Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@H:6]1[O:15][C@@H:16]1[C@@H:31]([OH:32])[C@@H:30]([O:33][C@@H:34]2[O:41][C@H:40]([CH2:42][OH:43])[C@@H:38]([OH:39])[C@H:36]([OH:37])[C@H:35]2[NH:44][C:45](=[O:47])[CH3:46])[C@@H:29]([CH2:48][OH:49])[O:28][C@H:17]1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:3])[CH3:2].C1C(=O)NC(=O)NC=1[C@@H]1O[C@H](COP(OP(O[C@H:73]2[O:78][C@H:77]([CH2:79][OH:80])[C@H:76]([OH:81])[C@H:75]([OH:82])[C@H:74]2[OH:83])(O)=O)(O)=O)[C@@H](O)[C@H]1O>[As](C)(C)(=O)[O-].[Na+].[Cl-].[Mn+2].[Cl-]>[C@@H:17]1([O:12][C@@H:9]2[C@@H:8]([CH2:13][OH:14])[O:7][C@@H:6]([O:15][C@@H:16]3[C@@H:31]([OH:32])[C@@H:30]([O:33][C@@H:34]4[O:41][C@H:40]([CH2:42][OH:43])[C@@H:38]([O:39][C@@H:73]5[O:78][C@H:77]([CH2:79][OH:80])[C@H:76]([OH:81])[C@H:75]([OH:82])[C@H:74]5[OH:83])[C@H:36]([OH:37])[C@H:35]4[NH:44][C:45](=[O:47])[CH3:46])[C@@H:29]([CH2:48][OH:49])[O:28][C@H:17]3[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C@H:10]2[OH:11])[O:28][C@H:29]([CH2:48][OH:49])[C@H:30]([OH:33])[C@H:31]([OH:32])[C@H:16]1[OH:15]
Reactant: O=c1cc([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)[nH]c(=O)[nH]1
Reactant: COC(=O)CCCCCO[C@@H]1O[C@H](CO)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)[C@H](O)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Agent: [Mn+2]
Agent: C[As](C)(=O)[O-]
Agent: [Cl-]
Product: COC(=O)CCCCCO[C@@H]1O[C@H](CO)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2NC(C)=O)[C@H](O)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1NC(C)=O
Reaction time: 22 h

Procedure:
A solution of compound 16 of Example 16 28 mg), UDP-galactose, (84 mg), bovine galactosyltransferase (5 U) and bovine serum albumin (3 mg) in 30 mM sodium cacodylate buffer (3 mL, pH 7.0) containing manganese chloride (40 umol) was incubated at 37° C. for 22 h. The reaction mixture was diluted to 20 mL and purified as described in Example 21. Yield of the product was 32 mg. The structural identity of titled compound 22 was unambiguously assigned by 1H- and 13C-n.m.r (see Tables 4 and 5, respectively).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Br[CH2:12][CH:13]1[CH2:18][CH2:17][Si:16]([CH2:25][CH2:26][CH2:27][CH:28]([F:30])[CH3:29])(C2C=CC=CC=2)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH2:12][C@H:13]2[CH2:14][CH2:15][Si@H:16]([CH2:25][CH2:26][CH2:27][CH:28]([F:30])[CH3:29])[CH2:17][CH2:18]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: CC(F)CCC[Si]1(c2ccccc2)CCC(CBr)CC1
Reactant: Oc1cc(F)c(F)c(F)c1
Product: CC(F)CCC[Si@H]1CC[C@H](COc2cc(F)c(F)c(F)c2)CC1

Procedure:
The general procedure of Example 9 was repeated using 3,4,5-trifluorophenol and 4-bromomethyl-1-(4-fluoropentyl)-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f41) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C([NH:5][C:6]([NH:8][CH:9]([CH2:17]O)[CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[S:7])(C)(C)C.[ClH:19]>C(O)C>[ClH:19].[ClH:19].[N:12]1[CH:13]=[CH:14][N:15]=[CH:16][C:11]=1[CH2:10][CH:9]1[CH2:17][S:7][C:6]([NH2:5])=[N:8]1
Reactant: CC(C)(C)NC(=S)NC(CO)Cc1cnccn1
Agent: Cl
Solvent: CCO
Product: NC1=NC(Cc2cnccn2)CS1

Procedure:
A solution of 7.2 g of N-(tert-butyl)-N′-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)ethyl]thiourea in 20 cm3 of 5N hydrochloric acid is heated at a temperature in the region of 110° C. for 20 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 55° C. and then taken up in ethanol and concentrated under the same conditions as above. The residue is chromatographed at atmospheric pressure on a column of silica gel (particle size 40-60μ; diameter 4 cm; height 30 cm), eluting with an acetic acid/water/ethyl acetate mixture (1/1/4 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. The oil obtained is taken up in ethanol and the precipitate obtained is filtered off and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C. to give 2.9 g of (4RS)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine dihydrochloride in the form of a brown solid melting at 190° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 3.23 (d, J=6 Hz: 2H); 3.43 (dd, J=11.5 and 5.5 Hz: 1H); 3.72 (dd, J=11.5 and 7.5 Hz: 1H); 4.74 (mt: 1H); 8.59 (broad s: 1H); 8.64 (broad s: 1H); 8.67 (broad s: 1H); 9.29 (unresolved complex: 1H); 9.77 (unresolved complex: 1H); 10.16 (broad s: 1H)].
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9].C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.O1CCCC1>[N:4]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])=[C:1]=[S:3]
Reactant: S=C=S
Reactant: COc1ccc(C(=O)O)cc1N
Agent: Cl
Agent: II
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)O)cc1N=C=S
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 3-amino-4-methoxybenzoic acid (0.25 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 6 hours. To the obtained reaction mixture, a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) was dropwise added over a period of 5 minutes at 0° C., followed by stirring at 0° C. for further 2.5 hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and mixed. Then, ethyl acetate (6 mL) was added, and the organic layer was separated and concentrated under reduced pressure to dryness. To the obtained residue, ethyl acetate (6 mL), water (2 mL), sodium hydrogencarbonate (6 mg, 0.07 mmol) and sodium sulfite (9 mg, 0.07 mmol) were added, the organic layer was separated and concentrated under reduced pressure to dryness to obtain 3-isothiocyanato-4-methoxybenzoic acid as a colorless solid (0.29 g, yield: 94%, HPLC purity: 99%, HPLC retention time: 3.5 min). LC-MS ES-208 (retention time: 21.6 min, condition 3).
Reaction SMILES: FC1C=CC([N:8]2C3C(=CC(N)=CC=3)C=N2)=CC=1.[F:18][C:19]([F:30])([F:29])[C:20](=O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.[BH4-].[Na+].[OH-].[Na+]>ClCCl.Cl[Ti](Cl)(Cl)Cl.CO>[C:22]1(/[CH:21]=[C:20](/[NH2:8])\[C:19]([F:30])([F:29])[F:18])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: O=C(Cc1ccccc1)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N/C(=C/c1ccccc1)C(F)(F)F
Reaction time: 20 h

Procedure:
To a solution of 100 mg (0.44 mmol) of 1-(4-fluorophenyl)-1H-indazol-5-ylamine in 5 mL of dichloromethane was added 60 μL (1.04 mmol) of 1,1,1-trifluoro-3-phenylpropan-2-one, 70 μL (0.97 mmol) of triethylamine followed by 130 μL (1.02 mmol) of TiCl4. The mixture was stirred for 20 hours and then MeOH was added followed by 200 mg (5.29 mmol) of sodium borohydride. After 1 hour, the mixture was diluted 50 mL of 1N aqueous NaOH and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by Combiflash chromatography using a EtOAc-hexanes (0-70% gradient) to provide 70 mg (37%) of [144-fluorophenyl)-1H-indazol-5-yl]-((E)-2-phenyl-1-trifluoromethylvinyl)amine as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([BH3-])#N.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: Brc1ccc2c(c1)CCN2
Yield: 70.1 %

Procedure:
5-Bromoindole (0.7 g, 3.6 mmol) was treated with sodium cyanoborohydride as in the method of Description 10 to yield the title compound (0.5 g, 71%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[N+:13]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)([O-:15])=[O:14]
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To 1-methoxy-3-nitro-5-(trifluoromethyl)benzene (2.21 g, 10.0 mmol) in DCM at 0° C. was added BBr3 (10 equivalents) dropwise over 5 minutes. The solution was allowed to warm to r.t overnight at which point it was quenched with sat. aqueous NaHCO3 and extracted with EtOAc. The organic, layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo to give 3-nitro-5-(trifluoromethyl)phenol (778 mg, 3.76 mmol, 37%), 1H NMR (300 MHz, DMSO-d6) δ 11.22 (s, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.51 (s, 1H); LC-MS (ESI) m/z 208 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([NH2:24])[CH2:20][CH2:19]1.CN(C)CCN(C)C>O1CCOCC1>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19]1
Reactant: CN1CCN(N)CC1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CN(C)CCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-3-nitrobenzenesulfonamide (1 g), 4-methylpiperazin-1-amine dihydrochloride (1 g) and N1,N1,N2,N2-tetramethylethane-1,2-diamine (3 mL) in dioxane (10 mL) was refluxed for 12 hours, cooled to ambient temperature and filtered. The filtrate was added to a silica gel column (Analogix, SF65-200 g) and purified by eluting with 1-5% methanol/dichloromethane).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH:3]=[O:4].[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]([CH3:8])([CH:3]([OH:4])[CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH:6]=[CH2:7]
Reactant: C=CCC(C)(C)C=O
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(C)(C)C(O)CCCC
Temperature: -60 °C
Yield: 100 %

Procedure:
15 g (133 mmol) of 2,2-dimethyl-4-pentenal was added to 600 mL of THF in a 2 L, 3-neck flask, flushed with N2, and sealed with rubber stoppers. The reaction mixture was cooled to −60° C. in a dry ice/acetone bath. Butyllithium solution (2.5 M in hexane, 64.4 mL, 160.7 mmol) was added 4-5 mL at a time from a 20 mL glass syringe. The reaction temperature, was kept at −65° C., during addition and afterwards was stirred for an additional hour. The reaction mixture was allowed to warm to −5° C. over 1 hour, cooled to −60° C. again, and slowly quenched with ammonium chloride solution (10.5 g/200 mL water, 200 mmol). THF was evaporated using a rotary evaporator, keeping the water bath temperature set at 30° C. The resultant aqueous solution was first extracted with CH2Cl2 (3×200 mL), and then with ether (1×200 mL). The organic extracts were combined, dried, and concentrated on a rotary evaporator (30° C. water bath) to yield 22.64 g of 4,4-dimethyl-non-1-en-5-ol, TLC Rf=0.67 (1:1 ethyl acetate:hexanes, visualization by I2). 1H NMR (CDCl3, 500 MHz) δ (ppm): 5.86 (m, 1H), 5.06 (m, 1H), 5.03 (s, 1H), 3.26 (d, 1H), 2.15 (m, 1H), 1.95 (m, 1H), 1.5 (m, 2H), 1.3 (m, 4H), 0.95, (t, 3H), 0.90 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35]1([CH2:41][C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([C:42](=[O:43])[CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Product: O=C(Cc1ccccc1)N1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1

Procedure:
The title compound, MS: m/e=604.1 (M+H+), was prepared in accordance with the general method of example 38 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and phenylacetylchloride.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][CH:26]=1)[CH:20]([NH:36]C(OC(C)(C)C)=O)[C:19]2=[O:44])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[NH2:36][CH:20]1[C:19](=[O:44])[N:18]2[CH:21]1[S:22][CH2:23][C:24]([C:25]1[S:29][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][CH:26]=1)=[C:17]2[C:15]([OH:16])=[O:14]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccccc4)s3)CSC12
Solvent: O=C(O)C(F)(F)F
Product: NC1C(=O)N2C(C(=O)O)=C(c3cnc(-c4ccccc4)s3)CSC12
Yield: 100.8 %

Procedure:
2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-phenyl-thiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (5.7 g) is treated with trifluoroacetic acid (57 cc) for 20 minutes at 20° C. and the reaction mixture is then concentrated to dryness under reduced pressure (0.2 mm Hg; 0.03 kPa) at 30° C. The residue is taken up in ethyl acetate (100 cc), which is evaporated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. This residue is triturated with isopropyl ether (100 cc). The solid is filtered off, washed with isopropyl ether (3×50 cc) and dried under reduced pressure (0.2 mm Hg; 0.03 kPa) at 20° C. 7-Amino-2-carboxy-8-oxo-3-(2-phenyl-thiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.3 g) is obtained in the form of an ochre solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25]I)[CH:12]=3)[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(#N)C>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH3:23])[N:13]([CH2:24][CH2:25][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)[CH:12]=[C:11]2[C:9]1[N:8]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]2[CH:10]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCI)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCOCC3)c2cc1OC

Procedure:
But using 1 g of 5-fluoro-2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 0.223 g of potassium carbonate and 0.28 ml of morpholine in 100 ml of acetonitrile. 0.83 g of 2-[5,6-dimethoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:25](O)=[O:26])=[C:11]([OH:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N=C=N.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][C@@H:47]([NH2:54])[C:48]3[O:52][N:51]=[C:50]([CH3:53])[N:49]=3)=[CH:42][CH:41]=2)[CH:36]=[CH:37][C:38]=1[F:39]>C1COCC1.ClCCCl>[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][C@@H:47]([NH:54][C:25]([C:12]3[CH:13]=[C:14]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[OH:28])=[O:26])[C:48]3[O:52][N:51]=[C:50]([CH3:53])[N:49]=3)=[CH:42][CH:41]=2)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)c(OCc2ccccc2)cc1O
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Agent: N=C=N
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1noc([C@@H](Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)NC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)c(OCc3ccccc3)cc2O)n1
Reaction time: 12 h
Yield: 20.6 %

Procedure:
To a solution of 6-Benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (52 mg, 0.13 mmol) in THF:DCE (1:1, 2 mL) was added PS-Carbodiimide resin (0.14 g, 1.3 mmol/g) and 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (0.03 g, 0.09 mmol) and stirred for 12 h, resin was filtered and washed with EtOAc (5 mL), filtrate was concentrated and silicagel chromatography of the residue gave pure 6-Benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.013 g).
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[NH:4][C:5]1=[O:11].C1(=O)[NH:17][C:16](=O)[CH:15]=C1.O1C=CC=C1.BrCC#N>CC(C)=O.CN(C=O)C>[O:12]=[C:3]1[N:4]([CH2:15][C:16]#[N:17])[C:5](=[O:11])[CH:6]2[CH:2]1[CH:1]1[O:10][CH:7]2[CH2:8][CH2:9]1
Reactant: O=C1C=CC(=O)N1
Reactant: O=C1NC(=O)C2C3CCC(O3)C12
Agent: N#CCBr
Solvent: c1ccoc1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: N#CCN1C(=O)C2C3CCC(O3)C2C1=O

Procedure:
Synthesis took place in analogy to Example VI a from 10-oxa-4-azatricyclo[5.2.1.02,6]decane-3,5-dione (obtainable from maleimide and furan from Diels-Alder reaction for example as described by Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T.; J Org Chem 1997, 62, 4088-4096 and subsequent hydrogenation as described by Ansell, M. F.; Caton, M. P. L.; North, P. C.; Tetrahedron Lett. 1982, 23, 2811) and bromoacetonitrile with the exception that acetone was used as solvent in place of DMF. The substance was employed as crude product in the next reaction.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[O:28])[CH:13]=[C:14]([C:16]3[N:20](CC4C=CC=CC=4)[N:19]=[N:18][N:17]=3)[O:15][C:10]=2[C:9]([CH2:29][CH2:30][CH3:31])=[CH:8][CH:7]=1.[H][H]>[Pd].C(O)C>[CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[O:28])[CH:13]=[C:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:15][C:10]=2[C:9]([CH2:29][CH2:30][CH3:31])=[CH:8][CH:7]=1
Reactant: CCCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnnn3Cc3ccccc3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnn[nH]3)oc12

Procedure:
A solution of 2.96 parts of 5-[5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1-benzopyran-2-yl]-N-benzyltetrazole in 500 parts of ethanol was stirred at 60°C, with 0.096 parts of 5% palladium on charcoal, in an atmosphere of hydrogen for 111/2 hours. The reaction mixture was cooled, was filtered and the solvent removed by evaporation to give a residue which was chromatographed on silica gel. Careful elution with chloroform and chloroform/acetone gave 0.16 parts of 5-[5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1-benzopyran-2-yl]tetrazole, m.p. 199°-200°C (after recrystallisation from ethanol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14](C(OC(C)(C)C)=O)[CH2:15][C:16]2[CH:21]=[C:20]([N:22]3[C:26]([C:27]([F:30])([F:29])[F:28])=[N:25][N:24]=[N:23]3)[CH:19]=[CH:18][C:17]=2[O:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@@H:9]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=O)(C)(C)C.[ClH:49].C(O)C>O1CCOCC1>[ClH:49].[ClH:49].[CH2:32]([O:31][C:17]1[CH:18]=[CH:19][C:20]([N:22]2[C:26]([C:27]([F:29])([F:30])[F:28])=[N:25][N:24]=[N:23]2)=[CH:21][C:16]=1[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOc1ccc(-n2nnnc2C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCOc1ccc(-n2nnnc2C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
From 3-{tert-butoxycarbonyl-[2-(1-butoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-amino}-[2S,3S]-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (345 mg, 0.51 mmol) using 4M-hydrogen chloride in dioxan (5 ml) at 40° C. to give the title compound as a white crystals from ethanol (218 mg). Found C, 51.78; H, 5.62; N, 15.13; C24H29F3N6O.2HCl.0.5H2O (556.46), requires C,51.80; H, 5.80; N, 15.10%. Mass spectrum (thermospray +ve) m/e 475 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[C:4]#[N:5].[Cl:18]N1C(=O)CCC1=O.O.CCOCC>C(Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([CH3:17])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][C:8]=1[Cl:18])[C:4]#[N:5]
Reactant: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1Cl
Reaction time: 48 h

Procedure:
To a solution of 484 mg (2 mmol) of 3-methyl-2-(4-trifluoromethylphenylamino)butyronitrile in 5 ml of carbon tetrachloride was added 267 mg (2 mmol) of N-chlorosuccinimide. The mixture was heated at 65°. After about 48 hours, the mixture was poured into water and ether. The organic fraction was separated, washed with water and brine, dried over sodium sulfate, and solvent removed to give 3-methyl-2-(2-chloro-4-trifluoromethylphenylamino)butyronitrile in virtually quantitative yield.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]([C:24]#[N:25])[C:19](=[O:23])[NH:20][C:21]=3[CH3:22])=[CH:12][CH:11]=2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[C:18]([C:24]#[N:25])[C:19](=[O:23])[NH:20][C:21]=2[CH3:22])=[CH:14][CH:15]=1
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(OCCCN)cc1
Yield: 67.7 %

Procedure:
A solution of 1.885 g (4.70 mmol) of 5-(4-phthalimidopropyloxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile and 251 μl (5.17 mmol) of hydrazine monohydrate in 50 ml of ethanol is heated 16 hr at reflux. The volatiles are removed under vacuum and the residue is taken up in 15 ml of 1:1 CHCl3 :CH3 and flashchromatographed through a 6 inch length column of silica gel (90:10:2 CHCl3 :CH3OH:NH4OH). The solid obtained form the chromatography is recrystallized from CHCl3 :CH3OH to give 901 mg of 5-(4-aminopropyloxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile as a yellow powder. 1H-NMR (d6 -DMSO): δ 1.80 (t,2H); 2.73 (t,2H); 3.70 (s broad, 2H); 4.03 (t,2H); 6.92 (d,2H); 7.20 (d,2H); 7.85 (s, 1H).