, MeOH and ether. Drying under vacuum afforded 160 mg (60%) of the title compound 11. By HPLC analysis this product contained ˜5% of unreacted 10. The crude acid was used in the next step without additional purification.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:23].Br[CH2:25][C:26]#[N:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:25][C:26]#[N:27]
Reactant: Oc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCOc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A mixture of 1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthol (351 mg, 0.918 mmol), prepared in step 1 of Example 3, bromoacetonitrile (77 μL, 1.11 mmol) and cesium carbonate (1.505 g, 4.62 mmol) in 25 mL of acetone was stirred under nitrogen at room temperature for 19 h (overnight). The reaction was concentrated under reduced pressure to remove the acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted three times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give {[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}acetonitrile (382 mg, 99%) as a light tan solid, mp 157-160° C. Elemental Analysis for C21H13BrN2OS Calc'd: C, 59.87; H, 3.11; N, 6.65. Found: C, 59.56; H, 3.28; N, 6.56.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[CH2:32][CH2:31][C:19]3([CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]([OH:29])=[O:28])[C:21](=[O:30])[CH2:20]3)[CH2:18][CH2:17]2)=[CH:10][CH:9]=1>C(O)(=O)C.O=[Pt]=O>[C:3]([OH:5])(=[O:4])[CH3:2].[C:27]([OH:29])(=[O:28])[CH3:26].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][C:19]3([CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]([OH:29])=[O:28])[C:21](=[O:30])[CH2:20]3)[CH2:31][CH2:32]2)[CH2:10][CH2:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)CN1C(=O)CC2(CCN(CCc3ccncc3)CC2)CC1=O
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)CC2(CCN(CCC3CCNCC3)CC2)CC1=O

Procedure:
To a solution of 0.5 g (1.25 mmol) of the compound from Example 26. Step C in 40 ml 90% acetic acid were added 100 mg PtO2. The mixture was filled into an autoclave and hydrogenated at 20 atm and room temperature for 22 h. The solvent was removed under reduced pressure, and the residue was stirred with ether. The insoluble title compound was separated and dried in vacuo.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][NH2:9].[C:10](#[N:14])/[CH:11]=[CH:12]/[CH3:13]>C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][NH:9][CH:12]([CH3:13])[CH2:11][C:10]#[N:14]
Reactant: NCCCC1OCCO1
Reactant: C/C=C/C#N
Solvent: CCOC(C)=O
Product: CC(CC#N)NCCCC1OCCO1
Temperature: 100 °C
Yield: 92.6 %

Procedure:
49.85 g (0.38 mol) of 3-[1,3]-dioxolan-2-yl-propylamine and 43.34 g (0.646 mol) of crotono-nitrile are combined in a 200 ml round-bottomed flask and heated at 100° C. for 72 hours. After cooling, the brown mass is diluted with ethyl acetate and washed with water. The organic phase is dried over calcium carbonate and purified by filtration on silica gel (eluent: ethyl acetate). Evaporation of the solvent gives 69.8 g of 3-(3-[1,3]-dioxolan-2-yl-propylamino)butyronitrile as a reddish liquid which is used without further purification in the next stage.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][C@H:9]([CH2:12][C@H:13]([OH:38])[C@@H:14]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:15]([O:28][CH3:29])[CH2:16][C@@H:17]([CH3:27])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:10][OH:11]>N1C=CC=CC=1>[C:1]([O:11][CH2:10][C@H:9]([CH3:8])[CH2:12][C@H:13]([OH:38])[C@@H:14]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:15]([O:28][CH3:29])[CH2:16][C@@H:17]([CH3:27])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CO[C@@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)[C@H](OCc1ccccc1)[C@@H](O)C[C@@H](C)CO
Solvent: c1ccncc1
Product: CO[C@@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)[C@H](OCc1ccccc1)[C@@H](O)C[C@@H](C)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Pivaloyl chloride (870 microliters, 1.05 equiv) was added to a solution of (2R,4S,5R,6S,8R)-2,8-dimethyl-4-hydroxy-5-benzyloxy-6-methoxy-9-t-butyldimethylsilyloxynonanol 21 (Source: Askin, D.; Volante, R. P.; Reamer, R. A.; Ryan, K. M.; Shinkai, I.; Tetra. Lett., 1988, 29, 277.) (3.07 g, 6.75 mmol) in 50 ml of anhydrous pyridine at 0° C. The solution was warmed to 25° C. over 1 hr and then was stirred at 25° C. for 16 hr. The reaction mixture was quenched by the addition of 10 ml of saturated aqueous sodium bicarbonate solution and then partitioned between75 ml of water and 150 ml of diethyl ether. The aqueous phase was extractedwith an additional 2×100 ml portions of ether. The organic phases were combined, washed with 1×50 ml of water and 1×50 ml of saturated sodium chloride solution, and dried over magnesium sulfate. Concentration in vacuo gave 3.67 g of 22 as a crude oil. The oil was purified by chromatography on 180 g of silica gel eluting with 5:1 hexanes:ethylacetate to give 3.52 g of pivaloate 22 (97% yield). The material was homogeneous by 1H and 13C NMR.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[C:16]([F:19])([F:18])[F:17])=[O:8])[CH2:3]1.Cl[C:21]1[N:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1>>[CH3:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]([F:19])([F:17])[F:18])=[C:9]([C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:21]3[N:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)[CH2:3]2)=[O:8])[CH:14]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](N)C2)c1
Product: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](Nc3ccc(C(F)(F)F)nn3)C2)c1

Procedure:
In analogy to the procedure described for example 200, the title compound was prepared from ((R)-3-Amino-pyrrolidin-1-yl)-(5-methyl-2-trifluoromethyl-phenyl)-methanone (intermediate 13) and 3-chloro-6-trifluoromethyl-pyridazine (commercially available). (MH+) 419.3.
Reaction SMILES: [N+]([C:4]1C=C(N)C=C[C:5]=1C(O)=O)([O-])=O.[F:14][C:15]1[C:23]([F:24])=[C:22]([NH2:25])[C:21]([F:26])=[C:20]([F:27])[C:16]=1[C:17]([OH:19])=[O:18].C(O)C.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:14][C:15]1[C:23]([F:24])=[C:22]([NH2:25])[C:21]([F:26])=[C:20]([F:27])[C:16]=1[C:17]([O:19][CH2:4][CH3:5])=[O:18]
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1c(F)c(F)c(N)c(F)c1F

Procedure:
Thus, in accordance with Reaction Scheme 6, 3-nitro-6-methyl-fluorobenzene (Aldrich) is subjected to oxidation, conversion of the resulting carboxylic acid to an acid chloride and thereafter to an ethyl ester, followed by reduction of the nitro group, to yield ethyl 2-fluoro-4-amino-benzoate (Compound C1). 3-Nitro-6-methyl-bromobenzene (Aldrich) and 3-nitro-6-methyl-chlorobenzene (Aldrich) are subjected to essentially to the same series of reactions to yield ethyl 2-bromo-4-amino-benzoate (Compound D1) and ethyl 2-chloro-4-amino-benzoate (Compound E1), respectively. 2-Nitro-4-aminobenzoic acid (Research Plus) is converted to its methyl ester (Compound F1) through the corresponding acid chloride. 2,3,5,6-Tetrafluoro-4-amino-benzoic acid (Aldrich) is esterified by treatment with ethanol in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine in CH2Cl2 to give ethyl 2,3,5,6-tetrafluoro-4-amino-benzoate (Compound G1). 2,4,6-Trifluorobenzoic acid (Aldrich) is converted to the methyl ester through the acid chloride, and the 4-fluoro atom is displaced by reaction with sodium azide, followed by hydrogenation, to yield methyl 2,6-difluoro-4-amino benzoate (Compound H1). Compounds C1, D1, E1, F1, G1 and H1 serve as amine reagents in accordance with Formula 7. Further examples of reagents in accordance with Formula 7 are nitro, fluoro, chloro, bromo and trifluoromethyl derivatives of amino substituted heteroaryl carboxylic acids, or their lower alkyl esters, such as ethyl 2-amino-4-chloropyridine 2-carboxylate, ethyl 5-amino-3-chloropyridine 5-carboxylate, and 3,4-dibromo-5-aminothiophene-2-carboxylic acid. The latter examples qcan be prepared by respective chlorination or bromination of 2-aminopyridine-5-carboxylic acid or of its ester, 3-aminopyridine-6-carboxylic acid or of its ester (described in WO 93/06086) and of 2-aminothiophene-5-carboxylic acid (described in PCT/US92/06485).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:1])([F:12])[F:13])=[C:4]2[C:8]([O:10][CH3:11])=[O:9])=[CH:17][CH:16]=1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of the product prepared in Step B (1160 mg, 6.0 mmol, 1 eq), 4-chlorophenylboronic acid (2.9 g, 18.0 mmol, 1 eq), Cu(OAc)2 (2.18 g, 12.0 mmol, 2 eq), 4A molecular sieves (3 g), pyridine (1.94 mL, 4.0 mmol, 4 eq) in DCM (40 mL) was stirred at room temperature for 2 days. The resulting suspension was filtered through CELITE, washed with DCM, and concentrated. The resulting residue was dry packed and purified by flash chromatography (120 g column) eluting with 4 to 8% EtOAc/heptane to yield methyl 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH3:2]>C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[Zn].[Cl-].[NH4+].O.C(O)C>[CH2:1]([CH:3]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[CH3:2]
Reactant: CCCCC(CC)COCCCNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCCCC(CC)COCCCNc1ccc(N)cc1

Procedure:
The N-[2-(3-ethylheptyloxy)ethyl]-4-nitro-1-aminobenzene (9) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[CH3:19])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[C:22]([O-])([O-])=O.[K+].[K+].IC>CC#N>[C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:22])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[CH3:19])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccc(O)cc12
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc2c(c1)c(C(C)=O)cn2CC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (3-acetyl-5-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (500 mg, 1.73 mmol) in CH3CN (15 mL) was added K2CO3 (358 mg, 2.59 mmol) and iodomethane (0.162 mL, 2.59 mmol). The reaction mixture was stirred at 50° C. overnight. Additional K2CO3 (716 mg, 5.18 mmol) and iodomethane (0.324 mL, 5.18 mmol) were added and heating was continued for an additional 2 days. Volatiles were evaporated, the reaction mixture was taken up in water and extracted twice with AcOEt. The combined organic phases were dried (Phase separator) and evaporated to give the title compound. MS (LC/MS): 304.0 [M+H]+, 629.0 [2M+Na]+; tR (HPLC conditions c): 4.92 min.
Reaction SMILES: [B-]C#N.[Na+].C(O)(=O)C.[F:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[C:20](=[N:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[N:47]=[C:46]([CH3:48])[O:45][N:44]=2)=[CH:39][CH:38]=1)[C:21]1[NH:25][C:24](=[O:26])[N:23]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29]([OH:31])=[O:30])[N:22]=1.Cl>CO.O.C(OCC)(=O)C.C1COCC1>[F:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[CH:20]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[N:47]=[C:46]([CH3:48])[O:45][N:44]=2)=[CH:39][CH:38]=1)[C:21]1[NH:25][C:24](=[O:26])[N:23]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29]([OH:31])=[O:30])[N:22]=1
Reactant: COc1cc(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Agent: Cl
Agent: [B-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
After adding 312 mg of sodium cyanotrihydroborate, 0.114 ml of acetic acid and 1.5 g of MS3A to a solution of 539 mg of 2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)benzoic acid in 40 ml of a methanol:THF=1:1 mixed solvent, the mixture was stirred at room temperature for 48 hours. Next, 0.7 ml of 5N hydrochloric acid was added, the reaction mixture was stirred at room temperature for 10 minutes, ethyl acetate and water were added, and filtration was performed with celite. The aqueous layer was extracted with 50 ml of ethyl acetate and dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (504 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=1)(=O)=O>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH2:22][O:23][C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[CH:25]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)OCCOc1ccc2c(c1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3c(c2)CCCC3)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with 2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl methanesulfonate (1.08 g). The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and extracted with dichloromethane. The organic layers were dried (Na2SO4), filtered and evaporated to give crude product. The material was purified by HPLC (dichloromethane-hexane; 4:1) to provide, after crystallization from diethyl ether-hexane, 0.86 g of alpha-oxo-4-[[2-(5,6,7,8-tetrahydro-2-naphthalenyloxy) ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 95°-99° C.
Reaction SMILES: [C:1](F)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11](I)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13]>C(Cl)Cl>[C:2]1([C:1](=[O:8])[C:11]([F:10])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(F)c1ccccc1
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1)C(F)(C(F)(F)F)C(F)(F)F
Temperature: -70 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
Under protective gas, 22 g (0.18 mol) of benzoyl fluoride and 55.3 g (0.18 mol) of perfluoroisopropyl iodide in 150 ml of CH2Cl2 are initially introduced into a round-bottomed flask. 45 g (0.18 mol) of phosphorous acid trisdiethylamide are added dropwise at about -70° C. The mixture is stirred for 12 hours at -70° C. and, after warming, worked up analogously to Example 1. 38.5 g (78%) of 1-phenyl-2,3,3,3-tetrafluoro-2-trifluoromethyl-propan-1-one of b.p. 90°-92° C./80 mbar are obtained.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13]([Cl:38])=[CH:14][C:15]2[N:21]3[CH2:22][CH2:23][CH2:24][C@@H:25]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C@H:20]3[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[O:17][C:16]=2[CH:37]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:38][C:13]1[C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:37][C:16]2[O:17][C:18]3[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=3[C@@H:20]3[C@H:25]([NH:26][C:27](=[O:32])[C:28]([F:30])([F:29])[F:31])[CH2:24][CH2:23][CH2:22][N:21]3[C:15]=2[CH:14]=1
Reactant: Nc1cc2c(cc1Cl)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)c(NS(=O)(=O)c4ccccc4)cc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 35 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
Benzenesulfonyl chloride (10 μL, 0.08 mmol) was added under N2 to trans-N-(8-amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (5.0 mg, 0.01 mmol) in 1 mL of CH2Cl2 and 2 μL (1.1 eq) of triethylamine. The resulting mixture was stirred at 35° C. for 4 h. After cooling the mixture was evaporated and the crude compound was purified by chromatography on silica. Elution with toluene/ethyl acetate 1:0→0:1 (gradient) gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-8-[(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (2.4 mg, 32%). Data: (m/z)=552 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH:3]=1.[Li]CCCC.[CH3:26][CH2:27][C:28](=[O:31])[CH2:29][CH3:30]>C1COCC1>[F:8][C:6]1[CH:7]=[C:2]([C:28]([OH:31])([CH2:29][CH3:30])[CH2:27][CH3:26])[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH:5]=1
Reactant: CCC(=O)CC
Reactant: COc1ccc(COc2cc(F)cc(Br)c2)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cc(F)cc(OCc2ccc(OC)c(OC)c2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-3-(3,4-dimethoxybenzyloxy)-5-fluorobenzene (Step 1) (1.02 g) in THF (10 mL) at -78° C. was added n-BuLi (1.5 mL of a 2.2M solution) dropwise. After 30 min. 3-pentanone (0.33 mL) was added and after 30 min. the bath was removed and the mixture stirred for 10 min. The reaction mixture was quenched with NH4OAc buffer and extracted with EtOAc. The organics were dried (MgSO4) and concentrated. Chromatography of the residue (silica gel; hexane/EtOAc (3:1) provided the title compound as a colorless oil.