Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13]Cl.Cl.[NH2:16]O.C([O-])=O.[Na+]>C(O)=O.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]#[N:16]
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: N#Cc1c(Cl)ccc2cc(Cl)cnc12

Procedure:
28.1 parts of 3,7-dichloro-8-chloromethylquinoline (Example 1), 6.95 parts of hydroxylamine hydrochloride and 13.6 parts of sodium formate in 200 ml of formic acid and 60 ml of water were stirred at 100° C. for 12 hours. The reaction solution was poured onto ice and the precipitated solid was filtered off with suction, washed neutral with water and dried. 19 parts of 3,7-dichloro-8-cyanoquinoline of melting point 222° C. were obtained. The yield corresponds to 78.5% of theory.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrCCCCCBr
Reactant: N#CCc1cccc(C(F)(F)F)c1
Product: N#CC1(c2cccc(C(F)(F)F)c2)CCCCC1
Yield: 96 %

Procedure:
The title compound was prepared from 2-(3-(trifluoromethyl)phenyl)acetonitrile (3.463 ml, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General Procedure J to yield 1-(3-(trifluoromethyl)phenyl)cyclohexane-carbonitrile (5.40 g, 90%) as a clear oil. 1H NMR (CDCl3) δ 1.26-1.39 (m, 1H), 1.76-1.88 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 7.51-7.60 (m, 3H), 7.73 (s, 1H). 13C NMR (CDCl3) δ 23.7, 25.0, 37.5, 44.6, 122.5, 125.0, 125.1, 126.0, 129.5, 130.0, 142.8,GC-MS m/z 253.
Reaction SMILES: [I:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O=[C:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[I:8])[N:9]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18](=[O:19])[NH:10]2
Reactant: Nc1cc(I)c(I)cc1N
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1nc2cc(I)c(I)cc2[nH]c1=O
Reaction time: 8 h

Procedure:
A solution was prepared from 0.9 g. of 4,5-diiodo-o-phenylenediamine and 25 ml. of ethanol. Five grams of diethyl ketomalonate were added and the resulting mixture was heated to refluxing temperature with stirring overnight. The reaction mixture was then cooled. Ethyl 6,7-diiodo-3,4-dihydro-3-oxo-2-quinoxaline carboxylate formed in the above reaction precipitated and was collected by filtration; yield=0.8 g.; mp=275°-276° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16](SC)SC)[C:4]=2[CH:3]=1.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:4][CH2:3][CH2:2][CH2:14][CH3:13])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]=2[CH:3]=1
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: CSC(SC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCC(CCCCCCCCCCCC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of 2,7-dibromo-9-(bis-methylsulfanyl-methylene)fluorene (4.28, 10 mmol) in dry THF (70 ml) at 0° C. under nitrogen, was added a solution of lithium tetrachlorocuprate (2 ml of a 0.1M solution in THF, 2 mol %). A solution of dodecylmagnesium bromide (22 ml of a 1.0M solution in diethyl ether, 0.022 mol) was added dropwise over 15 min. The reaction was stirred for 3 h at 0-5° C. before quenching with 5% NaOH (100 ml). The reaction was stirred for 10 min and then filtered through celite. The organic layer was separated and the aqueous layer further washed with ethyl acetate (100 ml). The combined organics were washed with brine (100 ml), dried (sodium sulfate), and concentrated under reduced pressure. The crude oil was further purified by filtration through a plug of silica (5 cm×5 cm) covered with a layer of basic alumina (1 cm×5 cm), eluting with petrol. After concentration the residue was recrystallized from isohexane to afford 4.2 of the product as white crystals (62%). Purity (HPLC>98%). 1H and 13C NMR spectra as expected.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:27]([N:28]=[C:29]=[O:30])=[CH:26][C:17]2[N:18]([CH2:23][C:24]#[CH:25])[C:19](=[O:22])[CH2:20][O:21][C:16]=2[CH:15]=1>>[CH2:7]([O:6][C:4]([CH:3]=[C:2]([NH:1][C:29](=[O:30])[NH:28][C:27]1[C:14]([F:13])=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH2:23][C:24]#[CH:25])[C:17]=2[CH:26]=1)[C:9]([F:10])([F:11])[F:12])=[O:5])[CH3:8]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: C#CCN1C(=O)COc2cc(F)c(N=C=O)cc21
Product: C#CCN1C(=O)COc2cc(F)c(NC(=O)NC(=CC(=O)OCC)C(F)(F)F)cc21

Procedure:
Analogously to the procedure described in Example 1, starting from ethyl 3-amino-4,4,4-trifluorocrotonate and 3,4-dihydro-7-fluoro-6-isocyanato-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine there is obtained 6-{3-[2-(ethoxycarbonyl)-1-trifluoromethyl-vinyl]ureido}-3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine (not isolated) and, after cyclization of this benzoxazine, there is obtained 3-[3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 1H-NMR (CDCl3, 60 MHz): 7.29 ppm (d, 1H), 6.99 ppm (d, 1H), 6.31 ppm (s, 1H), 4.85-4.61 ppm (m, 4H), 2.35 ppm (t, 1H): mass spectrum: m/e 383(20), M+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[F:10].[C-:11]#[N:12].[Na+].C1OCCOCCOCCOCCOC1>C(#N)C>[F:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[CH2:2][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Cc1ccc(F)c(CBr)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(F)c(CC#N)c1

Procedure:
(2-Fluoro-5-methyl-phenyl)-acetonitrile was prepared from 2-bromomethyl-1-fluoro-4-methyl-benzene and sodium cyanide in presence of a catalytic amount of 15-crown-5 in acetonitrile at ambient temperature over night in analogy to R. B. Katz et al., Tetrahedron 45, 1801 (1989): light yellow liquid; MS (EI): 149.1 (M+.).
Reaction SMILES: [NH2:1][C:2]1[S:19][C:5]2[CH2:6][N:7]([C:10](=[O:18])[C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1.[Cl:32][CH2:33][C:34](=O)[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].Cl.C(O)C>C(O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([N:7]2[CH2:8][CH2:9][C:4]3[C:3]4[C:2]([S:19][C:5]=3[CH2:6]2)=[N:1][C:34]([CH2:33][Cl:32])=[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:20]=4[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCN(C(=O)c2ccc(Cl)cc2)C3)cc1OC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(CCl)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=O)c1ccc(Cl)cc1)C3
Reaction time: 2.5 h
Yield: 47 %

Procedure:
A mixture of 2-amino-6-(4-chlorobenzoyl)-3-(3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (20.55 g), ethyl 4-chloroacetoacetate (8.17 g), hydrochloric acid-ethanol (23%, 7.34 g) and ethanol (80 ml) was stirred under refluxing conditions for 2.5 hours. The separating crystal was collected by filtration and recrystallized from ethyl acetate to yield ethyl 7-(4-chlorobenzoyl)-2-chloromethyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (12.38 g, 47%) as a light-yellow crystal having a melting point of 132 to 133° C. ##STR32##
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl-].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Zn+])=[CH:17][CH:16]=1.C(Cl)Cl>C1COCC1>[F:13][C:14]([F:23])([F:24])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: FC(F)(F)c1ccc(C[Zn+])cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2ccc(C(F)(F)F)cc2)cc1
Temperature: 70 °C
Yield: 54.8 %

Procedure:
Argon was bubbled through a mixture of methyl 4-bromobenzoate 42a (9.3 mmol, 2.0 g), 2 mL of THF, and 4-trifluoromethylbenzylzinc chloride (0.5 M in THF, 46.5 mmol, 93 mL) for 5 min. Pd(dffp)Cl2.CH2Cl2(0.5 mol, 409 mg) was added and the reaction tube was capped and heated at 70° C. for 16 h. The mixture was cooled and filtered through Celite. Water was added to the filtrate and the resulting solid was filtered off. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (silica gel, 0-10% EtOAc in heptane) to give 1.5 g (55%) of methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:37])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:18][N:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(F)cc2)nc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(F)cc2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
A mixture of 4-bromomethyl-2-(4-fluoro-phenyl)-thiazole-5-carboxylic acid ethyl ester (2.02 g, 5.89 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (1.49 g, 5.89 mmol) and potassium carbonate (1.22 g, 8.83 mmol) in anhydrous dimethylformamide (15 mL) was stirred at room temperature for 18 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (2.39 g): MS: (+) m/z 539.22 (M+Na+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([C:51]1[CH:52]=[C:53](B(O)O)[CH:54]=[CH:55][CH:56]=1)#[N:50]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:55]3[CH:54]=[CH:53][CH:52]=[C:51]([C:49]#[N:50])[CH:56]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3cccc(C#N)c3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
Aryl halide 9 was coupled to 3-cyanophenylboronic acid to give 29 on a 0.1 mmol scale via General Procedure H (58 mg, 60%): δH (400 MHz, CDCl3) 2.33 (s, 3H, CH3), 2.76 (s, 3H, CH3), 3.62 (s, 2H, CH2), 4.78 (s, 2H, CH2), 4.97 (s, 2H, CH2), 5.28 (s, 2H, CH2), 6.60-6.62 (m, 2H, CH), 7.14-7.28 (m, 12H, CH), 7.25-7.28 (m, 2H, CH), 7.38 (d, J=8.0 Hz, 2H, CH), 7.44-7.49 (m, 1H, CH), 7.54-7.57 (m, 3H, CH), 7.71 (dt, J=7.6 and 1.2 Hz, 1H, CH), 7.76 (s, 1H, CH), 7.78 (s, 1H, CH); δC (100 MHz, CDCl3) 21.4, 36.0, 51.4, 52.7, 67.0, 70.7, 112.9, 114.0, 118.6, 120.0, 120.9, 127.0, 127.1, 127.4, 128.0, 128.2, 128.2, 128.5, 128.6, 128.7, 129.5, 129.5, 129.6, 130.5, 130.8, 131.2, 133.1, 135.6, 135.7, 136.8, 138.2, 141.7, 143.3, 158.8, 165.2, 167.1, 167.7; LRMS (ES+) calcd for [C45H39N3O6S+H] 750.26. found 750.26.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCOCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:27]2[CH2:28][CH2:29][CH:24]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:25][CH2:26]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCCCC3)CC2)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (1.3 mL, 12.3 mmol), triethylamine (6.0 mL; 43.0 mmol) and 4-(piperidin-1-yl)piperidine (2.36 g; 14.0 mmol) in dioxane (10 mL) was heated at reflux for 18 hr. After cooling to room temperature the mixture was concentrated under reduced pressure and the residue dissolved in DCM (150 mL). The DCM solution was washed with saturated aqueous sodium bicarbonate and brine, then dried over magnesium sulfate and concentrated under reduced pressure to produce a yellow solid. Hexanes were added and the suspension briefly sonicated. The solid was collected by filtration and washed with hexanes to give 1-(4-nitrophenyl)-4-(piperidin-1-yl)piperidine (3.05 g) as a yellow solid. A solution of 1-(4-nitrophenyl)-4-(piperidin-1-yl)piperidine (3.05 g; 10.5 mmol) in ethanol (20 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (0.251 g) at room temperature for 17 hr. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give 4-[4-(piperidin-1-yl)piperidin-1-yl]benzenamine (2.01 g) as a purple/pink solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[F:13][C:12]([F:15])([F:14])[C:11]1[N:6]2[CH:5]=[N:4][C:3]([C:1]#[C:2][C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.17) (178 mg, 0.5 mmol) and commercially available 4-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a brown solid (176 mg, 69%). MS (ISN) 511.2 [(M+H)+]; mp 290° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>C1COCC1>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][Si@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: FC(F)(F)Oc1ccc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc1
Reactant: FCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: FCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1

Procedure:
3.1 g (20 mmol) of fluorobutyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.4 g (20 mmol) of 4'-(4-chloro-4-silacyclohexyl)-4-trifluoromethoxybiphenyl to obtain 4'-(trans-4-(4-fluorobutyl)-4-silacyclohexyl)-4-trifluoromethoxybiphenyl. The silacyclohexane rings of this product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 5.8 g of the trans isomers (yield 71%).
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH:5](OC)OC.Cl.[C:13]([NH:17][NH2:18])([CH3:16])([CH3:15])[CH3:14].Cl.O>CCO>[C:13]([N:17]1[CH:5]=[CH:4][CH:3]=[N:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(CC(OC)OC)OC
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)n1cccn1
Yield: 89.1 %

Procedure:
A mixture of 1,1,3,3-tetramethoxypropane (37 g, 226 mmol), tert-butyl-hydrazine hydrochloride (28 g, 226 mmol) and conc HCl (60 mL, 720 mmol) in EtOH (300 mL) was heated at reflux overnight. The mixture was poured into water and the resulting mixture was extracted with ether. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give 1-tert-butyl-1H-pyrazole (25 g, 89% yield). 1H NMR (400 MHz, DMSO-d6): δ7.73 (s, 1 H), 7.38 (s, 1 H), 6.17 (s, 1 H), 1.47 (s, 9 H); MS (ESI) m/z: 125.1 [M+H]+.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:13]([O:14]C(=O)C)[C@H:12]([O:18]C(=O)C)[C@@H:11]([CH2:22][O:23]C(=O)C)[O:10][C@H:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][C:34]2[CH:43]=[C:42]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=[CH:41]3)[C:35]=2[C:44](=[O:46])[CH3:45])[CH:28]=1)(=O)C.Cl>C1COCC1.CO>[OH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([OH:18])[C@@H:11]([CH2:22][OH:23])[O:10][C@H:9]1[C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[CH2:33][C:34]1[CH:43]=[C:42]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=[CH:41]2)[C:35]=1[C:44](=[O:46])[CH3:45]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3C(C)=O)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1c(Cc2cccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)cc2cccccc1-2
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Sodium methoxide (16 mg) was added to a solution of (2S,3S,4R,5R,6R)-2-[3-[(1-acetylazulen-2-yl)methyl]phenyl]-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.09 g) in THF-methanol (ratio: 1:1, 6.0 ml) at 0° C. and the mixture was stirred for two hours. After neutralizing with a cation exchange resin, the reaction mixture was added to 10% aqueous solution of hydrochloric acid under cooling with ice. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-(2-[3-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]benzyl]azulen-1-yl)ethanone (0.06 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32]([C@H:34]1[NH:46][CH2:45][C:37]2[NH:38][C:39]3[C:44]([C:36]=2[CH2:35]1)=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32]([C@H:34]1[NH:46][CH2:45][C:37]2[NH:38][C:39]3[C:44]([C:36]=2[CH2:35]1)=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([C@@H]1Cc2c([nH]c3ccccc23)CN1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C([C@@H]1Cc2c([nH]c3ccccc23)CN1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
197 mg (0.315 mmol) of the mixture of (2R*,4S*)-2-benzyl-1-((3S)-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl)carbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine diastereomers are reacted with 48 mg (1.26 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR47## is obtained as mixture of diastereomers in the form of white foam. TLC: methylene chloride/methanol/conc. ammonia (350:50:1) Rf =0.50, FD-MS: M+ =529.
Reaction SMILES: [N+:1](=[C:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])=[N-].[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[F:19])N>>[F:11][C:12]1[CH:13]=[C:14]([N:1]([C:3]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[OH:10])[C:3]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[OH:10])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: [N-]=[N+]=C1C(=O)CCCC1=O
Reactant: Nc1ccc(F)c(F)c1
Product: O=C1CCCC(O)=C1N(C1=C(O)CCCC1=O)c1ccc(F)c(F)c1

Procedure:
Following the procedure described in the Example 1, using 2-diazo-cyclohexane-1,3-dione and 3,4-difluoroaniline as starting materials to yield the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](N(C2C=CC=CC=2)C(=O)OC(C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:29](F)(F)[C:30](O)=O.ClCCl>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:30]2[CH:29]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:8])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccccc2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl (1-t-butoxycarbonylpiperidin-4-yl)phenylcarbamate (290 mg) was dissolved in trifluoroacetic acid-dichloromethane (10%, 20 mL) and stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was partitioned between aqueous sodium hydroxide (2M) and ether (30 mL). The organic layer was separated, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and cooled in ice. Di-t-butyldicarbonate (161 mg) was added and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was purified by MPLC on silica gel, eluting with EtOAc/Hexane (5:95) to give the title compound as a clear oil (141 mg), δH (CDCl3) 1.55 (9H, s), 1.59 (2H, m), 1.82 (2H, m), 2.58 (1H, m), 2.77 (1H, m), 3.64 (2H, br s), 4.16 (2H, m), 6.68-6.79 (2H, m), 7.01-7.26 (2H, m).
Reaction SMILES: [Br:1][C:2]1[C:7](=O)[C:6]([Br:9])=[CH:5][NH:4][CH:3]=1.P(Cl)(Cl)([Cl:12])=O.C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[Cl:12]
Reactant: O=c1c(Br)c[nH]cc1Br
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1c(Br)cncc1Br
Temperature: 100 °C

Procedure:
To 3,5-dibromo-4-(1H)-pyridone (W, 1.0 g, 3.97 mmol) was added phosphorous oxychloride (5 mL) and the mixture was heated at 100° C. for 2 h. The mixture was poured into ice/water (25 g) and basified by the addition of a saturated solution of sodium hydrogen carbonate. The mixture was extracted with dichloromethane (2×20 mL), the combined organic extracts were washed with saturated aqueous sodium chloride solution (25 mL), dried over sodium sulphate and concentrated under vacuum to obtain the title compound. MS (M+1): 271.8.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[C:23]([C:30](Cl)=[O:31])[N:24]2[CH3:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:5]([C@H:2]([NH:1][C:30]([C:23]1[N:24]([CH3:29])[C:25]2[C:21]([CH:22]=1)=[C:20]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:28]=[CH:27][CH:26]=2)=[O:31])[CH2:3][OH:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cn1c(C(=O)Cl)cc2c(OCc3ccccc3)cccc21
Product: Cn1c(C(=O)N[C@H](CO)Cc2ccccc2)cc2c(OCc3ccccc3)cccc21

Procedure:
From (S)-2-amino-3-phenylpropan-1-ol and 4-benzyloxy-1-methyl-1H-indole-2-carbonyl chloride the intermediate compound (S)-N-[1-benzyl-2-hydroxyethyl]-4-(benzyloxy)-1-methyl-1H-indole-2-carboxamide was prepared by a method analogous to that described in Example 23.